Neuroendocrine Regulation of Hydromineral Homeostasis.

Neuroendocrine Regulation of Hydromineral Homeostasis Andre de Souza Mecawi,1,2 Silvia Graciela Ruginsk,3 Lucila Leico Kagohara Elias,4 Wamberto Antonio Varanda,4 and Jose Antunes-Rodrigues*4 ABSTRACT Since the crucial evolutionary change from an aqueous to a terrestrial environment, all living organisms address the primordial task of equilibrating the ingestion/production of water and electrolytes (primarily sodium) with their excretion. In mammals, the final route for the excretion of these elements is mainly through the kidneys, which can eliminate concentrated or diluted urine according to the requirements. Despite their primary role in homeostasis, the kidneys are not able to recover water and solutes lost through other systems. Therefore, the selective stimulation or inhibition of motivational and locomotor behavior becomes essential to initiate the search and acquisition of water and/or sodium from the environment. Indeed, imbalances affecting the osmolality and volume of body fluids are dramatic challenges to the maintenance of hydromineral homeostasis. In addition to behavioral changes, which are integrated in the central nervous system, most of the systemic responses recruited to restore hydroelectrolytic balance are accomplished by coordinated actions of the cardiovascular, autonomic and endocrine systems, which determine the appropriate renal responses. The activation of sequential and redundant mechanisms (involving local and systemic factors) produces accurate and self-limited effector responses. From a physiological point of view, understanding the mechanisms underlying water and sodium balance is intriguing and of great interest for the biomedical sciences. Therefore, the present review will address the biophysical, evolutionary and historical perspectives concerning the integrative neuroendocrine control of hydromineral balance, focusing on the major neural and endocrine systems implicated in the control of water and sodium balance. © 2015 American Physiological Society. Compr Physiol 5:1465-1516, 2015.

Introduction The evolutionary rise of complexity in both plants and animals rested in two basic principles: on one side the maintenance of fundamental properties at the cellular level including many biochemical reactions and membrane transport systems; on the other, the development of control systems that could modify both biochemical reactions and membrane properties to face challenges imposed by the environment. To survive, that is, in order for the cell to survive, several strategies were naturally selected ranging from behavioral adaptation to the appearance of specialized systems in sensing environmental conditions and responding with appropriate actions, to complex motor and/or hormonal responses. In any case, the resultant effect is directed to maintain, create or modify osmotic gradients across cell membranes and to control the permeability to water in target cells. The result, in complex or in single-cell organisms, is the adequate control of intracellular and/or extracellular milieu to preserve life. One of the most remarkable principles that govern homeostasis is mass balance. According to this premise, in the absence of a chemical reaction, the amount of any substance flowing in and out of a system should be identical; therefore, any gain should be compensated by a proportional loss. If

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the inputs exceed the outputs, then mechanisms aimed at the elimination of the exceeding amounts are activated. However, if the outputs overcome the inputs, then specific responses to spare or to acquire more substrates are recruited. Most people ingest an average of 2.2 L of water in food and in liquids, and normal aerobic metabolism provides an additional 0.3 L of water per day. In contrast, the daily ingestion of sodium varies from 6 to 15 g, and variable amounts of other electrolytes, such as K+ , H+ , Ca2+ , HCO3 − , and HCO4 2− , are found in the diet. Sodium chloride (NaCl; for all abbreviations, please see Table 1) is the most abundant compound found in * Correspondence

to [email protected] of Physiological Sciences, Institute of Biology, Federal Rural University of Rio de Janeiro, Brazil 2 Department of Physiology, Faculty of Medicine, University of Malaya, Malaysia 3 Department of Physiological Sciences, Biomedical Sciences Institute, Federal University of Alfenas, Brazil 4 Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Brazil Published online, July 2015 (comprehensivephysiology.com) DOI: 10.1002/cphy.c140031 Copyright © American Physiological Society. 1 Department

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Hydromineral Homeostasis

Table 1

List of Abbreviations

Comprehensive Physiology

Table 1

(Continued)

Abbreviation Definition

Abbreviation

Definition

3-MST

3-Mercaptopyruvate sulphurtransferase

CVLM

Caudal ventral lateral medulla

3V

Third cerebral ventricle

CVO

Circumventricular organ

5-HT

Serotonin

DBB

Diagonal band of Broca

AC

Anterior commissural nucleus

DNP

Dendroaspis-type natriuretic peptide

ac

Anterior commissure

DRN

Dorsal raphe nucleus

ACE

Angiotensin converting enzyme

ECF

Extracellular fluid

ACTH

Adrenocorticotrophic hormone

ENaC

Epithelial sodium channel

Aldo

Aldosterone

ER-α

Estradiol receptor alfa

ANG 1-7

Angiotensin 1-7

ER-β

Estradiol receptor beta

ANG I

Angiotensin I

ERK

Extracellular regulated kinase

ANG II

Angiotensin II

FURO-CAP

Furosemide + low dose of captopril

ANG III

Angiotensin III

GABA

γ-aminobutyric acid

ANG IV

Angiotensin IV

GI

Gastrointestinal tract

ANP

Atrial natriuretic peptide

GPRC

G protein-coupled receptors

AP

Area postrema

H2 S

Hydrogen sulfide

AQP

Aquaporin

hnRNA

Heteronuclear ribonucleic acid

AT1

Type 1 angiotensin receptor

HO

Heme oxygenase

AT1A

Type 1A angiotensin receptor

HSD2

11β-hydroxy-steroid dehydrogenase type 2

AT1B

Type 1B angiotensin receptor

icv

Intracerebroventricular

AT2


IP3

Inositol triphosphate

AT3


LC

Locus coeruleus

AT4


LPBN

Lateral parabrachial nucleus

ATP

Adenosine triphosphate

LT

Lamina terminalis

AV3V

Anteroventral region of the third cerebral ventricle

MAPK

Mitogen-activated protein kinase

AVP

Arginine vasopressin

ME

Median eminence

BBB

Blood brain barrier

MnPO

Median preoptic nucleus

BNP

Brain natriuretic peptide

MR

Mineralocorticoid receptor

BNST

Bed nucleus of stria terminalis

mRNA

Messenger ribonucleic acid

cAMP

Cyclic monophosphate of adenosine

NaCl

Sodium chloride

CAT

Cysteine aminotransferase

NaHCO3

Sodium bicarbonate

CB1R

Type 1 cannabinoid receptors

Nax

Sodium sensors channels

CBS

Cystathionine-β-synthase

NIL

Hypophyseal neurointermediate lobe

CCK

Cholecystokinin

NO

Nitric oxide

cGMP

Cyclic monophosphate of guanosine

Nor

Noradrenaline

CHIP28

Channel-forming integral protein of 28 kDa

NOS

Nitric oxide synthase

CNP

Type C natriuretic peptide

nNOS

Neuronal nitric oxide synthase

CNS

Central nervous system

NP

Natriuretic peptide

CO

Carbon monoxide

NPRA

Type A natriuretic peptide receptor

CREB3L1

Cyclic AMP responsive element binding protein 3-like 1

NPRB

Type B natriuretic peptide receptor

CRH

Corticotrophin-releasing hormone

NPRC

Type C natriuretic peptide receptor

CSE

Cystathionine-γ-lyase

NST

Nucleus of the solitary tract

CSF

Cerebrospinal fluid

oc

Optic chiasm

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Table 1

(Continued)

Abbreviation

Definition

OXT

Oxytocin

OXTR

Oxytocin receptor

OVLT

organum vasculosum of the lamina terminalis

PaAP

Anterior parvocellular subdivision of the PVN

PaDC

Dorsomedial cap parvocellular portion of the PVN

PAG

Periaqueductal grey

PaLM

Lateral magnocellular portion of the PVN

PaMM

Medial magnocellular portion of the PVN

PaMP

Medial parvocellular portion of the PVN

PaPo

Posterior parvocellular group of the PVN

PBS

Buffered saline

PCMB

P-chloromercuribenzoate

PCMBS

P-chloromercuribenzene sulfonate

PeM

Periventricular magnocellular group of the PVN

PeP

Periventricular parvocellular group of the PVN

PeV

Periventricular parvocellular group of the PVN

PKA

Protein kinase A

PKC

Protein kinase C

PLC

Phospholipase C

Ras

GTPase

PRL

Prolactin

PVN

Paraventricular nucleus of the hypothalamus

RAS

Renin-angiotensin system

Ren

Renin

RVLM

Rostral ventral lateral medulla

SFO

Subfornical organ

shRNA

Small hairpin ribonucleic acid

SON

Supraoptic nucleus of the hypothalamus

Src

Kinase protein family

TRP

Transient receptor potential

TRPV

Transient receptor potencial vanilloid

TRPV1

Type 1 transient receptor potencial vanilloid

TRPV4

Type 4 transient receptor potencial vanilloid

TNFα

Tumor necrosis factor α

vlPAG

Ventrolateral periaqueductal gray

the extracellular fluid (ECF, please see all abbreviations in Table 1). Considering that water can readily move across cell membranes, the concentration of osmotically effective solutes in the ECF should be maintained within narrow limits of variation to avoid changes in cellular volume. Mammals regulate the volume and osmolality of their body fluids in response

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to stimuli arising from both intracellular and extracellular fluids. In general, the gastrointestinal tract excretes only approximately 100 mL of water and small amounts of electrolytes in feces. The primary final route for the excretion of water and sodium is represented by the kidneys, which, in humans, can eliminate urine with osmolality ranging from 50 to 1200 mosm/kg H2 O, according to body requirements. Despite their primary role in hydromineral homeostasis, the kidneys are not able to recover solvent and solutes that are lost through other systems. Consequently, the activation of behavioral mechanisms is essential to complement renal responses. Within this context, thirst can be defined as a sensation that triggers the behavior of water ingestion. In addition to thirst, sodium appetite can also be elicited in some cases (Fig. 1). Under dehydration conditions, these two behavioral responses are temporally dissociated: initially, the ingestion of water corrects hyperosmolality, allowing a partial reposition of volume; then, the ingestion of salt is initiated, which tends to correct any eventual dilution of the ECF that occurred after water intake. The fact that the search for salt normally occurs after the search for water shows that the decreased cell volume resulting from the osmotic imbalance is actually the more dramatic risk factor for the maintenance of homeostasis. In addition to behavioral changes, which are integrated in the central nervous system (CNS), neural inputs carried by mechanoreceptors, which monitor changes in blood pressure and in circulating volume, almost simultaneously modulate the activity of sympathoexcitatory and sympathoinhibitory brain nuclei, particularly producing effects on cardiac output and on vascular resistance. In parallel, renal responses are activated to modulate water and sodium excretion, which occurs by either a direct effect of neural elements and intrinsic renal mechanisms or a neuroendocrine-mediated response. In the following sections, the reader will find a more detailed description of the mechanisms controlling body fluid homeostasis, from the cellular environment to the whole body. Some evolutionary aspects of the development of effector systems will be discussed, and new perspectives concerning this field will be provided. In this context, this review encompasses a comprehensive discussion on several aspects of the subject. It starts with a discussion of the principles routinely used by physiologists, which govern water movement across membranes with special emphasis on the concept of osmolality, osmotic pressure and tonicity. This section is followed by an overview of the main evolutionary aspects of hormonal systems governing the hydromineral balance, in this sense arginine vasopressin (AVP) and oxytocin (OXT) emerge as the more ancient and conserved systems. Following this biophysical and evolutionary approach, we will give a brief historiography on the progress achieved on the study of the neuroendocrine systems involved in controlling hydromineral homeostasis. The next sections review the main advances in the field by looking at central and peripheral sensors mechanisms, the morphofunctional substrate related to the integration of these

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Breathing Water loss Eating and drinking Water and Sodium acquisition

Sweating Water and Sodium loss

Feces Water and Sodium loss

Urinary flow Water and Sodium loss

Figure 1

Primary paths for water and sodium management in the adult organism. The main input signal is rendered by water and sodium ingestion in liquids and food, although some water can also be produced by endogenous metabolism. The principal route for water and sodium excretion takes place in the kidneys. However, water can be lost during humidification of the inspired air and also through sweating. Sweat contains sodium (although sodium concentrations in sweat are smaller than in the plasma). Reproduced with the permission from Ruginsk and coworkers (2015) (399).

information leading to adequate systemic responses, and the neuroendocrine regulatory systems responsible for controlling the rate of water and sodium acquisition/loss. Lastly, we are integrating these sections with a comprehensive description of salt and water ingestion and excretion regulation during ingestive originated imbalances, physical exercises and along several stages of mammal’s life cycle.

Water Transport: Basic Concepts Life on earth evolved in an aqueous environment, the primordial sea, which supported most of the key physicochemical processes required for the survival of biological organisms. In fact, water comprises most of the mass of all living beings and is readily exchanged at surprising rates: humans take up and eliminate approximately 2 to 4 L of water daily, representing

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approximately 4% to 5% of their body weight. The water content of an organism is clearly divided among several compartments; the intracellular compartment is the most conspicuous and the one with the larger volume in mammals. Nevertheless, cells live in the extracellular compartment, Claude Bernard’s milieu intérieur (49), which is tightly controlled by several physiological mechanisms to maintain both volume and composition within strict boundaries compatible with life. The aqueous compartments are separated by membranes: the plasma membrane, in the case of the intracellular and interstitial fluid; the endothelium between the vascular and interstitial fluid; and so on. In any case, there is a constant and intense exchange of water between the compartments. Here, we will focus on the processes that are responsible for water movement across the limiting boundaries between these compartments. This issue is important for

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understanding how the organism acts to control volume flow and water homeostasis.

Osmosis and osmotic pressure: Equilibrium Osmosis, characterized by the bulk movement of water molecules across a membrane, is a phenomenon that has long been observed and studied (239). From plant cells to animal bladders, the general result can be explained in the same manner: water flows from a region of smaller solute concentration to a region of higher solute concentration. Although water movement through membranes (pig bladder) was readily observed by Nollet in 1748, the term osmosis was coined by the French scientist René Henri Dutrochet in the 1800s (194, 195, 296). Dutrochet performed a series of consistent observations regarding water transport in animal bladders and concluded that bladders containing a solution that was denser than the outside solution became turgid, and a hydraulic pressure would develop. Dutrochet further extended those observations by constructing an osmometer using a semipermeable membrane. Let us repeat this type of experiment by measuring the osmotic pressure of several solutions simultaneously. Assume that 4 thistle tubes, which are closed by a semipermeable membrane at their larger portion and which contain different solutions, are placed inside a container with pure water. The first tube contains 10 mmol/L sucrose; the second, 50 mmol/L sucrose; the third, 100 mmol/L sucrose; and the fourth, 50 mmol/L NaCl. The system is arranged such that at time zero the water levels in the tubes are identical to that in the container. Under these circumstances, we will observe that water begins to flow inside the thistle tubes until a certain height is reached, as shown in Figure 2 (arrows). At this point, there is no more net flux through the semipermeable membrane, and a hydraulic pressure P = 𝜌gh (where 𝜌 = the density of the solution, g = the acceleration of gravity, and h = the height of the solution column inside the thistle tube) develops in each case. As we can be see in Figure 2, the hydraulic pressure is different in each case and, by definition, equals the osmotic pressure (𝜋) of the solutions. Therefore,


the measurement of osmotic pressure assumes that an equilibrium state is reached in the system. In our case, P1 = 𝜋 1 < P2 = 𝜋 2 < P3 = 𝜋 3 = P4 = 𝜋 4 . Years later, Pfeffer, a German botanist, extended the initial observations made by Dutrochet and carefully measured the osmotic pressure of several solutions in an osmometer made with a porous glass membrane covered with copper ferricyanide. Pfeffer’ results led him to conclude that the osmotic pressure of a solution is proportional to the solute concentration and changes as the temperature is changed. Also note in Figure 2 that the fourth tube contains a salt solution and that its molar concentration is half that of the sucrose concentration in tube 3. Nevertheless, the equilibrium hydraulic pressures developed are approximately equal, as are the osmotic pressures of the solutions. This apparent inconsistency was first analyzed by another botanist, Hugo de Vries, at the end of the nineteenth century. de Vries measured plasmolysis in plant cells and observed that the molar concentration of a non-electrolyte substance required to induce plasmolysis was approximately twice that of a monovalent electrolyte, such as NaCl. Later, this finding led to the assumption that osmotic pressure is a property related to the number of particles per volume of a solution and not to the quality of the particles. In fact, there are other physicochemical properties of solutions, which depend essentially on the number of particles effectively dissolved and not on their nature, such as the vapor pressure depression, the boiling point increase and the freezing point depression. These parameters, together with the osmotic pressure, were collectively called colligative properties by F. Wilhelm Ostwald (393).

Relating osmotic pressure to solute concentration: The van’t Hoff law Following the above-mentioned arguments, we can now define osmotic pressure. Osmotic pressure corresponds to the excess of hydraulic pressure that must be applied to the side of a compartment containing a given solution, in relation to a compartment containing pure water, to make the net water flux (Jw ) between the two compartments equal to zero, that is, Jw = 0. Under this situation, the chemical potential difference of water between the two sides of the membrane should be equal, and the system would be at equilibrium. Therefore, we can write the following equation: = 𝜇w or 𝜇w 1 1 𝜇 01 + RT ln X1w + V w ⋅ P1 = 𝜇02 + RT ln X2w + V w ⋅ P2

Figure 2 A simple device to estimate the osmotic pressure of a solution. Thistle tube 1 contains 10 mmol/L sucrose; tube 2 contains 50 mmol/L sucrose, tube 3 contains 100 mmol/L sucrose, and tube 4 contains 50 mmol/L NaCl. Arrows indicate the final level of solution in the tubes.

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(1)

where R is the gas constant; T the absolute temperature; V w is the partial molal volume of water (approximately equal to 18 mL/mol); P1 and P2 are pressures; 𝜇 01 and 𝜇 02 are the standard chemical potential of water in the two compartments, which can be considered equal under isothermal conditions; and X1 and X2 are the mole fraction of the solvent (water in our case).

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1.15

RT ln X1w − RT ln X2w = V w ⋅ P2 − V w ⋅ P1

1.10

And (P2 − P1 ) =

RT ( Vw

ln X1w

− ln X2w

)

(2)

Considering side one as the side with pure water and the definition of mole fraction, it is easily observed that ln X1w = 0 and, ( ) nw ) RT RT ( 2 w ln X2 = ln w (P2 − P1 ) = n2 + nsolute Vw Vw 2 ( ) w solute n +n RT = ln 2 w2 n2 Vw ( [ ]) nsolute RT 2 (P2 − P1 ) = ln 1 + w (3) n2 V w

If we consider diluted solutions the term

nsolute 2 nw 2

is a

number much smaller than 1, and the logarithmic in Eq. (3) (ln[1 − x]; x =

nsolute 2 nw 2

) can be solved by expansion in a

Maclaurin’s series ln(1 + x) = x − 1 5 5 5

1 2 x 2

+

1 3 x 3

−

1 4 x 4

+

− …. A convenient and good approximation is to take only the first element of the series. This method simplifies Eq. (3) to the following equation: ( solute ) n2 (4) (P2 − P1 ) = RT V w ⋅ nw 2 ≅ V, that is, the Notably, for diluted solutions, V w ⋅ nw 2 partial molar volume of water multiplied by the number of moles of water, can be considered the total volume of the solution (V) or: ( solute ) n2 , = RT ⋅ csolute (P2 − P1 ) = RT 2 V where csolute is the solute concentration in side 2. 2 Finally, by definition, (P2 − P1 ) = 𝜋, which is the osmotic pressure of the solution containing the solute s, and: 𝜋 = RT

⋅ csolute 2

(5)

This equation was first formulated by Jacobus van’t Hoff (1887) based on the assumption that a diluted solution could be treated as an ideal gas. In this context, the term ideal indicates that Raoult’s law (vapor pressure is proportional to the mole fraction of solvent) applies for the solution (202). van’t Hoff proposed that the osmotic pressure was the result of the pressure exerted by the solute molecules on a semipermeable

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Osmotic coefficient

Rearranging Eq. (1), we have the following equations:

Sucrose

1.05

1.00 NaCl

0.95

0.90 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 Molal concentration

Figure 3

Osmotic coefficients for solutions of Sucrose and NaCl against their molal concentration. Data for NaCl was obtained from Appendix 8.10, Table 1 (page 483) and for sucrose from Appendix 8.6 Table 1 (page 478) from Robson and Stockes (1968) (397).

membrane. Thus, the osmotic pressure would correspond to the same pressure exerted by a given number of moles occupying the same volume as the solution. Therefore, for a solution containing several species of solutes, Eq. (5) should read: 𝜋 = RT

∑n i=1

ci

(6)

As previously noted, the above equation is valid for ideal solutions. Although physiological solutions can be considered “diluted,” these solutions are real and deviate from Eq. (6) because the activity coefficients of solutes are normally less than one. This deviation results in calculated osmotic pressures that are larger than those actually measured for a given solution. To circumvent this problem, we introduce a correction factor termed the osmotic coefficient (𝛄) in Eq. (6) to account for the nonideal behavior in relation to Raoult’s law. This deviation is particularly evident in electrolyte solutions where the dissociation of salts is not complete. Figure 3 provides an idea of the deviations seen for solutions of sucrose and NaCl at 25◦ C. Considering the above arguments, Eq. (6) is now rewritten as follows: ∑ (7) 𝜋 = RT 𝛾 i ⋅ ci Calculations for a 200 mmol NaCl solution are performed as follows: 𝜋 = (8.314 × 106 Pa/(K mol/cm3 ))(298 K) × (0.925.2.0.2 mol/cm3 ) π = 4.58 × 105 Pa = 4.58 atm This result corresponds to a water column of approximately 47 meters and tells us that physiological solutions have, in fact, quite high osmotic pressures. Additionally, note

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that the osmotic coefficients measured for a single electrolyte in a solution having a mixture of solutes may vary depending on the interactions between different solute molecules.

Table 2

Main Components of the Intracellular Fluid of Rat Muscle

Fibers

Concentration (mmol/kg water)

Charge (m-equiv/kg water)

Osmolality versus tonicity The measurement of osmotic pressure, as defined in the previous paragraph, requires that a semipermeable membrane, that is, a membrane permeable exclusively to the solvent, separates two solutions of different compositions. In the laboratory, this measurement is not always feasible, particularly if we do not know the molecular sizes of the substances in dissolution. To circumvent this problem, we can use any other colligative property. Two of these properties are more commonly used, namely, water vapor pressure depression and freezing point depression. Both parameters provide an estimate of the number of osmotically active particles present in a given volume of solution; specifically, these parameters measure the relation 𝜋/RT, and the resulting number is expressed in terms of the osmolality of the solution. By definition, we say that a 1 osmolal solution has one mole (or one Avogadro’s number) of dissolved particles per kg of solvent (water). Therefore, we refer to the osmotic pressure of a 1 osmolal solution as having 1 osmole/(kg H2 O). If the solute is nondissociable, then 1 osmole = 1 mole, and osmolality = mole/(kg H2 O). To correct for deviations from ideality and for a solution containing several solutes, the osmolality should also include the osmotic coefficient, as defined above, resulting in the following equation: Osmolality =

∑ i

𝛾 i ci

(8)

where ci represents the molal concentration of solute I, having an osmotic coefficient 𝛾 i . The terms osmolality and osmolarity (number of moles per liter of solution) are sometimes used interchangeably. Nevertheless, we should note that the volume occupied by one liter of water and the molarity of the solution are dependent on the temperature, whereas one kg of water will have always the same number of water molecules. Obviously, for very diluted solutions, both osmolarity and osmolality tend to be equal. If we consider the cytoplasm of a mammalian cell, then we will find that its composition includes a series of small electrolytes and proteins, all contributing to its total osmolality. This intracellular solution is in osmotic equilibrium with the ECF. Table 2, which is reproduced from the work of Burton (70), provides some quantitative examples of important solutes involved in maintaining intracellular osmolality. Although measurements of this type can be experimentally complicated and errors can be introduced, we should note that the estimated osmolality of the intracellular solution is approximately 300 mosm/kg H2 O, the same values found for interstitial fluid and for plasma. Table 2 references only ions and small molecules present in the cytoplasm. Nevertheless, there are also macromolecules, primarily proteins,

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Na+ K+ Mg++ Cl− HCO3 − Inorganic phosphate MgATP

18

+18

165

+165

3

+6

6

−6

10

−10

2

−3

9

−18

Phosphocreatine

34

−68

Creatine

13

0

Free aminoacids (protein forming)

24

0

Teurine

18

0

Anserine + carnosine

15

+8

Urea

5

0

Lactate

3

−3

TOTAL

325

+89

which behave as polyelectrolytes and which have net negative charges at the intracellular pH of ∼7.3. Charges in the side groups of those macromolecules would balance the +89 mEq/kg H2 O excess positive charges, thus contributing to maintaining the macroscopic electroneutrality of the cytoplasmic solution. In this context, it should be noted that the cell membrane is impermeable to proteins, making these molecules important contributors to the osmotic pressure equilibrium of the cell. In contrast, due to the small concentration of proteins in relation to that of the mobile ions, their contribution to the intracellular osmotic pressure is small. This contribution can be inferred from calculations of the distribution of the ions based on the Donnan equilibrium. Thus far, we have been considering a system where a semipermeable membrane separates two aqueous solutions with different osmotic pressures or osmolalities. Under specific conditions, cells can also behave as osmometers. For example, Figure 4 shows volume changes in cardiomyocytes exposed to solutions with different osmolarities (459). Hypoosmotic solutions induce an increase in volume relative to isosmotic solutions, and the opposite is observed upon exposure to a hyperosmotic solution. In this case, the authors changed osmolarities by adding and/or substituting NaCl in normal Tyrode’s solution for mannitol, which is an impermeant molecule. Clearly, the cell volume remained altered as long as the cell remained in contact with the hyperosmotic solutions, returning to its initial value upon return to the isosmotic environment. This type of response tells us that

1471


1T

0.5T

2T

1T Scattered light intensity

1T


Rel. volume

1.6 1.4 1.2 1.0 0.8 0.6 0

5

10

15 20 Time (min)

25

30

35

Cow

Rat

Human

Mouse

2

Figure 4

Swelling and shrinkage of rabbit cardiac myocytes when exposed to an isosmotic solution (330 mosm/L—marked as 1T in the graph), to a hyposmotic solution (165 mosm/L—marked as 0.5T in the graph) and to a hyperosmotic solution (660 mosm/L—marked as 2T in the graph). Axes in the figure were redrawn from the original to improve resolution. Reproduced with the permission from Suleymanian and Baumgarten (1996) (459).

mannitol does not permeate the cell membrane. In each case, there is a volume flow (Jv ), which is essentially a water flow (Jw ) during the transient phase of the volume change. Jv is zero after the cell volume becomes steady. At any time, we can assume that the flux of solute (Js ) is also zero. We can begin our analysis of this phenomenon by remembering that the following equilibrium condition holds true for any pair of solutions separated by a semipermeable membrane: ΔP = Δ𝜋 = RTΔcs

( [ (P2 − P1 ) =

Vw

ln 1 +

nsolute 2

])

nw 2

Thus, a hydrostatic pressure develops to balance the tendency of water to move from a region of higher chemical potential to one with a lower chemical potential, that is, there is an (Δ𝜇 w ) imposed across the semipermeable membrane by the difference in the concentration of the impermeable solute. Now, let us take a different look at Eq. (1), and instead of imposing an equilibrium condition from the beginning, we explicitly write the difference in the water chemical potential (Δ𝜇w ) existing between the two sides of the membrane: Δ𝜇w + 𝜇 01 + RT ln X1w + V w ⋅ P1 − 𝜇02 − RT ln X2w − V w ⋅ P2 (9) Or Δ𝜇w 1 = (RT ln X1w − RT ln X2w ) + (P1 − P2 ) 𝛻w 𝛻w

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Figure 5

Volume changes induced in red blood cells of cow, human, rat, and mouse by exposure to a 250 mmol/L urea inward directed gradient. Cells were initially bathed in PBS and urea added at time zero. The temporal evolution of volume decrease was estimated by measuring the intensity of scattered light. Axes in the figure were redrawn from the original to improve resolution.Traces of interest reproduced with permission from Liu and co-workers (2011) (274).

Using the same type of reasoning in describing Eqs. 3 to 5 for dilute ideal solutions, Eq. (10) can be written as follows: Δ𝜇 w = (ΔP − RTΔcsolute ) 𝛻w

(10)

(11)

Following Dawson (114), Eq. (11) can be used to describe the force acting on water to produce a flow under nonequilibrium conditions and can be rewritten as follows: Jvw = Lp (ΔP − RTΔcs )

In fact, we have observed (Eq. 3) that the difference in hydrostatic pressure for diluted solutions can be approximately described by the following equation: RT

120 Time (s)

(12)

where Lp is the hydraulic permeability coefficient of the semipermeable membrane. Now, let us consider a case where the cell membrane is selectively permeable to both the solute and solvent. This situation can be observed in Figure 5 (274). Upon exposing the cells to a 250 mmol/L urea gradient, the cell volume decreases; however, in contrast to that observed in Figure 4, the volume recovers its initial value observed under isosmotic conditions. This type of response tells us that the membrane is permeable to both urea and water. The kinetics of the responses for human and cow are somewhat slower than the kinetics for rat and mouse, indicating a higher permeability to urea in the first two cases in comparison with the latter. To account for this phenomenon, we begin by writing a general equation to describe the volume flow, under nonsteady state condition, namely: Jv = Jw + Js

(13)

where Jv is the volume flow, Jw is the water flow, and Js is the solute flux. Following Katchalsky and Curran (238), we can write a phenomenological equation to relate the flow and forces for Jw and Js to Jv . This results in the following equation: Jv = Lp ΔP + LPD Δ𝜋

(14)

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Column height

Sucrose

Urea

Time

Figure 6 Time course of the column height (or pressure) for a membrane impermeable to sucrose and permeable to urea. Experimental arrangement as in Figure 1. Arrows indicate the maximum pressure difference achieved in each case.

By assuming a situation where ΔP = 0, we can see that the coefficient LPD relates the volume flow to that of its component force, that is, the osmotic pressure gradient alone. For this reason, LPD is called the osmotic coefficient of the membrane. To better understand Eq. (14), let us go back to the experiment illustrated in Figure 2. To simplify, we will change the solution in tube #4 to 100 mmol/L urea and compare tube #4 with tube #3, which contains 100 mmol/L sucrose. In addition to this simplification, we will assume that the membrane in tube #3 is ideally semipermeable and that membrane #4 is permeable to water and permeable to some extent to urea. As discussed previously, the height of the column provides both an estimation of the volume of the compartments and of the hydrostatic pressure (ΔP) that develops in the system. Figure 6 shows the results of this experiment. For sucrose, the column height increases to a final steady level, where ΔP = Δ𝜋 = 𝛾RTΔc, and a true equilibrium is reached (arrow). Nevertheless, for urea, the column height increases to a maximum (arrow) and then decreases to zero. Equation (14) can be used to describe the above results. In both cases, “equilibrium” is reached when the variation in the column height with time is zero and when Jv is equal to zero. These points are indicated by the arrows in Figure 6. Imposing these conditions on Eq. (14) results in the following equation: 0 = LP ΔP + LPD Δ𝜋 ( ) L ΔP = − PD Δ𝜋 LP

and

LP ΔP = −LPD Δ𝜋

or (15)

L

Staverman (449) first noted that the term − LPD could be P used to measure the relative permeability of the membrane to the solute and solvent and called this term the reflection coefficient (𝜎). 𝜎=−

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LPD LP

(16)

The meaning of 𝜎 is quite straightforward: if the membrane does not discriminate between the solute and solvent at all, then 𝜎 = 0, that is, the solute molecules are indistinguishable from the solvent molecules. The solute molecules are not “reflected” by the membrane, meaning that these molecules are not filtered or sieved out by the membrane. In contrast, if the membrane “reflects” all solute molecules, we can still have a solvent flow but no solute flow because the membrane is impermeable to the solute. In this case, 𝜎 = 1, the solute is sieved out, and a true osmotic equilibrium will be present, with −LPD = LP and ΔP = Δ𝜋. In a solution having a mixture of different solutes, we must consider a particular 𝜎 for each one. ΔP ) = ( RTΔc By noting that 𝜎 = ( ΔP s )Jv =0 , we can also Δ𝜋 Jv =0 i see that 𝜎 is actually a measure of the degree of effectiveness of a given solute in inducing an osmotic pressure under osmotic equilibrium conditions. Note that RTΔcsi is the calculated osmotic pressure difference between two given solutions and corresponds to the maximum pressure difference that can be achieved across the membrane. In contrast, ΔP is the hydrostatic pressure difference that is effectively observed across the membrane. At this point, it is important to distinguish between a colligative property of the solution, which, as we have observed, depends exclusively on the number of active particles dissolved per volume, such as the osmolality, and on the osmotic pressure effectively developed across a membrane, which is measured as ΔP and which is dependent not only on the osmolality but also on the properties of the membrane. To solve this problem, physiologists normally use properties of blood plasma as references because this “milieu” is in osmotic equilibrium with the interstitial fluid, which is in osmotic equilibrium with the intracellular fluid. Measurements of plasma osmolality reveal a value of approximately 300 mosm/kg H2 O. Therefore, any solution having the same osmolality will be considered isosmotic. Larger osmolalities will result in hyperosmotic solutions, and the opposite will result in hypoosmotic solutions. Let us return for a moment to the results of the experiment shown in Figure 5. We note that, although the red cells were submitted to a hyperosmotic solution (PBS + 250 mmol/L urea), their volume at equilibrium is identical to that before the addition of urea to the external solution, that is, there is no resultant inflow of water under this point. This lack of inflow is because urea has reached a concentration equilibrium between the extra- and intracellular compartments due to its 𝜎 < 1. We say that urea is nonosmotically effective. In fact, placing red blood cells in a solution containing urea alone with any osmolality will cause hemolysis because water and urea will always flow to the intracellular space, leading to cells swelling and bursting. Therefore, new terminology must be introduced to address this problem, and we now refer to tonicity to describe the effectiveness of a solute in maintaining an osmotic pressure difference across a given membrane. We can classify solutions according to their tonicity by observing the direction of the water flow when a cell is exposed to these

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solutions. If the cell swells, then the swelling occurs because there was an inflow of water to the cytoplasm, and the solution is called hypotonic. If the cell shrinks, then the flow of water is directed outward, and the solution is called hypertonic. If there is no change in cell volume, then the solution is classified as isotonic. Solutions composed of a single solute with 𝜎 < 1 will always behave as hypotonic, despite their osmolality.

Water channels in the plasma membrane Although the concept of osmotic pressure is widely used and osmosis has been known to play a fundamental role in many biological and nonbiological processes since the beginning of the nineteenth century, the physical nature of water transfer remains a matter of debate. Several theories exist that attempt to explain the physical origin of osmosis; however, these theories normally fail in explaining all details. For deeper discussions concerning this point, the interested reader should refer to references 150, 151, 194, 202, 203, 239, 295, 296, 445, 502. In this section, we will primarily discuss the pathways involved in water transfer. We begin by recognizing that the passage of water through a biological membrane can occur by two distinct pathways: the lipid phase and through proteins imbedded in the membrane. Measurements of the osmotic permeability coefficient (Pf , which is estimated from the water flux induced by an osmotic gradient imposed across a membrane) of lipid bilayers were extensively studied from approximately 1970 to 1990 by several investigators (150). The conclusion was that Pf was relatively low and had a magnitude similar to Pd , which is the diffusional permeability to water measured using radioactive isotopes. In addition to this conclusion, the temperature dependence of the phenomenon was consistent with that observed in simple diffusional processes. These results suggested that water traverses lipid bilayers by a solubility-diffusion mechanism. Nevertheless, when the lipid bilayer is modified by the inclusion of antibiotics known to form pores, such as gramicidin and amphotericin, the ratio Pf /Pd is no longer equal to one, that is, the osmotic permeability coefficient is larger than the diffusional permeability coefficient. These results and other biophysical arguments led Finkelstein to formulate a general mechanism of water movement through membranes by noting that the ratio Pf /Pd should be equal to one when water moves by a solubility-diffusion mechanism. In contrast, a Pf /Pd larger than 1 would indicate that water is moving through pores (150, 151). Therefore, by looking at these coefficients, it should be possible to infer the pathways through which water is moving in biological membranes. In fact, the results obtained in different cells ranging from frog skin to red blood cells suggest the presence of water pores in biological membranes (104, 363, 391, 426, 487). In 1970, Macey and Farmer (279) reported the inhibition of water transport, that is, a decrease in LP , in red cells by p-chloromercuribenzoate (PCMB) and by p-chloromercuribenzene sulfonate (PCMBs), which react with sulfhydryl groups. The effect could be reversed by the

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addition of excess cysteine to the preparation. Using phloretin, the authors were also able to show a dissociation between the transport of solute and water and postulated that “It would appear that water channels transport water and very little else.” During the following decades, several studies were dedicated to demonstrating that water and solute transport could be dissociated in several cell types, such as red blood cells (280,440), kidney tubules (11,490,503) and frog urinary bladder (362,364). As we can see, most of the research performed at that time and during the following years was not directed toward the elucidation of the physics of osmosis itself. In fact, the major concern was to introduce a new concept to explain water transport in biological systems, namely, the prediction of the existence of proteins with functions intimately associated with the transport of water through biological membranes. Interesting considerations of the main findings and problems faced at the time can be found in Alleva and colleagues (8) and in Parisi and co-workers (365). On the biochemical side, several studies were dedicated to isolating a putative transmembrane protein that could be directly related to water transport. Efforts by Verkman group (481) and by Benga and collaborators (45, 46) resulted in the labeling of several proteins isolated from red blood cells, primarily the anion exchanger protein (band 3) and band 4.5, respectively. Although postulated to function as water pores, none of the proteins was isolated, reconstituted, and shown to transport water (3). This period ended with two important discoveries: (i) Zhang and collaborators in 1990 (523) demonstrated that Xenopus oocytes microinjected with total mRNA of kidney and red cells had their osmotic permeability coefficient increased several fold. These results led the author to conclude that “the expressed water channel from rat renal papilla had characteristics of the vasopressin-sensitive water channel”. (ii) The cloning and reconstitution of a 28 kDa channelforming integral protein (CHIP28), also from red blood cells, on Xenopus oocytes by the Peter Agre group (375, 376). This protein was later called Aquaporin. Preston and co-workers (376) microinjected oocytes with water or with RNA coding for CHIP28 and measured the osmotic permeability coefficient. These researchers observed that oocytes injected with this RNA had their permeability to water increased several fold in comparison with the control oocytes. In fact, oocytes expressing CHIP28 burst when placed in distilled water. Figure 7, which is taken from their work, dramatically illustrates their results. Curiously, the hypothesis that water channels were incorporated into the oocyte membrane after the injection of the genetic material was based primarily on measurements of Pw and Pd , as performed many years ago in several tissues and cells. From a molecular point of view, aquaporins are tetramers, with each monomer acting as an individual pore. Each monomer is composed of 6 transmembrane helices forming a right-handled bundle, named the AQP fold. A comprehensive discussion concerning the structural aspects of the aquaporins can be found in Tani and Fujiyoshi (467). Since their

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(A) 1.5

X

CHIP28

(B)

1.3

Control

Relative volume

1.4

1.2

0.5

1.1

1.5

2.5

3/5

Time (min) 1.0

0

1

2 3 Time (min)

4

5

Figure 7 Increased osmotic water permeability of Channel-forming integral protein of 28 kDa (CHIP28) RNAinjected Xenopus oocytes. After 72 h, control-injected and CHIP28 RNA-injected (10 ng) oocytes were transferred from 200 mosM to 70 mosM modified Barth’s buffer, and changes in size were observed by videomicroscopy. (A) Osmotic swelling of representative control-injected (open circles) and CHIP28 RNA-injected (filled squares) oocytes. Time of rupture is denoted (X). (B) Photos of injected oocytes at indicated times. Oocytes injected with CHIP28 RNA (3 min) or control (5 min) are denoted 3/5. Reproduced with the permission from Preston and coworkers (1992) (376).

discovery, aquaporins have been shown to be present in bacteria, plants and animals, with a large molecular diversity. In humans, 13 different water channels have been identified (AQP0-AQP12). These water channels are subdivided into two major groups according to their permeation properties: (i) aquaporins, which are permeable essentially to water (AQP0, 1, 2, 4, 5, 6, and 8). Aquaporins are present in the brain, and AQP4 is particularly studied because its mRNA has been found in the supraoptic nucleus of the hypothalamus (35, 36, 518). (ii) Aquaglyceroporins (AQP3, 7, 9, and 10), which transport water, glycerol, urea, and small neutral molecules. A third new group has been recently proposed, which is composed of AQP11 and AQP12, called superaquaporins. Superaquaporins are involved in the regulation of intracellular water transport, organelle volume and intravesicular homeostasis (179). The widespread distribution of aquaporins in mammalian tissues and cells explains several physiological relevant processes, varying from the mechanism responsible for the concentration/dilution of the urine by the kidneys; secretions of saliva, bile, tears and sweat; and generation of aqueous humor inside the eyes, to how the brain secretes and absorbs spinal fluid. The discovery of AQP2 in the apical membrane of the principal cells of collecting ducts of the kidney became the foundation for understanding how AVP acts to control water absorption in this portion of the nephron. As widely accepted, AVP is secreted by the neurohypophysis and initiates its effect by binding to

Volume 5, July 2015

type 2 (V2 ) AVP receptors, which is a G-protein-coupled receptor (GPCR), at the basolateral membrane of the collecting duct cells. This binding results in the activation of adenylyl cyclase and in the phosphorylation of serine residue 256 on the C-terminus of AQP2, which is induced by protein kinase A (PKA) (339). Phosphorylation triggers the translocation of vesicles containing AQP2 to the apical membrane, where are incorporated, thereby increasing the water permeability at this site (335, 343). The clinical implications of defective AQP2 functions were soon recognized. Deen and colleagues (124) reported that mutations in the gene encoding AQP2 are related to nephrogenic diabetes insipidus, resulting in the production of hypotonic urine. Xenopus oocytes microinjected with the mutated RNAs failed to increase their water permeability above that of oocytes injected with water (124). Several other defects in AQP2 and their clinical consequences have been reviewed by Nielsen and colleagues (336). To conclude, water transport has been the subject of intense scientific investigations for a long time. The importance of the theme encompasses such topics as water purification and maintenance of vital processes in a variety of organisms. The study of osmotic processes has a history of success due to the combination of carefully planned and executed experiments in both artificial and biological membranes, insightful and brilliant theoretical thoughts, and intellectual capacity to see results where there were none: CHIP28 was first considered a breakdown product of Rh blood group antigens (3).

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The Evolution of Hydromineral Homeostasis Control: From Single Cells to Complex Organisms All chemical elements in the universe are derived from hydrogen by a nuclear fusion process. Additionally, in the extremely high temperature required for nuclear fusion, all generated O2 is consumed by combination with other elements. In fact, water is the most abundant molecule in the universe, and the most common combination of oxygen with another element (348). In the first billion years, the earth was constantly bombarded by meteorites, which most likely heated the surface and promoted the evaporation of all (or almost all) the water. However, some fossils of primitive bacteria have been dated as 3.7 to 3.5 billion years old (412), during the Archean Eon, indicating that life on the earth may have begun in the absence of plentiful amounts of water in the liquid state. Because of the earth cooling during the Archean Eon, water rushed back due to the force of gravity and formed the large ocean that surrounded Pangaea. However, the composition of the primitive ocean solution was extremely different from today. For example, the total ionic concentration was much lower because Cl− and Ca2+ concentrations corresponded to only one percent of the current values and Na+ was approximately three to five times less concentrated. Furthermore, the gravitational force must also have been responsible for the large amount of CO2 precipitation. Therefore, we can assume that the primary ingredient of the primitive ocean should have been sodium bicarbonate (NaHCO3 ), in contrast to the current composition of the ocean, in which NaCl is more abundant (348). The theories that attempt to explain the emergence of cells assume that the synthesis of organic compounds in the pristine ocean and their agglomeration occurred because of their physicochemical affinities. As a consequence, our first multicellular ancestor most likely originated from this same primitive ocean (469). Thus, it is not difficult to understand the high the intra- and extracellular water content and the importance of Na+ as the primary ion in the extracellular medium of modern vertebrates, as well as why most species possess plasma ionic concentrations of approximately 1/3 of those concentrations observed in the ocean. Thus, because of how life on earth emerged, unicellular and multicellular organisms are surrounded by an extracellular medium rich in ions; thus, all biochemical reactions and physiological processes required for the maintenance of life occur in an aqueous medium primarily containing Na+ and Cl− (465). Cellular volume regulation in unicellular organisms has been a never-ending issue because this regulation is the first evolutionary step to partially individualize a biological system from the universe. Water molecules follow their chemical potential gradient until a steady state is achieved because cell membranes and/or walls of unicellular organisms are

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permeable to water. If the aqueous environment in which these organisms are inserted is hypotonic in relation to the intracellular medium, then the diffusional resultant force will move the water molecules into the cell. This net movement will continue until both sides of the membrane come to the same osmolality. Moreover, if the extracellular environment is hypertonic, then the same diffusional net flux will guide the water to move out of the organism. For a more detailed discussion concerning the mechanisms driving water movement across membranes, please refer to the section “Osmosis and osmotic pressure—equilibrium” at the beginning of this review. Unicellular organisms have developed several ways to solve their problem of cell volume regulation according to the adversities of the environment. For example, cysts and spores of fungi and bacteria can survive for long periods without any exchange with the environment, completely isolating themselves from the environment and preventing any movement of water, allowing individuals to address temporary adverse conditions. However, the vital processes are suspended in this situation until resuming activity when better ambient conditions occur (183). Bacteria, protozoa and unicellular algae also control their cellular volume, although their intracellular fluid has a much higher osmolality than the external medium. To resist elevated intracellular osmotic pressure and to prevent their lysis, bacteria and most algae are coated with rigid cellulose walls. This mechanism allows for the development of turgor pressure. Furthermore, to address the constant osmotic influx induced by elevated intracellular tonicity, protozoans have specialized mechanisms, such as contractile vacuoles (7) that pump water to the extracellular space in a process called “anisosmotic regulation of intracellular fluid.” Thus, unicellular organisms can control their intracellular volume both structurally (cellular wall) and functionally (contractile vacuoles). The evolution from single-cell to multicellular organisms was complex and among other factors, benefited from the emergence of certain tissues and systems directed to the regulation and maintenance of the steady-state internal environment (60). Vertebrates are virtually spread throughout all types of available habitats on the Earth, from saline and freshwater to extremely mesic and xeric environments (60). Undoubtedly, renal and neuroendocrine adaptations had to occur to control hydromineral homeostasis, allowing the great evolutionary success of vertebrates (62, 439, 465). The kidney is the primary organ involved in the control of extracellular volume and composition in mammals, with obvious morphophysiological diversity among the classes due to the wide range of habitats occupied by animals. In addition, several osmoregulatory organs have evolutionary emerged in vertebrates (gills, bladder, skin, and salt glands). Therefore, in the following paragraphs, we will provide a brief comparative analysis of the hydromineral neuroendocrine adaptations in the major classes of vertebrates, with the aim of understanding the evolutionary steps that

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resulted in the complex integrated mechanisms responsible for the extracellular volume and composition homeostasis in mammals. The renin-angiotensin system (RAS) is one of the most important endocrine systems involved in the control of kidney function and in the hydromineral balance in vertebrates. Renin, which is a proteolytic and activating enzyme from the RAS, has been identified in all tetrapods, bony fish and in some cartilaginous fish, with a primitive translational form (439). The angiotensinogen gene has been recently cloned in bony and in cartilaginous fish (500, 507), whereas the angiotensin I (ANG I) was identified in several species, from mammals to chondrichthyes and cyclostomes, showing high conservation in their amino acid sequences (465). Additionally, the angiotensin-converting enzyme (ACE), which cleaves ANG I into angiotensin II (ANG II), also has a widespread phylogenetic distribution from fish through amniotes (199, 373). Thus, those findings indicate an extremely ancient emergence of therasin vertebrates. The regulatory site of renal/systemic RAS activity is the juxtaglomerular apparatus, which is composed of juxtaglomerular cells, macula densa and extraglomerular mesangium. The juxtaglomerular cells are present in most vertebrates, from cartilaginous fish to mammals, overlapping with the importance of renin because these cells are the primary site of production and secretion for systemic renin. The macula densa cells are found in only birds and mammals, indicating that Na+ and Cl− regulation of renin secretion and, consequently, RAS activation appear coincidently with the definitive conquering of dry environments. Additionally, the extraglomerular mesangium seems to regulate juxtaglomerular and macula densa cells locally, finely controlling renin secretion (175). Those cells are found only in mammals, indicating the evolutionarily complex control of the RAS reached in this class (439). Regardless of the widespread presence of the RAS in vertebrates, only few studies exist concerning the regulation of glomerular filtration by ANG II in nonmammals, with negative results, indicating that the major physiological role of this system is well established in mammals (109,340,438). In contrast, ANG II strongly induces thirst and sodium appetite in virtually all vertebrate species tested, including bony fish, reptiles, avians, and mammals, showing a highly preserved role for ANG II in the behavioral regulation of hydromineral balance (154, 466). In mammals, ANG II also stimulates the production of aldosterone, which is the primary mineralocorticoid hormone that stimulates sodium reabsorption by the renal tubules. However, the role of adrenal corticoids in renal sodium management in nonmammalian vertebrates remains unclear. Aldosterone has been identified in the plasma of bony fish, amphibians, reptiles and avians (32, 407, 484). Some studies have demonstrated that adrenocorticoids may increase renal sodium reuptake in eels, snakes, turtles, lizards, and

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ducks (109), which suggests that aldosterone may have the same stimulatory effect on sodium reabsorption as that in mammals. Natriuretic peptides are primarily produced by cardiomyocytes and secreted directly into the blood; these hormones act in mammals to regulate renal excretion, cardiovascular function and sodium appetite (discussed in the following sections). Both atrial (ANP) and brain (BNP) natriuretic peptides have been found in several vertebrates, including fish, amphibians, birds, and reptiles, as well as in a range of mammals (80, 319). Similar to their function in mammals, these hormones also increase sodium and water excretion and decrease arterial pressure in eels, fish, frogs, turtles, and ducks (129, 185, 352, 380, 483). Those findings revealed an ancient role of natriuretic peptides synthesized by the heart to control hydromineral and cardiovascular homeostasis. Prolactin is a hormone produced by the lactotrophs from the anterior pituitary under hypothalamic control, and it has a primary role in stimulate milk production and secretion (457). Currently, more than 300 physiological functions and pharmacological effects of PRL have been reported in various species of mammals (54). PRL participation in the neuroendocrine control of hydromineral balance has been demonstrated in some bony fish and amphibians. The first demonstration of PRL role in osmoregulation in fish was in hypophysectomized killifishes, which were unable to survive in fresh water (69). PRL treatment restores the ability of these animals to live in freshwater (371). During the following decades, several studies were performed using different variants of PRL in different fish species, and generally, the results suggested that this hormone is important for preventing both the loss of sodium and the uptake of water, providing euryhaline fish with the ability to experience abrupt changes in environmental salinity (288). PRL binding was also detected along the proximal tubules of anurans (178). Studies performed in amphibians also suggested that PRL could also be involved in freshwater life adaptation, similar to bony fish, because the levels of this hormone and its receptor in kidneys and epidermis decreased when these animals were exposed to a hypertonic environment (190, 298). Because PRL is essential to some freshwater fish and amphibians but has no clear effects on renal tubules in avians and in mammals, the function of this hormone in the hydromineral balance seems to have been drastically reduced with the transition of vertebrates from water to land (298, 396, 451). Finally, the neurohormones AVP and OXT are directly involved in the hydromineral balance in mammals, acting on water and sodium excretion in kidneys and on behavioral and cardiovascular responses (24). OXT- and AVP-related peptides certainly originated early in the evolutionary pathways, being present in most invertebrates and in all vertebrate lineages, as shown in Table 3 (43, 199). Cartilaginous fish express five different forms of OXT-like peptides (glumitocin, aspargtocin, valitocin, asvatocin and phasvatocin) but only one AVP-like peptide, vasotocin. These animals

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Table 3


Structures of the Neurohypophyseal Peptides in Vertebrates Amino Acid

Peptide (animal group)

1

2

3

4

5

6

7

8

9

10

11

12

Glumitocin (ray)

C

Y

I

S

N

C

P

Q

G

Valitocin (shark)

-

-

-

Q

-

-

-

V

-

Aspartocin (shark)

-

-

-

N

-

-

-

L

-

Asvatocin (shark)

-

-

-

N

-

-

-

V

-

Phasvatocin (shark)

-

-

F

N

-

-

-

V

-

Isotocin (teleost)

-

-

-

-

-

-

-

I

-

Mesotocin (lungfish, marsupial)

-

-

-

Q

-

-

-

I

-

Hydrin I (amphibian)

-

-

-

Q

-

-

-

R

-

G

K

R

G

Hydrin II (amphibian)

-

-

-

Q

-

-

-

R

-

Arginine vasotocin (elasmobranch, bird)

-

-

-

Q

-

-

-

R

-

Phenypressin (marsupial)

-

F

F

-

-

-

-

R

-

Lysine vasopressin (marsupial, pig)

-

-

F

Q

-

-

-

K

-

Oxytocin (mammal)

-

-

-

Q

-

-

-

L

-

Arginine vasopressin (mammal)

-

-

F

Q

-

-

-

R

-

have an osmoregulatory mechanism involving urea synthesis and retention through renal urea transporters. In this sense, vasotocin seems to regulate renal urea transport mechanisms, similar to AVP in mammals (1). In contrast, the roles of OXTlike peptides in these animals remain unclear. In bony fish, most studies indicated that the two neurohypophyseal hormones, vasotocin and isotocin, are homologous to mammalian AVP and OXT, respectively. Both vasotocin and isotocin plasma concentrations increase in response to environmental salinity in bony fish, suggesting an osmoregulatory role for these peptides (252). Some pharmacological studies have shown that vasotocin administered in physiological doses induces an antidiuretic response, which appears to originate from glomerular filtration rate modulation rather than from tubular fluid reabsorption. However, vasotocin also increases renal water reabsorption, most likely acting via a V2 -mediated increase in tubular intracellular adenosine cyclic monophosphate (cAMP) levels, similar to the AVP effect on mammalian kidney (498). Concerning cartilaginous fish, the role of the OXT-related peptide isotocin in hydromineral balance requires clarification. In amphibians, four types of neurohypophysial hormones are found: three homologs of AVP (vasotocin, hydrin 1 and 2) and mesotocin, which is a homolog of OXT. In virtually all studied amphibia, the nephron, the urinary bladder, and the skin respond to vasotocin (via V2 receptors), increasing water reuptake. In turn, hydrin peptides are more related to water permeability of the skin and bladder than vasotocin but are devoid of antidiuretic activity (2). Similar to OXT in mammals, mesotocin seems to be a diuretic hormone in

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amphibians, similar to the effect found in Rana catesbiana; this effect is most likely mediated by dilation of the afferent glomerular arteriole (361). In both reptiles and avians, the homologs of AVP and OXT peptides are vasotocin and mesotocin, respectively. In reptiles, vasotocin seems to have a dual effect on the kidney, diluting the tubular fluid in the thin-intermediate segment and mediating water reabsorption along the final segments of the nephron (59). In avians, most evidence has indicated that vasotocin can act in renal vasculature and tubules, inducing antidiuresis by (i) constriction of afferent arterioles, (ii) reduction of the glomerular filtration rate, and (iii) increase of water reabsorption in the ascending and collecting tubules of the nephron (174). The water reabsorption induced by vasotocin in reptiles, avians, and mammals, seems to be mediated by V2 receptors, increased intracellular cAMP generation and aquaporin incorporation into cell membranes (59, 174). In turtles, mesotocin presents some antidiuretic effects only in high pharmacological doses (71). Additionally, hens treated with mesotocin after a sodium-load diet show an antidiuretic response with low doses and a diuretic response with higher doses (464). Thus, in reptiles and in avians, mesotocin is not a diuretic hormone, in contrast to its action in amphibians. Because AVP- and OXT-like peptides are found in all vertebrates, with variable roles in hydromineral balance, these neuropeptides seem to be part of an extremely ancient system involved in the control of the ECF volume and osmolality. Therefore, we can conclude that several neuroendocrine systems have emerged along the evolutionary pathway for controlling the loss and conservation of water and electrolytes.

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Historical Considerations: From Hypothalamic Lesions to Molecular Biology In this section, we wish to note the major conceptual steps that provide background to the current understanding of the peripheral and central homeostatic mechanisms controlling hydromineral balance in mammals. It should be emphasized at this point that the concepts presented in this paper have progressed following the advances of new technologies and methodological approaches. In the neurosciences, the early 1930s were marked not only by anatomical, histological and immunochemical studies but also by the employment of site-specific lesions and electrical stimulation. Within this context, one of the first areas to be explored was the involvement of the hypothalamus and pituitary system in the regulation of water balance (152). Based on these pioneer observations, Montemurro and Stevenson (323) published one of the first reports showing that lesions induced on the ventromedial hypothalamus reduced the water/food intake ratio, delayed the excretion of a water load, increased tubular water reabsorption and slightly increased plasma sodium concentrations. Additionally, studies performed during this same period in the United States by Andersson (14), Andersson and McCann (20, 21) and Andersson and co-workers (17) and in Brazil by Covian, Antunes-Rodrigues and their associates reinforced a central role for the hypothalamus in the control of water and salt homeostasis (23). In this regard, systematic studies using electrolytic lesions and electrical/chemical stimulation in rats demonstrated the participation of several CNS structures in the selective intake of water or NaCl. Furthermore, studies aimed at the anatomical characterization of the anterior hypothalamus also identified primary sensory structures involved in this homeostatic function. The circumventricular organs (CVOs) were characterized as osmosensitive regions responsible for specifically monitoring extracellular Na+ concentrations in the brain (300,301). These structures are devoid of the blood brain barrier (BBB) and are primarily located at the lamina terminalis (LT). According to these data, it was possible to demonstrate the existence of a neural circuitry (involving the septal area, anteroventral region of the third ventricle (AV3V), the amygdaloid complex, the hypothalamus, the olfactory bulb, the hippocampus, and the sensory and motor cortices) that controls sodium intake and/or excretion. A more detailed description of the primary CVOs can be found under the topic “Lamina terminalis.” Additionally, during the 1960s, Grossman published the first studies demonstrating the regulation of these brain structures by specific neurotransmitters through the administration of specific agonists and antagonists directly into the CNS. The primary findings at that time revealed that injections of adrenergic and cholinergic agonists into the hypothalamus were able to increase food and water intake, respectively (189). In contrast, carbachol administered into the third cerebral

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ventricle (3V), into the medial septal area and into several other CNS structures was shown to induce natriuresis and kaliuresis through the activation of muscarinic receptors (74, 75, 327, 328). Taken together, these findings supported a stimulatory role for cholinergic and alpha-adrenergic projections and an inhibitory beta-adrenergic-mediated action on sodium excretion. The development of the radioimmunoassay by Berson and Yalow in the 1960s has also made it possible to quantify hormones, drugs and other peptides in plasma under several experimental conditions. This technique represented an important tool for studies concerning system physiology, primarily for endocrinology and for neuroendocrinology. Using this method, changes in renal sodium and in water management could be correlated with plasma hormone levels. In 1986, Stricker and Verbalis showed that a slight decrease in plasma osmolality was able to decrease OXT and AVP secretion, despite the presence of a 30% reduction in plasma volume. The primary actions of the neuropeptides AVP and OXT on body fluid homeostasis are discussed in detail in the section “Initiating the effector responses: neuroendocrine systems: Hypothalamic neurohypophyseal peptides.” Furthermore, Baldissera and colleagues (38) demonstrated that the injection of carbachol into the AV3V region induced the release of AVP, OXT and ANP into the systemic circulation; this effect is associated with natriuresis and with antidiuresis. These data were some of the first used to propose that the natriuretic effects induced by cholinergic and osmotic stimulation were actually mediated by neuroendocrine changes. Later, Haanwinckel and co-workers (192) demonstrated that the direct stimulation of the AV3V region increases ANP plasma concentrations, whereas lesions induced on the AV3V region or on the median eminence (ME), as well as the removal of the neural lobe of the pituitary gland, completely disrupt ANP release induced by increases in the extracellular volume. These results indicated that the integrity of these areas of the CNS was essential for ANP release mediated, at least in part, by OXT, which was shown to act directly on cardiomyocytes to stimulate ANP release, thus producing natriuresis. These results were also consistent with a hypothetical pathway for the physiological control of ANP release involving the following: (i) peripheral components (mechanoreceptors in the cardiac atria, carotid and aortic sinuses and kidneys) and (ii) an afferent input arising from these structures to brainstem noradrenergic neurons and then to the AV3V region, which mediates systemic ANP release via activation of an hypothalamic ANPergic system (25). A more detailed explanation of the actions of OXT and ANP in mediating natriuretic responses is found in the section “Initiating the effector responses: neuroendocrine systems: Natriuretic peptides.” During the last sixty years, there was a massive methodological advance in biology research, which was also applicable for understanding how the CNS controls hydromineral balance. The following techniques/fields can be highlighted: (i) microscopy/imaging; (ii) hormones, neuropeptides and

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neurotransmitter measurements; (iii) protein isolation; and characterization; (iv) peptide synthesis; and (v) molecular biology. The refinement of immunohistochemical procedures made it possible to track neuronal pathways involved in the control of sodium and water balance, as well as areas participating in responses to different physiological challenges. Additionally, the labeling of the immediate-early genes products, such as the proteins of the c-Fos family, represented a great advance in attempts to identify which areas and which neuronal phenotypes were activated by each paradigm. Employing this methodological approach, McKinley and co-workers (299, 300) demonstrated that both the intracerebroventricular (icv) and intravenous (iv) infusions of ANG II induce c-Fos expression in neurons in the LT, hypothalamic supraoptic (SON) and paraventricular nuclei (PVN), bed nucleus of stria terminalis and central amygdaloid nucleus. These authors also observed that when ANG II was injected intravenously, more intense c-Fos immunoreactivity was found in the subfornical organ (SFO) and in the organum vasculosum of the lamina terminalis (OVLT). In contrast, when ANG II was icv administered, c-Fos expression was observed primarily in the median preoptic nucleus (MnPO). These results suggested that the route through which ANG II has access to the CNS consistently affects the neuronal groups recruited. The studies conducted by Godino (172,173) and by Badauê-Passos Jr (34) not only confirmed diencephalic, forebrain, and brainstem areas as part of a neuronal circuitry that regulates fluid balance but also correlated specific neuronal phenotypes to each of these structures. Changes performed selectively to ECF volume and/or osmolality in freely moving rats revealed that neuronal groups in the hypothalamus (PVN and SON, which contain vasopressinergic and oxytocinergic neurons), midbrain [dorsal raphe nucleus (DRN), which contains serotonergic cells) and medulla (which contains the catecholaminergic A1 (caudal ventral lateral medulla (CVLM), C1 (rostral ventral lateral medulla (RVLM)], A2 [nucleus of the solitary tract (NTS)], and A6 [locus coeruleus (LC) groups] are involved in the regulatory response to ECF imbalances (173, 290, 400). Additionally, Uschakov and co-workers (486), who combined c-Fos immunostaining and retrograde tracing techniques, identified double-labeled neurons in the LT of animals previously injected with a tracer into the ventrolateral periaqueductal gray (PAG) area and challenged with hypertonic saline or with water deprivation. These authors also noted that OVLT-PAG projections represented one of the most marked features observed. Similar studies were reported previously by Simerly and Swanson (428) and by Sly and colleagues (435). These groups were able to show direct connections arising from the LT to the brainstem, as well as to the kidneys. Also in the imaging field, another important advance was obtained by Denton (127) in his studies employing positron emission tomography technology. This group demonstrated that a positive correlation exists between increased plasma sodium concentrations (induced by a rapid iv infusion of hypertonic saline) and increased cerebral cortex activation,

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which is primarily observed at the anterior cingulate region, middle temporal gyrus and PAG. After the ingestion of water (satiation), a deactivation of the parahippocampal and frontal gyri was also observed by these authors. Therefore, these data are consistent with an important role of the anterior cingulate in the genesis of hypernatremia- and hyperosmolality-induced thirst (137). More recently, returning from the discussion of whole organisms to the cellular environment, several techniques have broadened the understanding of local systems and cellular interactions. The use of cultured cells and other in vitro or ex vivo strategies has consistently contributed to this field. Within this context, glial cells have been investigated as active partners in the processing of neural information. Due to their heterogeneous and ubiquitous distribution in the CNS, the morphological and functional relation between glia and neurons has been studied in several CNS areas, including in the hypothalamus (359), where those cells seem to regulate hormone secretion by magnocellular neurons of the PVN and SON (321, 471). Under conditions of chronic dehydration, astrocytes undergo morphological changes, including retraction of the astroglial processes, with a consequent decrease in the glial coverage of magnocellular neurons. Following specific challenges, a remodeling of synaptic contact and a change in the number of glutamatergic and γ-Aminobutyric acid (GABA)ergic synapses was also reported (368, 472). In contrast, in response to hypo-osmotic stimulation, astrocytes were shown to release the amino acid taurine within the SON (221). Then, this gliotransmitter activates glycine receptors in magnocellular neurons, inhibiting neurohypophyseal hormone secretion (220). Some reports also suggest that astrocytes may directly act as osmosensitive elements, participating in the neuro-humoral circuitry activated by osmotic changes. This hypothesis was recently reinforced by evidence provided by Yuan and colleagues (520). This group showed that (i) the expression of c-Fos in SON astrocytes induced by systemic hyperosmotic stimulation precedes the increased expression of the same protein in the neuronal population and that (ii) the osmotic-induced increase in c-Fos expression in neurons is disrupted by the use of an inhibitor of glial metabolism. In addition to taurine, astrocytes were previously demonstrated to produce and to release other transmitters and modulators, such as adenosine triphosphate (ATP), glutamate, inflammatory cytokines [tumor necrosis factor α (TNFα), interleukins and chemokines], nitric oxide (NO), and carbon monoxide (CO), thus modulating the neuronal environment (50, 181, 285, 450). Furthermore, many investigative studies have recently focused on the characterization of the machinery steps implicated in the production of a mature protein or peptide. Therefore, the quantitative or semi-quantitative analysis of messenger (m) and heteronuclear (hn) ribonucleic acid (RNA) has appeared as an important evaluation when dissociated effects are detected at transcriptional and translational levels. The hnRNA consists of the immediate copy of the coding regions of DNA derived from the transcriptional process. The

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mRNA, in turn, is a product of hnRNA splicing (removal of the intronic sequences). Previous reports in the literature have demonstrated that AVP hnRNA levels may be not correlated with plasma sodium concentrations (248). However, some studies suggest that this response may actually be derived from increased processing of hnRNA to mRNA or from an increase in degradation processes mediated by microRNAs and exosomes (212, 444). Accordingly, our group has previously demonstrated that a hypertonic increase in the ECF volume enhances the relative expression of AVP mRNA in the PVN and SON (401), which is consistent with previous findings showing increased c-Fos immunoreactivity in vasopressinergic cells under identical experimental conditions (400). In contrast, the same authors reported that both isotonic and hypertonic extracellular volume expansion increase OXT mRNA expression in the hypothalamus (401). Taken together, these results suggest that, in addition to stimulating hormone release from neurohypophyseal stores, alterations in ECF volume and osmolality are potential stimuli for de novo hormone synthesis. In addition to quantifying the absolute or relative contents of RNAs, it also became possible to determine their in situ anatomical localization using labeled probes and highly specific detection methods. However, several studies have demonstrated that mRNA expression is not always correlated with the expression of the mature protein. Indeed, Carter and Murphy (78) provided the first evidence that AVP and OXT mRNA expression induced by the intraperitoneal injection of hypertonic saline may be temporally disconnected from other events, such as neuronal activation. These authors demonstrated that magnocellular neurons could increase the poly(A) tail at the 3’ terminal of mRNA sequence when exposed to adverse environments. This effect apparently precedes any detectable change in the absolute content of mRNA and may be related to an increase in the stability of mRNA molecules (158). Although we cannot exclude the possibility that this mechanism may be observed following acute paradigms, most authors agree that this mechanism is more likely to occur as an adaptive response following prolonged exposure to an osmotic challenge. More recently, some studies have also been devoted to cataloging the transcriptome of brain nuclei implicated in body fluid homeostasis in an attempt to identify the molecular targets causing those alterations. For example, Hindmarch and colleagues, who employed high-standard genetic analysis, described how the transcriptome of the hypophyseal neurointermediate lobe (NIL), PVN, SON, SFO, and area postrema (AP) changes in response to a 3-day fluid deprivation. (204-206). In the NIL, PVN and SON, the expression of 52, 12, and 183 genes, respectively, significantly changed more than twofold in response to water deprivation. For example, the cAMP responsive element binding protein 3-like 1 (CREB3L1) was upregulated more than fourfold in the SON of dehydrated rats (205). Recently, the same group demonstrated that CREB3L1 acts as an osmotic-sensing regulator of AVP transcription in the rat hypothalamus (186). Therefore, the use of molecular tools to analyze global transcriptome

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expression from brain areas related to neuroendocrine control of hydromineral balance can represent a state of the art methodology to search for new regulators and molecular targets for studying these neuroendocrine systems. As a promising perspective in this field, the same group is now working on the development of viral vectors carrying sequences for small hairpin RNAs (shRNA), which can be injected directly into the CNS to promote in situ downregulation or upregulation of gene expression. In this context, the injection of a lentiviral vector expressing the full-length and constitutively active forms of CREB3 L1 simultaneously into the PVN and SON resulted in increased AVP biosynthesis, which strongly suggests a regulatory role for this gene in the expression of AVP (186).

Sensors Central osmoreceptors and Na+ sensors Andersson’s (15) pioneering studies demonstrated the involvement of the rostral and medial hypothalamus in the induction of thirst after brain hypertonic NaCl administration. Thereafter, disruption between osmotic-induced water intake and AVP was observed after induction of lesions in the AV3V region, which contains the OVLT (18, 67, 68, 301, 302 303, 304). Additionally, reports showed a marked antidiuretic response elicited by hypertonic NaCl or sucrose solutions infusion in the carotid artery, despite the absence of this response after the infusion of a hypertonic urea solution (141, 475, 476). These results suggested a central osmosensitive system in the AV3V that seemed to be dependent on cellular dehydration and related to the control of thirst, AVP release and renal water reabsorption. McKinley’s group also demonstrated that the icv injection of hypertonic saline was more effective in inducing thirst and antidiuretic responses than sucrose hypertonic solution (301, 304), suggesting the existence of a specific Na+ -sensor mechanism at the CNS level, first postulated by Andersson’s data and conceptions (14-16, 19). Because the OVLT and SFO (which are devoid of the BBB) are on the anterior portion of the third ventricle and because Na+ and sucrose do not easily surpass the BBB, both osmo- and Na+ -sensitive cells at the CNS should be primarily in the CVOs. In fact, McKinley and colleagues (305) demonstrated that hyperosmolality induced by water deprivation was related to intense c-Fos expression in the OVLT and MnPO and, to a lesser extent, in the SFO. These data suggested the LT as the primary osmo-/Na+ -sensitive area in the brain. Studies employing functional imaging strategies from the AV3V region demonstrated the activation of this area in rats and in humans submitted to hypertonic challenges (137, 324). Furthermore, the rate of action potentials in OVLT neurons increases as osmolality is incremented, in both the presence and absence of synaptic network interaction and even when these neurons are isolated (88, 494). Taking together, these findings suggest that the OVLT is the key osmosensitive brain area (58). However, as defined

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by Bourque (2008), “an osmoreceptor neuron must display an intrinsic ability to transduce osmotic perturbations into changes in the rate or pattern of action-potential discharge” (57). Based on this notion, the OVLT is not the only area that contains osmosensitive neurons because the neurons of the SFO and magnocellular neurons of the SON and PVN also demonstrated intrinsic osmosensitivity (13, 350, 378). Most studies investigating neural osmosensitivity and transduction mechanisms have been conducted in magnocellular neurons. Oliet and Bourque (351) demonstrated that the increase in cationic membrane conductance, which is responsible for the increase in firing rate in response to hypertonicity, is associated with a decrease in neuronal volume due to cell dehydration, suggesting that osmosensory transduction is an essential mechanical process activated by changes in osmolality. Furthermore, those authors also showed that cationic conductance and action potential firing rate changes were reversed by the restoration of cell volume (57, 525) (Fig. 8). The transient receptor potential (TRP) is a superfamily of cationic channels permeable to monovalent and divalent cations, which are activated by several stimuli (338). For example, subtypes 2 and 4 of TRP vanilloid (TRPV) channels are activate by osmolality changes (268, 331). Additionally, TRPV1 channels seem to be the primary isoform involved in central osmosensitivity because its signaling is essential to magnocellular and OVLT neuronal activation in response to hypertonicity (89, 458). Furthermore, TRPV1 knockout mice show impaired AVP secretion and water intake associated with the absent of depolarizing potentials in magnocellular and OVLT neurons in response to hypertonicity (88, 421). Additionally, OVLT and SON magnocellular neuron response to a hypertonic stimulus was blocked by ruthenium red, which is a nonselective TRPV inhibitor (89, 458). The same group also demonstrated that magnocellular neuron depolarization is dependent on a non-selective cationic conductance, which has an important Ca2+ compound (524). These data are consistent with the fact that TRPV channels are permeable to Ca2+ (338), suggesting that the activation of TRPV channels and the consequent Ca2+ influx could be responsible for osmosensory transduction in magnocellular and OVLT neurons (57). Glial cells also seem to be involved in the control of osmosensory transduction in magnocellular neurons. Hypoosmotic stress leads to taurine release from astrocytes into the SON (126, 221). In turn, taurine can act on magnocellular neurons via glycinergic receptors to inhibit AVP secretion during hypotonicity and/or hyponatremia (125, 221). In fact, Choe and co-workers (85) demonstrated that glial cells are the only source of taurine in the SON and that this gliotransmitter exerts a tonic inhibitory action on magnocellular neurons, which is inversely correlated with ECF tonicity. The participation of glial cells in the central Na+ -sensory mechanisms has been recently postulated. Nax channels are expressed in the CVOs and are responsible for monitoring plasma and cerebrospinal fluid (CSF) Na+ concentrations. Additionally, the SFO seems to be the primary site for sodium

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appetite control involving the Nax channel (342). The icv infusion of a hypertonic NaCl solution induced extensive water intake and salt aversion in control but not in Nax knockout mice (209). In the same work, those authors demonstrated that Nax overexpression in the knockout mice using an adenoviral vector into the SFO led to the recovery of the saltavoiding behavior. Watanabe and colleagues (499) demonstrated that salt-aversive behaviors induced by dehydration were absent in Nax knockout mice. Moreover, icv infusion of either mannitol or isotonic saline induced similar behavioral effects on water and sodium intake in both wild-type and Nax knockout mice, suggesting that Nax is particularly sensitive to extracellular sodium concentrations. In this context, mice and rats present considerable differences in brain Nax immunolabeling. Despite the presence of Nax in AVP and OXT magnocellular neurons in the SON and PVN of both animals, this channel is present in both neurons and glial cells in rats, whereas mice show Nax immunostaining only in glial cells of other brain nuclei (333). Shimizu and colleagues (424) demonstrated that the increase in plasma Na+ levels induced by dehydration influences glia-neuronal interaction via the coupling of Nax and glial metabolism in the following sequence of events: (i) increased Na+ concentrations in glial cytoplasm via Nax , (ii) increased Na+ /K+ -ATPase activity and ATP expenditure because Nax is coupled to this membrane enzyme, and (iii) stimulation of anaerobic glucose metabolism and lactate release by astrocytes. Furthermore, the same group demonstrated that the dehydration-induced lactate release by astrocytes activates SFO GABAergic neurons; this mechanism is presumably implicated in the control of salt intake by Nax channels.

Peripheral osmoreceptors and mechanoreceptors Similar to the CNS, peripheral organs also express different sensory mechanisms related to the control of hydromineral balance, represented by the digestive osmoreceptor system, vascular baroreceptors and cardiac volume receptors. Peripheral osmoreceptors are present in the digestive tract, primarily in the oropharyngeal cavity, gastrointestinal tract, liver, hepatic portal vein and mesentery (57). Several physiological findings support the involvement of peripheral osmoreceptors operating independent of the central ones in the control of hydromineral balance. For example, intragastric water loading or spontaneous water intake in osmotically stimulated animals leads to thirst satiety and to a reduction in plasma AVP before the correction of plasma osmolality (37, 52, 217, 453). Osmoreceptors at the hepatic portal vein can send afferent connections to the CNS and induce anticipatory osmoregulatory responses related to the prevention of hypertonicityinduced intake (193). In fact, hypertonic NaCl infusion into the hepatic portal vein induces AVP secretion, even without increasing plasma osmolality (87). In addition, intragastric hypertonic NaCl administration induces thirst and AVP secretion under basal conditions and decreases salt intake in sodium-depleted rats before plasma osmolality increases

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+30 mosmol kg–1

(A)

–30 mosmol kg–1

30 mV 20 s

(B)

(C) Isotonic

Hypotonic

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0 +60 Change in osmolality (mosmol kg–1)

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Volume

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–60 mosmol kg–1

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Figure 8 Transduction mechanism of osmorreceptor neurons. (A) Representative tracing from a magnocellular neuron membrane voltage variation in response to hyperosmolality (depolarization and increased action-potential firing) and hypo-osmolality (hyperpolarization and reduced action-potential firing); (B) graph showing the inverse correlation between extracellular fluid (ECF) osmolality and magnocellular neuron volume (nV, normalized to control volume); (C) diagram showing the magnocellular neurons changing ionic strength in response to hypotonic and hypertonic environments; (D) demonstration of the restoration of cell volume through suction applied to the recording pipette is able to reverse the reduction on cationic membrane conductance (G) caused by a hypo-osmotic stimulus in osmorreceptor neurons. (E) Conversely, demonstration of the restoration of cell volume through increased pipette pressure is able to reverse the increase in cationic membrane conductance caused by a hyperosmotic stimulus. Reproduced with the permission from Bourque (2008) (57).

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(72, 77, 86, 217, 453). Similar to most peripheral neural signals, information originating from peripheral osmoreceptors is carried to the NTS via the vagus nerve (58, 245, 337, 354). Recently, the cellular mechanisms of hepatic osmosensitive neurons (with cellular bodies at thoracic dorsal root ganglia) were demonstrated: these neurons show an inward current that is responsible for transducing changes in osmolality in a range of ∼15 mosm/kg. This mechanism is related to TRPV4 channels because TRPV4 knockout mice do not exhibit these currents or peripheral osmoreceptor activity in vivo (262). In turn, vascular baroreceptors are formed by terminations primarily in the adventitia of the carotid sinus and aortic arch, with the neuronal soma in the petrosal and nodose ganglia. When those arteries are stretched in response to arterial pressure changes, these neurons depolarize, and the action potentials travel centrally to the NTS (81) because the activation of the baroreceptors is dependent on a mechanical transduction that leads to an inward Ca2+ current (460). In turn, the NTS is responsible for retransmitting baroreceptor information to other brain areas related to the control of several neuroendocrine responses. The decrease in baroreceptor discharge caused by a reduction in arterial pressure induces several effects, such as an increase in sympathetic activity, an increase in plasma catecholamine and AVP concentrations, augmentation of renin release, with the consequent activation of the RAS, and a reduction in plasma OXT and ANP concentrations, which, acting together, contribute to restoring blood pressure. Conversely, the increase in pressure and/or volemia is accompanied by opposite responses (24). Additionally, the raphe nuclei may be stimulated via NTS by afferents from baroreceptors and may contribute to the stimulation of ANP release following blood volume expansion (385). A multisynaptic pathway that involves ascending neuronal catecholaminergic projections from the diagonal band of Broca (DBB) is responsible for the transient and selective GABAergic inhibition of the neurosecretory vasopressinergic neurons; baroreceptor activation induces a consistent increase in the firing rate of DBB neurons, which project to the SON (228, 229, 240, 355). Receptors in the aortic arch and carotid sinuses monitor changes in arterial blood pressure, whereas mechanoreceptors from the atrium and ventricles are sensitive to blood volume changes. These data are relayed through the vagal and glossopharyngeal nerves to the NTS in the brain stem, from which postsynaptic pathways modulate the activity of magnocellular neurons of the SON and PVN (24, 133, 420). Plasma ANP levels after volume expansion are decreased in rats submitted to carotid-aortic baroreceptor or renal deafferentation (25, 326). The evidence from these experiments, together with previous stimulation and lesion studies, indicate that volume expansion-induced ANP release is mediated by afferent baroreceptor inputs to the AV3V region, which increase ANP release via activation of the hypothalamic ANP neuronal system. A detailed description of the integrated response of volume receptors and ANP secretion can be found in the section “Natriuretic peptides.” In addition,

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extensive studies have demonstrated that volume expansion stretches the baroreceptors in the right atrium, carotid and aortic sinuses, and in the kidney, thereby increasing their afferent input to the NTS, which, in turn, can modulate several neuroendocrine responses related to hydromineral balance (374).

Central Integration: Morphofunctional Substrates Lamina terminalis The lamina terminalis (LT) is in the forebrain, adjacent to the anterior portion of the cerebral 3V, and is composed of the MnPO and two other CVOs, the SFO and the OVLT. The OVLT and the ventral portion of MnPO, together with both the preoptic periventricular region and the anterior periventricular hypothalamic area, constitute the AV3V, whose upward continuation contains the SFO (Fig. 9). The LT is recognized as one of the primary brain areas intimately linked to neuroendocrine and behavioral control of the hydromineral balance. The OVLT and SFO are influenced by circulating factors such as plasma ANG II, ANP, and osmolality and are directly related to the control of thirst, sodium appetite, arterial pressure, sympathetic activity, renal function and neurohypophyseal AVP and OXT secretion (28, 113, 164, 306). The margin of SFO and the dorsal cap region of OVLT have a subgroup of neurons that send several projections to the PVN and SON magnocellular

Other brain areas

SFO

D ac MnPO V

3V CSF

OVLT oc

Figure 9 Schematic organization of lamina terminalis (LT) structures. The LT is composed by dorsal (D) and ventral (V) parts of the median preoptic nucleus (MnPO) and two other CVOs, the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT). The OVLT and the ventral (V) portion of MnPO, together with both the preoptic periventricular region and the anterior periventricular hypothalamic area, constitute the anteroventral region of the third cerebral ventricle (AV3V). The LT nuclei are interconnected by the MnPO, which presents bidirectional projections between both the SFO and OVLT (dashed arrows in black). The LT nuclei are also hardly connected with other brain areas related to the control of sympathetic activity and neurohumoral and behavioral responses (arrows in gray).

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Blood-born stimuli ANG II SFO ANP AVP/OXT [Na+] Osmolality MnPO ac PVN

DRN

AP

LPBN OVLT

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oc SON

Neurohypophysis RVLM

AVP Renal water reuptake Vasoconstriction

OXT ANP secretion Natriuresis

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Control of sympathetic activity Peripheral osmoreceptors Chemo/baroreceptors Gustatory information

Figure 10

Sagittal illustration showing the main rat brain nucleus and connections related to the neural regulation of hydromineral balance. We can see the complex interconnections among the lamina terminalis nuclei [organum vasculosum of the lamina terminalis (OVLT), subfornical organ (SFO) and median preoptic nucleus (MnPO)], paraventricular (PVN) and supraoptic (SON) hypothalamic nucleus, midbrain dorsal raphe (DRN) and lateral parabrachial nucleus (LPBN), medullary nucleus of the solitary tract (NTS), area postrema (AP), caudal ventral lateral medulla (CVLM), and rostral ventral lateral medulla (RVLM). The blood-borne signals (ANG II, ANP, OXT, AVP, Na+ , and osmolality) are monitored by the circumventricular organs that responsible for transmitting these informations to others brain nuclei. Conversely, most of the peripheral afferents (baroreceptors, chemoreceptors, osmoreceptors, volume receptors and gustatory information) reach the NTS through the vagus and/or glossopharyngeal nerve, which redistribute this information to several brain areas. Finally, all humoral and sensory signals constitute multimodal information that are accurately integrated by the central nervous system, which use several neuroendocrine systems (neurohypophyseal, renin-angiotensin, sympathetic, and atrial natriuretic peptides systems) to control the extracellular volume and osmolality. ac, anterior commissural nucleus; ANG II, angiotensin II; ANP, atrial natriuretic peptide; AVP, vasopressin; oc, optic chiasm; OXT, oxytocin. Modified with permission from Bourque (2008) (57).

neurons, modulating AVP and OXT secretion (Fig. 10) (307, 320). The LT nuclei are interconnected by the MnPO, which presents bidirectional projections with both the SFO and OVLT (154, 271). The MnPO intermediates the communication between the SFO/OVLT and the hypothalamic magnocellular neurons because disynaptic pathways were characterized from both CVOs to the SON via a relay in the MnPO (349). Therefore, the LT acts as an integrative unit, being responsible for (i) sensing circulating factors that are unable to cross the BBB, a role primarily attributed to the SFO and OVLT; (ii) processing and integrating this information, through the intra and extra LT connections; and (iii) redistributing this information to other brain areas, such as the SON, PVN, DRN, LPBN, and NTS (269, 306, 307, 320) (Fig. 10). In this regard, it is difficult to determine a common feature of LT projections because neurons in this area may express both excitatory and inhibitory efferent fibers (191, 341). The LT also receives projections from diverse brain areas, such as from ascending noradrenergic and serotonergic neurons of the NTS and DRN/LPBN, respectively,

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which are also implicated in the control of hydromineral balance (231, 269). The LT seems to be the primary brain site responsible for detecting changes in plasma osmolality, leading to AVP release and thirst activation. The role of this area in the osmoregulation was demonstrated by several studies employing brain lesions, hypertonic saline microinjection and c-Fos immunostaining (18, 67, 68, 302, 303, 305). The mechanisms underlying the role of LT nuclei in monitoring extracellular osmolality and Na+ concentrations is further discussed in the specific section “Sensors.” Simpson and Routtenberg (430, 431) were the first to demonstrate that the LT structures are related to ANG II central actions. Later, Mendelsohn and colleagues (316) demonstrated the expression of ANG II receptors in the OVLT and SFO, confirming that both CVOs are likely to mediate the central actions of peripheral ANG II. Furthermore, Dourish and associates (130) demonstrated that drinking behavior induced by peripheral administration of ANG II is dependent on the AT1 , but not AT2 , receptors. Recently, the ability of

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ANG II infusions in the OVLT to stimulate salt appetite independently of SFO was demonstrated, confirming one possible distinction between the role of both nuclei in the control of ANG II-induced drinking behavior (153). The LT structures also express all components of the RAS, indicating that these nuclei constitute important sources of brain ANG II production, release and action as a neurotransmitter/neuromodulator (166, 198, 233, 267, 269, 270, 272, 419, 442). In fact, Lind’s group demonstrated an intense staining of angiotensinergic neuronal fibers projecting from the LT (primarily from the SFO) to several brain areas related to the control of hydromineral balance (269, 270). In summary, the role attributed to the LT on the neuroendocrine control of hydromineral balance results from three morphofunctional characteristics (Fig. 11): the presence of the OVLT and SFO nuclei (devoid of BBB), which are sensitive to systemic circulating factors that cannot directly penetrate the brain; the dense expression of RAS compounds (including the AT1 receptors), osmosensitive neurons and Na+ sensors channels (Nax ); and the intense network connections among the LT nuclei and other brain areas related to the control of sympathetic activity, as well as neuro-humoral and behavioral responses.

Hypothalamus and pituitary gland Considering evolutionary aspects, the hypothalamus is one of the most ancient segments of the anterior portion of the brain. Furthermore, this brain region is one of the first to reach complete development during embryological life, originating from the ventral portion of the diencephalon. The hypothalamus constitutes less than 1% of the total brain volume but directly or indirectly controls virtually all homeostatic functions of the body. The following anatomic clues are often used to delimit the hypothalamus: (i) rostrally, the anterior edge of the optic chiasm and LT; (ii) caudally, the posterior edge of mammillary nuclei; (iii) dorsally, the thalamus; and (iv) ventrally, the pituitary stalk and the pituitary gland. Although small, the hypothalamus concentrates many neuronal cells bodies that are grouped in several nuclei, which are implicated in the control of hydromineral homeostasis, body temperature, energy metabolism, light-dark cycle, autonomic tonus, memory, endocrine function, and sexual behavior, among other homeostatic responses. As observed in a coronal section, the hypothalamus has an extremely particular organization: (i) an internal portion, in which predominant cell bodies are grouped in nuclei, with a low number of fibers and (ii) an external area, in which the opposite feature is observed. Based on physiological and behavioral analyses (462), some authors recognize that the hypothalamus is better characterized in this view as periventricular, medial and lateral zones (97). According to this premise, the zone adjacent to the third cerebral ventricle (periventricular) would primarily contain neurons that project to the pituitary. In turn, the medial zone would consist of distinct cells clusters that receive inputs from the limbic system. Finally, the lateral zone

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would be primarily composed of a complex fiber system, with few neurons (427). Based on the organization of the medial zone, a rostrocaudal view of the hypothalamus shows three distinct areas: (i) rostrally, the anterior or supraoptic region; (ii) the median, tuberal or infundibular area; and (iii) caudally, the posterior or mammillary area. The brain region rostral to the optic chiasm that reaches the LT and anterior commissure (ac), which is known as the preoptic area, is physiologically related to the hypothalamus but anatomically originated from the telencephalon. In addition to the characteristic neural elements, the hypothalamus contains peptidergic neurons, which produce and secrete their products to the circulation, such as OXT and AVP, through the neurohypophysis. The activation of an action potential in peptidergic neurons determines an increased calcium influx at their terminals and the consequent release of vesicles containing neurohormones. The hypothalamic peptidergic neurons, which control the anterior pituitary function, constitute the parvocellular or tuberoinfundibular system. In contrast, the peptides released by the posterior pituitary are synthesized by hypothalamic neurons whose cells bodies are relatively larger than those cell bodies of the parvocellular system, which are named magnocellular neurons and whose functions will be discussed further in the following sections. The close relation between the hypothalamus and the pituitary gland was first recognized by Claudius Galenus, who was a prominent Roman physician, surgeon and philosopher. However, the function of the hypothalamus as the controller of all pituitary hormones was only described during the 20th century. At the floor of the third ventricle, the hypothalamus projects itself toward the pituitary, originating from the ME. This region is richly irrigated by a portal capillary system with a relative high permeability to molecules carried by the systemic circulation. Therefore, the ME is one of several areas of the brain that are devoid of the BBB and is considered by most authors as a CVO. Regarding its structure, the ME can be divided into three areas: (i) the inner ependymal layer, which covers the floor of the third ventricle; (ii) a middle fiber layer, which is crossed by axons that terminate at the pituitary posterior lobe; and (iii) the outer palisade zone, where the tuberoinfundibular fibers release the hypothalamic peptides that control the anterior pituitary function. In humans, the pituitary gland is composed of two parts: the anterior lobe or adenohypophysis (which is derived from the oral epithelium and constitutes almost 80% of the total gland volume) and the posterior lobe or neurohypophysis (which is derived from neural tissue). In most vertebrates, in addition to the pars distalis (anterior lobe) and the pars nervosa (posterior lobe), the pituitary contains the pars intermedia, which is involved in some protective responses in amphibians and in fish. In humans, the pars intermedia is physiologically active during fetal life, participating in CNS development, but is not functional after birth. Histologically, the anterior lobe is composed of five types of cells (corticotrophs, lactotrophs, gonadotrophs, thyrotrophs, and

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Figure 11

Diagram representing several mechanisms implied in the neuroendocrine control of hydromineral balance mediated by organum vasculosum of the lamina terminalis (OVLT) and subfornical organ (SFO). (A) The circumventricular organs (CVOs) are devoided of blood-brain barrier (BBB) and, consequently, they are able to sense circulating factors that are unable to cross the BBB, such as plasma angiotensin II (ANG II) acting on the CVOs ANG II type 1 receptors (AT1 ) receptors; (B) The OVLT and SFO also express all components of the renin-angiotensin system, which constitute the sources of brain ANG II synthesis, release and action as a neurotransmitter/neuromodulator; (C) OVLT and SFO are the primary brain site responsible for detecting changes in plasma osmolality, mechanism which seems to be mediated by the plasma membrane transient receptor potencial vanilloid (TRPV) receptors located in the osmorreceptors neurons; (D) the participation of glial cells in the central Na+ -sensory mechanisms mediated by sodium sensors channels (Nax ) channels expressed in the CVOs are responsible for monitoring plasma and cerebrospinal fluid Na+ concentrations; (E) The OVLT and SFO also receives projections from several brain areas related to the control of hydromineral and cardiovascular balance; (F) the lamina terminalis process and redistribute all collected information to other brain areas related to the neuroendocrine control of hydromineral balance. Thus, the lamina terminalis is a key part of the neuroendocrine control of thirst, sodium appetite, arterial pressure, sympathetic activity, renal function and neurohypophyseal vasopressin (AVP) and oxytocin (OXT) secretion. ACE, angiotensin converting enzyme; Agt, angiotensinogen; R1/R2/R3, different receptors for various neurotransmitters.

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somatotrophs). In turn, the neural lobe morphology is characterized by terminal arborizations of axons originating in the hypothalamus (magnocellular neurons), which is a rich and fenestrated vasculature, and by the presence of glial cells (pituicytes).

The hypothalamic paraventricular and supraoptic nuclei The magnocellular cell bodies are organized into two welldescribed hypothalamic areas, the PVN and the SON. From these sites, the axons of the magnocellular neurosecretory cells project to the posterior lobe of the pituitary gland, where these axons release the neurohormones AVP and OXT. The SON is bilateral to the optic chiasm and is composed exclusively of magnocellular neurons. The SON begins rostrally as a large structure and condenses caudally, terminating as the lateral border of the optic tract advances into the lateral hypothalamus. Posteriorly, a retrochiasmatic continuation of magnocellular neurons appears as a thin layer of cells lying along the surface between the optic tract and the third ventricle (31). Using quantitative analysis of the mRNA for AVP and for OXT, were identified three major phenotypes in the SON under basal conditions: (i) OXT neurons, (ii) AVP neurons, and (iii) OXT/AVP coexisting neurons (102, 512). Da Silva and coworkers (102) also demonstrate the coexpression of AVP and OXT mRNAs occurs in a significant number of SON and PVN magnocellular neurons, suggesting that these cells can potentially produce one or both peptides under increased demand for hormone secretion (Fig. 12). The magnocellular neurons are differentially distributed along the SON according to their phenotypes: oxytocinergic neurons often lie anterodorsally, whereas vasopressinergic neurons are generally posteroventral (461). Populations of multipolar and small somata neurons coexist with magnocellular secretory cells in the SON, and the role of these cells as interneurons has been speculated (134). In fact, the SON magnocellular neurons receive dense GABAergic innervation originating primarily from interneurons in the perinuclear zone of the SON. The lesion of this area was shown to impair cardiovascular-induced changes in AVP secretion (188). When compared with the SON, the PVN is relatively more complex. Several nomenclatures have been used in the literature to describe the PVN cytoarchitectonic organization, which is primarily based on the segregation of neurons into groups that share their output connections. Unlike the SON, the PVN has distinct groups of cells, which project not only to the neural lobe but also to the ME and to other CNS areas. Most of the reports agree that the two major cell clusters belonging to the hypothalamic neurohypophyseal system lie in two contiguous groups: the medial magnocellular portion (PaMM), which contains primarily OXT neurons, and the lateral magnocellular division (PaLM), which contains primarily AVP neurons. The PaMM group is anteromedial in the PVN, whereas the PaLM group lies dorsolaterally to the PaMM and has an extremely characteristic organization; the

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PaLM group is formed by a round and densely packed mass of AVP-positive cells outlined by a ring of OXT neurons. In addition to the PaMM and the PaLM, the PVN contains two so-called accessory groups, the periventricular magnocellular group (PeM) and the anterior commissural nucleus (AC) (31). According to the most commonly used terminology (31), the parvocellular PVN consists of six parts, three of which project primarily to the ME: (i) the anterior parvocellular subpopulation (PaAP), which coexists with the rostral magnocellular groups; (ii) the periventricular group (PeP), which lies adjacent to the third ventricle walls throughout the rostrocaudal extent of the PVN; and (iii) the medial parvocellular group (PaMP). Neurons in the PaMP portion project to some CVOs (such as the SFO, OVLT and pineal gland), which may be particularly important to the integration of homeostatic responses regulating hydromineral balance and cardiovascular function (261). A distinct group of parvocellular neurons project to other extrahypothalamic targets, particularly to autonomic centers in the brainstem and in the spinal cord: (i) the dorsomedial cap (PaDC), (ii) the ventral parvocellular portion (PaV), and (iii) the posterior subnucleus (PaPo). Furthermore, some vasopressinergic and oxytocinergic neurons originating from the PVN belong to the parvocellular or tuberoinfundibular system and project to the ME. Vasopressinergic parvocellular neurons have been identified in the PaMP and PaAP regions, where these neurons colocalize primarily with corticotrophin-releasing hormone (CRH), particularly after adrenalectomy (243), supporting the role of AVP as a secretagog of adrenocorticotrophic hormone (ACTH). A schematic representation of the SON and PVN subpopulations is shown in Figure 13. The use of combined methodological approaches revealed that direct projections to the PVN arise primarily from other intrahypothalamic areas and from the SFO and bed nucleus of stria terminalis (BNST) (409). These authors provided evidence that those areas projecting directly to the PVN primarily innervate parvocellular cell groups, whereas relatively few forebrain regions were shown to project directly to magnocellular neurons. Therefore, inputs from the hippocampal formation, amygdala and lateral septum seem to be indirectly delivered to magnocellular groups through short projections arising from other parts of the hypothalamus. The only known output of the SON and the major output of all magnocellular subpopulations of the PVN is to the posterior pituitary, whereas the parvocellular PVN projects primarily to the brainstem, to the spinal cord (via bidirectional pathways) and to the ME. Therefore, the hypothalamic neurohypophyseal system constitutes the final common pathway for secretion of AVP and OXT to the systemic circulation in response to stimuli, such as lactation and parturition (selective for OXT) and perturbations in water/sodium balance and blood pressure (for both AVP and OXT) (389). Furthermore, challenges to osmoregulation, which primarily stimulate AVP and OXT secretion from magnocellular neurosecretory groups of the PVN and SON, modulate the release of ACTH from

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Figure 12 Photomicrographs presenting immunoreactive AVP (red) and OXT (green) neurons in the supraoptic nucleus of euhydrated, water-restricted or salt-loaded rats (A1-C2). Merge images, exhibiting the colocalization of OXT and AVP in the same neuron (yellow) (A3-C3). Scale bar = 25 μm. OC = optic chiasm. In D are the number of immunoreactive neurons observed in each experimental condition (∗∗ P < 0.005). Reproduced with the permission from Da Silva and co-workers (2015) (102).

the anterior pituitary (138). This finding is supported by the anatomical evidence that approximately 10% of the total blood supply to the anterior pituitary is provided by the short portal vessels, which originate from the inferior hypophyseal artery in the posterior pituitary. Therefore, the fact that AVP

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is released by the tuberoinfundibular system directly into the ME, together with the evidence that magnocellular AVP modulates ACTH secretion, provides two important steps at which osmoregulatory mechanisms and stress-related responses can interact.

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Figure 13 Schematic organization of the PVN [gray (magnocellular) or white (parvocellular) areas delimited by dashed lines] and SON (black areas). The anterior parvocellular subpopulation (PaAP), which coexists with the anterior commissural (AC) magnocellular group, and the periventricular group (PeP), which lies adjacently to the third ventricle walls throughout the rostrocaudal extent of the PVN, are not shown here. Cir, circular accessory group; f, fornix; PaDC, dorsomedial cap of the PVN; PaLM, lateral magnocellular area of the PVN; PaMM, medial magnocellular area of the PVN; PaMP, medial parvocellular group of the PVN; PaPo, posterior parvocellular group of the PVN; PaV, ventral parvocellular part of the PVN; PeM, periventricular magnocellular group of the PVN; SOR, residual SON. Based on the organization revised by Armstrong (1995) (31).

Brainstem The brainstem corresponds to the caudal portion of the brain. It is situated between the spinal cord and diencephalon, ventral to the cerebellum. The brainstem is classically divided in caudal-rostrally into medulla oblongata (myelencephalon), pons (portion of metencephalon), and midbrain (mesencephalon). The brainstem provides primary motor and sensory innervation to the face and to the neck through the cranial nerves and works as a relay to most motor and sensory nerve connections of the rest of the body. The diencephalon, located rostrally next to the midbrain, forms with the brainstem a contiguous stem-like structure providing a mechanical support to the telencephalon. Along with the diencephalon, the brainstem also plays an important role in the autonomic and neuroendocrine control of cardiac, respiratory, and renal functions. Most of the peripheral afferents (i.e., from the arterial baroreceptors, chemoreceptors, osmoreceptors and volume receptors) that reach the NTS through the vagus nerve primarily use glutamate as a neurotransmitter. The NTS also receives inputs from the AP, the only CVO in the brainstem, which is also sensitive to circulating factors, such as ANG II. Conversely, NTS neurons project to several brain stem nuclei and to other brain areas, such as the hypothalamus. This direct and reciprocal connection of hypothalamic

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nuclei (particularly the PVN) with the NTS is involved in the neuroendocrine control of cardiovascular and hydromineral balance. The NTS also projects to a population of inhibitory neurons at the CVLM in the brainstem, which, in turn, project to the rostral ventral lateral medulla (RVLM). In this context, RVLM neurons are the most important in the mediation of the tonic and phasic control of sympathetic preganglionic neurons (171). Therefore, this circuitry is important for integrating the peripheral cardiovascular and hydromineral changes to an adequate response of sympathetic nervous activity, thus modulating other homeostatic responses, such as activation of the RAS. The AP and NTS also send direct projections to the LPBN and DRN, and both structures are important to the integrity of behavioral and neuroendocrine responses regarding hydromineral balance (314, 381). In turn, the NTS also receives gustatory inputs related to salty taste sensed by the tongue, acting as a possible integrating area of peripheral cardiovascular and hydromineral balance changes regarding gustatory information (314). The NTS, LPBN, and DRN are also reciprocally connected with forebrain structures, such as the hypothalamic PVN and SON, modulating AVP and OXT secretion (24, 314, 381). This neural circuitry is illustrated in Figure 10. As a result, brainstem nuclei have an important role in neuroendocrine control of hydromineral balance, acting by three basic mechanisms: (i) regulating sympathetic input to the kidneys to control sodium, water and renin secretion;

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(ii) modulating the activity of neuroendocrine systems involved in hydromineral balance (i.e., neurohypophyseal system); and (iii) controlling thirst and sodium appetite in response to volume and osmolality challenges.

The regulation of renal sympathetic activity Sympathetic fibers innervate renal tubules and vessels, as well as juxtaglomerular granular cells, modulating multiple renal functions, such as blood flow, glomerular filtration rate, solute and water transport, and hormone production and secretion (230). The sympathetic activation of kidneys leads to a release of norepinephrine near the glomerular arterioles, resulting in vasoconstriction, reduction of urinary output and activation of RAS by increased renin secretion from juxtaglomerular cells (515). Several neurotransmitters and circulating factors seem to be involved in the control of sympathetic activity and renal function. An ANG II-mediated presynaptic action at the renal level was shown to stimulate the release of norepinephrine by sympathetic nerve terminals in both tubular epithelial cells and vessels (53). Within this context, Handa and Johns demonstrated the administration of captopril or ANG II receptor antagonists attenuates the antinatriuretic response obtained by either low-frequency electrical stimulation or by reflex renal sympathetic nerve stimulation in rats (196, 197). The importance of ANG II and the sympathetic system interaction at the renal level is shown by the dramatic reduction of ANG II effects on sodium, chloride and water reabsorption in rats with kidney denervation (275). Conversely, ANP was shown to reduce renin secretion and vasoconstriction in response to renal nerve stimulation (208). Additionally, the RVLM has an important role in renal sympathetic outflow under resting conditions and after baroreflex response because excitation and inhibition of this area increases and decreases arterial pressure and renal sympathetic nerve activity, respectively (297). ANG II is able to potentiate the activity of RVLM neurons, whereas the AT1 receptor blockade reduces RVLM neuronal activity (253), suggesting an interplay between the control of sympathetic activity and the systemic and/or brain RAS. Furthermore, purinergic receptors expressed in NTS neurons are also involved in sympathetic outflow changes; agonists of adenosine type 2a receptors (A2a ) decrease renal sympathetic activity, whereas the agonists of adenosine type 1 receptors (A1 ) receptors increase this parameter (415). Additionally, Scislo and O’Leary (416) demonstrated that adenosine receptors in the NTS contribute to renal sympathoinhibition during the hypotensive phase of severe hemorrhage in anesthetized rats. The NTS noradrenergic (A2 ) neurons are also involved in the physiological hypertonicity-induced inhibition of renal sympathetic nerve activity. For example, Colombari and colleagues (90) demonstrated that renal vasodilatation in response to volume expansion is abolished by sinoaortic denervation, demonstrating the essential role of baroreceptors in the control of renal blood flow. Additionally, Pedrino and

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co-workers (366) demonstrated that chemical lesions of A2 noradrenergic neurons prevent renal sympathoinhibition induced by acute hypernatremia in rats. Taking together, these results indicate that sympathetic renal responses due to cardiovascular and hydromineral changes are dependent on the integration of baroreflex circuitry. The AP seems to have an important role in the systemic ANG II-mediated inhibition of baroreflex sensitivity and sympathetic activation. In rabbits with AP lesions, ANG II intravenous infusion did not change the maximum renal sympathetic nerve activity (406). Additionally, other local modulators can act on AP neurons to modulate renal sympathetic activity. The microinjection of adenosine into the AP decreased renal sympathetic nerve activity, heart rate and mean arterial pressure in rats, and these responses were reverted by the previous administration of a nonselective or A1-selective adenosine receptor antagonist or by the blockade of ATP-sensitive potassium channels (83). The same group showed that the microinjection of capsaicin into the AP increased renal sympathetic nerve activity, heart rate and mean arterial pressure in rats and that these effects were reverted by a capsaicin or glutamate NMDA receptor antagonist (514). Therefore, these data indicate that AP plays an important role in the modulation of renal sympathetic nerve activity and that this function could be mediated by several factors, including ANG II, glutamate and adenosine.

Regulation of neurohypophyseal system activity Catecholaminergic neurons of the NTS and RVLM project to oxytocinergic and vasopressinergic neurons of both the PVN and SON (115, 409, 410). The magnocellular division of the PVN and SON is primarily innervated by the A1 and A2 noradrenergic cell groups, and noradrenergic afferents have been shown to facilitate the activity of AVP and OXT neurons (264). Indeed, stimulation of the cervical vagus induces nuclear c-Fos expression in noradrenergic A1 neurons of the CVLM and excites AVP cells (116). Additionally, low-pressure receptors in the atrium tonically inhibit AVP release via a NTS-dependent pathway, whereas hypovolemia-induced AVP release occurs through a reduction in the activity of this inhibitory circuitry (264). Noradrenergic neurons in the LC are also implicated in the baroreflex-induced activation of the DBB, which integrates the regulatory pathway mediating baroreflex-induced inhibition of AVP and OXT secretion (99,187,264). In this context, Rodovalho and co-workers (398) demonstrated that lesions of the LC decrease the hemorrhage-induced AVP and OXT secretion, suggesting a stimulatory role for the inputs arising from the LC to magnocellular neurons and highlighting the importance of this pathway to the integrity of the hypovolemic neuroendocrine reflex. Additionally, the bilateral microinjection of noradrenaline into PVN stimulates AVP secretion, whereas microinjections of an α1 -adrenoceptor antagonist (dobutamine) or an α2 -adrenoceptor agonist (salbutamol) significantly reduce basal and icv ANG II-induced AVP

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secretion (488). Taken together, these results show that the noradrenergic system, is involved in the integration of peripheral information, such as the baroreflex, with neuroendocrine responses, thus modulating neurohypophyseal hormone secretion. Accordingly, AP lesions decrease AVP mRNA expression in the PVN and SON, as well as plasma concentrations of both hormones under basal conditions and after hyperosmolar or hypovolemic stimulation (30). However, the AP seems to be more sensitive to plasma sodium levels than to osmolality; AVP and OXT secretion is disrupted following intravenous hypertonic NaCl solution infusion in rats with AP lesions, whereas no deficit in AVP and OXT release is observed in response to increased osmolality originated by intravenous infusion of hypertonic mannitol (216). Furthermore, the same report also demonstrated that AP lesions did not affect plasma AVP and OXT in response to hypovolemia or OXT release stimulated by intravenous cholecystokinin. These results indicate that the AP is important for mediating AVP and OXT secretion in response to changes in plasma sodium concentrations; however, the AP may have not a pivotal role in neuroendocrine responses exclusively related to plasma osmolality and volume changes. The lateral parabrachial nucleus (LPBN) is another brainstem nucleus that sends projections to the SON and PVN. Jhamandas and colleagues (226) suggested a stimulatory role for LPBN neurons in SON magnocellular activity, which is most likely mediated by interneurons at the SON perinuclear zone. Furthermore, the same group demonstrated that projections from the PBN to both the magnocellular and parvocellular neurons of the PVN are predominantly excitatory and occur directly to both AVP and OXT neurons (227). In fact, the inhibition of LPBN using a local α2 -adrenoceptor agonist (moxonidine) microinjection significantly reduces AVP and OXT secretion in response to intragastric hypertonic saline administration. Additionally, the serotonergic input from the DRN to magnocellular neurons of the PVN and SON has been previously demonstrated (149, 260, 411). Pioneer studies demonstrated that brain serotonin system inhibitors decrease AVP secretion in response to dehydration, whereas the administration of a serotonin-releasing agent (fenfluramine) increased AVP secretion (222). In addition, systemic treatment with sertraline (a selective serotonin reuptake inhibitor) stimulates both AVP and OXT secretion (120). In this context, the serotonergic system seems to act primarily via 5-HT2 and 5-HT4 receptors to stimulate AVP secretion, whereas the activation of OXT neurons seems to be more complex, involving the 5-HT1A , 5-HT2 , 5-HT4 , and 5-HT3 receptors (234).

Regulation of thirst and sodium appetite Despite the well-documented increased plasma concentrations of ANG II because of reduced volume and/or blood pressure, Thornton and colleagues (474) partially dissociated

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the development of sodium appetite under these experimental conditions from ANG II central actions. These researchers suggested that the mechanism underlying hypertonic saline intake in response to the reduction in circulating blood volume and/or chronic hypotension might be directly related to the signaling of the peripheral volume and/or of pressure receptors to brainstem nuclei related to sodium appetite control. This hypothesis was suggested because the hypotensioninduced hypertonic saline intake was not blocked by an AT1 receptor antagonist (losartan), thus representing an ANG IIindependent response. In fact, other studies in the literature have corroborated these findings (29) but suggested that hypotension and ANG II seem to act jointly to induce sodium appetite (231, 232). Changes in circulating volume and/or arterial pressure alter NTS inputs to other brain areas, which induce ANG II release inside the BBB and lead to the stimulation of water and salt intake (154). Nevertheless, lesions of the NTS do not prevent thirst and salt appetite induced by extracellular volume depletion in rats (413). In contrast, rats with NTS lesions present an increased dipsogenic response to systemic ANG II administration when compared with control rats (414). In addition, rats with AP/NTS lesion intake more saline in comparison with control animals (92). Furthermore, the previous injection of α1 - or α2 -adrenergic agonists into the 3V significantly reduced ANG II-induced water intake (103). The literature also reported that damage to NTS and CVLM catecholaminergic neurons, as well as the icv microinjection of a α2 -adrenergic antagonist, inhibits hypertonic saline intake under different experimental models (9,91,408). Furthermore, the prior injection of a α2 -adrenergic agonist reversed the effects of OXT on the inhibition of hypertonic saline intake induced by sodium depletion (408). Together, these data indicate that the noradrenergic system of the brainstem generally produces an inhibitory effect on sodium appetite and thirst. An additional inhibitory control limiting sodium intake is mediated by postingestion feedback signaling, which is transmitted by the glossopharyngeal and vagus nerves via the NTS and LPBN to the forebrain (and other brain areas) (135, 314, 452, 453). In this context, several lines of evidence have raised the possibility of a physiological integration between the LPBN and DRN serotonergic neurons (161, 290, 314, 315), which would send information to forebrain structures, coordinating adjustments to sodium intake. Considering this concept, Margatho and colleagues (290) showed that DRN neurons exhibit an increased number of c-Fos and Fluorogold double-labeled neurons after blood volume expansion in mice previously subjected to intra-LPBN Fluorogold microinjections. This result reinforces the concept of a neuronal DRN projection to LPBN, which would be involved in the inhibition of sodium appetite. Menani and colleagues (314) reviewed the role of the LPBN on sodium appetite control. According to these authors, the deactivation of LPBN-associated inhibition by GABA or opioid agents leads to a marked increase of salt intake under

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Figure 14

Schematic diagram showing the modulation of the lateral parabrachial nucleus (LPBN) inhibitory mechanism by different neurotransmitters and its interaction with forebrain facilitatory mechanisms involved in the control of sodium intake. 5-HT, serotonin; ANG II, angiotensin II; AP, area postrema; CCK, cholecystokinin; CRH, corticotrophin-releasing hormone; OVLT, OVLT organum vasculosum of the lamina terminalis; SFO, subfornical organ; NTS, nucleus of the solitary tract. Reproduced with the permission from Menani and co-workers (2014) (314).

need-free conditions. Therefore, pharmacological manipulation of other LPBN neurotransmitter systems such as serotonin, noradrenaline, glutamate, cholecystokinin, CRH, and ATP potentiates salt intake in rats submitted to water and/or sodium appetite stimulation (Fig. 14). Likewise, Reis (381) extensively revised the role of the serotonergic system in salt appetite; the first evidence in this regard came from the use of agonists and antagonists of serotonin receptors, showing the involvement of 5-HT2C receptors in this response (334). Thereafter, brain serotonin depletion and DRN lesions increase salt intake in both need-free and need-induced conditions, clearly demonstrating the role of the DRN serotonergic system in the inhibition of sodium appetite (381). In a recent study conducted by Fonseca and collegues (157), the acute intra-DRN administration of a 5-HT1A agonist increased sodium intake in sodium-depleted rats, whereas repeated intraperitoneal or intra-DRN injections over 6 days resulted in a long-lasting reduction in cumulative sodium intake, demonstrating that the serotonergic system may be subject to desensitization. This finding represents a local auto-inhibition regulatory mechanism that may be potentially associated with changes in 5-HT1A receptor signaling. Concerning water intake, the LPBN seems to inhibit this behavior because lesions or pharmacological inhibition of this nucleus increases water intake induced by several physiological and pharmacological challenges in rats (136, 315, 346, 347). In contrast, the role of the DRN serotonergic system in the control of water intake is not clear; central 5-HT2C agonist injection inhibits

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water intake in need-induced conditions, whereas electrolytic lesions of DRN lead to an intense dipsogenic response in rats under need-free conditions (382-385).

Initiating Effector Responses: The Neuroendocrine Systems Hypothalamic neurohypophyseal peptides Both AVP and OXT are synthesized as pro-hormones by the magnocellular neurons of the PVN and SON. The mature AVP and OXT peptides contain nine amino acids and have a molecular weight of 1084 and 1007 kDa, respectively. The only differences between their molecular structures are at residue 3 (phenylalanine for AVP and isoleucine for OXT) and 8 (arginine for AVP and leucine for OXT). Once secreted, both AVP and OXT are freely transported in the systemic circulation and are rapidly metabolized by endopeptidases, which results in an extremely short half-life (5-10 min). The presence of disulfide bonds in these molecules is essential for determining their biological effects. The AVP peptide binds to three different subtypes of GPCRs: (i) V1a , expressed in the vascular smooth muscle, liver and CNS structures (such as the septal area, amygdala, BNST, nucleus accumbens, suprachiasmatic nucleus and NTS); (ii) V1b , expressed in the anterior pituitary; and (iii) V2 , expressed in the kidneys (119, 201, 482). The primary peripheral effect

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Max

10% decrease in volume/pressure Normal

Plasma (AVP)

observed following the interaction of AVP with V1a receptors is vasoconstriction. Based on the distribution of V1a receptors throughout the CNS, this receptor subtype may be the mediator of some of AVP central actions. In turn, V1b receptors mediate the stimulatory effect of AVP on ACTH release from corticotrophs. More recently, V1b receptors have also been identified in the hypothalamus, amygdala, cerebellum, and CVOs (201). Finally, V2 receptors mediate the antidiuretic effects of AVP; these receptors are expressed in the thick ascending limb of Henle’s loop and in principal and inner medullary cells of the collecting duct (344). Through interacting with V2 receptors, AVP stimulates not only the transcription of the gene encoding AQP2 but also the insertion of these water channels into the luminal membrane of cells, thus increasing water permeability and reabsorption (335, 343). OXT also binds to receptors belonging to the GPCR family. Due to the great structural homology, AVP/OXT agonists and antagonists lose their selectivity and specificity at high concentrations, acting at each other’s receptor systems. However, specific OXT receptors (OXTRs) are expressed in the myometrium, mammary glands, heart, blood vessels, thymus, ovaries, testicles and kidneys. In the macula densa and thin limb of Henle’s loop, OXTRs mediate distinct effects on renal function; however, it remains unclear whether these responses are mediated by different receptor subtypes (33). In some peripheral tissues, the binding of OXT to OXTRs induces an increase in intracellular calcium concentrations, producing a direct increase in the activity of calcium-dependent pathways. In the vascular endothelium, OXT was shown to promote calcium- and protein kinase C-dependent cellular proliferation and a vasodilatory response via stimulation of the nitric oxide pathway (473). In the heart, the identification of OXT and OXTRs in atrial myocytes (225) supported a functional role for this peptide not only in the autocrine/paracrine regulation of cardiac function but also in ANP release. In fact, OXT stimulates the release of ANP from the heart (143), increasing the concentration of this peptide in the systemic circulation (192). Then, these two peptides act synergistically to increase intracellular levels of guanosine cyclic monophosphate (cGMP), which determines the closing of sodium channels (ENaCs) in the apical membrane of distal nephron cells, producing an increase in natriuresis (437). According to these authors, the kaliuretic response induced by these hormones also appears to be mediated by cGMP-dependent mechanisms. Because sodium ions provide the osmotic gradient for water excretion/reabsorption, the OXT and ANP natriuretic effect also produces a diuretic response. A more detailed explanation of the mechanism underlying the actions of natriuretic peptides is found in the section “Natriuretic peptides.” The two primary stimuli regulating AVP release are ECF osmolality and volume (a major determinant of blood pressure). Increases as small as 1% to 2% in ECF osmolality are able to stimulate AVP secretion, whereas decreases of 10% to 15% in ECF volume or blood pressure are required to produce a similar effect on AVP release (454). These authors also demonstrated that hypovolemia and hyperosmolality had


10% increase in volume/ pressure

0 260

270

280

290

300

310

Plasma osmolality (mOsm/kg H2O)

Figure 15 Diagram representing the combined effects of volume and osmolality changes in vasopressin (AVP) plasma concentrations (arbitrary units). Under basal conditions AVP plasma concentrations are hypervolemia can further reduce these values. Conversely, hypovolemia (greater than 10% of blood volume) increases AVP secretion, although the main factor stimulating the secretion of this peptide is hyperosmolality. With decreased blood volume, the set point for hyperosmolalityinduced increase in AVP secretion is shifted to a lower plasma osmolality and the slope is increased. Increase in blood volume produces the opposite effects. Max: maximum. Reproduced with the permission from Koeppen and Stanton (2013) (246).

a synergistic effect on AVP secretion, which was greater than the simple addition of independent effects (Fig. 15). In turn, the primary stimuli for OXT secretion are suckling during lactation and the mechanical stimulation of the uterine cervix during labor. However, increased OXT plasma concentrations can also be found in response to enhanced ECF volume and osmolality (192). In water-deprived animals, which exhibit hypovolemia associated with plasma hyperosmolality, OXT plasma levels are increased, whereas the secretion of ANP is reduced. In fact, natriuretic systems are often inhibited by hypovolemia, even in the presence of hyperosmolality. Therefore, the increased OXT secretion observed in water-deprived rats is more consistent with the participation of this peptide in adaptative responses to stress (256) rather than in the excretion of excess ECF sodium amounts. Accordingly, increased OXT secretion has previously been reported in response to hemorrhage (313), an experimental paradigm in which the ECF osmolality is not altered. The effects of osmolality- and volume-induced changes in OXT and ANP plasma concentrations are summarized in Figure 16. In addition to their actions on peripheral targets, both AVP and OXT can exert important central effects. The injection of AVP into the cerebral ventricles promotes an increase in water intake (463). In contrast, the central administration of OXT inhibits salt intake (51, 456). This effect has also been confirmed by studies performed in OXT knockout animals, which exhibited an increased appetite for sodium when challenged with overnight fluid deprivation (12) and an attenuation of

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demonstrated that the juxtamembrane application of AVP promoted different effects, depending on the initial firing rate; AVP inhibited the previously activated cells and stimulated the inactive ones, thus reducing the heterogeneity of firing patterns among vasopressinergic neurons. Based on these findings, this effect would presumably be more efficient in terms of the coordination of hormone release to the required demand.

Renin-angiotensin-aldosterone system

Figure 16 Diagram representing the effects of volume and osmolality changes in oxytocin (OXT) and atrial natriuretic peptide (ANP) plasma concentrations. Increases in extracellular fluid (ECF) volume or venous return enhance the release of natriuretic peptides, particularly ANP, from the heart. ANP then stimulates the release of OXT from the neurohypophysis (upper panel). These two hormones act synergistically to increase renal sodium excretion. These responses are observed following both isotonic and hypertonic increases in ECF volume, with this latter experimental situation producing a greater effect on ANP and OXT release. Under decreased ECF volume (with unchanged ECF osmolality), ANP release is suppressed and OXT release is stimulated (lower panel).

hyperosmolality-induced hypophagia (395). More recently, Uchoa and co-workers (485) demonstrated that oxytocinergic projections from the hypothalamus to the brainstem mediate the increased meal-induced satiety-related response in experimental primary adrenal insufficiency. A recent and intriguing experimental finding is that both AVP and OXT can be released not only from neuronal axon terminals into the circulation but also from the somata and dendrites into the interstitial space (480); these mechanisms can be independently regulated. In the axon terminals, the action potential-induced depolarization opens Ca2+ channels, increasing intracellular Ca2+ concentrations and stimulating the release of large dense-cored vesicles containing the peptides; however, in somata and dendrites, the primary mechanism operating is the peptide-induced mobilization of intracellular Ca2+ stores. This latter effect is based on the evidence that OXTRs are expressed in oxytocinergic neurons and that these receptors would enhance intracellular calcium concentrations, initiating a short-loop and self-sustained mechanism to control the activity of these cells (162). In addition to acting directly on autoreceptors, the somatodendritic release of OXT triggers the release of endocannabinoids. Then, these lipid mediators act at type 1 cannabinoid receptors (CB1Rs) at the presynaptic terminals to inhibit glutamate release, thus decreasing the postsynaptic firing rate of oxytocinergic neurons (207). Similar to oxytocinergic cells, vasopressinergic neurons also express AVP autoreceptors (48). However, for AVP, the mechanisms underlying the somatodendritic release of peptide are quite complex. Gouzenes and co-workers (184)

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The starting point for the discovery of the RAS was the experiment performed by Tigerstedt and Bergman in 1898; the administration of the factor called “renin” found in kidney extracts increased blood pressure (41, 434, 479). Independent groups from Argentina and from the United States demonstrated the renal renin secretion and its action in increasing blood pressure (213, 247). During the following years, both groups also identified a new hypertensive factor on the renal vein, which was named hypertensin in Argentina and angiotonin in the United States (263,357). In 1958, the leaders conducting these experiments in Argentina (Eduardo Braun Menéndez) and in the United States (Irving H. Page) decided to unify the terminologies, choosing “angiotensin” to represent this compound (61). In 1943, the enzymatic substrate for renin was characterized as a plasma α2 -globulin (372). During the following two decades, several studies were conducted to understand the functioning of this system. Skeggs and colleagues (433) discovered ACE and published the amino acid sequence for ANG II. Finally, the same group obtained the first highly purified preparation of angiotensinogen in 1963 (434, for a review, see 41). The RAS is one of the primary neuroendocrine systems involved in the control of body fluid homeostasis in terrestrial vertebrates. Evolutionarily, this system has its origin with the emergence of renin (the key enzyme) in cartilaginous fish; however, the peak of its complexity, with respect to its feedback regulation, has been achieved in higher mammals, with complete juxtaglomerular apparatus formation (juxtaglomerular cells, macula densa and mesangial cells) (438). The control of renin and angiotensinogen synthesis and secretion are the primary limiting steps for systemic RAS activation. Renin is synthesized as the precursor prepro-renin, which is cleaved in the endoplasmic reticulum before the precursor polypeptide leaves ribosomal subunits. Thus, pro-renin emerges from the endoplasmic reticulum and is transported to the Golgi apparatus to continue through the secretory pathway. In the Golgi apparatus, pro-renin is cleaved to the enzymatically active form, renin, and is stored in the vacuolar system. Plasma renin is primarily synthesized and secreted by renal juxtaglomerular cells following an increase in intracellular cAMP and Ca2+ signaling pathways induced by systemic (low arterial pressure, reduced Na+ and Cl− ion content in the distal convoluted tubule and β1 -adrenergic stimulation) and local factors (i.e., NO and prostaglandins) (255, 325). Additionally, other tissues, such as the heart, blood vessels,

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adrenal, brain, testis, uterus, ovary, liver, subcutaneous tissue, submandibular gland, and intestine, also produce renin, which seems to have a predominant local role in contrast to renal renin (325). Plasma α2 -globuline angiotensinogen is primarily produced in the liver, although other organs may also significantly contribute to plasma angiotensinogen concentrations, as demonstrated in mice genetically modified to express different levels of angiotensinogen in adipose tissue (294). Similar to renin, several other organs, such as the kidney, heart, adrenal gland, white and brown adipose tissues, ovary and brain, also synthesize angiotensinogen (470). Human angiotensinogen is a protein that contains 452 amino acids, and the isolated protein exhibits two major forms, with molecular weights of 61.4 and 65.4 kDa. Once in the plasma, angiotensinogen is cleaved by renin, generating the decapeptide ANG I, which is a biological inactive product that must be cleaved to generate the biological active peptides of the RAS. One of the metabolic pathways for ANG I is dependent on the action of ACE, which is primarily expressed in the vascular endothelium cells as a transmembrane protein (highly expressed in lungs) but is also secreted in a soluble form to the plasma. This enzyme converts ANG I (by the removal of a single carboxy-terminal dipeptide) into ANG II, which is an octapeptide that is the first biologically active compound of the RAS. ACE also sequentially cleaves two carboxy-terminal dipeptides from bradykinin, inactivating this peptide (5). ANG II can be further converted to the hexapeptide ANG III by glutamyl aminopeptidase A (521) or to ANG 1-7 by the monopeptidase type 2 (ACE2) (148). ANG 1-7 can also be formed directly from ANG I by the action of endopeptidases, such as neprilysin. Additionally, membrane alanyl aminopeptidase N cleaves ANG III to the heptapeptide angiotensin IV (ANG IV) 79). Although some other peptides may be produced by alternative metabolic pathways, ANG II, ANG III, ANG IV and ANG 1-7 seem to be the primary biologically active peptides of the RAS (Fig. 17). RAS peptides bind to five receptors subtypes: AT1 , AT2 , AT3 , AT4 and Bradykinin

Angiotensinogen Renin ANG I ACE ANG II

Inactive peptides

ACE Endopeptidases

ANG 1-7

ACE2 AT1

MAS

AT2

?

AT4

AT3

Aminopeptidase A ANG III Aminopeptidase N ANG IV

Figure 17 Diagram representing the cascade of renin-angiotensin system components formation, enzymes involved in these processes and target receptors to each peptide.

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Mas receptors. ANG II and ANG III actions are mediated by AT1 and AT2 receptors, whereas ANG IV shows low affinity for both receptor subtypes and high and selective affinity for AT4 receptors. AT3 receptors have been proposed to bind to angiotensin peptide fragments; however, their transduction mechanisms remain unknown. In contrast, the transmembrane Mas receptor was recently identified as a unique receptor that binds ANG 1-7 (reviewed in 39, 82, 118, 509). Ganten’s group first demonstrated the presence of renin in the CNS, which was further confirmed by radioimmunoassay, immunocytochemistry, and in situ hybridization techniques (168, 273). Angiotensinogen is extensively distributed in the brain, showing a consistent correlation with ANG II and its receptors in the CNS (198, 233, 267, 272, 419, 442). Undoubtedly, ANG II is present in the neuronal cytoplasm: several immunohistochemical studies have demonstrated fibers containing ANG II in the hypothalamus, limbic system, SFO, sympathetic lateral column, medulla oblongata, caudate nucleus, putamen, and spinal cord (166, 198, 233, 272). A high correlation exists between the distribution of ANG II immunoreactive nerve terminals and AT1 receptors, suggesting that ANG II may be released from the presynaptic terminal to activate AT1 postsynaptic receptors (6,265). However, controversy exists in the literature regarding whether brain ANG II is synthesized intracellularly (from angiotensinogen) or extracellularly (by ACE catalytic action and then transported to the neuronal cytoplasm) (128, 166, 419, 509). Indeed, AT1 receptors are the primary mediators of ANG II effects in adults, including aldosterone secretion, renal water and sodium reabsorption, vascular constriction, sympathetic activity stimulation, thirst, and sodium appetite (237). Apparently, humans, rabbits and dogs do not express AT1 subtypes, whereas rodents show two highly homologous (95%) AT1 isoforms with extremely similar binding characteristics: AT1A and AT1B (118). In rats, AT1A mRNA and AT1B mRNA expression have been described in the brain, adrenal gland, heart, aorta, kidney, testis, lung, liver and pituitary gland. With the exception of adrenal and pituitary glands, where AT1B mRNA predominates, AT1A mRNA is primarily expressed compared with AT1B (6, 118, 244). Considering the similarity between these isoforms, it is difficult to assign specific actions for each one. However, differences in their tissue distribution and in their neuronal phenotypic expression may provide support for the specificities of actions for each receptor subtype. For instance, the drinking response induced by central ANG II administration is mediated by the AT1B receptor, whereas the increase in blood pressure involves AT1A receptor activation (112). Thirst and sodium appetite are essential physiological sensations that lead the animal to search for and obtain water and salt from the environment to restore ECF volume and composition. Therefore, most hydromineral imbalances are associated with changes in thirst and sodium appetite thresholds in mammals. In addition, stimuli such as intracellular and extracellular dehydration, sodium depletion and sympathetic activation increase renin secretion, plasma ANG II levels

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and, consequently, thirst and/or sodium appetite (154, 287). The first report of ANG II inducing thirst was obtained by Booth (1968), followed by Epstein and colleagues (1969) and Daniels-Severs and colleagues (1971), whereas its effect on sodium appetite was demonstrated later by Buggy and Fisher (56, 66, 108, 140). In turn, Beresford and Fitzsimons (47) demonstrated that the prior icv microinjection of an AT1 receptor antagonist, but not an AT2 receptor antagonist, abolished the drinking response induced by icv ANG II. Our group had also demonstrated that the icv microinjection of losartan (AT1 receptor antagonist) consistently reduced water and/or hypertonic saline nocturnal intake in response to ANG I and ANG II icv administration, sodium depletion induced by furosemide and furosemide + low-dose captopril (FUROCAP), water deprivation and hypertonic stimulation (310, 311). Peripheral ANG II does not cross the BBB due to its chemical nature, despite being a circulating hormone with a potent ability to induce thirst and sodium appetite via central AT1 receptors. These behavioral effects are achieved through CVOs, which are devoid of the BBB and, therefore, allow peripheral ANG II-mediated signaling in the CNS. The primary CVOs implicated in ANG II actions are the SFO, OVLT and AP (164, 329). The AP is involved in the ANG II pressor response, whereas the SFO and OVLT are related to the drinking, pressor and AVP secretion responses (164, 431). Lesions of all LT structures and/or SFO decrease ANG II-induced thirst, sodium appetite and AVP secretion (139, 320, 329, 402, 477, 501). Moreover, in situ hybridization and autoradiographic studies have identified ANG II AT1 receptors in the SFO and OVLT, confirming the role of circulating ANG II in the control of hydromineral balance through CVOs (6, 265). Moe and colleagues (322) and Yang and Epstein (519) demonstrated the importance of the cerebral synthesis of ANG II in inducing thirst and sodium appetite under different experimental models using pharmacological icv ACE blockade. In addition to the central actions of peripheral ANG II and to the synthesis of ANG II within the CNS from angiotensinogen, the CVO neurons were shown to uptake circulating ANG I and convert ANG I into ANG II, which can then be secreted inside the BBB (164), a mechanism also implicated in the induction of thirst and sodium appetite. This phenomenon can be observed in animals treated peripherally with low doses of captopril (ACE inhibitor) or submitted to the FUROCAP protocol. By inhibiting the synthesis of peripheral ANG II, these experimental approaches increase ANG I plasma concentrations, which culminates with the increase in salt and water intake, possibly related to the central conversion of ANG I to ANG II (310, 322, 367). Several studies have demonstrated the pleiotropism of intracellular signaling pathways activated by the AT1 receptor. This receptor is coupled to a Gq protein, and its activation is mediated by the binding of agonists, such as ANG II, which culminates with in the activation of phospholipase C (PLC), the consequent increase in intracellular inositol 3-phosphate

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(IP3 ) and the activation of protein kinase C (PKC). Additionally, AT1 receptors activate several other pathways, among which the mitogen-activated protein kinase (MAPKs) pathway and its effect can be dependent or independent of Gq protein activation (118, 219). Several distinct cascades for MAPKs have been described in mammals, including those cascades involving extracellular regulated kinase (ERK) types 1 (p42) and 2 (p44) (418). In this context, Daniels and colleagues (106, 107) demonstrated that ANG II-induced thirts, but not sodium appetite, occurs through the generation of IP3 following AT1 activation because ANG II effect is inhibited by PKC inhibitors. Conversely, these authors confirmed that ANG II-stimulated sodium appetite, but not thirst, is dependent on the activation of MAPK-mediated pathways in the brain (106). Taken together, both reports suggest that thirst and sodium appetite induced by ANG II are processed by distinct intracellular pathways. Indeed, ANG II-induced sodium appetite presents a longer latency than water intake (73), which could be related to the recruitment of these different intracellular pathways by ANG II. Recently, endogenous brain ANG II generation induced by the activation of RAS during FUROCAP model was shown to activate p44/42 MAPK signaling, which is implicated in the induction of sodium appetite but not thirst or AVP and OXT secretion in rats (145) (Fig. 18). In contrast to the well-defined AT1 actions, the physiological role of AT2 receptors in the neuroendocrine control of hydromineral balance still must be clarified. The blockade of central AT2 receptors increases AT1 -mediated effects, suggesting that the AT2 receptors counterregulate AT1 -mediated signaling in the brain (210). Deletion of AT2 receptors leads to ANG II hypersensitivity, as demonstrated by antinatriuretic and pressor responses, reinforcing the role for AT2 receptors as negative regulators for the biological effects of central AT1 receptors (63). In turn, ANG III seems to be an important component of the central ANG II-mediated responses because the central microinjection of a selective aminopeptidase A inhibitor reduces the pressor response to ANG II in rats (379). Furthermore, ANG II-induced thirst is reduced by the immunoneutralization of aminopeptidase A, indicating that water intake is also dependent on central ANG III actions (443,510). Conversely, ANG IV seems to have antagonic effects on ANG II, given that ANG IV acting on AT4 receptors induces vasodilation and increases cerebral blood flow (250, 332). In turn, ANG 1-7 is not able to induce thirst or sodium appetite in rats even in large doses (282). Acute or chronic ANG II icv administration induces hypertensive response and increases water intake; however, in transgenic mice with increased expression of ACE2, this response was attenuated (147). Additionally, chronic treatment with D-Ala7-ANG 1-7 (an ANG 1-7 antagonist) abolishes this effect, suggesting that ANG 1-7 can be involved in hypertensive and drinking responses elicited by ANG II icv (146). Central ANG II is also related to the control of neurohypophyseal hormone secretion, as demonstrated by in vivo

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Ras

Src

ERK 1/2

Sodium appetite

tin

AT1

s rre

β-A

ANG II

PKC

Thirst

γ ANG II

β

AT1

Gq α

Ca2+

DAG

Neurotransmitters release

Endoplasmic reticulum

IP3 Ca2+

PLC PIP2

Figure 18 Diagram demonstrating the intracellular pathway activated by AT1 receptors. The AT1 receptor is coupled to a Gq protein which activate the phospholipase C (PLC) enzyme, responsible for cleave the phosphatidylinositol bisphosphate (PIP2, a plasma membrane phospholipid) producing inositol 3-phosphate (IP3 ) and diacilglicerol (DAG). The IP3 is responsible for increase intracellular Ca2+ concentration, while the DAG activates the protein kinase C (PKC). Additionally, AT1 receptors activate several other pathways, such as mitogen-activated protein kinase (MAPKs) pathway which include extracellular regulated kinase types 1 and 2 (ERK 1/2), and its effect can be dependent or independent (mediated by β-arretin) of Gq protein activation. Daniels and co-workers (2005; 2009) demonstrated that ANG II-induced thirst is depent of PKC pathway activation, while ANG II-induced sodium appetite is depent of MAPK pathway activation, demonstrating that thirst and sodium appetite induced by ANG II are processed by distinct intracellular pathways (106, 107). Src, kinase protein family; Ras, GTPase.

studies showing that ANG II icv injection induces c-Fos expression in magnocellular neurons of the PVN and SON, also increasing AVP and OXT mRNA expression and their secretion (113,387,513). Was also demonstrated that both AT1 and V1 receptors of the SON are involved in thirst and sodium appetite induced by ANG II microinjection into the septal area (22, 404). In addition, ANG III seems to exert a tonic control over AVP neuronal activity because an aminopeptidase A inhibitor reduces the firing rate of vasopressinergic cells (527). ANG II was also shown to interact with OXT and NPs. Accordingly, the central administration of OXT reduces ANG II-induced sodium appetite in rats (51). Furthermore, the central administration of an OXTR antagonist increases ANG II-induced sodium intake, without affecting water intake (455, 456). The use of an α-adrenoceptor agonist blocked ANG II-induced drinking behavior, and this response was associated with an increased release of ANP from ANPergic neurons (42). Likewise, icv ANP treatment inhibited ANG II- and dehydration-induced drinking in rats (26). Therefore, these results suggest that OXT and ANP can be counterregulators of ANG II-induced sodium appetite.

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More recently, Shigemura and colleagues (423) have demonstrated that AT1 receptors are co-expressed with ENaC (an amiloride-sensitive salt taste receptor) in taste cells. Chorda tympani nerve recordings have shown that ANG II suppresses amiloride-sensitive taste responses to NaCl and that this effect was reversed by AT1 receptor blockade. These intriguing results showed for the first time that the tongue is a peripheral target for circulating ANG II, suggesting that the reduction of amiloride-sensitive response to salt mediated by this hormone may contribute to increased sodium intake. This concept is completely new in the literature and indicates that ANG II can directly act in a broader manner than expected to stimulate sodium intake. Therefore, the use of AT1 antagonists to treat hypertension may have effects on sodium taste and, consequently, on sodium intake, in addition to its direct effects on controlling blood pressure, resulting in an additional contribution to reducing blood pressure.

Mineralocorticoids In addition to directly inducing thirst and sodium appetite, ANG II stimulates the secretion of mineralocorticoids,

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primarily aldosterone, from the adrenal glands. These hormones play an important role in renal sodium reabsorption and in sodium appetite induction (121, 390, 394). Mineralocorticoids are secreted in response to body sodium deficiency (such as sodium deprivation or sodium depletion), with ANG II being the primary secretagog (259). In a crucial experiment, Richter (394) demonstrated that sodium appetite could be induced even in the absence of mineralocorticoids because of hyponatremia due to the absence of renal sodium reabsorption mediated by aldosterone. Furthermore, in a subsequent study, Richter demonstrated that the administration of mineralocorticoid consistently increased hypertonic saline intake in rats (390). Unlike ANG II, which simultaneously induces thirst and sodium appetite, mineralocorticoids specifically induce sodium appetite (505). However, this effect is achieved only by the administration of supraphysiological doses or after chronic administration because the acute single administration of a physiological dose induces a small effect on sodium intake (506). Furthermore, the effect of aldosterone on sodium intake is strongly potentiated by glucocorticoids and by ANG II, and in combination with these two hormones, physiological doses of mineralocorticoid become effective in inducing sodium intake, demonstrating the synergic action of these hormones in the regulation of sodium appetite (155, 277). In this context, Geerling and co-workers (169) demonstrated the existence of aldosterone-sensitive neurons in the NTS, which coexpress mineralocorticoid receptor (MR) and the enzyme 11β-hydroxy-steroid dehydrogenase type 2 (HSD2). This enzyme inactivates glucocorticoids, which have higher plasma concentrations, allowing the predominant action of aldosterone in these NTS neurons. Using c-Fos nuclear immunostaining, these authors also demonstrated that these neurons are activated by a low sodium diet (169). Therefore, this neuronal population in the NTS is sensitive to aldosterone, and this sensitivity is caused by selective HSD2 enzyme expression in MR-expressing neurons (165). Conversely, Sakai and associates (405) demonstrated that the amygdala participates in aldosterone-mediated actions on the induction of sodium appetite. These authors demonstrated that local MR knockdown abolishes sodium intake evoked by aldosterone, whereas the microinjection of aldosterone into the amygdala stimulates sodium appetite. Therefore, both NTS and amygdala appear to participate in the central actions of aldosterone to induce sodium appetite, with NTS HSD2expressing neurons selectively responding to mineralocorticoids. Indeed, Geerling and Loewy (170) demonstrated a bidirectional connection between the NTS HSD2 neurons and the central nucleus of the amygdala neurons, which explain the crucial role of these nuclei in the induction of sodium appetite evoked by mineralocorticoids.

Natriuretic peptides One of the first observations later attributed to natriuretic hormones was a description dating back to the mid-ninth

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century that Roman divers exhibited an increased diuretic response following immersion in water (immersion-induced diuresis). Considering our current knowledge, this event can be explained by the increased pressure exerted by the water on the extremities, abdomen and thorax, which increases venous return to the heart, resulting in dilation of the atrium and the consequent release of ANP. Stretch-stimulated ANP secretion is dependent on the activation of specific potassium channels in cardiomyocytes (345). The first experimental evidence in the literature for the existence of a natriuretic hormone was reported during the 1950s in a study that investigated the involvement of the heart in the control of urinary excretion (200). These experiments were based on the expansion of a balloon in the right atrium, which produced diuresis in the experimental animals. In 1956, Kisch conducted electron microscopy studies and described the presence of membrane-bound secretory granules in atrial myocytes (242). This evidence was confirmed later by several other groups (55, 224). Sedláková and colleagues (417) reported an increase in the natriuretic response in cows and dogs infused with saline. Subsequent studies resulted in the purification of a hypothalamic natriuretic factor, which was believed to be an OXT analog. Later, Orias and McCann confirmed that both AVP and OXT exhibit natriuretic properties (353). Some years later, Davis and Freeman (111) described the existence of a circulating natriuretic factor in dogs submitted to crossed-circulation experiments. Based on these findings, it was proposed that the atria distension would generate afferents inputs carried to the CNS by the vagus nerve. The idea of a natriuretic hormone also came from experiments conducted by De Wardener and Clarkson (122), who demonstrated that body fluid expansion-induced natriuresis could occur without any significant change in kidney physiology. However, one of the most important discoveries at that time was made by De Bold and associates in 1981 (117). These authors showed that rat atrial (but not ventricular) extracts caused impressive natriuretic and diuretic effects when intravenously injected. A couple of years later, the molecular structure of ANP was characterized by the same group (156). A vasodilatory action of atrial extracts on vascular smooth muscle cells was also reported later (100, 159). The classic family of natriuretic peptides (NPs) is composed of ANP, BNP, C-type natriuretic peptide and Dendroaspis-type natriuretic peptide (DNP). More recently, other members have been added, including urodilatin, guanylin, uroguanylin, and adrenomedullin. In some species, particularly in rodents, OXT has an extremely important natriuretic effect. Most of these peptides have been named according to the site from which these peptides were first isolated and identified or from which these peptides exert their primary biological effects. Accordingly, ANP was first identified in the atria, and BNP was first isolated from porcine brain tissue, although its major sources are actually cardiac ventricles. CNP is predominantly produced by the CNS but is also found at extremely low concentrations in the peripheral

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circulation. In addition, DNP was originally isolated from the venom of the Dendroaspis angusticeps or green Mamba snake. Urodilatin is produced at renal level by the alternative cleavage of pro-ANP in the distal tubules. Both guanylin and uroguanylin are predominantly expressed in the intestinal epithelium, where these peptides seem to participate in the transport of sodium and water by the GI tract. Finally, adrenomedullin is a ubiquitously expressed peptide that was first isolated from pheochromocytoma, which is a type of adrenal medulla tumor (for a review of the specific characteristics of the NPs, please see 360). In the present section, we will focus on discussing the actions of ANP, BNP, CNP, DNP, and OXT on the renal handling of sodium. A more detailed description of OXT structure and function can be found in the previous section, titled “Initiating the effector responses: neuroendocrine systems: Hypothalamic neurohypophyseal peptides.” Similar to other peptides, ANP, BNP, CNP, and DNP are cleaved from prepro-hormones. The four active peptides hold a great structural homology; these peptides exhibit a disulfide bond linking two cysteines; this bond is essential for determining their biological effects (360). Both ANP and BNP bind to type A natriuretic peptide receptors (NPRAs), whereas CNP binds to type B natriuretic peptide receptors (NPRBs) (360). NPRAs and NPRBs are associated with type A and B guanylyl cyclase, respectively; however, it has been speculated that the activation of the soluble isoform of this enzyme by gaseous modulators, such as NO and CO, also modulates NP-induced actions at the vascular and renal levels. Indeed, the hyperosmolality-induced release of ANP is inversely correlated with NO production by the medial basal hypothalamus in vitro (177). In contrast, BNP-induced NO production generates an anti-ischemic response in isolated hearts (132). The local production of NO by the kidneys does not affect the ANP-induced natriuretic effect (437). Furthermore, all the NPs bind with high affinity to type C natriuretic peptide receptors (NPRCs), which do not exhibit the intracellular sequences of the other two receptor subtypes (kinasehomology and guanylyl cyclase domains). After binding to NPRCs, NPs are internalized and, therefore, removed from the circulation. For this reason, NPRCs are also known as “clearance receptors.” The NPs and NPRs are produced and expressed by a wide variety of tissues, demonstrating the physiological relevance of these hormones. In the CNS, their expression is predominant in the hypothalamus and brainstem structures related to the neural control of body fluid homeostasis. Therefore, the existence of a central peptidergic system regulating the circulating levels of NPs and other hormones has been proposed. According to this hypothesis, cardiac ANP release would signal the CNS, which, in turn, downregulates ANP release from the heart. Although systemic ANP poorly penetrates the brain, making ANP unlikely to generate a negative feedback effect, it is reasonable to assume that increased brain levels of ANP originating from ANPergic neurons elicited by a specific

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challenge would provide sufficient local concentrations to inhibit neuronal secretory activity in an autocrine manner. For example, when administered directly into the AV3V region, ANP or CNP decreases plasma ANP concentrations in volume-expanded rats without changing mean arterial pressure and heart rate (377). Furthermore, the central administration of ANP was shown to reduce AVP and OXT secretion induced by dehydration and by hemorrhage (4). The effects of ANP and BNP on the electrical activity of SON vasopressinergic neurons were characterized by a decrease in the firing rate and membrane hyperpolarization (4). These authors also demonstrated that these responses were mimicked by an analog of cGMP, as well as by a specific inhibitor of cGMP phosphodiesterase, strongly suggesting that the inhibitory effects of NPs on vasopressinergic neurons are mediated by cGMP. Interestingly, the administration of ANP into the SON did not affect depolarizing responses induced by local hypertonicity but abolished synaptic excitation of magnocellular neurons following hypertonic stimulation of the OVLT (392). Considering that magnocellular neurons receive afferent glutamatergic inputs arising from OVLT osmoreceptors, these authors hypothesized that central ANP may inhibit osmotically induced neurohypophyseal hormone secretion through presynaptic inhibition of glutamatergic synapses on these cells. Indeed, lesions of structures involved in the central integrative function of hydroelectrolytic balance (ME, AV3V region, and posterior pituitary) completely disrupted the extracellular volume expansion-induced increase in ANP plasma concentrations (27). The natriuretic and diuretic effects of the NPs are induced by three primary mechanisms: (i) a reduction in peripheral vascular resistance, particularly in the renal afferent arterioles, an effect that is mediated by cGMP-dependent and cGMPindependent pathways and that is achieved through alterations in vascular smooth muscle contractility and proliferative processes (144); (ii) a decrease in sodium reabsorption in the medullary portions of the collecting duct (522); and finally, (iii) a decrease in AVP secretion, therefore reducing water permeability in the distal nephron (516). In addition to contributing to the reduction of ECF volume, the NPs also exhibit other antihypertensive properties: (i) antagonism of the RAS, with inhibition of renin and aldosterone release, consequently decreasing the effects of the related hormones on behavioral, cardiovascular, and renal responses; (ii) inhibition of peripheral sympathetic activity; and (iii) negative chronotropic and inotropic effects on the heart (143) (Figs. 19 and 20). The effects of NPs on the cardiovascular system have been recently emphasized because of the evidence that these hormones may be involved in estrogen-induced cardioprotective effects in women. For example, short-term estrogen replacement therapy not only is able to successfully reduce blood pressure but also induces an increase in plasma concentrations of ANP precursor (236). Furthermore, NPs have also been used as important tools for the diagnosis and prognosis of cardiovascular diseases. Considering that the rat thymus

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expresses NPs and their receptors, a role for these hormones in immune function has also been speculated (495). Aldo

Increasing the Complexity: Local Modulators

AVP

Ren

ANP

ANG II

Figure 19

Schematic representation of the main actions of atrial natriuretic peptide (ANP) on body fluid homeostasis. The dashed lines represent inhibitory actions of ANP on: (i) the release of vasopressin (AVP) by the neurohypophysis; (ii) the production and release of aldosterone (Aldo) from the medullar portion of the adrenal gland; (iii) the production and release of renin (Ren) from the renal juxtamedular apparatus; and (iv) the release of norepinephrine (Nor) from sympathetic terminals innervating blood vessels. ANP actions decreasing Ren activity produce the impairment of the conversion of the precursor angiotensinogen to angiotensin I (ANG I) and, consequently, decrease angiotensin II (ANG II) production. The combined effects of decreased ANG II, AVP, and Nor release contribute to ANP-induced vasodilation, although a direct action of ANP decreasing vascular resistance has been already recognized. The reduced ANG II production and secretion is also involved in the diminished production of Aldo.

GTP ANP

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Figure 20

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Atrial natriuretic peptide (ANP) binds to NPRA and NPRC, which are expressed by the basolateral membrane of tubular cells. The binding of ANP or other natriuretic peptides to NPRC produces the internalization of the ligand-receptor complex, which is then degraded or recycled. NPRA, in turn, exhibits an intracellular guanylyl cyclase (GS) domain. ANP binding to NPRA stimulates the production of cyclic monophosphate of guanosine (cGMP), which is responsible for the natriuretic effect of ANP, characterized by the closing of epithelial Na+ channels (ENaCs) located in the apical membrane of distal tubular cells. The activity of the enzyme phosphodiesterase (PD), which converts cGMP to GMP, may be increased by angiotensin II (ANG II) increased circulating levels, thus reducing ANP-mediated natriuretic effects. This mechanism is particularly involved in the pathogenesis of congestive heart failure.

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Neurons produce and secrete many chemical mediators. These substances act as either neurotransmitters and neuromodulators, which are released into the interstitial space and act as paracrine and/or autocrine signals, or neurohormones, exerting their effects at distant targets through the systemic circulation. In addition to acetylcholine, which was the first neurotransmitter to be discovered, many other small molecules have been identified in the CNS, including neuropeptides. Most neuropeptides are synthesized as protein precursors, which often contain the sequence of more than one active peptide. Neuropeptides are commonly released by limited and selected proteolysis of the precursor, which occurs inside secretory vesicles. The classical neurotransmitters are composed of a group of biogenic amines and some amino acids and purines. Biogenic amines are the catecholamines (dopamine, norepinephrine, and epinephrine), serotonin and histamine. Biogenic amines are synthesized from amino acids: (i) catecholamines are derived from tyrosine by successive catalytic pathways; (ii) serotonin is produced in a two-step reaction from the amino acid tryptophan; and (iii) histamine is derived from the decarboxylation of the amino acid histidine. The primary amino acids implicated in neurotransmission are glutamate, glycine, and GABA. The first two are derived from metabolic pools, whereas GABA is produced from glutamate. In turn, purines include at least ATP and adenosine. Several examples of the coexistence of classic neurotransmitters and neuroactive peptides in the same terminals have been described, determining synergistic effects on postsynaptic cells. More recently, gaseous modulators have been included in the increasing list of substances with effects on neuronal activity. Soluble gases are signaling molecules with a short half-life that exert their actions in an autocrine or paracrine manner. The most well-known gaseous neuromodulator is NO, which is synthesized from L-Arginine by the enzyme nitric oxide synthase (NOS) and rapidly diffuses to the extracellular space (358). In 1998, the discovery of the vasodilatatory properties of NO in the vascular smooth muscle cells mediated by the endothelial isoform of the NOS was awarded with the Nobel Prize in Physiology and Medicine, and since then, many physiological and pathological effects have been attributed to NO, such as involvement in the control of neuroendocrine function. The expression of the neuronal isoform of NOS (nNOS) is increased by dehydration in the magnocellular neurons of the PVN and SON (64, 493). The intracerebroventricular injection of L-NAME, which is a nonselective NOS inhibitor, leads to an increased secretion of both AVP and OXT (235, 386, 387), as well as increased water

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and sodium intake (404). These neuroendocrine effects produced by the administration of L-NAME are also associated with an increase in the firing rate and a decrease in the resting electronegativity of magnocellular neurons (489). In addition, Soares and colleagues (437) demonstrated that OXT administration induced a significant increase in the renal excretion of nitrate, which is a NO metabolite, and that the prior administration of L-NAME is able to inhibit not only this response but also OXT-induced natriuresis. These data, together with the evidence provided by the same authors that the renal tubules and arterioles are immunoreactive to NOS, suggest that this gaseous modulator constitutes an important factor in the control of renal sodium handling, either acting directly on ion transport or by controlling blood flow through the renal capillary beds. Another gas presenting an important physiological function is CO, which is endogenously synthesized by action of the enzyme heme oxygenase (HO) on the heme group. This reaction produces not only CO but also biliverdin and iron (283,284). Endogenously produced CO stimulates AVP (285) and OXT release (249). In addition, in vitro inhibition of HO inhibits the hyperosmolality-induced OXT release from the medium incubation (176). Studies also suggest that the kidneys express both the inducible (type 1) and constitutive (type 2) HO isoforms, with these enzymes predominantly expressed in the medullary portion (215,528). In the kidney, locally produced CO apparently modulates hemodynamic events, such as the control of blood flow (223), as well as the transport of ions and water (223). In addition to the individually produced effects, the gaseous modulators CO and NO appear to interact in the control of hydroelectrolytic balance. In this context, Gomes and co-workers (176) demonstrated that the use of an HO inhibitor increases the hyperosmolality-induced production of L-citrulline (an equimolar coproduct of NO synthesis) by the medial basal hypothalamus in vitro. Few studies in the literature have been devoted to elucidating the role of hydrogen sulfide (H2 S) in neuroendocrine and renal responses related to hydroelectrolytic homeostasis. However, considering the recent evidence suggesting that H2 S can interact with NO and CO (286), a growing interest has been focused on this modulator because the other two aforementioned gaseous molecules exhibit pronounced effects on these systems. H2 S is endogenously produced by the CNS of rodents (497) and humans (180). This molecule is synthesized from L-Cysteine by the action of two primary enzymes, cystathionine-β-synthase (CBS), and cystathionineγ-lyase (CSE). Recently, Shibuya and co-workers (422) demonstrated the existence of other H2 S-generating enzymes, 3-mercaptopyruvate sulfurtransferase (3-MST) and cysteine aminotransferase (CAT), in the CNS of CBS-knockout mice. The first reports in the literature regarding H2 S primarily described its toxicity, although it has been previously demonstrated that, at low concentrations, H2 S actually protects the organism against oxidative stress (241). Accordingly, a recent study demonstrated that the experimental use of a CSE inhibitor decreases adriamycin-induced renal damage (160).

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However, at high concentrations, H2 S was shown to stimulate the formation of reactive oxygen and nitrogen species (517). In the periphery, Zhao and colleagues (526) also showed that H2 S plays an important vasodilatatory action, which is associated with the activation of ATP-dependent potassium channels. For review about gaseus neurotransmitters controlling hydromineral balance, please see Ruginsk and co-workers (399).

Integration Between Salt and Water Ingestion and Excretion Ingestive-originated imbalances Under normal conditions, the addition of sodium without water to the ECF produces a transitory increase in the osmolality of this compartment. However, highly effective homeostatic mechanisms act in coordination to decrease water excretion and to increase water ingestion and reabsorption, thus producing a resultant isotonic increase in ECF volume, which is proportional to the amount of solute added. Conversely, if water without solute were added to the ECF compartment, then a decrease in the osmolality would be observed. According to mass balance, if the ingestion of water or sodium is greater than the excretion (positive balance), then mechanisms aimed at the elimination of the exceeding amounts are activated. The kidneys are the primary final route for water and sodium excretion. However, water and electrolytes can be lost to a lesser extent through the skin, respiratory system and gastrointestinal tract. In contrast, if the outputs exceed the inputs (negative balance), then the kidneys, together with the cardiovascular, motor and neuroendocrine systems, initiate a coordinated action to replenish (through increased reabsorption and ingestion) water and/or sodium to maintain adequate tissue perfusion. Hyponatremia constitutes an extremely common finding of inadequate replacement of electrolytes during prolonged exercise. In this case, the intake of water without electrolytes dilutes the ECF, consequently decreasing the osmotic gradient in this compartment, leading to cell swelling. Considering that the brain is enclosed within a rigid skull, many neurologic manifestations could be observed following hyponatremia and brain swelling, such as confusion, headache, loss of motor coordination, and even death. A more detailed explanation of the effects of exercise on body fluid homeostasis can be found in the following section.

Hydromineral balance management during physical exercise It is believed that the human tegument contains between 2 and 3 million sweat glands, which are primarily composed of transport epithelium. The initial step for sweat production is the secretion of an isotonic solution, whose composition is similar to interstitial fluid. As this fluid is carried

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through the duct to the skin, sodium and chloride ions are absorbed, resulting in hypotonic sweat. Increased sweating can be observed in response to enhanced environmental temperatures and to physical exercise. However, individuals cannot sustain increased sweat production if proportional replenishment of fluids and electrolytes does not occur, as discussed previously. Furthermore, in addition to the sympathetic nervous system, both oxytocinergic and vasopressinergic preautonomic neurons of the hypothalamus are involved in the regulation of heart rate and cardiac output during the increased circulatory demand provided by physical exercise (318). In this context, OXT released within the solitary-vagal complex increases vagal outflow to the heart, thus augmenting reflex bradycardia (403). Interestingly, acute exercise increases OXT content in the brainstem of trained, but not sedentary, rats, suggesting that central OXT may restrain exercise-induced tachycardia in trained individuals (317). The same group also demonstrated that, although a decrease in the brainstem oxytocinergic system (evaluated by OXT mRNA expression and OXTR density) was observed in spontaneously hypertensive rats, exercise training remained effective in increasing OXT mRNA expression in this experimental group (293). A role for OXT and other NPs in the cardioprotective responses has also been speculated. A deficient secretion of NPs is linked to impaired diuresis and vasodilatation, as well as to increased sympathetic tonus and aldosterone production (508). Indeed, obese patients with low plasma concentrations of NPs exhibit volume expansion associated with sodium retention (468). Furthermore, low levels of ANP and BNP are associated with the occurrence of local degenerative processes in cardiomyocytes (508). Recently, the expression of OXTR gene was shown to be decreased in the heart of insulinresistant obese mice, an effect that is not reversed by voluntary running (65). These authors also observed a lower mRNA expression for BNP in obese animals, with no changes in ANP or CNP. Conversely, AVP concentrations in the systemic circulation seem to be elevated in a dose-related manner as the intensity of exercise increases but are reduced with training at absolute submaximal exercise (496). This author also speculated that a decreased metabolization rate (due to adaptative changes in renal and hepatic blood flow) could contribute to these increased plasma levels of AVP observed during exercise. Although the excretion rate of free water is normally increased by exercise, a hypervolemic state has also been reported after physical training (95). A more recent study proposed that the increased sweat loss together with the hyperosmolality originated by increased sodium and lactate concentrations are indeed the primary factors stimulating AVP secretion and thirst in a group of individuals submitted to high-intensity intermittent exercise (308). Exercise also increases blood pressure, and this response is primarily attributed to increased muscular demand for substrates. An exaggerated pressor response during exercise

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can be used as a predictor for the development of hypertension (432). In hypertensive individuals, the magnitude of the increase in systolic pressure during exercise is used as a determinant of left ventricular hypertrophy (388), as well as for the assessment of stroke risk (254). The redistribution of blood flow that follows exercise is achieved through a coordinated action of the autonomic and RAS. The secretion of catecholamines from the adrenal medulla initiates the mobilization of glucose and free fatty acids, which, in turn, activate other endocrine glands to secrete hormones that potentiate fuel recruitment and that regulate hydromineral balance. Increased sympathetic activity directly stimulates renin release from the kidneys, thus activating the RAS. In addition, decreased renal perfusion and reduced sodium concentrations that reach the macula densa may also contribute to renin release during exercise (142). As discussed previously, the major effects of the RAS are vasoconstrictor, natriorexigenic, and dipsogenic responses (primarily attributed to ANG II), as well as increased sodium reabsorption at the renal level (primarily attributed to aldosterone).

Lifelong Neuroendocrine Control of Hydromineral Balance Several adaptations in hydromineral balance control are observed during different stages of life, such as pregnancy, development, adulthood, and aging. Furthermore, genderrelated specificities may account for the differences in the management of water and sodium between males and females. In this section, we will briefly discuss some of these points, emphasizing developmental/programming and aging-related mechanisms, as well as estrogen-mediated modulation of neuroendocrine responses involved in the homeostatic control of ECF volume and osmolality. In the search for the causes of certain adult diseases, in the past few years, an increasing interest has been focused on the phenomenon of developmental programming, which is often called the “developmental origins of adult disease” hypothesis (40). The neuroendocrine systems that regulate hydromineral balance are not excluded from this process because many studies indicate that several challenges during critical periods of early life can modify behavioral and neuroendocrine responses related to water and sodium balance in adult life. Indeed, fetal undernutrition leads to lifelong morphofunctional renal abnormalities and hypertension in rats (258). In addition, perinatal malnutrition seems to increase both water and salt intake in rats (10, 257, 436). In humans, salty taste and sensitivity to salt are also related to fetal growth and weight at birth (425, 429). Several studies also demonstrated that changes in hydromineral balance during pregnancy and lactation, such as dehydration and sodium depletion, are able to induce lifelong changes in thirst and sodium appetite in both experimental animals and humans (93, 94, 98, 101, 167, 266, 330). Accordingly, Macchione and

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colleagues (278) showed that rats raised on a rich sodium environment exhibit enhanced water intake associated with increased c-Fos expression in the SFO, SON, and PVN AVP neurons. Additionally, our group demonstrated that RAS blockade during pregnancy and lactation in rats decreases water and sodium intake in response to cellular and extracellular dehydration and in response to peripheral and brain RAS stimulation (309). These behavioral changes can be, at least in part, attributed to alterations in renal morphophysiological changes induced by RAS inhibition (292, 309). Furthermore, Xu’s group demonstrated that a nonregimented lifestyle during pregnancy and lactation, such as smoking and excess sugars in the diet, can induce several changes in brainrasand program adult thirst and sodium appetite in animal models (218, 289, 511). Additionally, alcohol consumption during pregnancy increases AVP and water intake in adult offspring (131). Collectively, these results indicate that many alterations during development are able to permanently program adult neuroendocrine function controlling hydromineral balance (Fig. 21). For review about perinatal programming of hydromineral balance, please see Mecawi and coworkers (312).

Life style Hydromineral challenges Neuroendocrine disturbances Cardiovascular challenges Dietary composition Use of drugs

During the reproductive phase of life, males and females show normal differences in the neuroendocrine control of hydromineral balance. All reproductive hormones seem to influence neurohypophyseal hormone secretion, thirst and sodium appetite, blood pressure and renal function. For this reason, women have a greater risk of developing hyponatremia, whereas men show a greater chance of developing hypertension (446). Antunes-Rodrigues and colleagues (23) first reported a spontaneous decrease in sodium intake during estrus compared with a higher sodium intake during diestrus in female rats. Indeed, most studies indicated that estradiol is the primary sexual hormone regulating hydromineral balance because estradiol directly promotes thirst attenuation in response to cellular and extracellular dehydration and ANG II-induced stimulation (76, 251, 310, 311, 491). Furthermore, Mecawi and associates (310, 311) demonstrated that the inhibition of central AT1 receptors during need-induced thirst and sodium appetite responses is significantly attenuated by estrogen in rats. These results are consistent with an inhibitory effect of estradiol on brain RAS (123). In addition, we showed that estrogen treatment reduces water and sodium intake in response to acute and chronic hypotension in ovariectomized rats (29). Viva’s group also revealed that estrogen-mediated

Programming Thirst Sodium appetite Kidney damage Hypertension

? Next generation

Environment Figure 21 Scheme presenting potential consequences of diverse environmental factors (lifestyle, hydromineral balance and/or challenges, neuroendocrine disturbances, dietary composition, and drug use) at various stages of developmental programing of thirst and sodium appetite, and also the predisposition to pathological conditions such as hypertension and/or kidney damage. Reproduced with the permission (graphical abstract) from Mecawi and co-workers (2015) (312).

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inhibition of sodium intake in female rats is associated with changes in c-Fos expression in serotonergic DRN neurons related to a known sodium appetite-inhibitory circuitry (105). Furthermore, several reports have also demonstrated a stimulatory effect of estradiol on basal and stimulus-induced AVP, OXT and ANP secretion (44, 369, 504). Recently, we have demonstrated a positive effect of estradiol on AVP and OXT secretion as well as on the activation of oxytocinergic and vasopressinergic neurons of the SON and PVN in response to osmotic stimulation induced by hypertonic extracellular volume expansion and hypovolemic shock (313,492) (Fig. 22). These findings are strongly supported by evidence that estradiol receptor beta (ER-β) is expressed in the magnocellular AVP and OXT neurons of SON and PVN, whereas estradiol receptor alpha (ER-α) is expressed in afferent osmosensitive and ANG II-responsive neurons of the LT projecting to the hypothalamic nuclei (214, 441). Therefore, the modulation exerted by estradiol on AVP and OXT neuronal activity and secretion could be promoted by either a direct effect on the hypothalamus or by an indirect mechanism initiated in the LT or DRN serotonergic neurons. In fact, Stachenfeld’s group demonstrated that estrogen increases the threshold for osmotic-induced AVP secretion and thirst (447, 448). Taken together, these data indicate that estrogen participates in the neuroendocrine control of hydromineral balance by the following mechanisms: (i) changing the responsiveness of the PVN and SON neurosecretory system; (ii) increasing the release of natriuretic factors ANP and OXT; iii) decreasing brain ANG II responsiveness via modulation of AT1 -mediated signaling and brain RAS components expression; (iv) increasing DRN serotonergic activity; and finally, (v) attenuating basal and need-induced thirst and sodium appetite. In contrast, elderly people exhibit an increased risk for developing hydromineral imbalances. Severe dehydration or hyponatremia are common reasons for increased morbidity and mortality in aged people (96). Aging-related fluid disturbances are particularly important in women because during the postmenopause period, due a drop in sexual hormones, the risk for the development of hydromineral-related disturbances and hypertension increases to the same extent as in aged-paired men (291, 446). In contrast, the use of hormone therapy to prevent several changes in cardiovascular function, bone metabolism and sexual physiology can disturb hydromineral balance and increase the risk of cancer development in postmenopausal women (84, 446). Briefly, three particular aspects of neuroendocrine control during aging can be addressed: (i) some reports revealed that vasopressinergic neuronal activity and AVP secretion are altered in elderly individuals in both animal and human models (163, 182, 211, 276). The most commonly observed alteration in this population is augmented osmoreceptor sensitivity and basal/osmotic-dependent AVP secretion (96, 110). (ii) Animal models and human studies have demonstrated agingrelated reduction in sodium appetite [356, 478). Interestingly, in humans, these changes in sodium appetite appear only after

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the postmenopause period, again showing the importance of sexual hormones in the control of water and sodium balance (356). Alterations in both AVP secretion and salt intake may explain the prevalent hyponatremia observed in aged people. (iii) Conversely, elderly people and aged rats show a decrease in water intake following several challenges, primarily related to an increased threshold for the osmotic triggering of thirst sensation (281,370). This apparent reduction of thirst perception and water intake with aging impairs the behavioral mechanism of hyperosmolality correction and is most likely closely related to the dehydration commonly observed in elderly people (96).

Conclusion In most homeostatic systems, a given challenge activates a respective sensory system, which, in turn, recruits one or more specialized areas of the CNS to elicit the appropriate effector responses and to restore previous/basal conditions. The mechanisms involved in the regulation of hydroelectrolytic balance are complex, extremely sensitive and accurate, involving central, cardiovascular, endocrine and renal responses. Afferents inputs are represented by (i) mechanoreceptors (baroreceptors and volume receptors) in the cardiovascular system and (ii) osmoreceptors and Na+ receptors in the periphery and in the CNS. Inputs performed by these sensory systems are conveyed to specific areas of the CNS, with the hypothalamic neurohypophyseal system the final common route for these integrative circuitries. Simultaneously, behavioral responses are modulated; the selective stimulation or inhibition of motivational and locomotor aspects directly affects the search for and acquisition of water and/or sodium. Finally, the primary systemic effectors targeting renal management of fluid and electrolytes are composed of the sympathetic autonomic system and hormones (AVP, OXT, NPs, and RAAS), which are released by a wide variety of endocrine cells. With the development of molecular biology, global expression analysis (genomes, proteomes, and transcriptomes), bioinformatics, epigenetics, the ability to control gene expression, and genetic engineering, our perspectives concerning the study of hydromineral balance have been consistently broadened in recent decades. It is now possible to establish extremely convincing and complimentary hypotheses concerning the mechanisms underlying water and sodium management based on upcoming functional results (obtained by the use of advanced methodological strategies), as well as on behavioral clues provided by the pioneer lesion-based studies conducted in the early 1960s. However, the major challenge for the future in this field is to match a deeper understanding of the local mechanisms (types and properties of receptors, ion channels, and signaling cascades) with the overview regarding how an intact organism (considering gender- and age-specific mechanisms) maintains a homeostatic balance of body fluids when exposed or reexposed to different challenges.

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Figure 22

The effects of estradiol cypionate (EC, 10 or 40 μg/kg) on the activation of neurohypophyseal systems in response to hemorrhage in OVX rats. In A and B are showed, respectively, the plasma vasopressin and oxytocin levels in basal condition and after hemorrhage. The number of animals/group is shown in the respective bar. ∗ P < 0.05, ∗∗ P < 0.01, and ∗∗∗ P < 0.001 between basal and hemorrhage levels. +P < 0.05, ++P < 0.01, and +++P < 0.001 between the OVX-oil and OVX-EC groups. In C are showed representative photomicrographs (coronal sections) of the SON showing c-Fos/AVP immunoreactive neurons in sham or hemorrhage rats pretreated with oil or EC. In detail, the SON is shown in a small magnification. Scale bar: 100 μm. Reproduced with the permission from Mecawi and coworkers (2011) (313).

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Acknowledgements The authors would like to thank all the members of their research groups and partners who contributed to the development of research in this area and also the Brazilian funding agencies (Sao Paulo State Research Foundation (FAPESP), Fundaça˜ o Carlos Chagas Filho de Amparo a` Pesquisa do Estado do Rio de Janeiro (FAPERJ), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), and Coordenacao de Aperfeiçoamento de Pessoal de Nivel Superior (CAPES) for providing financial support. Dr. Mecawi is also funded by a High Impact Research grant from the University of Malaya (UM.C/625/1/HIR/MOHE/MED/22 H-20001E000086).

References 1. 2. 3. 4. 5.

6. 7. 8. 9.

10. 11.

12. 13. 14. 15. 16. 17. 18. 19.

Acher R, Chauvet J, Chauvet MT, Rouille Y. Unique evolution of neurohypophysial hormones in cartilaginous fishes: Possible implications for urea-based osmoregulation. J Exp Zool 284: 475-484, 1999. Acher R, Chauvet J, Rouillé Y. Adaptive evolution of water homeostasis regulation in amphibians: Vasotocin and hydrins. Biol Cell 89: 283-291, 1997. Agre P. Aquaporin water channels. Nobel Lecture, 2003. Akamatsu N, Inenaga K, Yamashita H. Inhibitory effects of natriuretic peptides on vasopressin neurons mediated through cGMP and cGMPdependent protein kinase in vitro. J Neuroendocrinol 5: 517-522, 1993. Alhenc-Gelas A, Corvol P. Molecular and physiological aspects of angiotensin I converting enzyme. The Endocrine System: Endocrine Regulation of Water and Electrolyte Balance: Handbook of Physiology. Oxford: Oxford University Press, 2000, pp. 3-58. Allen AM, Moeller I, Jenkins TA, Zhuo J, Aldred GP, Chai SY, Mendelsohn FA. Angiotensin receptors in the nervous system. Brain Res Bull 47: 17-28, 1998. Allen RD, Naitoh Y. Osmoregulation and contractile vacuoles of protozoa. Int Rev Cytol 215: 351-394, 2002. Alleva K, Chara O, Amodeo G. Aquaporins: Another piece in the osmotic puzzle - FEBS Lett 586: 2991-2999, 2012. Almeida RL, David RB, Constancio J, Fracasso JF, Menani JV, De Luca LA Jr. Inhibition of sodium appetite by lipopolysaccharide: Involvement of a2-adrenoceptors. Am J Physiol Regul Integr Comp Physiol 301: R185-R192, 2011. Alwasel SH, Barker DJ, Ashton N. Prenatal programming of renal salt wasting resets postnatal salt appetite, which drives food intake in the rat. Clin Sci 122: 281-288, 2012. Al-Zahid G, Schafer JA, Troutman SL, Andreoli TE. Effect of antidiuretic hormone on water and solute permeation, and the activation energies for these processes, in mammalian cortical collecting tubules: Evidence for parallel ADH-sensitive pathways for water and solute diffusion in luminal plasma membranes. J Membr Biol 31: 103-129, 1977. Amico JA, Morris M, Vollmer RR. Mice deficient in oxytocin manifest increased saline consumption following overnight fluid deprivation. Am J Physiol Regul Integr Comp Physiol 281: R1368-R1373, 2001. Anderson JW, Washburn DL, Ferguson AV. Intrinsic osmosensitivity of subfornical organ neurons. Neuroscience 100: 539-547, 2000. Andersson B. Polydipsia caused by intra hypothalamic injections of hypertonic NaCl solutions. Experientia 15: 157-158, 1952. Andersson B. The effect of injections of hypertonic NaCl-solutions into different parts of the hypothalamus of goats. Acta Physiol Scand 28: 188-201, 1953. Andersson B. Regulation of water intake. Physiol Rev 58: 582-603, 1978. Andersson B, Jobin M, Olsson K. Stimulation of urinary salt excretion following injections of hypertonic NaCl-solution into the 3rd brain ventricle. Acta Physiol Scand 67: 127-128, 1966. Andersson B, Leksell LG, Lishajko F. Perturbations in fluid balance induced by medially placed forebrain lesions. Brain Res 99: 261-275, 1975. Andersson B, McCann SM. A further study of polydipsia evoked hypothalamic stimulation in the goat. Acta Physiol Scand 33: 333-346, 1954.

Volume 5, July 2015


20. Andersson B, McCann SM. Hypothalamic control of water intake. J Physiol 129: 44P, 1955. 21. Andersson B, McCann SM. The effect of hypothalamic lesions on the water intake of the dog. Acta Physiol Scand 35: 312-320, 1956. 22. Antunes VR, Camargo GM, Saad R, Saad WA, Luiz AC, Camargo LA. Role of angiotensin II and vasopressin receptors within the supraoptic nucleus in water and sodium intake induced by the injection of angiotensin II into the medial septal area. Braz J Med Biol Res 31: 1597-1600, 1998. 23. Antunes-Rodrigues J, Covian MR. Hypothalamic control of sodium chloride and water intake. Acta Physiol Lat Am 13: 94-100, 1963. 24. Antunes-Rodrigues J, de Castro M, Elias LL, Valença MM, McCann SM. Neuroendocrine control of body fluid metabolism. Physiol Rev 84: 169-208, 2004. 25. Antunes-Rodrigues J, Machado BH, Andrade HA, Mauad H, Ramalho MJ, Reis LC, Silva-Netto CH, Favaretto ALV, Gutkowska J, McCann SM. Carotid-aortic and renal baroreceptors mediate the atrial natriuretic peptide release induced by blood volume expansion. Proc Natl Acad Sci U S A 89: 6828-6831, 1992. 26. Antunes-Rodrigues J, McCann SM, Rogers LC, Samson WK. Atrial natriuretic factor inhibits dehydration- and angiotensin II induced water intake in the conscious, unrestrained rat. Proc Natl Acad Sci U S A 82: 8720-8723, 1985. 27. Antunes-Rodrigues J, Ramalho MJ, Reis LC, Menani JV, Turrin Q, Gutkowska J, McCann SM. Lesions of the hypothalamus and pituitary inhibit volume-expansion-induced release of atrial natriuretic peptide. Proc Natl Acad Sci U S A 88: 2956-2960, 1991. 28. Antunes-Rodrigues J, Ruginsk SG, Mecawi AS, Margatho LO, Cruz JC, Vilhena-Franco T, Reis WL, Ventura RR, Reis LC, Vivas LM, Elias LL. Mapping and signaling of neural pathways involved in the regulation of hydromineral homeostasis. Braz J Med Biol Res 46: 327-338, 2013. 29. Araujo IG, Elias LL, Antunes-Rodrigues J, Reis LC, Mecawi AS. Effects of acute and subchronic AT1 receptor blockade on cardiovascular, hydromineral and neuroendocrine responses in female rats. Physiol Behav 122: 104-112, 2013. 30. Arima H, Kondo K, Murase T, Yokoi H, Iwasaki Y, Saito H, Oiso Y. Regulation of vasopressin synthesis and release by area postrema in rats. Endocrinol 139: 1481-1486, 1998. 31. Armstrong WE. Hypothalamic supraoptic and paraventricular nuclei. The Rat Nervous System. New York: Academic Press, 1995. 32. Arnason SS, Rice GE, Chadwick A, Skadhauge E. Plasma levels of arginine vasotocin, prolactin, aldosterone and corticosterone during prolonged dehydration in the domestic fowl: Effect of dietary NaCl. J Comp Physiol B 156: 383-397, 1986. 33. Arpin-Bott MP, Waltisperger E, Freund-Mercier MJ, Stoeckel ME. Two oxytocin-binding site subtypes in rat kidney: Pharmacological characterization, ontogeny and localization by in vitro and in vivo autoradiography. J Endocrinol 153: 49-59, 1997. 34. Badauê-Passos D Jr, Godino A, Johnson AK, Vivas L, AntunesRodrigues J. Dorsal raphe nuclei integrate allostatic information evoked by depletion-induced sodium ingestion. Exp Neurol 206: 86-94, 2007. 35. Badaut J, Fukuda AM, Jullienne A, Petry KG. Aquaporin and brain diseases. Biochim Biophys Acta 1840: 1554-1565, 2014. 36. Badaut J, Lasbennes F, Magistretti PJ, Regli L. Aquaporins in brain: Distribution, physiology, and pathophysiology. J Cereb Blood Flow Metab 22: 367-378, 2002. 37. Baertschi AJ, Pence RA. Gut-brain signaling of water absorption inhibits vasopressin in rats. Am J Physiol Regul Integr Comp Physiol 268: R236-R247, 1995. 38. Baldissera S, Menani JW, dos Santos LF, Favaretto AL, Gutkowska J, Turrin MQ, McCann SM, Antunes-Rodrigues J. Role of the hypothalamus in the control of atrial natriuretic peptide release. Proc Natl Acad Sci U S A 86: 9621-9625, 1989. 39. Ballermann BJ, Onuigbo MAC. Angiotensins. Compr Physiol 2011, Supplement 22: Handbook of Physiology, The Endocrine System, Endocrine Regulation of Water and Electrolyte Balance: 104-155. First published in print 2000. Doi: 10.1002/cphy.cp070304. 40. Barker DJ, Eriksson JG, Forsén T, Osmond C. Fetal origins of adult disease: Strength of effects and biological basis. Int J Epidemiol 3: 1235-1239, 2002. 41. Basso N, Terragno NA. History about the discovery of the reninangiotensin system. Hypertension 38:1246-1249, 2001. 42. Bastos R, Favaretto AL, Gutkowska J, McCann SM, AntunesRodrigues J. Alpha-Adrenergic agonists inhibit the dipsogenic effect of angiotensin II by their stimulation of atrial natriuretic peptide release. Brain Res 895: 80-88, 2001. 43. Beets I, Janssen T, Meelkop E, Temmerman L, Suetens N, Rademakers S, Jansen G, Schoofs L. Vasopressin/oxytocin-related signaling regulates gustatory associative learning in C. elegans. Science 338: 543-545, 2012. 44. Belo NO, Silva-Barra J, Carnio EC, Antunes-Rodrigues J, Gutkowska J, Dos Reis AM. Involvement of atrial natriuretic peptide in blood

1507


45.

46. 47.

48. 49. 50.

51.

52. 53. 54.

55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72.

pressure reduction induced by estradiol in spontaneously hypertensive rats. Regul Pept 117: 53-60, 2004. Benga G, Popescu O, Borza V, Pop VI, Muresan A, Mocsy I, Brain A, Wrigglesworth JM. Water permeability in human erythrocytes: Identification of membrane proteins involved in water transport. Eur J Cell Biol 41: 252-262, 1986a. Benga G, Popescu O, Pop VI, Holmes RP. (Chloromercuri) benzenesulfonate binding by membrane proteins and the inhibition of water transport in human erythrocytes. Biochem 25: 1535- 1538, 1986b. Beresford MJ, Fitzsimons JT. Intracerebroventricular angiotensin IIinduced thirst and sodium appetite in rat are blocked by the AT1 receptor antagonist, Losartan (DuP753), but not by the AT2 antagonist, CGP 42112B. Exp Physiol 77: 761-764, 1992. Berlove DJ, Piekut DT. Co-localization of putative vasopressin receptors and vasopressinergic neurons in rat hypothalamus. Histochemistry 94: 653-657, 1990. Bernard C. An Introduction to the Study of Experimental Medicine. New York: Schumann, 1949. Biancardi VC, Son SJ, Sonner PM, Zheng H, Patel KP, Stern JE. Contribution of central nervous system endothelial nitric oxide synthase to neurohumoral activation in heart failure rats. Hypertension 58: 454463, 2011. Blackburn RE, Demko AD, Hoffman GE, Stricker EM, Verbalis JG. Central oxytocin inhibition of angiotensin-induced salt appetite in rats. Am J Physiol Regul Integr Comp Physiol 263: R1347-R1353, 1992. Blair-West JR, Gibson AP, Woods RL, Brook AH. Acute reduction of plasma vasopressin levels by rehydration in sheep. Am J Physiol 248: R68-R71, 1985. Boke T, Malik KU. Enhancement by locally generated angiotensin II of release of the adrenergic transmitter in the isolated rat kidney. J Pharmacol Exp Ther 226: 900-907, 1983. Bole-Feysot C, Goffin V, Edery M, Binart N, Kelly PA. Prolactin (PRL) and its receptor: Actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr Rev 19: 225-268, 1998. Bompiani GD, Farulla A, Perali L, Naro G. On the presence of particular cytoplasmatic osmiophilic bodies in cells of the myocardium of the left auricle of man. Atti Soc Ital Cardiol 21: 519-522, 1959. Booth DA. Mechanism of action of norepinephrine in eliciting an eating response on injection into the rat hypothalamus. J Pharmacol Exp Ther 160:336-348, 1968. Bourque CW. Central mechanisms of osmosensation and systemic osmoregulation. Nat Rev Neurosci 9: 519-531, 2008. Bourque CW, Oliet SH, Richard D. Osmoreceptors, osmoreception, and osmoregulation. Front Neuroendocrinol 15: 231-274, 1994. Bradshaw SD, Bradshaw FJ. Arginine vasotocin: Site and mode of action in the reptilian kidney. Gen Comp Endocrinol 126: 7-13, 2002. Braun EJ, Dantzler WH. Vertebrate renal system. Compr Physiol 2011, Supplement 30: Handbook of Physiology, Comparative Physiology: 481-576. First published in print 1997. Doi: 10.1002/cphy.cp130108. Braun-Menéndez E, Page IH. Suggested revision of nomenclature: Angiotensin. Science 127: 242, 1958. Bray AA. The evolution of the terrestrial vertebrates: Environmental and physiological considerations. Philos Trans R Soc Lond B Biol Sci 309: 289-322, 1985. Brede M, Hein L. Transgenic mouse models of angiotensin receptor subtype function in the cardiovascular system. Regul Pept 96: 125-132, 2001. Bredt DS, Hwang PM, Snyder SH. Localization of nitric oxide synthase indicating a neural role of nitric oxide. Nature 347: 768-770, 1990. Broderick TL, Wang D, Jankowski M, Gutkowska J. Unexpected effects of voluntary exercise training on natriuretic peptide and receptor mRNA expression in the ob/ob mouse heart. Regul Pept 188: 52-59, 2014. Buggy J, Fisher AE. Evidence for a dual central role for angiotensin in water and sodium intake. Nature 250: 733-735, 1974. Buggy J, Johnson AK. Anteroventral third ventricle periventricular ablation: Temporary adipsia and persisting thirst deficits. Neurosci Lett 5: 177-182, 1977a. Buggy J, Jonhson AK. Preoptic-hypothalamic periventricular lesions: Thirst deficits and hypernatremia. Am J Physiol 233: R44-R52, 1977b. Burden CE. The failure of hypophysectomized Fundulus heteroclitus to survive in freshwater. Biol Bull 110: 8-28, 1956. Burton RF. The composition of animal cells: Solutes contributing to osmotic pressure and charge balance. Comp Biochem Physiol B 76: 663-671, 1983. Butler DG, Snitman FS. Renal responses to mesotocin in Western painted turtles compared with the antidiuretic response to arginine vasotocin. Gen Comp Endocrinol 144: 101-109, 2005. Bykowski MR, Smith JC, Stricker EM. Regulation of NaCl solution intake and gastric emptying in adrenalectomized rats. Physiol Behav 92: 781-789, 2007.

1508


73. Camargo LA, Saad WA, de Luca LA Jr, Renzi A, Silveira JE, Menani JV. Synergist interaction between angiotensin II and DOCA on sodium and water balance in rats. Physiol Behav 55: 423-427, 1994. 74. Camargo LA, Saad WA, Netto CR, Gentil CG, Antunes-Rodrigues J, Covian MR. Effects of catecholamines injected into the septal area of the rat brain on natriuresis, kaliuresis and diuresis. Can J Physiol Pharmacol 54: 219-228, 1976. 75. Camargo LA, Saad WA, Silva Neto CR, Antunes-Rodrigues J, Covian MR. Effect of beta-adrenergic stimulation of the septal area on renal excretion of electrolytes and water in the rat. Pharmacol Biochem Behav 11: 141-144, 1979. 76. Carlberg KA, Fregly MJ, Fahey M. Effects of chronic estrogen treatment on water exchange in rats. Am J Physiol Endocrinol Metab 247: E101-E110, 1984. 77. Carlson SH, Beitz A, Osborn JW. Intragastric hypertonic saline increases vasopressin and central Fos immunoreactivity in conscious rats. Am J Physiol Regul Integr Comp Physiol 272: R750-R758, 1997. 78. Carter DA, Murphy D. Rapid changes in poly (A) tail length of vasopressin and oxytocin mRNAs form a common early component of neurohypophyseal peptide gene activation following physiological stimulation. Neuroendocrinol 53: 1-6, 1999. 79. Chai SY, Fernando R, Peck G, Ye SY, Mendelsohn FA, Jenkins TA, Albiston AL. The angiotensin IV/AT4 receptor. Cell Mol Life Sci 61: 2728-2737, 2004. 80. Chapeau C, Gutkowska J, Schiller PW, Milne RW, Thibault G, Garcia R, Genest J, Cantin M. Localization of immunoreactive synthetic atrial natriuretic factor (ANF) in the heart of various animal species. J Histochem Cytochem 33: 541-550, 1985. 81. Chapleau MW, Cunningham JT, Sullivan MJ, Wachtel RE, Abboud FM. Structural versus functional modulation of the arterial baroreflex. Hypertension 26: 341-347, 1995. 82. Chappell MC, Marshall AC, Alzayadneh EM, Shaltout HA, Diz DI. Update on the angiotensin converting enzyme 2-angiotensin (1-7)-Mas receptor axis: Fetal programing, sex differences, and intracellular pathways. Front Endocrinol 4: 201, 2014. 83. Chen S, Li DP, He RR. Effects of microinjection of adenosine into area postrema on heart rate, blood pressure and renal sympathetic nerve activity in rats. Sheng Li Xue Bao 52: 313-317, 2000. 84. Chlebowski RT, Anderson GL. Changing concepts: Menopausal hormone therapy and breast cancer. J Natl Cancer Inst 104: 517-527, 2012. 85. Choe KY, Olson JE, Bourque CW. Taurine release by astrocytes modulates osmosensitive glycine receptor tone and excitability in the adult supraoptic nucleus. J Neurosci 32: 12518-12527, 2012. 86. Choi-Kwon S, Baertschi AJ. Splanchnic osmosensation and vasopressin: Mechanisms and neural pathways. Am J Physiol Endocrinol Metab 261: E18-E25, 1991. 87. Chwalbinska-Moneta J. Role of hepatic portal osmoreception in the control of ADH release. Am J Physiol 236: E603-E609, 1979. 88. Ciura S, Bourque CW. Transient receptor potential vanilloid 1 is required for intrinsic osmoreception in organum vasculosum lamina terminalis neurons and for normal thirst responses to systemic hyperosmolality. J Neurosci 26: 9069-9075, 2006. 89. Ciura S, Liedtke W, Bourque CW. Hypertonicity sensing in organum vasculosum lamina terminalis neurons: A mechanical process involving TRPV1 but not TRPV4. J Neurosci 31: 14669-14676, 2011. 90. Colombari DS, Colombari E, Lopes OU, Cravo SL. Afferent pathways in cardiovascular adjustments induced by volume expansion in anesthetized rats. Am J Physiol Regul Integr Comp Physiol 279: R884-R890, 2000. 91. Colombari DS, Pedrino GR, Freiria-Oliveira AH, Korim WS, Maurino IC, Cravo SL. Lesions of medullary catecholaminergic neurons increase salt intake in rats. Brain Res Bull 76: 572-578, 2008. 92. Contreras R, Stetson P. Changes in salt intake after lesions of the area postrema and the nucleus of the solitary tract in rats. Brain Res 211: 355-366, 1981. 93. Contreras RJ, Kosten T. Prenatal and early postnatal sodium chloride intake modifies the solution preferences on adult rats. J Nutrition 113: 1051-1062, 1983. 94. Contreras RJ, Ryan KW. Perinatal exposure to a high NaCl diet increases the NaCl intake of adult rats. Physiol Behav 47: 507-512, 1990. 95. Convertino VA, Brock PJ, Keil LC, Bernauer EM, Greenleaf JE. Exercise training-induced hypervolemia: Role of plasma albumin, renin, and vasopressin. J Appl Physiol Respir Environ Exerc Physiol 48: 665-669, 1980. 96. Cowen LE, Hodak SP, Verbalis JG. Age-associated abnormalities of water homeostasis. Endocrinol Metab Clin North Am 42: 349-370, 2013. 97. Crosby EC, Woodburne RT. The comparative anatomy of the preoptic area and hypothalamus. Proc Assoc Res Nervous Mental Dis 20: 52169, 1940. 98. Crystal SR, Bernstein IL. Infant salt preference and mother’s morning sickness. Appetite 30: 297-307, 1998.

Volume 5, July 2015


99. 100. 101.

102.

103.

104. 105. 106. 107. 108. 109. 110. 111. 112. 113.

114. 115. 116. 117. 118. 119. 120.

121. 122. 123.

124.

Cunningham JT, Nissen R, Renaud LP. Norepinephrine injections in the diagonal band of Broca selectively reduce the activity of vasopressin supraoptic neurons in the rat. Brain Res 610: 152-155, 1993. Currie MG, Geller DM, Cole BR, Boylan JG, YuSheng W, Holmberg SW, Needleman P. Bioactive cardiac substances: Potent vasorelaxant activity in mammalian atria. Science 221: 71-73, 1983. Curtis KS, Krause EG, Wong DL, Contreras RJ. Gestational and early postnatal dietary NaCl levels affect NaCl intake, but not stimulated water intake, by adult rats. Am J Physiol Regul Integr Comp Physiol 286: R1043-R1050, 2004. Da Silva MP, Merino RM, Mecawi AS, Moraes DJ, Varanda WA. In vitro differentiation between oxytocin- and vasopressin-secreting magnocellular neurons requires more than one experimental criterion. Mol Cell Endocrinol. 400: 102-111, 2015. Da Silva RK, Menani JV, Saad WA, Renzi A, Silveira JE, Luiz AC, Camargo LA. Role of the alpha 1-, and alpha 2- and beta-adrenoceptors of the median preoptic area on the water intake, renal excretion, and arterial pressure induced by ANG II. Brain Res 717: 38-43, 1996. Dainty J, House CR. An examination of the evidence for membrane pores in frog skin. J Physiol 185: 172-184, 1966. Dalmasso C, Amigone JL, Vivas L. Serotonergic system involvement in the inhibitory action of estrogen on induced sodium appetite in female rats. Physiol Behav 104: 398-407, 2011. Daniels D, Mietlicki EG, Nowak EL, Fluharty SJ. Angiotensin II stimulates water and NaCl intake through separate cell signaling pathways in rats. Exp Physiol 94: 130-137, 2009. Daniels D, Yee DK, Faulconbridge LF, Fluharty SJ. Divergent behavioral roles of angiotensin receptor intracellular signaling cascades. Endocrinol 146: 5552- 5560, 2005. Daniels-Severs A, Ogden E, Vernikos-Danellis J. Centrally mediated effects of angiotensin II in the unanesthetized rat. Physiol Behav 7: 785-787, 1971. Dantzler WH. Comparative Physiology of the Kidney. Compr Physiol 2011, Supplement 25: Handbook of Physiology, Renal Physiology: 415-474. First published in print 1992. Doi: 10.1002/cphy.cp080111. Davies I, O’Neill PA, McLean KA, Catania J, Bennett D. Ageassociated alterations in thirst and arginine vasopressin in response to a water or sodium load. Age Ageing 24: 151-159, 1995. Davis JO, Freeman RH. Mechanisms regulating renin release. Physiol Ver 56: 1-56, 1976. Davisson RL, Oliverio MI, Coffman TM, Sigmund CD. Divergent functions of angiotensin II receptor isoforms in the brain. J Clin Invest 106: 103-106, 2000. Dawson CA, Jhamandas JH, Krukoff TL. Activation by systemic angiotensin II of neurochemically identified neurons in rat hypothalamic paraventricular nucleus. J Neuroendocrinol 10: 453-459, 1998. Dawson DC. Water Transport in the Kidney: Physiology and Pathophysiology. New York: Raven Press LTd, 1992. Day TA, Sibbald JR. Direct catecholaminergic projection from nucleus tractus solitarii to supraoptic nucleus. Brain Res 454: 387-392, 1988. Day TA, Sibbald JR, Smith DW. A1 neurons and excitatory amino acid receptors in rat caudal medulla mediate vagal excitation of supraoptic vasopressin cells. Brain Res 594: 244-252, 1992. De Bold AJ, Borenstein HB, Veress AT, Sonnenberg H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci 28: 89-94, 1981. De Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T. International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 52: 415-472, 2000. De Keyzer Y, Auzan C, Lenne F, Beldjord C, Thibonnier M, Bertagna X, Clauser E. Cloning and characterization of the human V3 pituitary vasopressin receptor. FEBS Lett 356: 215-220, 1994. De Magalhães-Nunes AP, Badauê-Passos D Jr, Ventura RR, Guedes Dda S Jr, Araújo JP, Granadeiro PC, Milanez-Barbosa HK, da Costa-eSousa RH, de Medeiros MA, Antunes-Rodrigues J, Reis LC. Sertraline, a selective serotonin reuptake inhibitor, affects thirst, salt appetite and plasma levels of oxytocin and vasopressin in rats. Exp Physiol 92: 913-922, 2007. De Nicola AF, Grillo C, González S. Physiological, biochemical and molecular mechanisms of salt appetite control by mineralocorticoid action in brain. Braz J Med Biol Res 25: 1153-1162, 1992. De Wardener HE, Clarkson EL. Natriuretic hormone. In: Seldin DW, Giebisch G, editors. The Kidney: Physiology and Pathophysiology. New York: Raven, 1985, pp. 1013-1031. Dean SA, Tan J, White R, O’Brien ER, Leenen FH. Regulation of components of the brain and cardiac renin-angiotensin systems by 17betaestradiol after myocardial infarction in female rats. Am J Physiol Regul Integr Comp Physiol 291: R155-R162, 2006. Deen PM, Verdijk MA, Knoers NV, Wieringa B, Monnens LA, Van Os CH, Van Oost BA. Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine. Science 264: 92-95, 1994.

Volume 5, July 2015


125. Deleuze C, Alonso G, Lefevre IA, Duvoid-Guillou A, Hussy N. Extrasynaptic localization of glycine receptors in the rat supraoptic nucleus: Further evidence for their involvement in glia-to-neuron communication. Neuroscience 133: 175-183, 2005. 126. Deleuze C, Duvoid A, Hussy N. Properties and glial origin of osmoticdependent release of taurine from the rat supraoptic nucleus. J Physiol 507: 463-471, 1998. 127. Denton D, Shade R, Zamarippa F, Egan G, Blair-West J, McKinley M, Fox P. Correlation of regional cerebral blood flow and change of plasma sodium concentration during genesis and satiation of thirst. Proc Natl Acad Sci U S A 96: 2532-2537, 1999. 128. Deschepper CF, Bouhnik J, and Ganong WF. Colocalization of angiotensinogen and glial fibrillary acidic protein in astrocytes in rat brain. Brain Res 374: 195-198, 1986. 129. Donald JA, Trajanovska S. A perspective on the role of natriuretic peptides in amphibian osmoregulation. Gen Comp Endocrinol 147: 47-53, 2006. 130. Dourish CT, Duggan JA, Banks RJA. Drinking induced by subcutaneous injection of angiotensin II in the rat is blocked by selective AT1 receptor antagonist DuP 753 but not by the selective AT2 receptor antagonist WL 19. Eur J Pharmacol 211: 113-116, 1992. 131. Dow-Edwards DL, Trachtman H, Riley EP, Freed LA, Milhorat TH. Arginine vasopressin and body fluid homeostasis in the fetal alcohol exposed rat. Alcohol 6: 193-198, 1989. 132. D’Souza SP, Davis M, Baxter GF. Autocrine and paracrine actions of natriuretic peptides in the heart. Pharmacol Ther 101: 113-129, 2004. 133. Duan YF, Winters W, MCcabe PM, Schneiderman EN. Cardiorespiratory components of the defense reaction elicited from the paraventricular nucleus. Physiol Behav 61: 325-330, 1997. 134. Dyball REJ, Kemplay SK. Dendritic trees of neurones in the rat supraoptic nucleus. Neuroscience 7: 223-230, 1982. 135. Edwards G, Beltzs T, Power J, Johnson Ak. Rapid-onset “need-free” sodium appetite after lesions of the dorsomedial medulla. Am J Physiol Regul Integr Comp Physiol 264: R1242-R1247, 1993. 136. Edwards GL, Johnson AK. Enhanced drinking after excitotoxic lesions of the parabrachial nucleus in the rat. Am J Physiol Regul Integr Comp Physiol 261: R1039-R1044, 1991. 137. Egan G, Silk T, Zamarripa F, Williams J, Federico P, Cunnington R, Carabott L, Blair-West J, Shade R, McKinley M, Farrell M, Lancaster J, Jackson G, Fox P, Denton D. Neural correlates of the emergence of consciousness of thirst. Proc Natl Acad Sci U S A 100: 15241-15246, 2003. 138. Elias LLK, Dorival-Campos A, Moreira AC. The opposite effects of short- and long-term salt loading on pituitary adrenal axis activity in rats. Horm Metab Res 34: 207-211, 2002. 139. Eng R, Miselis RR. Polydipsia and abolition of angiotensin induced drinking after transections of subfornical organ efferent projections in the rat. Brain Res 225: 200-206, 1981. 140. Epstein AN, Fitzsimons JT, Simons BJ. Drinking caused by the intracranial injection of angiotensin into the rat. J Physiol 200: 98-100, 1969. 141. Eriksson L, Fernández O, Olsson K. Differences in the antidiuretic response to intracarotid infusions of various hypertonic solutions in the conscious goat. Acta Physiol Scand 83: 554-562, 1971. 142. Fallo F. Renin-angiotensin-aldosterone system and physical exercise. J Sports Med Phys Fitness 33: 306-312, 1993. 143. Favaretto AL, Ballejo GO, Albuquerque-Araújo WI, Gutkowska J, Antunes-Rodrigues J, McCann SM. Oxytocin releases atrial natriuretic peptide from rat atria in vitro that exerts negative inotropic and chronotropic action. Peptides 18: 1377-1381, 1997. 144. Feil R, Lohmann SM, de Jonge H, Walter U, Hofmann F. Cyclic GMPdependent protein kinases and the cardiovascular system: Insights from genetically modified mice. Circ Res 93: 907-916, 2003. 145. Felgendreger LA, Fluharty SJ, Yee DK, Flanagan-Cato LM. Endogenous angiotensin II-induced p44/42 mitogen-activated protein kinase activation mediates sodium appetite but not thirst or neurohypophysial secretion in male rats. J Neuroendocrinol 25: 97-106, 2013. 146. Feng Y, Xia H, Cai Y, Halabi CM, Becker LK, Santos RA, Speth RC, Sigmund CD, Lazartigues E. Brain-selective overexpression of human Angiotensin-converting enzyme type 2 attenuates neurogenic hypertension. Circ Res 106: 373-382, 2010. 147. Feng Y, Yue X, Xia H, Bindom SM, Hickman PJ, Filipeanu CM, Wu G, Lazartigues E. Angiotensin-converting enzyme 2 overexpression in the subfornical organ prevents the angiotensin II-mediated pressor and drinking responses and is associated with angiotensin II type 1 receptor downregulation. Circ Res 102: 729-736, 2008. 148. Ferrario CM, Chappell MD. Novel angiotensin peptides. Cell Mol Life Sci 61: 2720-2727, 2004. 149. Ferris CF, Melloni RH Jr, Koppel G, Perry KW, Fuller RW, Delville Y. Vasopressin/serotonin interactions in the anterior hypothalamus control aggressive behavior in golden hamsters. J Neurosci 17: 4331-4340, 1997.

1509


150. Finkelstein A. Water Movement through Lipid Bilayers, Pores and Plasma Membrane: Theory and Reality. New Jersey: Wiley Interscience, 1987. 151. Finkelstein A, Andersen OS. The gramicidin A channel: A review of its permeability characteristics with special reference to the single-file aspect of transport. J Membr Biol 59: 155-171, 1981. 152. Fisher C, Ingrand WR, and Ranson S. Relation of hypothalamohypophyseal system to diabetes insipidus. Arch Neurol Psychiat 34: 124163, 1935. 153. Fitts DA, Starbuck EM, Ruhf A. Circumventricular organs and ANG II-induced salt appetite: Blood pressure and connectivity. Am J Physiol Regul Integr Comp Physiol 279: R2277-R2286, 2000. 154. Fitzsimons JT. Angiotensin, thirst, and sodium appetite. Physiol Rev 78: 583-686, 1998. 155. Fluharty SJ, Epstein AN. Sodium appetite elicited by intracerebroventricular infusion of angiotensin II in the rat: II. Synergistic interaction with systemic mineralocorticoids. Behav Neurosci 97: 746-758, 1983. 156. Flynn TG, de Bold ML, de Bold AJ. The amino acid sequence of an atrial peptide with potent diuretic and natriuretic properties. Biochem Biophys Res Commun 117: 859-865, 1983. 157. Fonseca, FV, Mecawi AS, Araujo IG, Almeida-Pereira G, MagalhãesNunes AP, Badauê-Passos D Jr, Reis LC. Role of the 5-HT1A somatodendritic autoreceptor in the dorsal raphe nucleus on salt satiety signaling in rats. Exp Neurol 217: 353-360, 2009. 158. Ford LP, Bagga PS, Wilusz J. The poly(A) tail inhibits the assembly of a 3′ -to-5′ exonuclease in an in vitro RNA stability system. Mol Cell Biol 17: 398-406, 1997. 159. Forssmann WG, Hock D, Lottspeich F, Henschen A, Kreye V, Christmann M, Reinecke M, Metz J, Carlquist M, Mutt V. The right auricle of the heart is an endocrine organ. Cardiodilatin as a peptide hormone candidate. Anat Embryol (Berl) 168: 307-313, 1983. 160. Francescato HD, Marin EC, Cunha F de Q, Costa RS, Silva CG, Coimbra TM. Role of endogenous hydrogen sulfide on renal damage induced by adriamycin injection. Arch Toxicol 85: 1597-1606, 2011. 161. Franchini LF, Johnson AK, de Olmos J, Vivas L. Sodium appetite and Fos activation in serotonergic neurons. Am J Physiol Regul Integr Comp Physiol 282: R235-R243, 2002. 162. Freund-Mercier MJ, Stoeckel ME, Klein MJ. Oxytocin receptors on oxytocin neurones: Histoautoradiographic detection in the lactating rat. J Physiol 480: 155-161, 1994. 163. Frolkis VV, Golovchenko SF, Medved VI, Frolkis RA. Vasopressin and cardiovascular system in aging. Gerontology 28: 290-302, 1982. 164. Fry M, Ferguson AV. The sensory circumventricular organs: Brain targets for circulating signals controlling ingestive behavior. Physiol Behav 91: 413-423, 2007. 165. Funder JW, Pearce PT, Smith R, Smith AI. Mineralocorticoid action: Target tissue specificity is enzyme, not receptor, mediated. Science 242: 583-585, 1988. 166. Fuxe K, Ganten D, Hokfelt T, and Bolme P. Immunohistochemical evidence for the existence of angiotensin II-containing nerve terminals in the brain and spinal cord in the rat. Neurosci Lett 2: 229-234, 1976. 167. Galaverna O, Nicola¨ıdis S, Yao SZ, Sakai RR, Epstein AN. Endocrine consequences of prenatal sodium depletion prepare rats for high needfree NaCl intake in adulthood. Am J Physiol Regul Integr Comp Physiol 269: R578-R583, 1995. 168. Ganten D, Marquez-Julio KP, Granger P, Haydul K, Karsunky KP, Boucher R, Genest J. Renin in dog brain. Am J Physiol 221: 17331737, 1971. 169. Geerling JC, Engeland WC, Kawata M, Loewy AD. Aldosterone target neurons in the nucleus tractus solitaries drive sodium appetite. J Neurosci 26: 411-417, 2006a. 170. Geerling JC, Loewy AD. Aldosterone-sensitive neurons in the nucleus of the solitary tract: Bidirectional connections with the central nucleus of the amygdala. J Comp Neurol 497: 646-657, 2006b. 171. Gilbey MP, Spyer KM. Essential organization of the sympathetic nervous system. Baillieres Clin Endocrinol Metab 7: 259-278, 1993. 172. Godino A, De Luca LA Jr, Antunes-Rodrigues J, Vivas L. Oxytocinergic and serotonergic systems involvement in sodium intake regulation: Satiety or hypertonicity markers? Am J Physiol Regul Integr Comp Physiol 293: R1027-R1036, 2007. 173. Godino A, Giusti-Paiva A, Antunes-Rodrigues J, Vivas L. Neurochemical brain groups activated after an isotonic blood volume expansion in rats. Neuroscience 133: 493-505, 2005. 174. Goldstein DL. Regulation of the avian kidney by arginine vasotocin. Gen Comp Endocrinol 147: 78-84, 2006. 175. Goligorsky MS, Iijima K, Krivenko Y, Tsukahara H, Hu Y, Moore LC. Role of mesangial cells in macula densa to afferent arteriole information transfer. Clin Exp Pharmacol Physiol 24: 527-531, 1997. 176. Gomes DA, Giusti-Paiva A, Ventura RR, Elias LL, Cunha FQ, Antunes-Rodrigues J. Carbon monoxide and nitric oxide modulate hyperosmolality-induced oxytocin secretion by the hypothalamus in vitro. Biosci Rep 30: 351-357, 2010.

1510


177. Gomes DA, Reis WL, Ventura RR, Giusti-Paiva A, Elias LL, Cunha FQ, Antunes-Rodrigues J. The role of carbon monoxide and nitric oxide in hyperosmolality-induced atrial natriuretic peptide release by hypothalamus in vitro. Brain Res 1016: 33-39, 2004. 178. Gona O. Uptake of 11sI-labelled prolactin by bullfrog kidney tubules: An autoradiographic study. J Endocrinol 93: 133-138, 1982. 179. Gonen T, Walz T. The structure of aquaporins. Q Rev Biophys 39: 361-396, 2006. 180. Goodwin LR, Francom D, Dieken FP, Taylor JD, Warenycia MW, Reiffenstein RJ, Dowling G. Determination of sulfide in brain tissue by gas dialysis/ion chromatography: Postmortemstudies and two case reports. J Anal Toxicol 13: 105-109, 1989. 181. Gordon GR, Baimoukhametova DV, Hewitt SA, Rajapaksha WR, Fisher TE, Bains JS. Norepinephrine triggers release of glial ATP to increase postsynaptic efficacy. Nat Neurosci 8: 1078-1086, 2005. 182. Goudsmit E, Fliers E, Swaab DF. Vasopressin and oxytocin excretion in the Brown-Norway rat in relation to aging, water metabolism and testosterone. Mech Ageing Dev 44: 241-252, 1988. 183. Gould GW. History of science-spores. J Appl Microbiol 101: 507-513, 2006. 184. Gouzènes L, Desarménien MG, Hussy N, Richard P, Moos FC. Vasopressin regularizes the phasic firing pattern of rat hypothalamic magnocellular vasopressin neurons. J Neurosci 18: 1879-1885, 1998. 185. Gray DA. Role of endogenous atrial natriuretic peptide in volume expansion diuresis and natriuresis of the Pekin duck. J Endocrinol 140: 85-90, 1994. 186. Greenwood M, Bordieri L, Greenwood MP, Rosso Melo M, Colombari DS, Colombari E, Paton JF, Murphy D. Transcription factor CREB3L1 regulates vasopressin gene expression in the rat hypothalamus. J Neurosci 34: 3810-3820, 2014. 187. Grindstaff RJ, Grindstaff RR, Sullivan MJ, Cunningham JT. Role of the locus ceruleus in baroreceptor regulation of supraoptic vasopressin neurons in the rat. Am J Physiol Heart Circ Physiol 279: H306-H319, 2000. 188. Grindstaff RR, Cunningham JT. Lesion of the perinuclear zone attenuates cardiac sensitivity of vasopressinergic supraoptic neurons. Am J Physiol Regul Integr Comp Physiol 280: R630-R638, 2001. 189. Grossman SP. Eating or drinking elicited by direct adrenergic or cholinergic stimulation of hypothalamus. Science 132: 301-302, 1960. 190. Guardabassi A, Muccioli G, Andreoletti GE, Pattono P, Usai P. Prolactin and interrenal hormone balance in adult specimens of Xenopus laevis exposed to hyperosmotic stress for up to one week. J Exp Zool 265: 515-521, 1993. 191. Gutman MB, Ciriello J, Mogenson GJ. Effects of plasma angiotensin II and hypernatremia on subfornical organ neurones. Am J Physiol 254: R746-R754, 1988. 192. Haanwinckel MA, Elias LK, Favaretto AL, Gutkowska J, McCann SM, Antunes-Rodrigues J. Oxytocin mediates atrial natriuretic peptide release and natriuresis after volume expansion in the rat. Proc Natl Acad Sci U S A 92: 7902-7906, 1995. 193. Haberich FJ. Osmoreception in the portal circulation. Fed Proc 27: 1137-1141. 1968. 194. Hammel HT, Scholander PF. Osmosis and Tensile Solvent. New York: Springer-Verlag, 1976. 195. Hammel HT. Forum on osmosis. I. Osmosis: Diminished solvent activity or enhanced solvent tension? Am J Physiol 237: R95-R107, 1979. 196. Handa RK, Johns EJ. Interaction of the renin-angiotensin system and the renal nerves in the regulation of rat kidney function. J Physiol 369: 311-321, 1985. 197. Handa RK, Johns EJ. The role of angiotensin II in the renal responses to somatic nerve stimulation in the rat. J Physiol 393: 425-436, 1987. 198. Healy DP, Printz MP. Distribution of immunoreactive angiotensin II, angiotensin I, angiotensinogen and renin in the central nervous system of intact and nephrectomized rats. Hypertension 6: 130-136, 1984. 199. Henderson IW. Endocrinology of the vertebrates. Compr Physiol 2011, Supplement 30: Handbook of Physiology, Comparative Physiology: 623-749. First published in print 1997. Doi: 10.1002/cphy.cp130110. 200. Henry JP, Gauer OH, Reeves JL. Evidence of the atrial location of receptors influencing urine flow. Circ Res 4: 85-90, 1956. 201. Hernando F, Schoots O, Lolait SJ, Burbach JP. Immunohistochemical localization of the vasopressin V1b receptor in the rat brain and pituitary gland: Anatomical support for its involvement in the central effects of vasopressin. Endocrinol 142: 1659-1668, 2001. 202. Hildebrand JH. Osmotic pressure. Science 12: 116-119, 1955. 203. Hildebrand JH. Forum on osmosis. II. A criticism of “solvent tension” in osmosis. Am J Physiol 237: R108-R109, 1979. 204. Hindmarch C, Fry M, Yao ST, Smith PM, Murphy D, Ferguson AV. Microarray analysis of the transcriptome of the subfornical organ in the rat: Regulation by fluid and food deprivation. Am J Physiol Regul Integr Comp Physiol 295: R1914-R1920, 2008. 205. Hindmarch C, Yao S, Beighton G, Paton J, Murphy D. A comprehensive description of the transcriptome of the hypothalamoneurohypophyseal

Volume 5, July 2015


206.

207.

208. 209.

210. 211. 212. 213. 214.

215. 216. 217. 218. 219. 220. 221.

222. 223. 224. 225. 226.

227. 228. 229. 230. 231.

system in euhydrated and dehydrated rats. Proc Natl Acad Sci U S A 103: 1609-1614, 2006. Hindmarch CC, Fry M, Smith PM, Yao ST, Hazell GG, Lolait SJ, Paton JF, Ferguson AV, Murphy D. The transcriptome of the medullary area postrema: The thirsty rat, the hungry rat and the hypertensive rat. Exp Physiol 96: 495-504, 2011. Hirasawa M, Schwab Y, Natah S, Hillard CJ, Mackie K, Sharkey KA, Pittman QJ. Dendritically released transmitters cooperate via autocrine and retrograde actions to inhibit afferent excitation in rat brain. J Physiol 559: 611-624, 2004. Hisa H. Control mechanisms of renal functions: Effects of cardiovascular drugs on vasoconstrictive and antinatriuretic stimuli in the in vivo kidney. Yakugaku Zasshi 120: 1395-1407, 2000. Hiyama TY, Watanabe E, Okado H, Noda M. The subfornical organ is the primary locus of sodium-level sensing by Na(x) sodium channels for the control of salt-intake behavior. J Neurosci 24: 9276-9281, 2004. Hohle S, Blume A, Lebrun C, Culman J, Unger T. Angiotensin receptors in the brain. Pharmacol Toxicol 77: 306-315, 1995. Hoogendijk JE, Fliers E, Swaab DF, Verwer RW. Activation of vasopressin neurons in the human supraoptic and paraventricular nucleus in senescence and senile dementia. J Neurol Sci 69: 291-299, 1985. Houseley J, LaCava J, Tollervey D. RNA-quality control by the exosome. Nat Ver Mol Cell Biol 7: 529-539, 2006. Houssay BA, Fasciolo JC. Demostración del mecanismo humoral de la hipertensión nefrógena. Bol Acad Nac Med 18: 342-344, 1937. Hrabovszky E, Kallo I, Steinhauser A, Merchenthaler I, Coen CW, Petersen SL, Liposits Z. Estrogen receptor-beta in oxytocin and vasopressin neurons of the rat and human hypothalamus: Immunocytochemical and in situ hybridization studies. J Comp Neurol 473: 315-333, 2004. Hu Y, Ma N, Yang M, Semba R. Expression and distribution of heme oxygenase-2 mRNA and protein in rat kidney. J Histochem Cytochem 46: 249-256, 1998. Huang W, Sved AF, Stricker EM. Vasopressin and oxytocin release evoked by NaCl loads are selectively blunted by area postrema lesions. Am J Physiol Regul Integr Comp Physiol 278: R732-R740, 2000a. Huang W, Sved AF, Stricker EM. Water ingestion provides an early signal inhibiting osmotically stimulated vasopressin secretion in rats. Am J Physiol Regul Integr Comp Physiol 279: R756-R760, 2000b. Hui P, Rui C, Liu Y, Xu F, Wu J, Wu L, Chen Y, Liao J, Mao C, Xu Z. Remodeled salt appetite in rat offspring by perinatal exposure to nicotine. Appetite 52: 492-497, 2009. Hunyady L, Catt KJ. Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II. Mol Endocrinol 20: 953-970, 2006. Hussy N, Deleuze C, Brès V, Moos FC. New role of taurine as an osmomediator between glial cells and neurons in the rat supraoptic nucleus. Adv Exp Med Biol 483: 227-237, 2000. Hussy N, Deleuze C, Pantaloni A, Desarmenien MG, Moos F. Agonist action of taurine on glycine receptors in rat supraoptic magnocellular neurones: Possible role in osmoregulation. J Physiol 502: 609-621, 1997. Iovino M, Steardo L. Effect of substances influencing brain serotonergic transmission on plasma vasopressin levels in the rat. Eur J Pharmacol 113: 99-103, 1985. Jackson KE, Jackson DW, Quadri S, Reitzell MJ, Navar LG. Inhibition of heme oxygenase augments tubular sodium reabsorption. Am J Physiol Renal Physiol 300: F941-F946, 2011. Jamieson JD, Palade GE. Specific granules in atrial muscle cells. J Cell Biol 23: 151-172, 1964. Jankowski M, Hajjar F, Kawas SA, Mukaddam-Daher S, Hoffman G, McCann SM, Gutkowska J. Rat heart: A site of oxytocin production and action. Proc Natl Acad Sci U S A 95: 14558-14563, 1998. Jhamandas JH, Harris KH, Krukoff TL. Parabrachial nucleus projection towards the hypothalamic supraoptic nucleus: Electrophysiological and anatomical observations in the rat. J Comp Neurol 308: 42-50, 1991. Jhamandas JH, Harris KH, Petrov T, Krukoff TL. Characterization of the parabrachial nucleus input to the hypothalamic paraventricular nucleus in the rat. J Neuroendocrinol 4: 461-471, 1992. Jhamandas JH, Renaud LP. A gamma-aminobutyric-acid-mediated baroreceptor input to supraoptic vasopressin neurones in the rat. J Physiol 381: 595-606, 1986a. Jhamandas JH, Renaud LP. Diagonal band neurons may mediate arterial baroreceptor input to hypothalamic vasopressin-secreting neurons. Neurosci Lett 65: 214-248, 1986b. Johns EJ, Kopp UC, Di Bona GF. Neural Control of Renal Function. Compr Physiol 1: 731-767, 2011. Johnson AK, Edwards GL. Central projections of osmotic and hypovolaemic signals in homeostatic thirst. In: Ramsay DJ, Booth DA, editors. Thirst: Physiological and Psychological Aspects. London: Springer-Verlag, 1991, pp. 149-175.

Volume 5, July 2015


232. Johnson AK, Thunhorst RL. Sensory mechanisms in the behavioral control of body fluid balance: Thirst and salt appetite. Prog Psychobiol Physiol Psychol 16: 145-176, 1995. 233. Johren O, Imboden H, Hauser W, Maye I, Sanvitto GL, Saavedra JM. Localization of angiotensin-converting enzyme, angiotensin II, angiotensin II receptor subtypes, and vasopressin in the mouse hypothalamus. Brain Res 757: 218-227, 1997. 234. Jørgensen HS. Studies on the neuroendocrine role of serotonin. Dan Med Bull 54: 266-288, 2007. 235. Kadekaro M and Summy-Long JY. Centrally produced nitric oxide and the regulation of body fluid and blood pressure homeostasis. Clin Exp Pharmacol Physiol 27: 450-459, 2000. 236. Karjalainen AH, Ruskoaho H, Vuolteenaho O, Heikkinen JE, Bäckström AC, Savolainen MJ, Kesäniemi YA. Effects of estrogen replacement therapy on natriuretic peptides and blood pressure. Maturitas 47: 201-208, 2004. 237. Kaschina E, Unger T. Angiotensin AT1/AT2 receptors: Regulation, signalling and function. Blood Press 12: 70-88, 2003. 238. Katchalsky A, Curran PF. Nonequilibrium Thermodynamics in Biophysics. Cambridge: Harvard University Press, 1975. 239. Kill F. Mechanism of osmosis. Kidney Int 21: 303-308, 1982. 240. Kimura T, Funyu T, Ohta M, Yamamoto T, Ota K, Shoji M, Inoue M, Sato K, Abe K. The role of GABA in the central regulation of AVP and ANP release and blood pressure due to angiotensin and carbachol, and central GABA release due to blood pressure changes. J Auton Nerv Syst 50: 21-29, 1994. 241. Kimura Y, Kimura H. Hydrogen sulfide protects neurons from oxidative stress. FASEB J 18: 1165-1167, 2004. 242. Kisch B. Electron microscopy of the atrium of the heart. I. Guinea pig. Exp Med Surg 14: 99-112, 1956. 243. Kiss JZ, Mezey E, Skirboll L. Corticotrophin-releasing factor immunoreactive neurons of the paraventricular nucleus become vasopressin-positive after adrenalectomy. Proc Natl Acad Sci U S A 81: 1854-1858, 1984. 244. Kitami Y, Okura T, Marumoto K, Wakamiya R, Hiwada K. Differential gene expression and regulation of type-1 angiotensin II receptor subtypes in the rat. Biochem Biophys Res Commun 188: 446-452, 1992. 245. Kobashi M, Adachi A. Effect of portal infusion of hypertonic saline on neurons in the dorsal motor nucleus of the vagus in the rat. Brain Res 632: 174-179, 1993. 246. Koeppen BM, Stanton BA. Regulation of body fluid osmolality: Regulation of water balance. In: Koeppen BM, Stanton BA, editors. Renal Physiology. Philadelphia: Elsevier, 2013, p. 79. 247. Kohlstaedt KG, Helmer OM, Page IH, Activation of renin by blood colloids. Proc Soc Exp Biol Med 39: 214-215, 1938. 248. Kondo N, Arima H, Banno R, Kuwahara S, Sato I, Oiso Y. Osmoregulation of vasopressin release and gene transcription under acute and chronic hypovolemia in rats. Am J Physiol Endocrinol Metab 286: E337-E346, 2004. 249. Kostoglou-Athanassiou I, Forsling ML, Navarra P, Grossman AB. Oxytocin release is inhibited by the generation of carbon monoxide as a neuromodulator. Mol Brain Res 42: 301-306, 1996. 250. Kramar EA, Harding JW, Wright JW. Angiotensin II- and IV-induced changes in cerebral blood flow roles of AT1, AT2, and AT4 receptor subtypes. Regul Pept 68: 131-138, 1997. 251. Krause EG, Curtis KS, Davis LM, Stowe JR, Contreras RJ. Estrogen influences stimulated water intake by ovariectomized female rats. Physiol Behav 79: 267-274, 2003. 252. Kulczykowska E. Response of circulating arginine vasotocin and isotocin to rapid osmotic challenge in rainbow trout. Comp Biochem Physiol A 118: 773-778, 1997. 253. Kumagai H, Oshima N, Matsuura T, Iigaya K, Imai M, Onimaru H, Sakata K, Osaka M, Onami T, Takimoto C, Kamayachi T, Itoh H, Saruta T. Importance of rostral ventrolateral medulla neurons in determining efferent sympathetic nerve activity and blood pressure. Hypertens Res 35: 132-141, 2012. 254. Kurl S, Laukkanen JA, Rauramaa R, Lakka TA, Sivenius J, Salonen JT. Systolic blood pressure response to exercise stress test and risk of stroke. Stroke 32: 2036-2041, 2001. 255. Kurtz A. Control of renin synthesis and secretion. Am J Hypertens 25: 839-847, 2012. 256. Lang RE, Heil JW, Ganten D, Hermann K, Unger T, Rascher W. Oxytocin unlike vasopressin is a stress hormone in the rat. Neuroendocrinol 37: 314-316, 1983. 257. Langley-Evans SC, Jackson AA. Rats with hypertension induced by in utero exposure to maternal low-protein diets fail to increase blood pressure in response to a high salt intake. Ann Nutr Metab 40: 1-9, 1996. 258. Langley-Evans SC, Welham SJ, Jackson AA. Fetal exposure to a maternal low protein diet impairs nephrogenesis and promotes hypertension in the rat. Life Sci 64: 965-974, 1999. 259. Laragh JH, Angers M, Kelly WG, Liebermann S. Hypotensive agents and pressor substances. The effect of epinephrine, norepinephrine,

1511


260.

261.

262.

263. 264. 265.

266. 267. 268.

269. 270. 271. 272. 273. 274.

275. 276. 277. 278.

279. 280. 281. 282.

283. 284. 285.

angiotensin II and others on the secretory rate of aldosterone in man. JAMA 174: 234-240, 1960. Larsen PJ, Hay-Schmidt A, Vrang N, Mikkelsen JD. Origin of projections from the midbrain raphe nuclei to the hypothalamic paraventricular nucleus in the rat: A combined retrograde and anterograde tracing study. Neuroscience 70: 963-988, 1996. Larsen PJ, Moller M, Mikkelsen JD. Efferent projections from the periventricular and medial parvicellular subnuclei of the hypothalamic paraventricular nucleus to circumventricular organs of the rat: A Phaseolus vulgaris-leucoagglutinin (PHA-L) tracing study. J Comp Neurol 306: 462-479, 1991. Lechner SG, Markworth S, Poole K, Smith ES, Lapatsina L, Frahm S, May M, Pischke S, Suzuki M, Ibañez-Tallon I, Luft FC, Jordan J, Lewin GR. The molecular and cellular identity of peripheral osmoreceptors. Neuron 69: 332-344, 2011. Leloir LF, Muñoz JM, Braun-Menéndez E, Fasciolo JC. La secreción de la renina y la formación de hipertensina. Rev Soc Arg Biol 16: 75-80, 1940. Leng G, Brown CH, Russell JA. Physiological pathways regulating the activity of magnocellular neurosecretory cells. Prog Neurobiol 57: 625-655, 1999. Lenkei Z, Palkovits M, Corvol P, Llorens-Cortès C. Expression of angiotensin type-1 (AT1) and type-2 (AT2) receptor mRNAs in the adult rat brain: A functional neuroanatomical review. Front Neuroendocrinol 18: 383-439, 1997. Leshem M, Maroun M, Del Canho S. Sodium depletion and maternal separation in the suckling rat increase its salt intake when adult. Physiol Behav 59: 199-204, 1996. Lewicki JA, Fallon JH, and Printz MP. Regional distribution of angiotensinogen in rat brain. Brain Res 158: 359-371, 1978. Liedtke W, Choe Y, Marti-Renom MA, Bell AM, Denis CS, Sali A, Hudspeth AJ, Friedman JM, Heller S. Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103: 525-535, 2000. Lind RW. Bi-directional, chemically specified neural connections between the subfornical organ and the midbrain raphe system. Brain Res 384: 250-261, 1986. Lind RW. Angiotensin and the lamina terminalis: Illustrations of a complex unity. Clin Exp Hypertens A 10: 79-105, 1988. Lind RW, Johnson AK. Subfornical organ-median preoptic connections and drinking and pressor responses to angiotensin II. J Neurosci 2: 1043-1051, 1982. Lind RW, Swanson LW, Ganten D. Organization of angiotensin II immunoreactive cells and fibers in the rat central nervous system. An immunohistochemical study. Neuroendocrinol 40: 2-24, 1985. Lippoldt A, Fuxe K, and Luft FC. A view of renin in the brain. J Mol Med 79: 71-73, 2001. Liu F, Lei T, Bankir L, Zhao D, Gai X, Zhao X, Yang B. Erythrocyte permeability to urea and water: Comparative study in rodents, ruminants, carnivores, humans, and birds. J Comp Physiol B 181: 65-72, 2011. Liu FY, Cogan MG. Atrial natriuretic factor does not inhibit basal or angiotensin II-stimulated proximal transport. Am J Physiol 255: 434437, 1988. Lucassen PJ, Salehi A, Pool CW, Gonatas NK, Swaab DF. Activation of vasopressin neurons in aging and Alzheimer’s disease. J Neuroendocrinol 6: 673-679, 1994. Ma LY, McEwen BS, Sakai RR, Schulkin J. Glucocorticoids facilitate mineralocorticoid-induced sodium intake in the rat. Horm Behav 27: 240-250, 1993. Macchione AF, Caeiro XE, Godino A, Amigone JL, AntunesRodrigues J, Vivas L. Availability of a rich source of sodium during the perinatal period programs the fluid balance restoration pattern in adult offspring. Physiol Behav 105: 1035-1044, 2012. Macey RI, Farmer REL. Inhibition of water and solute permeability in human red cells. Biochim Biophys Acta 211: 104-106, 1970. Macey RI. Transport of water and urea in red blood cells. Am J Physiol 246: C195-C203, 1984. Mack GW, Weseman CA, Langhans GW, Scherzer H, Gillen CM, Nadel ER. Body fluid balance in dehydrated healthy older men: Thirst and renal osmoregulation. J Appl Physiol 76: 1615-1623, 1994. Mahon JM, Allen M, Herbert J, Fitzsimons JT. The association of thirst, sodium appetite and vasopressin release with c-fos expression in the forebrain of the rat after intracerebroventricular injection of angiotensin II, angiotensin-(1-7) or carbachol. Neuroscience 69: 199-208, 1995. Maines MD. The heme oxygenase system: A regulator of second messenger gases. Annu Rev Pharmacol Toxicol 37: 517-554, 1997. Mancuso C. Heme oxygenase and its products in the nervous system. Antioxid Redox Signal 6: 878-887, 2004. Mancuso C, Kostoglou-Athanassiou I, Forsiling ML, Grossman AB, Preziosi P, Navarra P, Minotti G. Activation of heme oxygenase and consequent carbon monoxide formation inhibits the release of arginine vasopressin from rat hypothalamic explants. Molecular linkage between

1512


286. 287. 288. 289. 290. 291. 292. 293. 294.

295. 296. 297. 298.

299. 300. 301. 302.

303.

304. 305. 306.

307. 308. 309.

310.

311.

heme catabolism and neuroendocrine function. Mol Brain Res: 50: 267276, 1997. Mancuso C, Navarra P, Preziosi P. Roles of nitric oxide, carbon monoxide, and hydrogen sulfide in the regulation of the hypothalamicpituitary-adrenal axis. J Neurochem 113: 563-575, 2010. Mann JFE, Johnson AK, Ganten D, Ritz E. Thirst and the reninangiotensin system. Kidney Int Suppl 32: S27-S34, 1987. Manzon LA. The role of prolactin in fish osmoregulation: A review. Gen Comp Endocrinol 125: 291-310, 2002. Mao C, Liu R, Bo L, Chen N, Li S, Xia S, Chen J, Li D, Zhang L, Xu Z. High-salt diets during pregnancy affected fetal and offspring renal renin-angiotensin system. J Endocrinol 218: 61-73, 2013. Margatho LO, Godino A, Oliveira FR, Vivas L, Antunes-Rodrigues J. Lateral parabrachial afferent areas and serotonin mechanisms activated by volume expansion. J Neurosci Res 86: 3613-3621, 2008. Maric-Bilkan C, Gilbert EL, Ryan MJ. Impact of ovarian function on cardiovascular health in women: Focus on hypertension. Int J Womens Health 6: 131-139, 2014. Marin ECS, Francescato HD, Silva CGA, Costa RS, Coimbra TM. Early Events in Kidneys from Rats Exposed to Losartan During Lactation. Nephron Exp Nephrol 119: 49-57, 2011. Martins AS, Crescenzi A, Stern JE, Bordin S & Michelini LC. Hypertension and exercise training differentially affect oxytocin and oxytocin receptor expression in the brain. Hypertension 46: 1004-1009, 2005. Massiera F, Bloch-Faure M, Ceiler D, Murakami K, Fukamizu A, Gasc JM, Quignard-Boulange A, Negrel R, Ailhaud G, Seydoux J, Meneton P, Teboul M. Adipose angiotensinogen is involved in adipose tissue growth and blood pressure regulation. FASEB J 15: 2727-2729, 2001. Mauro A. Nature of solvent transfer in osmosis. Science 126: 252-253, 1957. Mauro A. Forum on osmosis. III. Comments on Hammel and Scholander’s solvent tension theory and its application to the phenomenon of osmotic flow. Am J Physiol 237: R110-R113, 1979. Mayorov DN, Head GA. Influence of rostral ventrolateral medulla on renal sympathetic baroreflex in conscious rabbits. Am J Physiol Regul Integr Comp Physiol 280: R577-R587, 2001. Mazzi V, Lodi G, Guardabassi A. Prolactin in the transition from water to land environment: Evidence from amphibians. In: Serio M, Martini L, editors. Animal Models in Human Reproduction. New York: Raven Press, 1980, pp. 35-47. McKinley MJ, Badoer E, Oldfield BJ. Intravenous angiotensin II induces Fos-immunoreactivity in circumventricular organs of the lamina terminalis. Brain Res 594: 295-300, 1992. McKinley MJ, Badoer E, Vivas L, Oldfield BJ. Comparison of c-fos expression in the lamina terminalis of conscious rats after intravenous or intracerebroventricular angiotensin. Brain Res Bull 37: 131-137, 1995. McKinley MJ, Blaine EH, Denton DA. Brain osmoreceptors, cerebrospinal fluid electrolyte composition and thirst. Brain Res 70: 532537, 1974. McKinley MJ, Denton DA, Leventer M. Adipsia in sheep caused cerebral lesions. In: De Caro G, Epstein AN, Massi M, editors. The Physiology of Thirst and Sodium Appetite. New York: Plenum Press, 1986, pp. 321-326. McKinley MJ, Denton DA, Park RG, Weisinger RS. Ablation of subfornical organ does not prevent angiotensin-induced water drinking in sheep. Am J Physiol Regul Integr Comp Physiol 250: R1052-R1059, 1986. McKinley MJ, Denton DA, Weisinger RS. Sensors for antidiuresis and thirst - osmoreceptors or CSF sodium detectors? Brain Res 141: 89-103, 1978. McKinley MJ, Hards DK, Oldfield BJ. Identification of neural pathways activated in dehydrated rats by means of Fos-immunohistochemistry and neural tracing. Brain Res 653: 305-314, 1994. McKinley MJ, Mathai ML, McAllen RM, McClear RC, Miselis RR, Pennington GL, Vivas L, Wade JD, Oldfield BJ. Vasopressin secretion: Osmotic and hormonal regulation by the lamina terminalis. J Neuroendocrinol 16: 340-347, 2004. McKinley MJ, McAllen RM, Davern P, Giles ME, Penschow J, Sunn N, Uschakov A, Oldfield BJ. The sensory circumventricular organs of the mammalian brain. Adv Anat Embryol Cell Biol 172: 1-127, 2003. Mears SA, Shirreffs SM. The effects of high-intensity intermittent exercise compared with continuous exercise on voluntary water ingestion. Int J Sport Nutr Exerc Metab 23: 488-497, 2013. Mecawi AS, Araujo IG, Rocha FF, Coimbra TM, Antunes-Rodrigues J, Reis LC. Ontogenetic role of angiontensin-converting enzyme in rats: Thirst and sodium appetite evaluation. Physiol Behav 99: 118-124, 2010. Mecawi AS, Lepletier A, Araujo IG, Fonseca FV, Reis LC. Oestrogenic influence on brain AT1 receptor signalling on the thirst and sodium appetite in osmotically stimulated and sodium-depleted female rats. Exp Physiol 93: 1002-1010, 2008. Mecawi AS, Lepletier A, Araujo IG, Olivares EL, Reis LC. Assessment of brain AT1-receptor on the nocturnal basal and angiotensin-induced

Volume 5, July 2015


312. 313.

314. 315. 316. 317. 318.

319. 320. 321. 322. 323. 324.

325.

326.

327. 328. 329. 330. 331. 332. 333.

334. 335.

336.

thirst and sodium appetite in ovariectomised rats. J Renin Angiotensin Aldosterone Syst 8: 169-175, 2007. Mecawi AS, Macchione AF, Nuñez P, Perillan C, Reis LC, Vivas L, Arguelles J. Developmental programing of thirst and sodium appetite. Neurosci Biobehav Rev. 41: 1-14, 2015. Mecawi AS, Vilhena-Franco T, Araujo IG, Reis LC, Elias LL, AntunesRodrigues J. Estradiol potentiates hypothalamic vasopressin and oxytocin neuron activation and hormonal secretion induced by hypovolemic shock. Am J Physiol Regul Integr Comp Physiol 301: 905-915, 2011. Menani JV, De Luca LA Jr, Johnson AK. Role of the lateral parabrachial nucleus in the control of sodium appetite. Am J Physiol Regul Integr Comp Physiol 306: R201-R210, 2014. Menani JV, Johnson AK. Lateral parabrachial serotonergic mechanisms: Angiotensin-induced pressor and drinking responses. Am J Physiol Regul Integr Comp Physiol 269: R1044-R1049, 1995. Mendelsohn FA, Quirion R, Saavedra JM, Aguilera G, Catt KJ. Autoradiographic localization of angiotensin II receptors in rat brain. Proc Natl Acad Sci U S A 81: 1575-1579, 1984. Michelini LC. Oxytocin in the NTS: A new modulator of cardiovascular control during exercise. Ann N Y Acad Sci 940: 206-220, 2001. Michelini LC. Differential effects of vasopressinergic and oxytocinergic pre-autonomic neurons on circulatory control: Reflex mechanisms and changes during exercise. Clin Exp Pharmacol Physiol 34: 369-376, 2007. Mifune H, Suzuki S, Nokihara K, Noda Y. Distribution of immunoreactive atrial and brain natriuretic peptides in the heart of the chicken, quail, snake and frog. Exp Anim 45: 125-133, 1996. Miselis RR, Shapiro RE, Hand PJ. Subfornical organ efferents to neural systems for control of body water. Science 205: 1022-1025, 1979. Miyata S, Hatton GI. Activity-related, dynamic neuron-glial interactions in the hypothalamo-neurohypophysial system. Microsc Res Tech 56: 143-157, 2002. Moe KE, Weiss ML, Epstein AN. Sodium appetite during captopril blockade of endogenous angiotensin II formation. Am J Physiol Regul Integr Comp Physiol 247: R356-R365, 1984. Montemurro DG, Stevenson JA. The localization of hypothalamic structures in the rat influencing water consumption. Yale J Biol Med 28: 396-403, 1955. Morita H, Ogino T, Fujiki N, Tanaka K, Gotoh TM, Seo Y, Takamata A, Nakamura S, Murakami M. Sequence of forebrain activation induced by intraventricular injection of hypertonic NaCl detected by Mn2+ contrasted T1-weighted MRI. Auton Neurosci 113: 43-54, 2004. Morris BJ. Renin. Compr Physiol 2011, Supplement 22: Handbook of Physiology, The Endocrine System, Endocrine Regulation of Water and Electrolyte Balance: 1-58. First published in print 2000. Doi: 10.1002/cphy.cp070301. Morris M, Alexander N. Baroreceptor influences on plasma atrial natriuretic peptide (ANP): Sinoaortic denervation reduces basal levels and the response to an osmotic challenge. Endocrinol 122: 373-375, 1988. Morris M, McCann SM, Orias R. Evidence for hormonal participation in the natriuretic and kaliuretic responses to intraventricular hypertonic saline and norepinephrine. Proc Soc Exp Biol Med 152: 95-98, 1976. Morris M, McCann SM, Orias R. Role of transmitters in mediating hypothalamic control of electrolyte excretion. Can J Physiol Pharmacol 55: 1143-1154, 1977. Morris MJ, Wilson WL, Starbuck EM, Fitts DA. Forebrain circumventricular organs mediate salt appetite induced by intravenous angiotensin II in rats. Brain Res 949: 42-50, 2002. Mouw DR, Vander AJ, Wagner J. Effects of prenatal and early postnatal sodium deprivation on subsequent adult thirst and salt preference in rats. Am J Physiol 234: F59-F63, 1978. Muraki K, Iwata Y, Katanosaka Y, Ito T, Ohya S, Shigekawa M, Imaizumi Y. TRPV2 is a component of osmotically sensitive cation channels in murine aortic myocytes. Circ Res 93: 829-838, 2003. Naveri L. The role of angiotensin receptor subtypes in cerebrovascular regulation in the rat. Acta Physiol Scand Suppl 630: 1-48, 1995. Nehme B, Henry M, Mouginot D, Drolet G. The expression pattern of the Na(+) sensor, Na(X) in the hydromineral homeostatic network: A comparative study between the rat and mouse. Front Neuroanat 6: 26, 2012. Neill JC, Cooper SJ. Selective reduction by serotonergic agents of hypertonic saline consumption in rats: Evidence for possible 5-HT1C receptor mediation. Psychopharmacol 99: 196-201, 1989. Nielsen S, Chou CL, Marples D, Christensen EI, Kishore BK, Knepper MA. Vasopressin increases water permeability of kidney collecting duct by inducing translocation of aquaporin-CD water channels to plasma membrane. Proc Natl Acad Sci U S A 92: 1013-1017, 1995. Nielsen S, Frokiaer J, Marples D, Kwon TH, Agre P, Knepper MA. Aquaporins in the kidney: From molecules to medicine. Physiol Rev 82: 205-244, 2002.

Volume 5, July 2015


337. Niijima A. Afferent discharges from osmoreceptors in the liver of the guinea pig. Science 166: 1519-1520, 1969. 338. Nilius B, Owsianik G, Voets T, Peters JA. Transient receptor potential cation channels in disease. Physiol Rev 87: 165-217, 2007. 339. Nishimoto G, Zelenina M, Li D, Yasui M, Aperia A, Nielsen S, Nairn AC. Arginine vasopressin stimulates phosphorylation of aquaporin 2 in rat renal tissue. Am J Physiol Renal Physiol 276: F254-F259, 1999. 340. Nishimura H. Endocrine control of renal handling of solutes and water in vertebrates. Renal Physiol 8: 279-300, 1985. 341. Nissen R, Renaud LP. GABA receptor mediation of median preoptic nucleus-evoked inhibition of supraoptic neurosecretory neurones in rat. J Physiol 479: 207-216, 1994. 342. Noda M, Sakuta H. Central regulation of body-fluid homeostasis. Trends Neurosci 36: 661-673, 2013. 343. Noda S, Sasaki T. Trafficking mechanism of water channel aquaporin-2. Biol Cell 97: 885-892, 2005. 344. Nonoguchi H, Owada A, Kobayashi N, Takayama M, Terada Y, Koike J, Ujiie K, Marumo F, Sakai T, Tomita K. Immunohistochemical localization of V2 vasopressin receptor along the nephron and functional role of luminal V2 receptor in terminal inner medullary collecting ducts. J Clin Invest 96: 1768-1778, 1995. 345. Ogawa T, Forero M, Burgon PG, Kuroski de Bold ML, Georgalis T, de Bold AJ. Role of potassium channels in stretch-promoted atrial natriuretic factor secretion. J Am Soc Hypertens 3: 9-18, 2009. 346. Ohman LE, Johnson AK. Lesions in lateral parabrachial nucleus enhance drinking to angiotensin II and isoproterenol. Am J Physiol Regul Integr Comp Physiol 251: R504-R509, 1986. 347. Ohman LE, Johnson AK. Brain stem mechanisms and the inhibition of angiotensin-induced drinking. Am J Physiol Regul Integr Comp Physiol 256: R264-R269, 1989. 348. Ohno S. The reason for as well as the consequence of the cambrian explosion in animal evolution. J Mol Evol Suppl 44: S23-S27, 1997. 349. Oldfield BJ, Hards DJ, McKinley MJ. Projections from the subfornical organ to the supraoptic nucleus in the rat – ultrastructural identification of an interposed synapse in the median preoptic nucleus using a combination of neuronal tracers. Brain Res 558: 13-19, 1991. 350. Oliet SH, Bourque CW. Properties of supraoptic magnocellular neurones isolated from the adult rat. J Physiol 455: 291-306, 1992. 351. Oliet SH, Bourque CW. Mechanosensitive channels transduce osmosensitivity in supraoptic neurons. Nature 364: 341-343, 1993. 352. Olson KR, Duff DW. Cardiovascular and renal effects of eel and rat atrial natriuretic peptide in rainbow trout, Salmo gairdneri. J Comp Physiol B 162: 408-415, 1992. 353. Orias R, McCann SM. Natriuretic effect of alpha melanocyte stimulating hormone - MSH) in hypophysectomized or adrenalectomized rats. Proc Soc Exp Biol Med 139: 872-876, 1972. 354. Osaka T, Kobayashi A, Inoue S. Vagosympathoadrenal reflex in thermogenesis induced by osmotic stimulation of the intestines in the rat. J Physiol 540: 665-671. 2002. 355. Otake K, Kondo K, Oiso Y. Possible involvement of endogenous opioid peptides in the inhibition of arginine vasopressin release by gammaaminobutyric acid in conscious rats. Neuroendocrinol 54: 170-174, 1991. 356. Otsuka R, Kato Y, Imai T, Ando F, Shimokata H. Decreased salt intake in Japanese men aged 40 to 70 years and women aged 70 to 79 years: An 8-year longitudinal study. J Am Diet Assoc 111: 844-850, 2011. 357. Page IH, Helmer OM. A crystalline pressor substance: Angiotonin. Proc Center Soc Clin Invest 12: 17, 1939. 358. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327: 524-526, 1987. 359. Panatier A, Oliet SH. Neuron-glia interactions in the hypothalamus. Neuron Glia Biol 2: 51-58, 2006. 360. Pandey KN. Biology of natriuretic peptides and their receptors. Peptides 26: 901-932, 2005. 361. Pang PKT, Sawyer WH. Renal and vascular responses of the bullfrog (Rana catesbeiuna) to mesotocin. Am J Physiol 235: F151-F155, 1978. 362. Parisi M, Bourguet J. The single file hypothesis and the water channels induced by antidiuretic hormone. J Membr Biol 71: 189-193, 1983. 363. Parisi M, Bourguet J. Water channels in animal cells: A widespread structure? Biol Cell 55: 155-157, 1985. 364. Parisi M, Bourguet J, Ripoche P, Chevalier J. Simultaneous minute by minute determination of unidirectional and net water fluxes in frog urinary bladder. A reexamination of the two barriers in series hypothesis. Biochim Biophys Acta 556: 509-523, 1979. 365. Parisi M, Dorr RA, Ozu M, Toriano R. From Membrane Pores to Aquaporins: 50 Years Measuring Water Fluxes. J Biol Phys 33: 331343, 2007. 366. Pedrino GR, Freiria-Oliveira AH, Almeida Colombari DS, Rosa DA, Cravo SL. A2 noradrenergic lesions prevent renal sympathoinhibition induced by hypernatremia in rats. PLoS One 7: e37587, 2012. 367. Pereira DT, Menani JV, De Luca LA Jr. FURO/CAP: A protocol for sodium intake sensitization. Physiol Behav 99: 472-481, 2010.

1513


368. Perlmutter LS, Tweedle CD, Hatton GI. Neuronal/glial plasticity in the supraoptic dendritic zone in response to acute and chronic dehydration. Brain Res 361: 225-232, 1985. 369. Peysner K, Forsling ML. Effect of ovariectomy and treatment with ovarian steroids on vasopressin release and fluid balance in the rat. J Endocrinol 124: 277-284, 1990. 370. Phillips PA, Bretherton M, Johnston CI, Gray L. Reduced osmotic thirst in healthy elderly men. Am J Physiol Regul Integr Comp Physiol 261: R166-R171, 1991. 371. Pickford GE, Phillips JG. Prolactin, a factor in promoting survival of hypophysectomized killifish in fresh water. Science 130: 454-455, 1959. 372. Plentl AA, Page IH, Davis WW. The nature of renin activator. J Biol Chem 147: 143-153, 1943. 373. Polanco MJ, Mara IM, Agapito MT, Recio JM. Angiotensin-converting enzyme distribution and hypoxia response in mammal, bird and fish. Gen Comp Endocrinol 79: 240-245, 1990. 374. Potts JT. Neural circuits controlling cardiorespiratory responses: Baroreceptor and somatic afferents in the nucleus tractus solitarius. Clin Exp Pharmacol Physiol 29: 103-111, 2002. 375. Preston GM, Agre P. Isolation of the cDNA for erythrocyte integral membrane protein of 28 kilodaltons: Member of an ancient channel family. Proc Natl Acad Sci U S A 88: 11110-11114, 1991. 376. Preston GM, Carroll TP, Guggino WB, Agre P. Appearance of water channels in Xenopus oocytes expressing red cell CHIP28 protein. Science 256: 385-387, 1992. 377. Puyó AM, Vatta MS, Donoso AS, Bianciotti LG, Fernández BE. Central natriuretic peptides regulation of peripheral atrial natriuretic factor release. Regul Pept 90: 93-99, 2000. 378. Qiu DL, Shirasaka T, Chu CP, Watanabe S, Yu NS, Katoh T, Kannan H. Effect of hypertonic saline on rat hypothalamic paraventricular nucleus magnocellular neurons in vitro. Neurosci Lett 355: 117-120, 2004. 379. Reaux A, Fournie-Zaluski MC, David C, Zini S, Roques BP, Corvol P, Llorens-Cortes C. Aminopeptidase A inhibitors as potential central antihypertensive agents. Proc Natl Acad Sci U S A 96: 13415-13420, 1999. 380. Reinhart GA, Zehr JE. Atrial natriuretic factor in the freshwater turtle Pseudemys scripta: A partial characterization. Gen Comp Endocrinol 96: 259-269, 1994. 381. Reis LC. Role of the serotoninergic system in the sodium appetite control. An Acad Bras Cienc 79: 261-283, 2007. 382. Reis LC, Ramalho MJ, Antunes-Rodrigues J. Central serotonergic modulation of drinking behavior induced by water deprivation: Effect of a serotonergic agonist (MK-212) administered intracerebroventricularly. Braz J Med Biol Res 23: 1335-1338, 1990. 383. Reis LC, Ramalho MJ, Antunes-Rodrigues J. Central serotonergic modulation of drinking behavior induced by angiotensin II and carbachol in normally hydrated rats: Effect of intracerebroventricular injection of MK-212. Braz J Med Biol Res 23: 1339-1342, 1990. 384. Reis LC, Ramalho MJ, Antunes-Rodrigues J. Brain serotoninergic stimulation reduces the water intake induced by systemic and central betaadrenergic administration. Braz J Med Biol Res 25: 529-536, 1992. 385. Reis LC, Ramalho MJ, Favareto ALV, Gutkowska J, McCann SM, Antunes-Rodrigues J. Participation or the ascending serotonergic system in the stimulation of atrial natriuretic peptide release. Proc Natl Acad Sci U S A 91: 12022-12026, 1994. 386. Reis WL, Giusti-Paiva A, Ventura RR, Margatho LO, Gomes DA, Elias LL, Antunes-Rodrigues J. Central nitric oxide blocks vasopressin, oxytocin and atrial natriuretic peptide release and antidiuretic and natriuretic responses induced by central angiotensin II in conscious rats. Exp Physiol 92: 903-911, 2007. 387. Reis WL, Saad WA, Camargo LA, Elias LL, Antunes-Rodrigues J. Central nitrergic system regulation of neuroendocrine secretion, fluid intake and blood pressure induced by angiotensin-II. Behav Brain Funct 6: 64, 2010. 388. Ren JF, Hakki AH, Kotler MN, Iskandrian AS. Exercise systolic blood pressure: A powerful determinant of increased left ventricular mass in patients with hypertension. J Am Coll Cardiol 5: 1224-1231, 1985. 389. Renaud LP, Bourque CW. Neurophysiology and neuropharmacology of hypothalamic magnocellular neurons secreting vasopressin and oxytocin. Prog Neurobiol 36: 131-169, 1991. 390. Rice KK, Richter CP. Increased sodium chloride and water intake of normal rats treated with desoxycorticosterone acetate. Endocrinol 33: 106-115, 1943. 391. Rich GT, Shaafi I, Romualdez A, Solomon AK. Effect of osmolality on the hydraulic permeability coefficient of red cells. J Gen Physiol 52: 941-954, 1968. 392. Richard D, Bourque CW. Atrial natriuretic peptide modulates synaptic transmission from osmoreceptor afferents to the supraoptic nucleus. J Neurosci 16: 7526-7532, 1996. 393. Richet G. The osmotic pressure of the urine - from Dutrochet to Korányi, a trans-European interdisciplinary epic. Nephrol Dial Transplant 16: 420-424, 2001.

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394. Richter CP. Increased salt appetite in adrenalectomized rats. Am J Physiol 115: 155-161, 1936. 395. Rinaman L, Vollmer RR, Karam J, Phillips D, Li X, Amico JA. Dehydration anorexia is attenuated in oxytocin-deficient mice. Am J Physiol Regul Integr Comp Physiol 288: R1791-R1799, 2005. 396. Roberts JR, Dantzler WH. Micropuncture study of avian kidney: Effect of prolactin. Am J Physiol Regul Integr Comp Physiol 262: R933-R937, 1992. 397. Robson RA, Stockes RH. Appendix 8.6 and 8.10. In: Robinson RA, Stokes RH, editors. Electrolyte Solutions. 2nd ed.; reprinted and revised. London, UK: Butterworths, 1968, pp. 478 and 483. 398. Rodovalho GV, Franci CR, Morris M, Anselmo-Franci JA. Locus coeruleus lesions decrease oxytocin and vasopressin release induced by hemorrhage. Neurochem Res 31: 259-266, 2006. 399. Ruginsk SG, Mecawi AS, Da Silva MP, Reis WL, Coletti R, Lima JBM, Elias LLK, Antunes-Rodrigues J. Gaseous modulators in the control of the hypothalamic neurohypophyseal system. Physiology 30: 127-138, 2015. 400. Ruginsk SG, Oliveira FR, Margatho LO, Vivas L, Elias LL, AntunesRodrigues J. Glucocorticoid modulation of neuronal activity and hormone secretion induced by blood volume expansion. Exp Neurol 206: 192-200, 2007. 401. Ruginsk SG, Uchoa ET, Elias LL, Antunes-Rodrigues J. CB(1) modulation of hormone secretion, neuronal activation and mRNA expression following extracellular volume expansion. Exp Neurol 224: 114-122, 2010. 402. Ruhf AA, Starbuck EM, Fitts DA. Effects of SFO lesions on salt appetite during multiple sodium depletions. Physiol Behav 74: 629-636, 2001. 403. Russ RD, Walter BR. Oxytocin augments baroreflex bradycardia in conscious rats. Peptides 15: 907-912, 1994. 404. Saad WA, Camargo LAA, Guarda IFMS, Santos TAFB, Guarda RS, Simões S, Saad WA, Simões S, Antunes-Rodrigues J. Interaction between supraoptic nucleus and septal area in the control of water, sodium intake and arterial blood pressure induced by injection of angiotensin-II. Pharmacol Biochem Behav 77: 667-674, 2004. 405. Sakai RR, McEwen BS, Fluharty SJ, Ma LY. The amygdala: Site of genomic and nongenomic arousal of aldosterone-induced sodium intake. Kidney Int 57: 1337-1345, 2000. 406. Sanderford MG, Bishop VS. Central mechanisms of acute ANG II modulation of arterial baroreflex control of renal sympathetic nerve activity. Am J Physiol Heart Circ Physiol 282: H1592-H1602, 2002. 407. Sandor T, Fazekas AG, Robinson BH. The biosynthesis of corticosteroids throughout the vertebrates. In: Chester-Jones I, Henderson IW, editors. General, Comparative and Clinical Endocrinology of the Adrenal Cortex. London: Academic Press, 1976, pp. 25-142. 408. Sato MA, Sugawara AM, Menani JV, De Luca LA Jr. Idazoxan and the effect of intracerebroventricular oxytocin or vasopressin on sodium intake of sodium-depleted rats. Regul Pept 69: 137-142, 1997. 409. Sawchenko PE, Swanson LW. The organization of noradrenergic pathways from the brainstem to the paraventricular and supraoptic nuclei in the rat. Brain Res 257: 275-325, 1982. 410. Sawchenko PE, Swanson LW. The organization of forebrain afferents to the paraventricular and supraoptic nuclei of the rat. J Comp Neurol 218: 121-144, 1983. 411. Sawchenko PE, Swanson LW, Steinbusch HW, Verhofstad AA. The distribution and cells of origin of serotonergic inputs to the paraventricular and supraoptic nuclei of the rat. Brain Res 277: 355-360, 1983. 412. Schopf JW. Microfossils of the early archean apex chert: New evidence of the antiquity of life. Science 260: 640-646, 1993. 413. Schreihofer AM, Anderson BK, Schiltz JC, Xu L, Sved AF, Stricker EM. Thirst and salt appetite elicited by hypovolemia in rats with chronic lesions of the nucleus of the solitary tract. Am J Physiol Regul Integr Comp Physiol 276: R251-R258, 1999. 414. Schreihofer AM, Stricker EM, Sved AF. Nucleus of the solitary tract lesions enhance drinking, but not vasopressin release, induced by angiotensin. Am J Physiol Regul Integr Comp Physiol 279: R239-R247, 2000. 415. Scislo TJ, Kitchen AM, Augustyniak RA, O’Leary DS. Differential patterns of sympathetic responses to selective stimulation of nucleus tractus solitarius purinergic receptor subtypes. Clin Exp Pharmacol Physiol 28: 120-124, 2001. 416. Scislo TJ, O’Leary DS. Adenosine receptors located in the NTS contribute to renal sympathoinhibition during hypotensive phase of severe hemorrhage in anesthetized rats. Am J Physiol Heart Circ Physiol 291: H2453-H2461, 2006. 417. Sedláková E, Lichardus B, Cort JH. Plasma saluretic activity: Its nature and relation to oxytocin analogs. Science 164: 580-582, 1969. 418. Seger R, Krebs EG. The MAPK signaling cascade. FASEB J 9: 726-735, 1995. 419. Sernia C. Location and secretion of brain angiotensinogen. Regul Pept 57: 1-18, 1995. 420. Share L. Role of vasopressin in cardiovascular regulation. Physiol Rev 68: 1248-1284, 1988.

Volume 5, July 2015


421. Sharif-Naeini R, Witty MF, Séguéla P, Bourque CW. An N-terminal variant of Trpv1 channel is required for osmosensory transduction. Nat Neurosci 9: 93-98, 2006. 422. Shibuya N, Tanaka M, Yoshida M, Ogasawara Y, Togawa T, Ishii K, Kimura H. 3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain. Antioxid Redox Signal 11: 703-714, 2009. 423. Shigemura N, Iwata S, Yasumatsu K, Ohkuri T, Horio N, Sanematsu K, Yoshida R, Margolskee RF, Ninomiya Y. Angiotensin II modulates salty and sweet taste sensitivities. J Neurosci 33: 6267-6277, 2013. 424. Shimizu H, Watanabe E, Hiyama TY, Nagakura A, Fujikawa A, Okado H, Yanagawa Y, Obata K, Noda M. Glial Nax channels control lactate signaling to neurons for brain [Na+] sensing. Neuron 54: 59-72, 2007. 425. Shirazki A, Weintraub Z, Reich D, Gershon E, Leshem M. Lowest neonatal serum sodium predicts sodium intake in lowbirth weight children. Am J Physiol Regul Integr Comp Physiol 292: R1683-R1689, 2007. 426. Sidel VW, Solomon AK. Entrance of water into human red cells under an osmotic pressure gradient. J Gen Physiol 41: 243-257, 1957. 427. Simerly RB. Anatomical substrates of hypothalamic integration. In: Paxinos G, editor. The Rat Nervous System. New York: Academic Press, 1995, pp. 353-376. 428. Simerly RB, Swanson LW. Projections of the medial preoptic nucleus: A Phaseolus vulgaris leucoagglutinin anterograde tract-tracing study in the rat. J Comp Neurol 270: 209-242, 1988. 429. Simonetti GD, Raio L, Surbek D, Nelle M, Frey FJ, Mohaupt MG. Salt sensitivity of children with low birth weight. Hypertension 52: 625-630, 2008. 430. Simpson JB, Routtenberg A. Subfornical organ lesions reduce intravenous angiotensin-induced drinking. Brain Res 88: 154-161, 1975. 431. Simpson JB, Routtenberg A. Subfornical organ: A dipsogenic site of action of angiotensin II. Science 20: 379-381, 1978. 432. Singh JP, Larson MG, Manolio TA, O’Donnell CJ, Lauer M, Evans JC, Levy D. Blood pressure response during treadmill testing as a risk factor for new-onset hypertension. The Framingham heart study. Circulation 99: 1831-1836, 1999. 433. Skeggs LT Jr, Kahn JR, Shumway NP. Preparation and function of the hypertensin-converting enzyme. J Exp Med 103: 295-305, 1956. 434. Skeggs LT, Lentz KE, Hochstrasser H, Kahn JR. The purification and partial characterization of several forms of hog renin substrate. J Exp Med 118: 73-98, 1963. 435. Sly DJ, McKinley MJ, Oldfield BJ. Activation of kidney-directed neurons in the lamina terminalis by alterations in body fluid balance. Am J Physiol Regul Integr Comp Physiol 281: R1637-R1646, 2001. 436. Smart JL, Dobbing J. Increased thirst and hunger in adult rats undernourished as infants: An alternative explanation. Br J Nutr 37: 421-430, 1977. 437. Soares TJ, Coimbra, TM, Martins RA, Pereira ACF, Cárnio EC, Branco LGS, Albuquerque-Araujo WIC, De Nucci G, Favaretto ALV, Gutkowska J, McCann SM, and Antunes-Rodrigues J. Atrial natriuretic peptide and oxytocin induce natriuresis by release of GMPc. Proc Natl Acad Sci U S A 96: 278-283, 1999. 438. Sokabe H. Phylogeny of the renal effects of angiotensin. Kidney Int 6: 263-271, 1974. 439. Sokabe H, Ogawa M. Comparative studies of the juxtaglomerular apparatus. Int Rev Cytol 37: 271-327, 1974. 440. Solomon AK, Chasan B, Dix JA, Lukacovic MF, Toon MR, Verkman AS. The aqueous pore in the red cell membrane: Band 3 as a channel for anions, cations, nonelectrolytes, and water. Ann NY Acad Sci 414: 79-124, 1984. 441. Somponpun SJ, Johnson AK, Beltz T, Sladek CD. Estrogen receptoralpha expression in osmosensitive elements of the lamina terminalis: Regulation by hypertonicity. Am J Physiol Regul Integr Comp Physiol 287: R661-R669, 2004. 442. Song K, Allen AM, Paxinos G, and Mendelsohn FA. Mapping of angiotensin II receptor subtype heterogeneity in rat brain. J Comp Neurol 316: 467-484, 1992. 443. Song L, Wilk S, Healy DP. Aminopeptidase A antiserum inhibits intracerebroventricular angiotensin II-induced dipsogenic and pressor responses. Brain Res 744: 1-6, 1997. 444. Sontheimer EJ. Assembly and function of RNA silencing complexes. Nat Rev Mol Cell Biol 6: 127-138, 2005. 445. Soodak H, Iberall A. Forum on osmosis. IV. More on osmosis and diffusion. Am J Physiol 237: R114-R122, 1979. 446. Stachenfeld NS. Hormonal changes during menopause and the impact on fluid regulation. Reprod Sci 21: 555-561, 2014. 447. Stachenfeld NS, Keefe DL. Estrogen effects on osmotic regulation of AVP and fluid balance. Am J Physiol Endocrinol Metab 283: E711E721, 2002. 448. Stachenfeld NS, Splenser AE, Calzone WL, Taylor MP, Keefe DL. Sex differences in osmotic regulation of AVP and renal sodium handling. J Appl Physiol 91: 1893-1901, 2001.

Volume 5, July 2015


449. Staverman AJ. The theory of measurement of osmotic pressure. Recueil 70: 344-352, 1951. 450. Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNFalpha. Nature 440: 1054-1059, 2006. 451. Stier CT Jr, Cowden EA, Friesen HG, Allison ME. Prolactin and the rat kidney: A clearance and micropuncture study. Endocrinol 115: 362367, 1984. 452. Stricker EM, Curtis KS, Peacock KA, Smith JC. Rats with area postrema lesions have lengthy eating and drinking bouts when fed ad libitum: Implications for feedback inhibition of ingestive behavior. Behav Neurosci 111: 623-632, 1997. 453. Stricker EM, Hoffmann ML. Presystemic signals in the control of thirst, salt appetite, and vasopressin secretion. Physiol Behav 91: 404-412, 2007. 454. Stricker EM, Verbalis JG. Interaction of osmotic and volume stimuli in regulation of neurohypophyseal secretion in rats. Am J Physiol 250: R267-R275, 1986. 455. Stricker EM, Verbalis JG. Central inhibitory control of sodium appetite in rats: Correlation with pituitary oxytocin secretion. Behav Neurosci 101: 560-567, 1987. 456. Stricker EM, Verbalis JG. Central inhibition of salt appetite by oxytocin in rats. Regul Pept 66: 83-85, 1996. 457. Stricker P, Grueter R. Action du lobe anterieure de l’hypophyse sur la monteée laiteuse. Compt Rend Soc Biol 99: 1978-1980, 1928. 458. Sudbury JR, Ciura S, Sharif-Naeini R, Bourque CW. Osmotic and thermal control of magnocellular neurosecretory neurons—Role of an N-terminal variant of trpv1. Eur J Neurosci 32: 2022-2030, 2010. 459. Suleymanian MA, Baumgarten CM. Osmotic gradient-induced water permeation across the sarcolemma of rabbit ventricular myocytes. J Gen 107: 503-514, 1996. 460. Sullivan MJ, Sharma RV, Wachtel RE, Chapleau MW, Waite LJ, Bhalla RC, Abboud FM. Non-voltage-gated Ca2+ influx through mechanosensitive ion channels in aortic baroreceptor neurons. Circ Res 80: 861-867, 1997. 461. Swaab DR, Pool LW, Nijveldt F. Immunofluorescence of vasopressin and oxytocin in the rat hypothalamo-nuerohypophyseal system. J Neurol Transm 36: 195-215, 1975. 462. Swanson LW. The hypothalamus. In: Bjorklund A, Hokfelt T, Swanson LW, editors. Handbook of Chemical Neuroanatomy - Integrated Systems of the CNS. Amsterdam: Elsevier, 1987, pp. 1-124. 463. Szczepańska-Sadowska E, Sobocińska J, Sadowski B. Central dipsogenic effect of vasopressin. Am J Physiol 242: R372-379, 1982. 464. Takahashi T, Kawashima M, Yasuoka T, Kamiyoshi M, Tanaka K. Diuretic and antidiuretic effects of mesotocin as compared with the antidiuretic effect of arginine vasotocin in the hen. Poult Sci 74: 890892, 1995. 465. Takei Y, Joss JM, Kloas W, Rankin JC. Identification of angiotensin I in several vertebrate species: Its structural and functional evolution. Gen Comp Endocrinol 135: 286-292, 2004. 466. Takei Y. Comparative physiology of body fluid regulation in vertebrates with special reference to thirst regulation. Jpn J Physiol 50: 171-186, 2000. 467. Tani K, Fujiyoshi Y. Water channel structures analysed by electron crystallography. Biochim Biophys Acta 1840: 1605-1613, 2014. 468. Taylor JA, Christenson RH, Rao K, Jorge M, Gottlieb SS. B-type natriuretic peptide and N-terminal pro B-type natriuretic peptide are depressed in obesity despite higher left ventricular end diastolic pressures. Am Heart J 152: 1071-1076, 2006. 469. Tessera M. Life began when evolution began: A lipidic vesicle-based scenario. Orig Life Evol Biosph 39: 559-564, 2009. 470. Tewksbury DA. Angiotensinogen. Compr Physiol 2011, Supplement 22: Handbook of Physiology, The Endocrine System, Endocrine Regulation of Water and Electrolyte Balance: 59-80. First published in print 2000. Doi: 10.1002/cphy.cp070302. 471. Theodosis DT. Oxytocin-secreting neurons: A physiological model of morphological neuronal and glial plasticity in the adult hypothalamus. Front Neuroendocrinol 23: 101-135, 2002. 472. Theodosis DT, Paut L, Tappaz ML. Immunocytochemical analysis of the GABAergic innervation of oxytocin- and vasopressin-secreting neurons in the rat supraoptic nucleus. Neuroscience 19: 207-222, 1986. 473. Thibonnier M, Conarty DM, Preston JA, Plesnicher CL, Dweik RA, Erzurum SC. Human vascular endothelial cells express oxytocin receptors. Endocrinol 140: 1301-1309, 1999. 474. Thornton SN, Sanchez A, Nicola¨ıdis S. An angiotensin-independent, hypotension induced, sodium appetite in the rat. Physiol Behav 57: 555-561, 1995. 475. Thrasher TN. Osmoreceptor mediation of thirst and vasopressin secretion in the dog. Fed Proc 41: 2528-2532, 1982. 476. Thrasher TN, Brown CJ, Keil LC, Ramsay DJ. Thirst and vasopressin release in the dog: An osmoreceptor or sodium receptor mechanism? Am J Physiol Regul Integr Comp Physiol 238: R333-R339, 1980.

1515


477. Thunhorst RL, Beltz TG, Johnson AK. Effects of subfornical organ lesions on acutely induced thirst and salt appetite. Am J Physiol Regul Integr Comp Physiol 277: R56-R65, 1999. 478. Thunhorst RL, Beltz TG, Johnson AK. Effects of aging on mineralocorticoid-induced salt appetite in rats. Am J Physiol Regul Integr Comp Physiol 305: R1498-R1505, 2013. 479. Tigerstedt R, Bergman PG. Niere und Kreislauf. Skand Arch Physiol 8: 223-271, 1898. 480. Tobin V, Leng G, Ludwig M. The involvement of actin, calcium channels and exocytosis proteins in somato-dendritic oxytocin and vasopressin release. Front Physiol 3: 261, 2012. 481. Toon MR, Verkman AS. The aqueous pore in the red cell membrane. Ann NY Acad Sci 414: 97-124, 1983. 482. Tribollet E, Barberis C, Dreifuss JJ, Jard S. Autoradiographic localization of vasopressin and oxytocin binding sites in rat kidney. Kidney Int 33: 959-965, 1988. 483. Tsukada T, Takei Y. Integrative approach to osmoregulatory action of atrial natriuretic peptide in seawater eels. Gen Comp Endocrinol 147: 31-38, 2006. 484. Uchiyama M, Maejima S, Wong MK, Preyavichyapugdee N, Wanichanon C, Hyodo S, Takei Y, Matuda K. Changes in plasma angiotensin II, aldosterone, arginine vasotocin, corticosterone, and electrolyte concentrations during acclimation to dry condition and seawater in the crab-eating frog. Gen Comp Endocrinol 195: 40-46, 2014. 485. Uchoa ET, Zahm DS, de Carvalho Borges B, Rorato R, AntunesRodrigues J, Elias LL. Oxytocin projections to the nucleus of the solitary tract contribute to the increased meal-related satiety responses in primary adrenal insufficiency. Exp Physiol 98: 1495-1504, 2013. 486. Uschakov A, McGinty D, Szymusiak R, McKinley MJ. Functional correlates of activity in neurons projecting from the lamina terminalis to the ventrolateral periaqueductal gray. Eur J Neurosci 30: 2347-2355, 2009. 487. Ussing HH. Transport of electrolytes and water across epithelia. Harvey Lect 59: 1-30, 1965. 488. Veltmar A, Culman J, Qadri F, Rascher W, Unger T. Involvement of adrenergic and angiotensinergic receptors in the paraventricular nucleus in the angiotensin II-induced vasopressin release. J Pharmacol Exp Ther 263: 1253-1260, 1992. 489. Ventura RR, Aguiar JF, Antunes-Rodrigues J, Varanda WA. Nitric oxide modulates the firing rate of the rat supraoptic magnocellular neurons. Neuroscience 155: 359-365, 2008. 490. Verkman AS, Lencer WI, Brown D, Ausiello DA. Endosomes from kidney collecting tubule cells contain the vasopressin-sensitive water channel. Nature 333: 268-269, 1988. 491. Vijande M, Costales M, Marin B. Sex difference in polyethylenglycolinduced thirst. Experientia 34: 742-743, 1978. 492. Vilhena-Franco T, Mecawi AS, Elias LL, Antunes-Rodrigues J. Oestradiol potentiates hormone secretion and neuronal activation in response to hypertonic extracellular volume expansion in ovariectomised rats. J Neuroendocrinol 23: 481-489, 2011. 493. Villar MJ, Ceccatelli S, Ronnqvist M, Hoffelt T. Nitric oxide synthase increases in hypothalamic magnocellular neurons after salt loading in the rat. An immunohistochemical and in situ hybridization study. Brain Res 644: 273-281, 1994. 494. Vivas L, Chiaraviglio E, Carrer HF. Rat organum vasculosum laminae terminalis in vitro: Responses to changes in sodium concentration. Brain Res 519: 294-300, 1990. 495. Vollmar AM, Wolf R, Schulz R. Co-expression of the natriuretic peptides (ANP, BNP, CNP) and their receptors in normal and acutely involuted rat thymus. J Neuroimmunol 57: 117-127, 1995. 496. Wade CE. Response, regulation, and actions of vasopressin during exercise: A review. Med Sci Sports Exerc 16: 506-511, 1984. 497. Warenycia MW, Goodwin LR, Benishin CG, Reiffenstein RJ, Francom DM, Taylor JD, Dieken FP. Acute hydrogen sulfide poisoning. Demonstration of selective uptake of sulfide by the brainstem by measurement of brain sulfide levels. Biochem Pharmacol 38: 973-981, 1989. 498. Warne JM, Harding KE, Balment RJ. Neurohypophysial hormones and renal function in fish and mammals. Comp Biochem Physiol B 132: 231-237, 2002. 499. Watanabe E, Hiyama TY, Shimizu H, Kodama R, Hayashi N, Miyata S, Yanagawa Y, Obata K, Noda M. Sodium-level-sensitive sodium channel Na(x) is expressed in glial laminate processes in the sensory circumventricular organs. Am J Physiol Regul Integr Comp Physiol 290: R568-R576, 2006. 500. Watanabe T, Inoue K, Takei Y. Identification of angiotensinogen genes with unique and variable angiotensin sequences in chondrichthyans. Gen Comp Endocrinol 161: 115-122, 2009. 501. Weisinger RS, Denton DA, Di Nicolantonio R, Hards DK, McKinley MJ, Oldfield B, Osborne PG. Subfornical organ lesion decreases sodium appetite in the sodium-depleted rat. Brain Res 526: 23-30, 1990.

1516


502. Weiss TF. Cellular Biophysics. Cambridge: The MIT Press, 1996. 503. Whittembury G, Carpi-Medina P, Gonzalez E, Linares H. Effect of para-chloromercuribenzenesulfonic acid and temperature on cell water osmotic permeability of proximal straight tubules. Biochim Biophys Acta 775: 365-373, 1984. 504. Windle RJ, Forsling ML. Variations in oxytocin secretion during the 4-day oestrous cycle of the rat. J Endocrinol 136: 305-311, 1993. 505. Wolf G. Sodium appetite elicited by aldosterone. Psychon Sci 1: 211212, 1964. 506. Wolf G, McGovern JF, Dicara LV. Sodium appetite: Some conceptual and methodologic aspects of a model drive system. Behav Biol 10: 27-42, 1974. 507. Wong MK, Ge W, Woo NY. Positive feedback of hepatic angiotensinogen expression in silver sea bream (Sparus sarba). Mol Cell Endocrinol 263: 103-111, 2007. 508. Woods RL. Cardioprotective functions of atrial natriuretic peptide and B-type natriuretic peptide: A brief review. Clin Exp Pharmacol Physiol 31: 791-794, 2004. 509. Wright JW, Harding JW. Brain renin-angiotensin - A new look at an old system. Prog Neurobiol 95: 49-67, 2011. 510. Wright JW, Morseth SL, Abhold RH, Harding JW. Pressor action and dipsogenicity induced by angiotensin II and III in rats. Am J Physiol Regul Integr Comp Physiol 249: 514-521, 1985. 511. Wu L, Mao C, Liu Y, Shi A, Xu F, Zhang L, Xu Z. Altered dipsogenic responses and expression of angiotensin receptors in the offspring exposed to prenatal high sucrose. Peptides 32: 104-111, 2011. 512. Xi D, Kusano K, Gainer H. Quantitative analysis of oxytocin and vasopressin messenger ribonucleic acids in single magnocellular neurons isolated from supraoptic nucleus of rat hypothalamus. Endocrinol 140: 4677-4682, 1999. 513. Xu Z, Herbert J. Regional suppression by water intake of c-fos expression induced by intraventricular infusions of angiotensin II. Brain Res 659: 157-168, 1994. 514. Xue BJ, He RR. Changes in heart rate, blood pressure and renal sympathetic nerve activity induced by microinjection of capsaicin into area postrema in rats. Sheng Li Xue Bao 52: 435-439, 2000. 515. Yamaguchi N, Suzuki-Kusaba M, Hisa H, Hayashi Y, Yoshida M, Satoh S. Interaction between norepinephrine release and intrarenal angiotensin II formation during renal nerve stimulation in dogs. Cardiovasc Pharmacol 35: 831-837, 2000. 516. Yamamoto S, Morimoto I, Yanagihara N, Kangawa K, Inenaga K, Eto S, Yamashita H. C-type natriuretic peptide suppresses argininevasopressin secretion from dissociated magnocellular neurons in newborn rat supraoptic nucleus. Neurosci Lett 229: 97-100, 1997. 517. Yan SK, Chang T, Wang H, Wu L, Wang R, Meng QH. Effects of hydrogen sulfide on homocysteine-induced oxidative stress in vascular smooth muscle cells. Biochem Biophys Res Commun 351: 485-491, 2006. 518. Yang M, Gao F, Liu H, Yu WH, Sun SQ. Temporal changes in expression of aquaporin-3, -4, -5 and -8 in rat brains after permanent focal cerebral ischemia. Brain Res 1290: 121-132, 2009. 519. Yang ZF, Epstein AN. Blood-borne and cerebral angiotensin and the genesis of salt intake. Horm Behav 25: 461-476, 1991. 520. Yuan H, Gao B, Duan L, Jiang S, Cao R, Xiong YF, Rao ZR. Acute hyperosmotic stimulus-induced Fos expression in neurons depends on activation of astrocytes in the supraoptic nucleus of rats. J Neurosci Res 88: 1364-1373, 2010. 521. Yugandhar VG, Clark MA. Angiotensin III: A physiological relevant peptide of the renin angiotensin system. Peptides 46: 26-32, 2013. 522. Zeidel ML. Renal actions of atrial natriuretic peptide: Regulation of collecting duct sodium and water transport. Annu Rev Physiol 52: 747759, 1990. 523. Zhang R, Logee KA, Verkman AS. Expression of mRNA coding for kidney and red cell water channels in Xenopus oocytes. J Biol Chem 265: 15375-15378, 1990. 524. Zhang Z, Bourque CW. Calcium permeability and flux through osmosensory transduction channels of isolated rat supraoptic nucleus neurons. Eur J Neurosci 23: 1491-1500, 2006. 525. Zhang Z, Kindrat AN, Sharif-Naeini R, Bourque CW. Actin filaments mediate mechanical gating during osmosensory transduction in rat supraoptic nucleus neurons. J Neurosci 27: 4008-4013, 2007. 526. Zhao W, Zhang J, Lu Y, Wang R. The vasorelaxant effect of H2 S as a novel endogenous gaseous K(ATP) channel opener. EMBO J 20: 6008-6016, 2001. 527. Zini S, Demassey Y, Fournie-Zaluski MC, Bischoff L, Corvol P, Llorens-Cortes C, Sanderson P. Inhibition of vasopressinergic neurons by central injection of a specific aminopeptidase A inhibitor. Neuroreport 9: 825-828, 1998. 528. Zou AP, Billington H, Su N, Cowley AW Jr. Expression and actions of heme oxygenase in the renal medulla of rats. Hypertension 35: 342-347, 2000.

Volume 5, July 2015

Neuroendocrine regulation and homeostasis.

The endocannabinoid system and the neuroendocrine control of hydromineral balance.

Neuroendocrine Regulation of Metabolism.

Regulation of Potassium Homeostasis.

Neuroendocrine regulation of plasma angiotensinogen.

Neuroendocrine regulation of maternal behavior.

Epigenetic regulation of cholesterol homeostasis.

Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism.

Acupuncture stimulation and neuroendocrine regulation.

Photoperiodic regulation of neuroendocrine-gonadal activity.

Neuroendocrine regulation of lactation and milk production.

Regulation of glucose homeostasis by GLP-1.

Regulation of germ line stem cell homeostasis.

Regulation of sleep homeostasis by sexual arousal.

The Regulation of Iron Absorption and Homeostasis.

Regulation of postnatal bone homeostasis by TGFβ.

MicroRNAs and the regulation of intestinal homeostasis.

Regulation of Energy Homeostasis by GPR41.

Regulation of leucocyte homeostasis in the circulation.

miRNA regulation of nutrient homeostasis in plants.

Achieving global perfect homeostasis through transporter regulation.

Endocrine and neuroendocrine regulation of fathering behavior in birds.

Editorial: Hormonal and Neuroendocrine Regulation of Energy Balance.

Neuroendocrine regulation of pulsatile luteinizing hormone secretion in elderly men.