Progress in NeurobiologyVol. 39, pp. 179 to 207, 1992 Printed in Great Britain. All rights r'-~erved
0301-0082/92/$15.00 © 1992PergamonPress Ltd
CENTRAL NERVOUS ANGIOTENSIN II RESPONSIVENESS IN BIRDS ECKHART SIMON, RODIG~ Gm~STS~tO~ and DAVID A. GRAY Max-Planck-lnstitutf~r physiologischeund klinischeForschung, William G. Kerckhoff-lnstitut, D-6350 Bad Nauheim, Germany (Received 11 November 1991)
CONTENTS 1. Introduction 2. Control of circulating Angiotensin II in birds 3. Angiotensin II specific systems in the rostral brainstem of birds as compared to mammals 3.1. Neuronal systems and interconnections 3.2. ANGII as a brain-intrinsic peptide 3.3. ANGII receptors in duck brain with special reference to the rostral brainstem 3.3.1. ANGII receptor characterization and localization 3.3.2. ANGII receptor regulation 4. Centrally mediated physiological actions of Angiotensin II in birds 4.1. Drinking as a behavioural activity in salt and fluid balance 4.2. Blood pressure control 4.3. Central control of the antidiuretic hormone 4.4. Control of salt gland activity 4.5. Physiological consequences of central ANGII actions 5. Angiotensin II responsive neurones 5.1. Distribution and properties of ANGII responsive rostral brainstem neurones 5.2. Correlation between functional and neuronal responses to centrally acting ANGII in the duck 5.3. Topography of neuronal ANGII responsiveness pertinent to salt and fluid balance 5.4. Interconnections of the avian PVN as a major effector in salt and fluid balance 6. Conclusions Acknowledgements References
1. INTRODUCTION
demonstrated neuronal A N G I I responsivity on either side of the BBB (Felix and Akert, 1974; Okuya et al., 1987). Compared with mammals the avian osmoregulatory system has been studied less frequently, with the premise that control of salt and fluid balance in general, and the actions of A N G I I in particular, are virtually identical in mammals and birds. With special respect to A N G I I this presumption was found to be basically true for the physiology and biochemistry of systemic A N G I I formation (Chan and Holmes, 1971; Nishimura, 1980, 1987; Wilson, 1984a, 1989), for its function in the control of mineralocorticoid release (Klingbeil, 1985; Gray et al., 1989) and for the physiological range of A N G I I plasma concentrations (Simon et al., 1989; Wilson, 1989). As the result, the osmoregulatory system of birds has been scarcely considered from the viewpoint that its analysis might disclose properties that are more difficult to elucidate in mammals. Indeed, salt and fluid balance of birds was found to differ to some degree from that of mammals, generally and with special regard to the actions of ANGII, and in ways that seemed especially helpful in the analysis of central nervous receptive functions in salt and fluid balance.
Stimulation of drinking was discovered early in both mammals and birds as one of the foremost, central effects of angiotensin II (ANGII) (Fitzsimons, 1972, 1980; Kobayashi et al., 1980). This discovery opened a new field of research on the central actions of a peptide hormone, which until then was primarily considered a peripherally acting hormone, not directly controlled by the hypothalamo-pituitary system. While originally concentrating on the function of A N G I I as a messenger to the brain, these studies were soon greatly expanded by the discovery of the brain renin-angiotensin system (FischerFerrero et al., 1971; Ganten et al., 1971). The demonstrations of angiotensinergic neurones in the brain (Lind et al., 1985) and of high affinity central nervous binding sites for A N G I I (Mendelsohn et al., 1984) on either side of the blood-brain barrier (BBB) have provided structural correlates to discriminate between central actions of circulating A N G I I on the one hand, and of A N G I I as a brain-intrinsic messenger/modulator on the other (Phillips, 1987). Brainstem sites for which specific transducer functions of A N G I I were postulated have also been probed electrophysiologically in mammals and have JPN 39/2--e
179 180 180 180 183 184 184 188 189 189 190 192 193 194 194 195 196 198 202 202 203 203
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E. SIMONet al.
(a) Contrary to mammals, arterial blood pressure of conscious birds is not substantially raised by increasing the level of circulating ANGII, unless physiological concentrations are exceeded (Nishimura and Bailey, 1982; Simon-Oppermann et al., 1984; Wilson and West, 1986). Interestingly, the vascular system of birds is similarly insensitive to antidiuretic hormone (ADH), and even arterial hypotension was produced when the plasma level of ADH was increased beyond its physiological range in chickens (Ames et al., 1971) and ducks (Brummermann and Simon, 1990). Thus, putative central actions of the circulating hormones may be analyzed in birds with less baroreceptor reflex interference than in mammals. (b) Avian species that are genetically adapted to saline or marine habitats, excrete excess salt with the help of supraorbitally located salt secreting glands (Schmidt-Nielsen 1960; Holmes and Phillips, 1985; Simon and Gray, 1989; Gerstberger, 1991). Such glands do not exist in mammals. The avian salt glands are under direct central nervous control via parasympathetic efferents (Fringe et al., 1958; Ash et al., 1969) and, thus, represent an effector system in which all components are accessible to neurophysiological analysis. (c) Not least, birds differ from mammals in that a cluster-like type of sub-organization of brainstem nuclei, which is particularly prominent in reptiles, has in part been preserved in birds but has almost completely vanished in mammals (Oksche, 1976, 1978; Korf, 1984). This particular neuronal cytoarchitecture implies a more distinct grouping of functionally equivalent neurones and should facilitate the electrophysiological characterization of functionally different neurones in the rostral brainstem of birds (Kanosue et al., 1990; Matsumura and Simon, 1990a). Reviewing the currently available evidence for ANGII responsive neurones in the brain of birds has to include the effects of the peptide on centrally controlled regulatory activities as well as their structural correlates, which have provided the basis for electrophysiological analysis. Particular attention will be given to those ANGII effects which are relevant for body fluid homeostasis and associated cardiovascular adjustments, since experimental evidence in birds for the role of ANGII as a circulating hormone and as a messenger to and within the brain in the control of salt and fluid balance and circulation, has become as similarly conclusive as in mammals.
cleavage from the protein angiotensinogen is tightly controlled by renin, a specific protease of mainly renal origin. The components of this sequence are termed the renin-angiotensin system (RAS). The RAS and the intrarenal juxtaglomerular complex of the macula densa evolved early in the phylogeny of vertebrates and are also active in birds (Chan and Holmes, 1971; Nishimura, 1980; Wilson, 1984a, b, 1989). As in mammals, the state of activity of the RAS in birds seems to be strongly volume dependent. Hypotensive haemorrhage in pigeons (Chan and Holmes, 1971) and in chickens (Nishimura and Bailey, 1982) enhanced renin activity. In the quail haemorrhage (of an unspecified degree) increased the plasma concentration of ANGII (Kobayashi and Takei, 1982.) In the kelp gull plasma ANGII concentration was shown to rise in proportion with blood volume loss in the range of 0-20% of estimated blood volume (Gray, 1987; Simon-Oppermann et al., 1988). Water deprivation as a means to induce volume depletion in both the intra- and extravascular compartments of the extracellular fluid volume also consistently increased plasma ANGII to degrees that were correlated in the ostrich (Gray et al., 1988), kelp gull, cape gannet and jackass penguin (Gray and Erasmus, 1988) with body weight loss and generally with the rise in plasma osmolality as an indicator of dehydration (Simon et al., 1989). Levels of circulating ANGII which temporarily rose as high as 300 fmol/ml were observed in ducks during acclimation to maximum chronic salt stress (Gray and Simon, 1985) and in Japanese quail during 48 hr of dehydration (Takei et al., 1988). Conversely, extracellular volume expansion by intravenous loading with isosmotic saline lowered plasma ANGII in kelp gulls (Gray, 1987). Volume expansion in ducks with isosmotic and slightly hyperoncotic dextran, which remained confined to the intravascular compartment and substantially increased the plasma concentration of the notably blood volume sensitive atrial natriuretic factor (ANF), had little influence on the ANGII plasma concentration (Keil et al., 1991). Thus, in duck plasma, ANGII levels seem to be correlated more closely with the interstitial than the intravascular compartment, as indicated also by the observation that the gradual increase in ANGII plasma levels during physiological adaptation of ducks to chronic salt stress was associated with an extracellular volume reduction that was confined to the extravascular compartment whereas blood volume remained unchanged (Brummermann and Simon, 1990).
2. CONTROL OF CIRCULATING ANGIOTENSIN H IN lm~Ds
3. ANGIOTENSIN H SPECIFIC SYSTEMS IN THE ROSTRAL BRAIN'STEM OF BIRDS AS COMPARED TO ~ M M A L S
The active peptide in birds is 5vaI-ANGII, an analog to 5ile-ANGII found in most mammals, and both have comparable biological activities in birds and mammals (Nakayama et al., 1973; Evered and Fitzsimons, 1981a). Formation of ANGII as a circulating hormone seems to be basically identical in birds and mammals. By the action of the ubiquitous convetting enzyme the active octapeptide is ultimately cleaved from the decapeptide angiotensin I, whose
3. I. NEURONALSYSTEMSAND INTERCONNECTIONS Important neuronal structures involved in the control of salt and fluid balance are located in the most rostral extension of the brainstem. Compared to mammals, the anatomical evaluation of the brain of birds reveals multiple homologies in this region with a topography similar to that in mammals, if the
234
M °o
4
~SFO ,o.
I " MC"':!!F qi!:
FIG. 1. Schematic presentation o f a sagittal section (upper left) through a duck's hypothalamus according to the histological section (lower left). S F O = s u b f o r n i c a l organ, A C = a n t e r i o r commissure, OVLT = organum vasculosum laminae terminalis. AV3V = rostral and closely periventricular section of hypothalamus; VIII = third cerebral ventricle, M C = projection of the parasagittally located magnocellular portion of the paraventricular nucleus on the sagittal plane, PCh = choroid plexus. EM = median eminence. Schematic frontal sections (1-4, right) present coronal sections approximately along the planes that are indicated in the upper left schema (1-4). TSM = septomesencephalic tract.
181
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ANGIOTENSINII IN BIRDS
difference between mammals and birds in the stereotaxic position of the base of the brain, relative to the horizontal plane of the skull is taken into consideration (Karten and Hodos, 1967) (Fig. 1). As one of the notable quantitative differences, the supraoptic nucleus (SON) is less developed in birds, relative to the paraventricular nucleus (PVN) and, thus, the latter contributes more to the neurosecretory hypothalamo-neurohypophyseal system (Swanson and Sawchenko, 1983; Korf, 1984). As in mammals, two circumventricular organs (CVOs) are located in the rostral and dorsal border of the avian third ventricle which are considered as important target structures for ANGII: the organum vasculosum laminae terminalis (OVLT) occupies the most rostral and ventral extension of the ventricular wall; the subfornical organ (SFO) is located immediately dorsal to the anterior commissure (AC) in the roof of the third ventricle (Bosler, 1977; Takei et al., 1978; Kuenzel and Masson, 1988). Dorsal to the OVLT, a narrow band of neurones seems to represent a homolog to the median preoptic nucleus (MePO) of mammals (Kuenzel and Van Tienhoven, 1982) which is considered a major centre of integration in salt and fluid balance (McKinley et aL, 1989; Thrasher, 1989), receiving inputs from the OVLT (Camacho and Phillips, 1981) and SFO (Miselis, 1981). Periventricular clusters of neurones adjacent to the OVLT in the most rostral lateral parts of the third ventricular wall are present in birds and seem to correspond to the anteroventral third ventricle (AV3V) region in mammals which is also important as a site of neuronal integration in salt and fluid balance (Brody and Johnson, 1980). Taken together, a large degree of homology seems to exist between structures in the most rostral extension of the avian third ventricle, especially with regard to the arrangement of CVOs and hypothalamic nuclei (McKinley et al., 1990) that has been termed "forebrain receptor band for ANGII" (Plunkett et al., 1987) in mammals because of its target function for both circulating and brainintrinsic ANGII. 3.2. ANGII ASA BRAIN-INTRINSICPEPTIDE The presence of ANGII, together with all the components of a RAS, in brain tissue (Ganten et al., 1978) and of nerve fibers and neurones containing the peptide (Lind et aL, 1985; Imboden et al., 1987, 1989), have been amply confirmed for mammals. Taking the rostral hypothalamus of the rat as a well documented example, both immunoreactive nerve fibers and somata were found in the PVN, SON, and medial preoptic area. Immunoreactive terminals were also found in the region of the MePO, while immunereactive fiber tracts were particularly prominent in both the internal and external lamina of the median eminence. Among the rostral CVOs, the SFO was shown to contain both immunoreactive fibers and cells, whereas in the OVLT, ANGII-immunopositive staining was confined to nerve fiber varicosities. Synaptosomal endings were also found to contain renin as well as converting enzyme activity (Paul et al., 1985). The expression of the ANGII converting enzyme mRNA in the rat brain was reported just recently following the localization of the enzyme by
183
employing quantitative in vitro autoradiography (Chai et al., 1987; McKinley et al., 1990; Whiting et al., 1991). Both expression of specific mRNA and enzymatic activity were found in the SFO, the choroid plexus, the caudate putamen and the cerebel. lum. In birds, the ANGII-immunoreactive system of the brain has not yet been systematically mapped. A first immunocytochemical search was carried out in the hypothalamus of the duck (Ramieri et al., 1984) with an ANGII antibody that showed 10% cross reactivity with ANGIII in radioimmunological studies (Gray and Simon, 1985). In a subsequent study on the duck and quail hypothalamus, scattered ANGII positive somata of neurones were found in the SON and PVN. Positively staining fibers were sparsely distributed in the anterior hypothalamic region but formed a more distinct bundle in the third ventricular floor that extended throughout the inner layer of the median eminence (Ramieri, 1988) (Fig. 2). These preliminary data in two bird species suggest that the distribution of ANGII-immunoreactive cells and fibers does not basically differ in the mammalian and avian rostral brainstems. Peptide extracts obtained from chicken as well as duck brains and separated by reversed phase HPLC clearly revealed the presence of ANGII-like peptides co-eluting with bird-specific Sval-ANGII as proven by specific ILIA. With values of 50-80 fmol immunoreactive ANGII per g tissue wet weight, however, hypothalamic ANGII concentrations proved to be even lower than those reported for the rat central nervous system, suggestive of fast enzymatic degradation of the peptide (Hermann et al., 1984; Gray and Simon, 1985; Gerstberger, unpublished observation). Further evidence for a brain-intrinsic ANGIIsystem in birds has been provided by the comparative radioimmunological analysis of ANGII concentrations in the blood and cerebrospinal fluid (CSF) of conscious ducks (Gray and Simon, 1987). In euhydrated animals ANGII concentration in cisternal CSF was about 50% of that in blood plasma. In ducks deprived of water for 48 hr or chronically acclimated to hypertonic saline, ANGII concentrations were increased in each compartment. Interestingly, upon rehydration ANGII levels in the CSF had significantly decreased at a time when plasma ANGII levels had not yet changed significantly (Fig. 3). This observation was also made in dogs (Simon-Oppermann et al., 1986) and suggests for both mammals and birds that the generation of ANGII in the brain and in the circulation are controlled independently in accordance with the view that ANGII in the CSF is derived from the brain-intrinsic RAS and not from circulating ANGII for which the BBB is virtually impermeable (Ganong, 1984). To our knowledge, neither the central nervous distribution of renin- or cathepsinlike enzymes, nor of the converting enzyme cleaving the precursor angiotensin I (ANGI) to yield ANOII have been demonstrated in the brain of any avian species. Preliminary studies in the duck indicate processing of radiolabelled avian ANGI to ANGII using homogenized choroid plexus tissue and HPLC technology (Gerstberger, unpublished observation).
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E. SIMONet al.
characterized pharmacologically by competitive displacement of radiolabelled lsar-Sile-ANGII from its target sites. The labelled ANGII antagonist bound to duck hypothalamic membrane fractions could be 200 fully displaced by both the unlabelled antagonist and mammalian as well as avian ANGII with Ka values of 0.9, 1.8 and 1.3 nu, respectively. Avian-specific 100 ANGIII and ANGI as well as the ANGII antagonist ~sar-Sala-ANGII exhibited low affinities with Ka I CSF values in the micromolar range, while peptides such 0 as angiotensinogen, Sarg-vasotocin, mesotocin or substance P could not compete with radioligand binding (Gerstberger et al., 1987b; Gerstberger, unpublished observation). This sequence of potencies for the ANGII-specific binding sites proved to be comparable with that obtained for duck adrenal .~, 310 1 tissue (Gray et al., 1989), but differed from reports using rat HTS tissue with regard to the rather high affinities of ANGIII and ~sar-Sala-ANGII for the 290 21 20 mammalian ANGII receptor (Mann et al., 1981; Mendelsohn et al., 1984). Avian ANGII receptor Ibefore I tafter I ,l$0minaftm'l molecules might therefore represent a new type of 24-48 h cl~ydratlon r~ydration ANGII-specific binding sites in the vertebrate kingdom in general. Fie. 3. Osmolality (lower ordinate) and ANGII conTo identify discrete neuronal entities in the central eentration (upper ordinate) in plasma (dots) and cerebrospinal fluid (CSF, circles) of conscious ducks in the state of nervous system bearing ANGII-specific binding sites, normal hydration, after 24--48hr of water deprivation, and autoradiography enabled the exact histological local150min after rehydration. Numerals indicate number of ization and spatial distribution of ANGII receptors measurements. Asterisks indicate mean values which were in the brain of various mammals such as the rat sJt,nit~antly different (*P < 0.01, **P < 0.005) from their (Mendelsohn et al., 1984; Gehlert et al., 1986a; preceding values. (Simon-Oppermann et al., 1988, Saavedra et al., 1986; Tsutsumi and Saavedra, 1991), modified.) rabbit (Mendelsohn et al., 1988), dog (Speth et al., 1985), sheep (McKinley et al., 1986) and human (McKinley et al., 1987; Allen et al., 1988). With 3.3. ANGII RECEPTORSIN DUCKBRAINWITHSPECIAL regard to lower vertebrates and birds in particular, the duck brain exclusively has been screened for REFERENCETO THE ROSTRALBRAINSTEM binding sites specific for ANGII (Gerstberger et al., 1987a, b) (Table 1). Neuronal structures outside the 3.3.1. A N G H receptor characterization and BBB, such as the SFO and OVLT, and therefore localization accessible to blood-borne ANGII (Fig. 4), were To act on central nervous structures, both blood- prominently labelled in all species investigated includborne ANGII and ANGII of neuronal/glial origin ing the duck, and the same holds true for the interact as "first messengers" with membrane-intrin- neurosecretory system of the median eminence with sic receptor proteins with subsequent activation or high receptor densities found in the duck median inhibition of intracellular signal transduction path- eminence for both its anterior and posterior section. ways. To identify central nervous ANGII receptive Autoradiographical Scatchard analysis of putative mechanisms, binding studies have been performed ANGII binding sites in consecutive tissue sections of almost exclusively in the rat brain with additional the rat SFO and median eminence resulted in high receptor characterization in the central nervous sys- receptor densities of 175 and 50 fmol/mg protein, tern of some rodents and calves using radioactively respectively (Plunkett et al., 1987), with comparative labelled ANGII of high specific activity (Bennett and quantitative data in avian species not being available. Snyder, 1976; Harding et aL, 1981). Enriched Similar to results obtained in the rat, competitive membrane fractions of the rat hypothalamus-- displacement studies carried out for the duck thalamus-svptum (HTS) region as a source for the SFO revealed the same potency of various ANGII specific ANGII binding proteins revealed a dis- analogs to displace radiolabelled lsar-Sile-ANGII as sociation constant (Ko) of 0.2-5.5 nM for the ligand- demonstrated for hypothalamic tissue preparations receptor compkx at receptor densities of 8-15 fmol/ (Gerstberger et al., 1987b). nag protein depeading on the study performed (Sirett Scattered specific labelling of the choroid plexus et al., 1977; Mann et al., 1981; Mendeisohn et al., (PCh) could be found in the duck brain, indicative of 1983, 1984; Leun8 et al., 1991). Comparable data the putative regulatory action of circulating ANGII could be obtained for the freshwater acclimated on trans-epithelial transport in the process of CSF Pekin duck with a hypothalamic ANGII receptor production by PCh epithelial cells. Through alterdensity of 4 fmol/mg protein at a dissociation con- ation of PCh blood flow or ion transport, marked stant of 1.2nM when using radiolabelled avian changes in the local environment of periventricular ANGII as ligand (Gentberjer et aL, 1987a, b). The neurones and glial cells might, thus, be provoked by duck hypothalamic ANGII receptor could further be ANGII as described for the rat (Maktabi et al., 1990). 300
301/ =
1
"
r
dt
B FtG. 4. Autoradiographic localization of ANGII-spccific binding sites in coronal sections of the adult duck brain using [125I] nsar-Sile-ANGII as radioligand. (A): Specific ANGII binding sites could be labelled in the subfornical organ (SFO), the AV3V region and the amygdala-analogous structure of the nucleus taeniae (TN). (B-D): Binding of the radioligand to the subfornical organ (SFO) of a saltwater-(B) and freshwater-acclimated (C) duck. Non-specific binding is demonstrated in (D) (Gerstberger et al., 1987b). Bars represent 1 ram. 185
Fro. 5. Autoradiographic localization of ANGII-specific binding sites in embryonic and juvenile duck brains using [~25I]-ANGII as radioligand. One day before hatching (A, B), ANGII-spexific binding sites can be located in the paraventricular nucleus (PVN), the amygdala-analogous structure of the nucleus taeniae (TN) and the ventromedial hypothalamic nucleus (VMN): Labelling of the subfornical organ (SFO) is demonstrated eight days (C) and one day (D) before, as well as 3 days (E) and 14 days (F) after hatching. The choroid plexus (ClaP) is labelled only in very early embryonic stages (C) and scattered binding only returns in adulthood. (Courtesy of Mr A. R. Mfiller). Bars represent 1 mm.
186
ANOIOTENSlN II is BraDS
187
TABLE I. DmTmmmoN oF ANGII BtNDINGSrrEs L~ V,~mOUSCENTRALNmtvotm STRUC1'tm~ OUTSIDE(UPPER SECTION)AND INSIDE(LOWERSECTION)THEBLOOD--BaAINB ~ OFT ~ RAT, R.~arr, DoG, SH~P, HUM~ ANDDUCK Rat AH AP
+++ ++
Rabbit
Dog +++ +++ ++ +++
OVLT
++
+ +++ ++
~h
++
+
ME
PI SFO AMYG ARC AV3V DMX IO LS MnPO NTS OB PVN SCN SON
+
0 +++
++ +
+++ ++ ++ ++ +++ +++ +++ +++ +++
0 +++ ++ + 0 ++ ++ +++ + ++
Sheep
Human
Duck
+++ +++
+ + ++ +
++
++ +++
++ +++
+
++ +++
0 +++
+++ ++ +++
+ +++ +++ ++
++ +++ +++
+++ +++ ++
+ ++
0 ++
+++ +++ + +++ +++ +++ +
+++ + + ++ ++ ++ + +
Abbreviations: AH = adenohypophysis, AMYG ffi amygdala complex, AP ffi area postrema, ARC -- arcuate nucleus, AV3V = anterio-ventral third ventricular region, DMX = dorsal vagal motor nucleus, IO = inferior olivary complex, LS = lateral septum, ME = median eminence, MnPO = median preoptic nucleus, NTS = nucleus of the solitari tract, OB = olfactory bulb, OVLT = organum vasculosum laminae terminalis, PCh •ffi choroid plexus, PI = pineal gland, PVN ffi paraventricular nucleus, SCN ffi suprachiasmatic nucleus, SFO = subfornical organ, SON--supraoptic nucleus. (For references see text.) (0,+,+ + , + + +) reflect optical semi-quantitative ratings.
Of other CVOs located in the ependymal lining of the third cerebral ventricle, the pineal gland was endowed with A N G I I receptors in the dog and duck, with negative results reported only for the rabbit and sheep, thus, reflecting possible species variations, while the subcommissural organ proved to be devoid of ANGII-specific binding sites. Periventricular areas within the BBB and possibly relayed to the OVLT and/or SFO such as the MePO and the AV3V region (McKinley et aL, 1990), expressed ANGII-specific binding sites in all species examined, suggestive of the important role that A N G I I may play as a brain-intrinsic modulator in hydromineral homeostasis. This view is supported by the presence of A N G I I binding sites in the A D H synthesizing nuclei, both the PVN and SON, of the duck as well as many mammalian species (Fig. 4). In addition, distinct periventricular sites containing mostly fibers and only few perikarya, and possibly representing fiber connections between the SFO and median eminence, were marked by labelled A N G I I in the avian brain, as were the ventromedial hypothalamic nucleus and components of the thalamic habenular complex. Neuroanatomical areas reciprocally connected to the autonomic centres of the duck hypothalamus such as the lateral septum or amygdala-analogous entities (nucleus taeniae) could be labelled with the radioligand to moderate and high degrees, respectively. With regard to the septum, this observation is comparable to findings in the brain of the rat, mouse, hamster, rabbit, dog and human (Harding et al., 1981; McKinley et al., 1987; Mendelsohn et al., 1988). In summary, A N G I I specific binding sites could be localized in hypothala-
mic nuclei and areas both inside and outside the BBB possibly involved in modulatory functions within the regulatory circuits of body fluid homeostasis in both birds and mammals. Among the A N G I I binding sites outside the hypothalamic and adjacent brain regions, those in the lower brainstem of mammals, especially in the locus coeruleus, area postrema, nucleus of the solitary tract and adjacent motor nuclei (Sirret et al., 1977; Mendelsohn et al., 1984; Heal), et al., 1986; Diz et al., 1987) have received attention as putative targets mediating part of the modulatory actions of A N G I I on circulatory control. This assumption rests on studies on dogs (Joy and Lowe, 1970; Gildenberg et aL, 1973; Atsuhiro et al., 1986; Averill et al., 1987) and rats (Casto and Phillips, 1984; Rettig et al., 1986; Unger et ai., 1988; Muratani et al., 1991). With special respect to the area postrema, sustained alterations of circulatory control were not observed in animals with chronic lesions (Zandberg et al., 1977; Haywood et al., 1980). Further, a less specific relationship cannot be excluded between circulatory responses mediated by the area postrema and the more general chemoreceptor properties of this structure which have been implicated in the generation of emesis (Carpenter et al., 1988). F o r birds, the only evidence for A N G I I receptors in the lower brainstem has been provided by studies on the duck (Gerstberger et al., 1987a, unpubfished observation) which demonstrated a distribution similar to that in mammals (Table 1). As a target for physiological actions of A N G I I , the lower brainstem of birds has not been studied, so far. However, considering that physiological changes in A N G I I plasma concentration did
188
E. SIMONet al.
not affect arterial blood pressure (Simon-Oppermann et al., 1984), possible target functions on the blood side of the BBB do not seem to be functionally relevant in cardiovascular control of birds. As demonstrated for most peptidergic and nonpeptidergic receptor proteins, binding hormones or neurotransmitters with high affinity, the presence of more than one subtype of ANGII-specific binding site has been postulated (Chiu et al., 1989). To pharmacologically differentiate between the ANGII receptor subtypes ATe, which is sensitive to sulfhydryl reducing agents, and AT2, non-peptidic imidazole ligands were used as A N G I I specific receptor antagonists (Chang and Lotti, 1989; Chiu et al., 1989) to displace radiolabelled ANGII or its antagonist ~sar-Sile-ANGII from rat central nervous binding sites. Regions consistent with known actions of angiotensin II such as the OVLT, SFO, PVN, PCh, median eminence or nucleus of the solitary tract contained AT~ receptor subtypes exclusively, while AT2-type receptors could be localized in the thalamus, lateral septum and medullary structures such as the locus coeruleus, medial geniculate nucleus and the inferior olive (Gehlert et al., 1990; Rowe et al., 1991; Song et al., 1991; Tsutsumi and Saavedra, 1991). Until now, a functional response cannot be attributed to the AT 2 subclass of A N G I I receptors. With values for the inhibitor constants of 10-500 nM in the case of the AT:specific antagonist and even higher values for the AT2-antagonist, further investigations seem necessary to specify imidazole ligands as valuable tools in central ANGII receptor research. Autoradiographical binding studies in the duck central nervous system revealed a marked displacement of both monoradioiodinated 5vaI-ANGII and lsar-Sile-ANGII from all hypothalamic and amygdala-complex binding sites in the presence of sulfhydryl reducing agents, indicative of AT~ type prevalence (Gerstberger, unpublished observation). With regard to second messenger systems possibly involved in signal transduction coupled to A N G I I receptors in the brain, only limited information is available. Using primary neuronal and astrocyte glial cultures prepared from 1-day-old rat hypothalami, ANGII-specific binding sites were characterized in both cell types with prevalence of the A T : t y p e in glial cells and the AT2-type in neuronal cells (Raizada et al., 1987; Sumners and Myers, 1991; Sumners et al., 1991). In the astrocyte glial cultures, ANGII increased inositol phospholipid hydrolysis, while in neuronal cultures neither the IP3/DAG system, nor the formation of cyclic AMP could be modulated by the presence of ANGII in the medium (Sumners et al., 1990). On the other hand, basal cellular cyclic GMP (cGMP) concentrations are decreased by A N G I I in a time- and concentration-dependent way in the neuronal, but not glial culture system (Sumners and Myers, 1991), while cGMP increased in a murine neuroblastoma cell line (Gilbert et al., 1984). For the avian central A N G I I receptive system, neither data concerning the presence of glial A N G I I binding sites nor the role of putative second messengers have been obtained so far.
3.3.2. A N G H
receptor regulation
In the rat, ANGII plays a role in the central control of salt intake within the first few weeks after birth, and the number of whole brain A N G I I receptors is maximal in two-week-old rat pups. Autoradiographical analysis revealed a marked increase in A N G I I binding sites in the various medullary nuclei of the pup's brain as compared to the adult stage, and the existence of additional cerebellar cortical binding sites no longer present in the adult animal (Leshem and Epstein, 1989; Tsutsumi and Saavedra, 1991). With regard to age-dependent expression of hypothalamic ANGII binding sites of the AT:type, ATt receptor densities proved to be higher in young as compared to adult rats in the SFO, while the suprachiasmatic nucleus and the PCh were endowed with lower AT~ receptor concentrations. Labelling was comparable in both groups of animals in the PVN and SON. In the Pekin duck, preliminary investigations were performed at the embryonic stages 8 and I day(s) before hatching as well as 3 and 14 days after hatching, using radiolabelled birdspecific 5val-ANGII as radioligand (Fig. 5). Both the ADH-synthesizing PVN and the amygdalaanalogous structure of the nucleus taeniae were endowed with A N G I I binding sites at day 1 before hatching, while at the early embryonic stage these structures could not be clearly identified histologically or through receptor autoradiography. In contrast, the PCh of the lateral ventricles were heavily stained at day 8 before hatching with progressively weaker labelling in later pre- and posthatching periods. The pineal gland revealed high binding capacity throughout all stages of development, whereas the median eminence appeared not to express receptor proteins before hatching. The SFO as the prime target organ of circulating ANGII showed slight labelling at day 1 before hatching with gradual increase in the binding signal up to adulthood (Fig. 5). These data might reflect the development of the hypothalamic ANGII receptive system in structures playing a role in the central control of body fluid homeostasis in the duck starting even before hatching. As mediator of the dipsogenic effects of circulating and possibly also central ANGII in birds and mammals, the SFO-intrinsic ANGII receptive system undergoes up- and down-regulation, with regard to receptor density primarily, depending on the status of the extracellular fluid volume (ECFV). In rats chronically dehydrated for 5 days, only the anterior pituitary and the SFO revealed a significant increase in ANGII receptor density with constant values for the PVN, MePO and OVLT. Chronic dietary sodium depletion, on the other hand, reduced the expression of functional SFO binding sites specific for ANGII (Hwang et al., 1986; Nazarali et al., 1987; Ray et al., 1990). In addition to these, experimentally induced alterations in ECFV, persistent high arterial pressure as found in the genetically hypertensive SHR rat or after repeated stress, increased the density of A N G I I binding sites in the SFO and components of the ADH-synthesizing neuroendocrine circuit (C~hlert et al., 1986b). Unlike experimental dehydration in mammals which can be maintained only for a limited
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FIG. 6. Dose dependent water intake (ordinate) of pigeons in response to intracranial and intraperitoneal injections of ANGII at doses between 100 fmol and 1 #mol (abscissa). Numerals in brackets indicate number of measurements. (Evered and Fitzsimons, 1981a, modified.) length of time, the Pekin duck can be adapted chronically to hypertonic saline as drinking fluid, due to the presence of their supraorbital salt glands (Simon, 1982), with a restricted degree of permanent dehydration (Gray et al., 1987). Acclimation to hypertonic sodium intake in these birds induced a stimulation of the peripheral and central RAS (Gray and Simon, 1987) associated with a marked up-regulation of ANGII binding sites in the SFO exclusively (Gerstberger et al., 1987a, b). Thus, saltwater-acclimated birds showed a three-fold rise in ANGII receptor density in the SFO with unchanged binding affinity, at elevated plasma and cerebrospinal fluid ANGII immunoreactivity (Fig. 4). This hypersensitivity of the central nervous ANGII system due to augmentation of both the hormonal/neuromodulatory signal and membrane-intrinsic receptive elements under conditions of ECFV depletion represents a rare example of signal transfer enhancement in the vertebrate kingdom.
4. CENTRALLY MEDIATED PHYSIOLOGICAL ACTIONS OF ANGIOTENSIN H IN BIRDS 4.1. DRINKING AS A BEHAVIOURAL ACTIVITY IN SALT AND FLUID BALANCE
As in mammals, ANGII-induced drinking has also been well studied in birds, and there can be little doubt that central targets are required for ANGII to induce this response. ANGII infused intravenously at sufficiently high rates or injected into the rostral brainstem or third ventricle was shown to stimulate drinking in the sparrow (Wada et aL, 1975), pigeon (Evered and Fitzsimons, 1976, 1981a; Kaufman and Peters, 1980; Barraco et al., 1984), quail (Takei, 1977a; Kobayashi and Takei, 1982), fowl (Snapir et al., 1976; Schwob and Johnson, 1977), duck (DeCaro et al., 1980), and turkey (Denbow, 1985). For each route of application the dose dependence of the amount of water drunk could be demonstrated (Fig. 6). Attempts were made by means of stereo-
189
taxicallycontrolledintracerebralANGII injectionsto localize the specific target structures involved. Data obtained in the pigeon (Evered and Fitzsimons, 1981a) and quail (Kobayashi and Takei, 1982) showed that periventricular sites in the ventral preoptic area (POA) close to the midline were particularly sensitive. Furthermore, injections directly into the SFO and the dorsal third ventricle near its junction with the lateral ventricles were particularly effective (Takei, 1977b). In all, the locations of these sites were shown to correspond to the distribution of ANGII receptors in the duck hypothalamus (Gerstberger et al., 1987a, b), including the SFO, the POA and the AV3V region. Catecholaminergie fiber tracts running from the quail POA towards the SFO appear important in the stimulation of water intake elicited by ANGII injection into the POA as proven by the ineffectiveness of ANGII to stimulate drinking after fiber transsection. Information relayed by ANGII and perceived by the POA might, thus, require catecholaminergic nerve fiber inputs in order to be transferred properly (Takei et aL, 1979). The presence of both tyrosine-hydroxylase immunoposirive fibers and ,q- as well as a2-specific adrenoceptors in the SFO of the duck also suggest catecholaminergic modulation at the SFO target site of central ANGII action (Gerstberger et aL, 1992). The results of pharmacological studies to test the specificity of ANGII in eliciting drinking in birds, though not fully consistent, have supported the function of ANGII as a natural, centrally acting dipsogen. ANGII-induced drinking in pigeons was inhibited by lsar:ile-ANGII and tsar-Sleu-ANGII (DeCaro et al., 1982), but lsar-Sala-ANGII was ineffective as an inhibitor, while the action of ANGIII as an agonist was only 1% of that of ANGII (Evered and Fitzsimons, 1981b). In turkeys, tsar-Sala-ANGII attenuated but did not completely abolish ANGII induced drinking (Denbow, 1985). The neurones of the SFO which are directly accessible to blood-borue agents were considered early as the most likely rostral brainstem target in both mammals and birds (Fitzsimons, 1980) where circulating ANGII acts to stimulate drinking and other effectors of salt and fluid balance. Similar to evidence in mammals (Thrasher et al., 1982), experiments in the pigeon showed that drinking in response to blood-borne ANGII was diminished after lesioning or isolating the SFO, which also attenuated the drinking response to acute hypovolemia, while water deprivation as a dipsogenic stimulus involving hypertonicity was not impaired (Massi et aL, 1986). Less clear is the role of the OVLT in mammals, and in birds this organ has not been systematically studied. The question whether or not exogenously induced increases in plasma ANGII within the physiological range may affect water intake has not been definitely settled for mammals (Andersson et al., 1984; Phillips 1987). As far as birds are concerned, studies in one pigeon (Evered and Fitzsimons, 1981a) showed that the threshold doses for the stimulation of water intake by intravenous ANGII infusions of 15 min duration were in the order of 3-15 pmol/min/kg body weight. When selecting intravenous infusions of about 0.3 ml/min of hypertonic (0.5 M) saline for 15 min, or of equally hypertonic sucrose or mannitol
E. SIMON et al.
190 40
[mlI] i 30
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| II OL
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I 0.15
I 0,30
Conc~ratJon of NaO so0utlon~
I 0.4.5
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FIG. 7. Drinking (ordinate) of pigeons in response to infusions into the third cerebral ventricle (abscissa) of hypertonic saline of increasing concentrations at a rate of 2/zl/min for 10min (circles) and to administration of ANGII (dots) together with the hypertonic infusions. (Fitzsimons et al., 1982, modified.) solutions, as a dipsogenic stimulus in normally hydrated pigeons, drinking was distinctly augmented when the hypertonic stimulus was combined with 3 nmol ANGII (Fitzsimons et ai., 1982). These data clearly indicate that the levels at which circulating ANGII was dipsogenic in pigeons, or capable of potentiating the effects of other dipsogenic stimuli, were well within the physiological range, considering the relationship between plasma ANGII concentrations and ANGII infusion rates determined in ducks (Gray and Simon, 1985) and gulls (Gray and Erasmus, 1989). Higher threshold infusion rates for ANGII were determined by other authors in pigeons (Kaufman and Peters, 1980) and in quail (Takei, 1977a). However, the minimum doses evaluated as dipsogenic appear to be more pertinent, because drinking, as a complex behavioural reaction, may be subject to impeding motivational and physiological influences that cannot be controlled by the experimenter. If one compares the dipsogenic potency of systemically and intracranially applied ANGII, the latter route requires, as a rule, much smaller amounts of ANGII to become effective in both mammals and birds (Fitzsimons, 1980) (Fig. 6). In the quail, a single dose of 5 pmol ANGII was sufficient to elicit drinking when injected directly into the preoptic area or into the SFO (Takei, 1977b, Kobayashi and Takei, 1982). In the pigeon, the threshold dose for drinking of ANGII administered into the third ventricle was between 10 and 100 fmol, as compared to 0.1-1.0 /~mol with single intraperitoneal ANGII injections, while with intravenous application the dipsogt~c threshold dose of ANGII was between 3 and 15 pmol/min/kg body w~isht ~ a i a t e r e d for 15 min (Evered and Fitzsimons, 1981a). Similar to the combination of ANGII with osmotic stimuli in systemic applications, the dose-dependent drinking r e -
sponse to intracranial 10rain infusions of 2/~l/min hypertonic saline with increasing NaCI concentrations was augmented in an approximately additive fashion, when 10 pmol ANGII were added to the hypertonic infusate (Fig. 7). Deducing from generally lower ANGII doses, greater physiological relevance of the intracranial as compared with the systemic route of ANGII action, however, does not seem to be justified. Intracranial doses of ANGII were usually delivered in both mammals and birds in small volumes (in the order of 1 #1) and, therefore, ANGII concentrations in the central infusates were usually in the order of 1-100 pmol/ml, i.e. much higher than in circulating blood or in the CSF. For this reason it is difficult to use dosage as a basis from which to draw conclusions concerning the physiological significance, if comparisons are made between putative ANGII receptors on the blood and brain side of the BBB. On the other hand, the high ANGII concentrations used for intracranial stimulations are no argument against the physiological relevance of the observed effects. According to histochemical evidence, ANGII is strongly compartmentalized in the brain, being stored at presumably very high concentrations in nerve fibers and synaptic varicosities. Therefore, high concentrations might well occur at localized sites, when brain-intrinsic ANGII is released, for instance, at synaptic junctions. Comparisons between the effects of ANGII, acting either from the blood or the brain side of the BBB, are further complicated by the possibility that permeation across the BBB may not be symmetrical for ANGII circulating in the blood or being released, and injected respectively, into the brain or CSF at high concentrations. Tanycytes, which are located in the ependyma but may reach the pial surface of the brain with their processes, have been implicated as carriers for ANGII from the CSF into the interstitial compartment of the brain and even into the CVOs (Andersson et al., 1984; Phillips 1987). Further speculations take into consideration so-called CSF-contacting neurones (Vigh and Vigh-Teichmann, 1973; Leonhardt, 1980; Bruni et al., 1985) which send dendrites across the ependyma and, within the CVOs, might be capable of sensing both circulating and intracerebral ANGII (Buranarugsa and Hubbard, 1979; Andersson et al., 1984). These speculations would imply that ANGII and various analogs, respectively, may penetrate the BBB more easily from the brain to the blood side than vice versa. Supportive evidence for this hypothesis can be drawn from the observation, that the intracranial application of the ANGII antagonist ~sar-Sala-ANGlI prevented the binding of blood-borne [125I]-ANGII to the CVOs (Van Houten et al., 1983). 4.2. BLOODPRESSURECONTROL As indicated in the introduction, a number of studies suggest that direct vasoconstrictor actions of ANGII are not physiologically relevant in birds. Slight increases in blood pressure by 5-10 mm Hg were observed in conscious pigeons when approximately 15 pmol/min/kg body weight ANGII was infused i.e. (Evered and Fitzsimons, 1981a). In anacsthetiz~ chickens bolus injections of 10-1000 pmol/kg
ANOIOTENSINII n~ BIRDS anti AVT I.v.
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FIG. 8. Mean arterial pressure (MABP), heart rate and respiratory frequency of ducks responding typically with arterial hypertension and tachycardia (left part) to intracvrebroventricular (i.c.v.) infusion of 2pmol/min/kg body weight over 10 rain. Preceding intravenous (i.e.) infusion of an AVT-antiserum (right part) attenuates the responses to i.c.v. ANGII infusion. (Gerstherger et al., 1984a). body weight ANGII produced biphasic blood pressure changes consisting of a short-lasting initial drop and a subsequent dose-dependent rise (Nishimura et al., 1982). In conscious chickens the primary depressor action of ANGII injections was more pronounced and the subsequent pressor response was observed only with doses of 0.5 and 1.0nmol ANGII (Nakamura et al., 1982). Continuous ANGII infusion at a rate of 200 pmol/min/kg body weight in conscious chickens caused an initial depressor response which was restored within 5 rain, but in the further course of the infusion arterial pressure tended to decrease continuously (Goto et al., 1986). Injection and infusion studies in conscious ducks showed that an estimated threshold plasma concentration of 2000 fmol/ml ANGII, which is clearly beyond the physiological range, had to be surpassed before measurable rises in blood pressure could bc detected (Simon-Oppermann et aI., 1984). The absence of a generalized vasoconstrictor response to A N G I I applies equally to 5vaI-ANGII and 5ile-ANGII (Brummermann and Simon, 1990). Apparently smooth muscle cellsdo not possess sufficient A N G I I binding sitesand/or intraccllularsecond messenger systems necessary for activation of constriction. N o constrictor effects were detected when avian aortic, sciatic and pulmonary arteries were tested/n vitro for the effectsof A N G I I (Somlyo et al., 1967; Moore et aL, 1981). This would conform to evidence in vivo according to which the pressor responses of birds to pharmacological doses of A N G I I are caused indirectly, as the result of the facilitatory action of A N G I I on catecholamine secretion, an action c o m m o n throughout vertebrate
191
phylogeny (Wilson, 1984b). This mode of action is suggested by the observation that in chickens and ducks doses of 1 nmol/kg body weight ANGII had to be administered in order to se¢ appreciable prcssor responses which were, however, associated with large rises in plasma norepinephrine keels (Wilson and West, 1986). Blockade of r,-receptors enhanced the early hypotensive and diminished the subsequent pressor actions of 200 and 500 pmol/kg body weight ANGII in anaesthetized chickens (Nishimura et al., 1982). The hypertensive component of the blood pressure responses to ANGII doses of I nmol/kg body weight was substantially diminished by reserpine pretreatment (Wilson and Butler, 1983). As a conclusion, the inability of physiological levels of circulating ANGII to trigger pressor responses by acting peripherally in both conscious and anaesthetized birds allows us to state with greater certainty than in mammals, that the circulating hormone does not trigger physiological pressor responses by a central action on any of the putative hypothalamic and lower brainstem ANGII receptors. Interestingly, the antidiuretic hormone, in both the avian form 8arg-vasotocin (AVT), and the mammalian form, 8arg-vasopressin (AVP), does not increase blood pressure in birds when administered peripherally. Large doses rather had a hypotensive effect in chickens (Ames et al., 1971; Wilson and West, 1986) and ducks (Wilson and West, 1986; Brummermann and Simon, 1990). For this response, as well as for the early hypotensive response to ANGII, a direct relaxing effect on the vascular walls has been taken into consideration (Wilson, 1989). This assumption would be in accordance with the surprising observation that progressive increases in both AVT and ANGII plasma concentration in the course of acclimation of ducks to severe salt stress were associated with a distinct decrease in arterial pressure (Brummermann and Simon, 1990). Blood pressure responses to centrally applied ANGII have been little studied in birds. Intracranial injections of ANGII in pigeons at sites where drinking could be elicited with doses of I pmol, did not increase arterial pressure, and a slight pressor response was seen only with a dose of I nmol (Evered and Fitzsimons, 1981a). On the other hand, circumscribed perfusions of the third ventricular lumen of conscious ducks in the state of diuresis with ANGII at a rate of 2 pmol/min/kg body weight for 10 min and at sites where antidiuretic responses could be elicited, increased arterial blood pressure by some 30 mmHg, and doubled heart rate (Gerstberger et al., 1984a) (Fig. 8). Since an overflow of ANGII into the circulation was unlikely and, moreover, would not explain the hypertensive response, these effects must have been elicited on the brain side of the BBB. The response pattern strongly suggests that cardiovascular sympathetic innervation was stimulated and possibly also cardio-inhibitory parasympathetic innervation inhibited during third ventricular ANGII perfusion. An interesting observation was that systemic application of an AVT antiserum not only abolished the antidiuretic effect of centrally administered ANGII but also reduced the hypertensive response (Fig. 8), despite the well-founded fact that systemic AVT produces arterial hypo- rather than
192
E. SIMON et al. 15
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FIG. 9. Perfusion of third cerebral ventricle (i.c.v.) at 5 #l/min for 10 min with ANGII at concentrations between 100 fmol/ml and 1 nmol/ml (2 fmol/10 min/kg body weight to 20 pmol/10min/kg body weight) in ducks made diuretic by continuous intravenous infusion of 1 ml/min hypotonic (200 mOsmol/l) saline: ANGII i.c.v, dose-dependently increased AVT plasma levels (AAVT) and amounts of urine retained during 30 min, relative to average steady state excretion rate (AUv) as an indicator of antidiure=s: (Gerstbcrger et al., 1984a.) hypertension in birds. This seems to suggest that intracranially acting A N G I I released AVT as a secondary mediator which acted on brain structures that were also accessible to blood-borne AVT-antiserum, i.e. most likely one of the CVOs. A further observation was that the effects of third ventricular A N G I I perfusion could be elicited only in the rostroventral part of the third ventricle. The critical importance of the site of perfusion might explain the discrepancy of presser responses in ducks (Gerstberger et al., 19Ma) and negative results in pigeons (Evered and Fitzsimons, 1981a). 4.3. CENTRAL CONTROL OF THE ANTIDIURETIC HORMONE
ANGII as a centrally acting stimulator for ADH release has been frequently studied in mammals. While antidiuretic responses to centrally applied A N G I I were a consistent response, divergent results have been obtained with systemic application and have precluded a clear answer to the question whether stimulation of A D H release by circulating A N G I I is physiologically relevant (Reid, 1984). Theoretically, A N G I I as a volume-controlled hormone would be a plausible mediator for volume influences on A D H release, in addition to inhibitory inputs from cardiovascular high and low pressure afferents which, as in mammals, are also relevant in avian volemic control of ADH (Simon-Oppermann et ai., 1980). However, where plasma A N G I I levels could be estimated m mammals, doses of A N G I I effective in eliciting antidiuresis were above the physiological range (Phillips, 1987). The same seems to apply for birds. In the quail the intraperitoneal A N G I I dose required to double resting AVT plasma concentration amounted to 100 nmol/kg body weight
(Kobayashi and Takei, 1982). In hydrated chickens receiving intravenous A N G I I infusions only the highest rate of 200 pmol/min/kg body weight raised plasma AVT concentration significantly (Gore et al., 1986). In conscious salt and fluid loaded ~ with a resting plasma A N G I I concentration of 50 fmol/ml, increasing the hormone concentration for 2 hr to levels of 700 fmol/ml by intravenous infusion did not influence plasma AVT concentration (Gray et al., 1986). In the kelp gull sustained increases in plasma A N G I I from a level of 60 fmol/ml to a level o f over 300 fmol/ml did not alter plasma AVT levels and, when the same A N G I I infusion was given together with hypertonic saline, the rise of plasma AVT was not larger than with the hypertonic stimulus alone (Gray and Erasmus, 1989). So far, effects of centrally administered A N G I I on AVT plasma concentration in birds have been determined in only one species, the duck. In conscious animals made diuretic by continuous infusion with isotonic fluid at a rate of I ml/min, the anterior third ventricle was locally push-pull perfused at a rate of 5/~l/min with artificial CSF to which different amounts of A N G I I were added, Taking the peffusion as an infusion, which clearly overestimated the amounts of A N G I I a d m i n : ~ ' e d , the threshold amount of ANGII to be infused intraventricutarly within 10rain In order to induce measurable antidiuresis was 20 fmol/kg body weight. In the dose range from 20 fmol/kg body weight to 20 pmol/kg body weight, both plasma AVT concentration and the amounts of urine retained, relative to the rate of fluid infusion increased dose-dependently in a strictly parallel fashion (Gerstbcrger et aL, 1984a) (Fig. 9). Interestingly, the efficiency of centrally ~ r e d A N G I I in eliciting antidiurcsis critically ~ on the site of local perfusion. Consistent r e s p o n m were
ANOIOTENSINII
IN
BIRDS
193
ANGII
in the cephalic circulation (Gcrstberger et aL, 1984c) was shown to control salt gland activity and to be 1-1 0.6 monitored at periventricular sites in the rostral extvnsion of the third cerebral ventricle (Gerstbergcr et al., ~ 0.5 1984b). Activation of salt gland secretion by ECFV 0.4 expansion (Hanwell et al., 1972; Hammel et al., 1980) 0.3 is of comparable importance, although differently expressed in other bird species (Hughes, 1987). ECFV control of salt gland activity seems to be mainly 0.1 mediated by afferent signals reflecting changes in the interstitial compartment (Simon, 1982). Fluid excretion by the kidneys and salt excretion by the salt I I I I I glands are closely matched, as demonstrated in ducks 0 60 120 180 210 exposed to various combinations of salt and fluid [min] loading (Simon and Gray, 1989). FIE;. 10. Salt gland activity (usmolal excretion) in conscious The closely interdependent excretory functions of ducks loaded by continuous intravenous infusion of the hormonally controlled kidneys and the neuraily 0.4 ml/min saline at 1000mOsmol/kg: Inhibitory effect of controlled salt glands have directed early attention ANGII infused into the third cerebral ventricle for 10 rain towards possible hormonal contributions, especially at a rate of 2 pmol/min/kg body weight (Gtrstberger et aL, by osmoregulatory hormones, to the control of salt 19s4a). gland activity (Holmes, 1975; Holmes and Phillips, 1985; Gerstberger, 1991). Among many hormones obtained only when the push-pull system was located tested ANGII could be identified as an inhibitory in the anterior third ventricle, whereas more posterior hormone (Hammel and Maggert, 1983; Butler, 1984; positions made peffusions ineffective. Taken together Wilson e t a / . , 1985). The observation of inhibitory the results in the duck agree with those of numerous actions of ANGII, when administered into the rostral studies in mammals which show stimulation of ADH third ventricle (Gerstberger et ai., 1984a), suggested release and antidiuresis as a consistent effect of the existence of central targets for ANGII, at least on intracranially infused ANGII (Reid, 1984; Phillips, the brain side of the BBB (Fig. I0). The idea that salt 1987). The strong dependence of the antidiuretic gland inhibition by circulating ANGII might be effect on the site of perfusion points to structures on centrally mediated as well, was suggested by the time the brain side of the BBB which are located in the course of salt gland secretion when ANGII was rostral extension of the third ventricle (Gerstberger intravenously infused in saline loaded ducks (Gray et al., 1987b). e t a / . , 1986), and was further supported by the absence of ANGII receptors in the salt gland tissue (Gerstberger et al., 1987a).. The ability of circulating 4.4. CONTROLOF SALT GLAND ACTIVITY ANGII to inhibit salt gland activity at plasma conThe salt secreting glands function as auxiliary centrations within the physiological range was clearly excretory organs in avian species living in marine or demonstrated in kelp gulls. When plasma ANGII estuarine habitats (Schmidt-Nielsen, 1960; Peaker concentration was increased from its control level of and Linz¢ll, 1975). No such system exists in mam- 60fmol/ml to 120, 270 and 840fmol/ml by intramals. Salt gland secretion in birds is efferently con- venous infusions of 5, 15 and 45pmol/min/kg trolled by the secretory portions of the cranial ANGII, salt gland output was dose-dependently parasympathetic nerves, with tonicity of the body reduced by 10, 40 and 60% (Gray and Erasmus, fluid and ECFV as the regulated variables. Tonicity 1989) (Fig. 11). 5 pmol.kg'l.mln
"1
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FIG. 11. Salt gland activity (osmolal excretion) in kelp gulls, induced and maintained by intravenous (i.v.) infusion of 0.3 ml/min saline at 1200mOsmol/kg. Dose-dependent inhibition of salt gland secretion by I hr i.v. infusions of ANGII at rates of 5, 15, and 45 pmol/min/kg body weight (Gray and Erasmus 1989).
194
E. SIMONet al.
Infuaion of 1000 mOsrn NaCI ( 0.98 ml/mln -1 i.v.) MCh (10 pglmin -1 i.v.)
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FIG. 12. Na + secretion by the salt glands of a duck in response to continuous intravenous (i,v.) infusion of hypertonic saline. ANGII injected i.v. temporarily inhibits salt gland secretion stimulated by parasympathetic, cholinergic efferents. Subsequent ganglionic blockade by i.v. injection of mecamylamine produces a long-lasting suppression of natural salt gland innervation, but salt gland activity can be restored by i.v. infusion of a cholinergic agonist (methacholine bromide, MCh), during which, however, i.v. injection of ANGII no longer inhibits salt gland secretion. (Butler et al., 1989, modified.)
Central mediation of ANGII-induced salt gland inhibition was confirmed by studies on ducks in which an intravenous dose of 2 nmol ANGII transiently suppressed salt gland secretion induced by continuous saline loading, whereas the same dose was completely ineffective, when the natural parasympathetic activation of the glands was replaced by pharmacological stimulation with a cholinergic agonist (Butler et al., 1989) (Fig. 12). Modulation of parasympathetically controlled glandular activity by a circulating hormone that acts exclusively via a central target, appears rather unique as a physiological phenomenon. 4.5. PHYSIOLOGICALCONSEQUENCESOF CENTRAL
A N G I I ACTIONS The multiplicity of the centrally-mediated actions of A N G I I described above underscore the concept that this peptide plays a vital role in avian volume regulation. More specifically, these effects of A N G I I are consistent with the generally accepted idea that A N G I I functions as an agent to maintain ECFV by preventing or minimizing ECFV shrinkage. However, whereas in mammals the centrally-mediated actions of plasma-borne A N G I I and those of the brainintrinsic hormone are identical, in birds some divergence exists between the central actions of A N G I I on targets on the blood and brain side of the BBB The physiological effects of systemic ANGII, which are mediated via central target sites, are restricted to dipsogenesis and the inhibition of salt gland function
in birds which possess them. These actions of ANGII are designed to reduce salt and fluid loss and, at the same time, stimulate the intake o f both. When taken together with other physiological actions of circulating ANGII demonstrated in birds, inchatin8 the stimulation of sodium retaining aldosterone and a direct antinatriuretic/antidiuretic effect (Gray et al., 1989; Gray and Erasmus, 1989), then the sigl~Lfw,ance of systemic A N G I I in avian osmoregulation can be appreciated. Although centrally applied A N G I I also initiates dipsogenesis and salt gland inhibition counteracting hypovolaemia, ANGII as a neuropeptide has supplementary effects which exceed and reinforce those of the systemic hormone. A N G I I acting on the brain side of the BBB in addition increases renal water conservation by stimulating ADH release, and its hypertensive effect might contribute to the maintenance of proper cardiovascular filling under conditions of emergency by activating the autonomic vasoconstrictor system to reduce vascular compliance.
5. ANGIOTENSIN H RESPONSIVE NEUltONES Physiological analysis has shown that centrally mediated actions of A N G I I on either side of the BBB contribute in a co-ordinated manner to the control of salt and fluid balance in mammals and birds. In the two classes of vertebrates the distributions o f high alfmity binding sites for A N G I I I n the region of the "forebraln receptor band" (Plunkett et al., 1987)
ANGIOTENSlNII IN BraDS
195 ANG II 10"7 M
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FIo. 13. ExtraceUularly recorded activity of a SFO neurone in a tissue slice from duck hypothalamus showing dose-dependent activation when the slice was superfused with medium containing ANGII (horizontal bars) at three different concentrations (Matsumura and Simon, 1990a). seem to be largely homologous, although this subject has been much less studied in birds. Theories about the structural design of the rostral brainstem network controlling salt and fluid balance have been put forward repeatedly for mammals (McKinley et aL, 1989; Thrasher, 1989; Honda et al., 1990) but not for birds, partly because of the paucity of data and partly under the premise that the mammalian and avian integrative systems are largely homologous. Since data on neuronal ANGII responsiveness in birds have only recently been provided (Matsumura and Simon, 1990a, b), their interpretation needs to be related to corresponding data obtained in mammals. 5.1. DISTRmUTIONAND PROPERTIESOF ANGII RESPONSIVEROSTRALBRAINSTEMNEURONES Numerous studies in mammals have confirmed that the distribution of electrophysiologically identified neuronal ANGII responsiveness in the rostral brainstem is to a large extent congruent with the autoradiographically determined distribution of ANGII receptors. Most frequently demonstrated was the SFO as a site where exposure of neurones to ANGII consistently affected substantial fractions of neurones, with increases in activity as the prevailing response (Felix and Akert, 1974; Phillips and Felix, 1976; Felix and Schlegel, 1978; Okuya et al., 1987). ANGII responsive neurones were also found in the OVLT (Knowles and Phillips, 1980; Sayer et al., 1984). Structures on the brain side of the BBB exhibiting neuronal ANGII responsiveness were the neurosecretory nuclei, SON and PVN (Nicoll and Barker, 1971; Harding and Felix, 1987), and the AV3V region (Gronan and York, 1978; Okuya et al., 1987). Neuronal activation by ANGII and hypertonic stimulation applied to the third ventricle were shown to converge on neurosecretory cells (Akaishi et al., 1980), with ANGII being involved as a transmitter (Akaishi et al., 1981). ANGII responsive neurones demonstrated in the medial and lateral septal area (Huwyler and Felix, 1980) and lateral hypothalamus (Wayner et aL, 1973) were tentatively associated with the control of water intake. The specificity of ANGII as a mostly excitatory peptide is supported by the attenuating or suppressive effects of locally administered ANGII antagonists which were tested in several of the cited studies. Some uncertainty exists, as to whether ANGII or des-~asp-ANGII (ANGIII) is the biologically relevant compound in the stimulation of SFO neurones in cats and rats (Felix and Schlegel, 1978; Harding and Felix, 1987).
For the avian rostral brainstem, knowledge about neuronal ANGII responsiveness has been provided, so far, only by studies on ducks. The distribution of ANGII responsive neurones was systematically analyzed in ducks which had been raised on freshwater (freshwater ducks). In this condition the salt glands were not activated and plasma osmolalities and concentrations of osmoregulatory hormones corresponded to those of the commonly used laboratory mammals. Hypothalamic tissue slices were taken from these ducks and extracellular recordings were made in vitro in a perfusion chamber with subsequent histological examination of the topography of the recording sites (Matsumura and Simon, 1990a). Stimulations were made by adding ANGII in known amounts to the perfusion medium and, for control reasons, by altering its osmolality. In freshwater ducks, ANGII responsive neurones were encountered most frequently in the SFO in which 65% of the recorded neurones consistently responded with activation to 10-7~a ANGII added to the perfusion medium. In the anterior third ventricle region where scattered ANGII binding sites had been demonstrated, only 2 out of 22 neurones were activated by ANGII, however, with large increases in discharge rates similar to those of SFO neurones. In the dorsal periventricular region, where neurones had been found to be excitable by hypertonic stimulations (Kanosue et aL, 1990), and in the magnocellular portion of the PVN only 1 out of 37, and 4 out of 81 neurones, respectively, responded to ANGII, and the responses were distinctly weaker than those in the SFO and anterior third ventricle. For the SFO neurones, ANGII responsiveness was clearly dose-dependent with a threshold concentration in the perfusion chamber of 10-gM ANGII (Fig. 13), and responsive neurones were successively recruited when ANGII concentration in the perfusate was raised from 10 -9 to 10-7 M. The majority of neurones retained their ANGII responsiveness in a low-Ca2+/high-Mg2÷ perfusion medium which blocked synaptic transmission, as verified by the abofition of responses to remote electrostimulation. Responsiveness to ANGII was reversibly blocked by Isar-SileANGII, and neither ANGII-responsive nor -insensitive SFO neurones were influenced by bird-specific ANGIII (Fig. 14). This is in accordance with the competitive displacement of radiolabelled ANGII from its SFO target site by various ANGII analogs revealing high affinity for the antagonist ~sar-Sile-ANGII and low atfmity for ANGIII
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FIG. 14. Traces of discharge rate recorded from a SFO neurone in a tissue slice from duck hypothalamus which was superfused with medium containing ANGII, ANGIII and the specific ANGII receptor antagonist ;sar-Sile-ANGII (SARILE). The neurone responds to ANGII with activation (first trace), is not responsive to ANGIII (second trace), without alteration of the subsequent response to ANGII (third trace), however, it loses responsivity to ANGII during co-infusion of SARILE, (fourth trace), which is subsequently restored (fifth trace) after superfusion with SARILE-free medium. (Matsumura and Simon, 1990b.) (Gerstberger et al., 1987b; Gerstberger, unpublished observation). 5.2. CORRELATIONBETWEENFUNCTIONALAND NEURONALRESPONSESTO CENTRALLYACTING A N G I I IN THE DUCK Despite the fact that knowledge about A N G I I responsive neurones in the brainstem of birds is currently limited to the duck, this species seems to offer particularly favourable conditions for the assessment of the specificity of the observed neuronal responses. First, the roles of tonicity and A N G I I in central control of the two independent osmoregulatory effector organs, the salt glands and kidneys, have been thoroughly analyzed in ducks (Simon and Gray, 1989; Simon-Oppermann and Gerstberger, 1989). Second, structural information about central interconnections relevant in the control of osmoregulatory effectors (Korf et al., 1982) and about the distribution of A N G I I receptors (Gerstberger e t a / . , 1987b) and sites of tonicity perception (Kanosue et al., 1990) have been provided for the duck rostral brainstem. In ducks with active salt glands, due to acclimation to hypertonic saline as their drinking fluid (saltwater ducks), hypertonic stimuli and A N G I I applied to either side of the BBB were shown to act oppositely to each other, in that secretion was activated by osmotic stimulation (Gcrsthergar eta/., 1984b, c) but inhibited by A N G I I (C~rstbergor et al., 1984a; Gray et al., 1986). However, in the control of antidiuresis
the actions of centrally applied A N G I I and of systemic or intraventricular increases in tonicity were concurrent, in that AVT release was enhanced by each stimulus (C_)¢rstherger et al., 1984a-c). The fact that the actions of hypertonicity and A N G I t were concurrent in the control of one ¢ffoctor but opposing in the control of another effcctor, excluded the possibility that the two stimuli wen) monitored by one set of neurones, but rather postulated that separate sets of neurones must exist which were responsive to either ANGII or hypertonic stimulation. Indeed, neurones in the duck's rostral brainstem respon~ng to A N G I I and hypertonic stimulations were found to be separate from each other (Matsmmura and Simon, 1990a). Among 18 A N G I I responsive SFO neurones exposed to 20 mosmol/kg rises in tonicity by adding NaCI to the perfusate, only 1 neurone was slightly activated and 1 neurone inhibited, whereas the incidence of responses to changes in tonicity was sim~ificantly larger among 65 ANGII-insens/tive neurones tested in the periventricular brain tissue 0 2 stimulations and 8 inhibitions). Especially in the dorsal periventricular region where mmmensitive neurones were found to be particularly ¢onetmtrated 0gdtaotue et al., 1990), A N G I I binding was little according to autoradiographic analysis (Gentberser et al., 1987a). As in mammals (De Bold et a/., 1981; Gene~ and Cantin, 1985; Laragh and Atlas, 1988), atrial natriuretic factor (ANF) is also relevant in birds as a hormone controlling salt and fluid balmme (CrreB and Wideman, 1986; Springate et al., 1987; Gray
ANG[OT~S]~II IN BIRDS 20
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FIG. 15. Traces of discharge rate of an ANGII responsive neurone in the SFO of a duck (A) and a rat (B). (Courtesy of Dr H. Schmid.) (A) Response of a duck SFO neurone to superfusion with ANGII (10 -7 M) and to combined superfusion with chicken atrial natriuretic factor (chANF) and porcine brain natriuretic peptide (pBNP) at the same concentration. There was no effect of the natriuretic hormones on resting discharge rate or on the response to ANGII. (B) Response of a rat SFO neurone to superfusion with ANGII (10-7 M) and rat atrial natriuretic factor (rANF) at the same concentration. The neurone is activated by ANGII and inhibited by rANF.
et al., 1991a). A high density of A N F receptors could be demonstrated in the SFO of ducks (Schfitz et al., 1992). Unfike in mammals, however, where a high incidence of simultaneous responsiveness to A N G I I and A N F of SFO neurones is indicated by studies in rats (Hattori et ai., 1988), recent experiments on duck SFO neurones showed that responsiveness to A N F was not exhibited, as a rule, by neurones responsive to A N G I I (Schmid, personal communication). In accordance with a preceding study (Matsumura et al., 1990a), the majority of 56 neurones recorded extracellularly in the duck SFO in an in vitro preparation were activated by superfusion with 10-7M ANGII, but among 24 A N G I I responsive neurones tested for A N F responsiveness, none changed its activity during superfusion with either rat A N F (rANF) or chicken A N F (chANF), which most probably is the native A N F in ducks as well (Gray et al., 1991b), or porcine brain natriuretic peptide (pBNP) (Fig. 15). Rat SFO neurones recorded under identical experimental conditions also revealed A N G I I responsiveness, however, unlike in ducks 8 out of 10 A N G I I responsive rat SFO neurones decreased their spontaneous firing rate when supeffused with 10-7 M rANF (Fig. 15) and pBNP, as well as with chANF which had to be administered in some neurones at a slightly higher concentration of 3 x 1 0 - T M to be effective. This comparison strongly suggests that, similar to the relationship between osmoresponsiveness and A N G I I responsiveness, a more distinct functional separation exists in birds, as compared to mammals, also with regard to neuronal responsiveness to A N G I I on the one hand, and to A N F and related peptides on the other.
The question of whether A N G I I responsiveness and responsiveness to changes in tonicity in mammals are carried by separate sets of neurones has not yet been clarified. For the SFO the data are somewhat controversial, with either no evidence (Buranarugsa and Hubbard, 1979) or with positive evidence (Gutman et al., 1988) for combined neuronal osmotic and ANGII-responsivenc~s in rats being demonstrated. The possibility has been considered that synaptic interactions in the SFO of rats may result in combined responsiveness of neurones to A N G I I and osmotic stimulations (Buranarugsa and Hubbard, 1988). In the rat OVLT, responsiveness to A N G I I and to changes in tonicity seemed to be partially carried by the same neurones (Sayer et al., 1984). The neuronal network which has been proposed as necessary for the generation of osmoreceptive signals in mammals (Honda et al., 1990) comprises structures such as the SON and the AV3V region where A N G I I receptors, as well as A N G I I responsiveness, have been demonstrated. The distribution of A N G I I responsive neurones in the rostral bralnstem of the duck deviated to some extent from the distribution of receptors. Unlike in mammals, A N G I I responsive neurones were very scarcely found in the magnoceUular neurosecretory regions of the PVN (Matsumura et al., 1990a), although scattered A N G I I receptors could be demonstrated in both the SON and PVN of the duck (Gerstberger et al., 1987a, b). The function of the A N G I I receptors in the vicinity of the magnucellular neurones in the duck's PVN is currently n o t clear. On the other hand, the agreement between
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FIG. 16. Compamon of frac,tio~ of AN~H ~ n s i v e SFO neurones recorded in hypothalamic tissue from freshwater ~ : ~ saltwater ( $ W ) d ~ at 4 different ANGII concentrations in the perfusion medium. Numerals above columns indicate number of neurones investigated in each group and at each concentration. (Matsumura and Simon, 1990b).
electrophysiological and autoradiographical analysis was virtually perfect for the SFO, where a particularly high ANGII receptor density corresponded to a high fraction of ANGII responsive neurones. Moreover, the physiological significance of ANGII responsiveness in the SFO could be endorsed by the observation of concerted changes in circulating ANGII levels, density of ANGII receptors and neuronal ANGII responsiveness in ducks as the result of acclimation to high salt intake. Saltwater ducks acclimated to saline as their only water supply, that is two-fold higher in concentration (600 mosmol/kg) than normal body fluid osmolality (Brummermann and Simon, 1990), cope with this situation indefinitely. This degree of salt stress is associated with plasma hypertordcity, elevated levels of AVT and chronic elevations of ANGII plasma levels in the range of 50-200 fmol/ml that are most likely the result of a reduced interstitial fluid volume (Gray et al., 1987) at unchanged blood volume (Brummermann and Simon, 1990). Saltwater ducks exhibited a distinctly higher ANGII receptor density in the SFO than ducks on freshwater (Gerstberger et ai., 1987b) (Fig. 4). Upregulation of ANGII receptor density in the SFO of saltwater ducks seems to correspond to ANGII receptor upregulation in the SFO of rats subjected to severe water deprivation (Nazarali et al., !987) which, however, can be maintained only temporarily. When hypothalamic tissue slices from freshwater and saltwater ducks were compared with regard to their ANGII responsiveness in the SFO, the sensitivity of ANGII responsive neurones was increased 10-fold in the SFO of saltwater ducks and the fractions of neurones ~ n d i n g to ANGH at a given concentration were latser in compa~son to freshwater ducks (Matsumura u d Simon, 1990b) (Fig. 16). Thus, salt acclimation in ducks produ__c~_congraent into'eases in plasma A N G | I levels, enhanced ANGII receptor density in the SFO and enhanced responsiveness of SFO neurones to ANGII.
5.3. TOPOGRAPHYOF NEURONAL A N G I I RESPONSIVENESSPERTINENTTO SALT AND FLUID BALANCE
In both mammals and birds, the most plausible function of ANGII responsive neurones in the CVOs, i.e. on the blood side of the BBB, would be monitoring of the circulating hormone. At some depth in the brainstem tissue, neuronal ANGII responsiv~ss, e.g. in the neurosecretory nuclei, may reflect the function of ANGII as a synaptic tranmnitter. At the brain side of the BBB, ANGII responsive nenmn~, especially those located more closely to the w m ~ lar ependyma might also be naturally ~ b y ANGII as a neuromodulator, being either near the site of its action or transported with the interstitial and ventricular CSF. In mammals, putative functions as peptide receptors or interneurones have been assi~ed to A N ~ I responsive rostral brainstem structures a~ording to supplementary evidence derived from experiments and from tracing neuronal connections by labelling or with e i e c t r o p h y s i ~ means (McKinley et al., 1989; Thrasher, 1989;:]beutque and Renaud, 1990). Corresponding models of the neuronal circuitry controlting salt and fluid balance in. chide pathways from the SFO and OVLT to the neurosecretory nuclei which either pass throuah, or are relayed in, the median preoptic and AV3V regions and which contain angiotensinersic (Honda et:aL, 1990; Jhamandas et al., 1989) as well as A~qOIl responsive neurones. Experimental ~ ~ be obtained for the ability of circulafi~ ANOII to increase the excitability of SON and 1 ~ mmmm:s in the rat through action on the SFO with ~ t relay of information to hypothalam~ ~ o r y cells (Ferguson and Renaud, 1986; ~ eta/., 1989). On the other hand, mutual between the same regions have been ~ , z m m tial for the ~ t i o n of the o s m ~ v e ~ in mammals (Honda et al., 1990). The intricate of neurones subserving different functions w i t t ~ file
FIG. 17. (A) Retrogradely labelled neurones (*) in the subependymal periventricular layer @I) shown in a frontal section of the duck hypothalamus, with ventricular cavity (V III) to the right and the site of horseradish peroxidase (I-IRP) application (arrowhead) in the magnocellular centre (mc) of the paraventricular nucleus to the left. This site had previously been identified by antidiuresis evoked in the conscious animal by micro-electrostimulation at the site of subsequent iontophoretic application of HRP (Korf et al., 1982). (B) Golgi impregnation of a frontal section of the duck hypothalamus with ventricular cavity to the right. The lower part shows a magnocellular neurone (MCN) of the paraventricular nucleus, of which a dendrite is contacted by a neurite (arrows) originating from a conspicuous subependymal neurone (*). The same neurone is shown at larger magnification in the upper part to demonstrate its dendritic process (arrowheads) penetrating the ependymal layer. (Korf et al., 1983.)
ANOIOTENSINII IS BraDS
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FIo. 18. Upper part: Schematic presentation of afferent projections (double circles) to the neurosecretory magnocellular neurones of the paraventricular nucleus of the duck (PEN, fat circle with efferent projection to the posterior pituitary, PP), as evaluated by retrograde labelfing with horseradish peroxidase (HRP). Sofid lines represent neurones which were marked rctrogradely after application of minute amounts of HRP and presumably project monosynaptically. Interrupted lines represent neurones which were labelled only after more voluminous HRP deposits and presumably project polysynaptically. Note that there are monosyuaptic projections from the contralateral PVN (npv) and from the ipsilateral subependymal neurones (pl) shown in Fig. 17A. (Korf, 1984.) Lower Part: Schematic presentation of brain regions (double rectangles) to which the paraventricular nucleus (PVN) of the duck was found to project efferently. Connections were evaluated with anterograde tracing techniques after HRP injection into the PVN region and immunocytochemically by means of antibodies against vasotocin and neurophysin. (Korf, 1984.) neuronal network controlling ~ h and fluid balance in mammals has posed major problems in delineating specific receptive functions against integrative functions of the neurones involved. In mammals, interconnections between the hypothalamic antidiuretic system and medullary structures presumably pertinent in circulatory control were shown to involve both angiotensinergic neurones (Lind et al., 1985) and lower brainstem A N G I I binding sites (Mendelsohn et al., 1984), the latter being particularly prominent in the locus coeruleus and nucleus of the solitary tract regions and in the area postrema as a circumventricular organ, where JPN ~/2--F
receptors should at least in part be accessible to circulating ANGII. In mammals, A N G I I responsive neurones in these regions have been implicated in the mediation of central adjustments of cardiovascular innervation (Papas et al., 1990), apart from multimodel chemoreceptor functions of area postrema neurones (Carpenter et al., 1988). Comparable studies on birds do not exist. For birds electrophysiological evaluation of neuronal responsiveness to A N G I I and to hypertonic stimulation in hypothalamic tissue slices from ducks has revealed that, unlike in mammals, neurones in the magnocellular neuroendocrine portion of the duck
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PVN were only weakly responsive to each of the two stimuli. Responsiveness to hypertonic stimulation on the brain side of the BBB in the duck hypothalamus was confined to an identifiable group of parvocellular, periventricular neurones in the dorsal third ventricle (Kanosue et al., 1990), where ANGII responsiveness was virtually absent (Matsumura et al., 1990a). On the other hand, the frequently encountered A N G I I responsive neurones in the SFO were, as a rule, not osmosensitive. The more distinct separation of neuronal properties found in the brainstem of the duck, as compared to several mammals, seems to reflect the more distinct spatial separation of functionally diverse sets of neurones that is implicit in the cluster cytoarchitecture of the avian brainstem (Oksche, 1978). In contrast to the duck, no clear distinction can presently be made in mammals between the contributions to osmoresponsiveness provided by interneurones, putative receptors and the neurosecretory neurones themselves (Honda et al., 1990). 5.4. INTERCONNECTIONSOF THE AVIANPVN AS A MAJOR EFFECTORIN SALTAND FLUID BALANCE Taking the magnocellular portion of the PVN as a central neuroendocrine effector system, the afferent connections to this nucleus were retrogradely traced in conscious ducks as a first approach to the elucidation of the integrative neuronal network serving salt and fluid balance of birds (Korf et al., 1982), Antidiuresis in response to micro-electrostimulation within the PVN by means of a stereotaxically inserted microelectrode was used to identify the location of the magnocellular neurohormonal effector neurones of the PVN. Subsequently small amounts of horseradish peroxidase (HRP) were deposited electrophoretically at the site of stimulation. Histological examination by diaminobenzidine staining of the label in histological sections prepared 2-5 days after micromarking, disclosed monosynaptic projections of hypothalamic, as well as extrahypothalamic, origin to the magnocellular centre of the PVN (Fig. 17A). In particular, a distinct group of monosynaptically projecting neurones from the dorsomedially located subependymal region corresponded to the site where neurones had been shown to respond to local hypertonic stimulation (Kanosue et al., 1990). This laminar, subependymal cluster of cells fell into the category of CSF contacting neurones (Fig. 17B), as demonstrated by Golgi impregnation of neurones in the magnocellular and subependymal regions of the PVN (Korf et al., 1983; Panzica et al., 1986). With regard to further afferent projections to the PVN (Fig. 18, upper part), inputs from sites of neuronal A N G I I responsiveness, especially from the SFO, were marked only if the HRP deposits in the PVN region exceeded the border of the magnoceUular portion and, thus, had to be considered as polysynaptic (Kerr, 1984). Inputs from the AV3V region and OVLT as putative sites of neuronal A N G I I responsiveness were also found not to be monosynaptic. This arrangement corresponded well with functional and electrophysiological evidence according to which A N G I I responsiveness and perception of tonicity in the duck should reside in different
neurones, in order to permit their synergistic interaction in the control of AVT release and their antagonistic interaction in the control of salt gland activity. Since the lower brainstem of birds has not yet been probed for neuronal ANGII responsiveness, no information is currently available as to what extent A N G I I is an important mediator/modulator in the transfer of information from this region to the PVN. However, considering the general analogy between mammals and birds, the involvement of both angiotensinergic neurones and lower brainstem neurones endowed with ANGII receptors is a likely assumption. In the duck, retrograde labelling of lower brainstem projections to the PVN suggested multisynaptic inputs from the area postrema but monosynaptic inputs from the nucleus of the solitary tract region. When considering the efferent projections of the PVN in the duck (Fig. 18, lower part), it becomes clear that they mostly include brain regions from where neurones project to the PVN, mono- or polysynaptically, including those sites, where high-affinity binding of A N G I I had been demonstrated (Korf, 1984). Thus, most brain targets for ANGII seem to be connected reciprocally with the PVN as a major effector system in efferent osmoregulatory control (Fig. 18).
6. CONCLUSIONS The distribution of angiotensinergic systems and of targets for A N G I I in the central nervous system of birds was shown to be basically identical with that in mammals. The implication of A N G I I as a mediator/modulator in central control of salt and fluid balance, as suggested by the results of numerous studies on mammals, has received support with regard to osmoregulatory effector activities that are common to both classes of vertebrates, and by study, ing the control of secretion by the salt glands as an additional, bird-specific osmoregnlatory effector organ. The absence of peripheral vasomotor effects on physiological levels of circulating A N G I I in the avian class has strengthened the idea that mediation of physiological central actions of A N G I I on circulatory control is restricted to targets on the brain side of the BBB. Brain intrinsic angiotensinergic systems and their targets, thus, are important in the coordination of mechanisms controlling appropriate cardiovascular filling by adjusting intake and output of water and electrolytes, as well as the compliance of the cardiovascular system. With regard to the central neuronal mechanisms involved, the available evidence indicates that for birds, receptive functions for A N G I I on the one hand and for body fluid tonicity on the other are more distinctly separate, both functionally and spatially, than in mammals. In the SFO as an a u t o ~ ' a p h ically identified target for both circulating A N G I I (Gerstberger et al., 1987a) and A N F (Schiitz et al., 1992) at least a functional separation seems to e ~ t in as much as simultaneous neuronal r e s p o n s i v e ~ to A N G I I and A N F has n o t been observed, so far, in the duck (Schmid, personal communication),
ANGIO'EF.NSIN II IN BraDS
quite unlike the situation in the rat (Hattori et al., 1988). In all, these observations correspond to the view that the cluster organization of the avian rostral brainstem implies a more distinct separation of neuronal functions and, thus, might generally provide more favourable conditions in birds than in mammals for the independent characterization of the various receptive functions accomplished by brainstem neurones. Acknowledgements--The important contributions of Dr K. Kanosue, Dr H.-W. Korf, Dr K. Matsumura, Dr H. Sehmid, Dr H. Schiitz and Dr C. Simon-Oppermann to the experimental work carried out in the authors' laboratories are gratefully acknowledged. Part of the experimental work was supported by the Deutsche Forschungsgemeinschaft (Si 230/4-4,/4-5, /8-1).
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0301-0082/92/$15.00 © 1992PergamonPress Ltd
CENTRAL NERVOUS ANGIOTENSIN II RESPONSIVENESS IN BIRDS ECKHART SIMON, RODIG~ Gm~STS~tO~ and DAVID A. GRAY Max-Planck-lnstitutf~r physiologischeund klinischeForschung, William G. Kerckhoff-lnstitut, D-6350 Bad Nauheim, Germany (Received 11 November 1991)
CONTENTS 1. Introduction 2. Control of circulating Angiotensin II in birds 3. Angiotensin II specific systems in the rostral brainstem of birds as compared to mammals 3.1. Neuronal systems and interconnections 3.2. ANGII as a brain-intrinsic peptide 3.3. ANGII receptors in duck brain with special reference to the rostral brainstem 3.3.1. ANGII receptor characterization and localization 3.3.2. ANGII receptor regulation 4. Centrally mediated physiological actions of Angiotensin II in birds 4.1. Drinking as a behavioural activity in salt and fluid balance 4.2. Blood pressure control 4.3. Central control of the antidiuretic hormone 4.4. Control of salt gland activity 4.5. Physiological consequences of central ANGII actions 5. Angiotensin II responsive neurones 5.1. Distribution and properties of ANGII responsive rostral brainstem neurones 5.2. Correlation between functional and neuronal responses to centrally acting ANGII in the duck 5.3. Topography of neuronal ANGII responsiveness pertinent to salt and fluid balance 5.4. Interconnections of the avian PVN as a major effector in salt and fluid balance 6. Conclusions Acknowledgements References
1. INTRODUCTION
demonstrated neuronal A N G I I responsivity on either side of the BBB (Felix and Akert, 1974; Okuya et al., 1987). Compared with mammals the avian osmoregulatory system has been studied less frequently, with the premise that control of salt and fluid balance in general, and the actions of A N G I I in particular, are virtually identical in mammals and birds. With special respect to A N G I I this presumption was found to be basically true for the physiology and biochemistry of systemic A N G I I formation (Chan and Holmes, 1971; Nishimura, 1980, 1987; Wilson, 1984a, 1989), for its function in the control of mineralocorticoid release (Klingbeil, 1985; Gray et al., 1989) and for the physiological range of A N G I I plasma concentrations (Simon et al., 1989; Wilson, 1989). As the result, the osmoregulatory system of birds has been scarcely considered from the viewpoint that its analysis might disclose properties that are more difficult to elucidate in mammals. Indeed, salt and fluid balance of birds was found to differ to some degree from that of mammals, generally and with special regard to the actions of ANGII, and in ways that seemed especially helpful in the analysis of central nervous receptive functions in salt and fluid balance.
Stimulation of drinking was discovered early in both mammals and birds as one of the foremost, central effects of angiotensin II (ANGII) (Fitzsimons, 1972, 1980; Kobayashi et al., 1980). This discovery opened a new field of research on the central actions of a peptide hormone, which until then was primarily considered a peripherally acting hormone, not directly controlled by the hypothalamo-pituitary system. While originally concentrating on the function of A N G I I as a messenger to the brain, these studies were soon greatly expanded by the discovery of the brain renin-angiotensin system (FischerFerrero et al., 1971; Ganten et al., 1971). The demonstrations of angiotensinergic neurones in the brain (Lind et al., 1985) and of high affinity central nervous binding sites for A N G I I (Mendelsohn et al., 1984) on either side of the blood-brain barrier (BBB) have provided structural correlates to discriminate between central actions of circulating A N G I I on the one hand, and of A N G I I as a brain-intrinsic messenger/modulator on the other (Phillips, 1987). Brainstem sites for which specific transducer functions of A N G I I were postulated have also been probed electrophysiologically in mammals and have JPN 39/2--e
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(a) Contrary to mammals, arterial blood pressure of conscious birds is not substantially raised by increasing the level of circulating ANGII, unless physiological concentrations are exceeded (Nishimura and Bailey, 1982; Simon-Oppermann et al., 1984; Wilson and West, 1986). Interestingly, the vascular system of birds is similarly insensitive to antidiuretic hormone (ADH), and even arterial hypotension was produced when the plasma level of ADH was increased beyond its physiological range in chickens (Ames et al., 1971) and ducks (Brummermann and Simon, 1990). Thus, putative central actions of the circulating hormones may be analyzed in birds with less baroreceptor reflex interference than in mammals. (b) Avian species that are genetically adapted to saline or marine habitats, excrete excess salt with the help of supraorbitally located salt secreting glands (Schmidt-Nielsen 1960; Holmes and Phillips, 1985; Simon and Gray, 1989; Gerstberger, 1991). Such glands do not exist in mammals. The avian salt glands are under direct central nervous control via parasympathetic efferents (Fringe et al., 1958; Ash et al., 1969) and, thus, represent an effector system in which all components are accessible to neurophysiological analysis. (c) Not least, birds differ from mammals in that a cluster-like type of sub-organization of brainstem nuclei, which is particularly prominent in reptiles, has in part been preserved in birds but has almost completely vanished in mammals (Oksche, 1976, 1978; Korf, 1984). This particular neuronal cytoarchitecture implies a more distinct grouping of functionally equivalent neurones and should facilitate the electrophysiological characterization of functionally different neurones in the rostral brainstem of birds (Kanosue et al., 1990; Matsumura and Simon, 1990a). Reviewing the currently available evidence for ANGII responsive neurones in the brain of birds has to include the effects of the peptide on centrally controlled regulatory activities as well as their structural correlates, which have provided the basis for electrophysiological analysis. Particular attention will be given to those ANGII effects which are relevant for body fluid homeostasis and associated cardiovascular adjustments, since experimental evidence in birds for the role of ANGII as a circulating hormone and as a messenger to and within the brain in the control of salt and fluid balance and circulation, has become as similarly conclusive as in mammals.
cleavage from the protein angiotensinogen is tightly controlled by renin, a specific protease of mainly renal origin. The components of this sequence are termed the renin-angiotensin system (RAS). The RAS and the intrarenal juxtaglomerular complex of the macula densa evolved early in the phylogeny of vertebrates and are also active in birds (Chan and Holmes, 1971; Nishimura, 1980; Wilson, 1984a, b, 1989). As in mammals, the state of activity of the RAS in birds seems to be strongly volume dependent. Hypotensive haemorrhage in pigeons (Chan and Holmes, 1971) and in chickens (Nishimura and Bailey, 1982) enhanced renin activity. In the quail haemorrhage (of an unspecified degree) increased the plasma concentration of ANGII (Kobayashi and Takei, 1982.) In the kelp gull plasma ANGII concentration was shown to rise in proportion with blood volume loss in the range of 0-20% of estimated blood volume (Gray, 1987; Simon-Oppermann et al., 1988). Water deprivation as a means to induce volume depletion in both the intra- and extravascular compartments of the extracellular fluid volume also consistently increased plasma ANGII to degrees that were correlated in the ostrich (Gray et al., 1988), kelp gull, cape gannet and jackass penguin (Gray and Erasmus, 1988) with body weight loss and generally with the rise in plasma osmolality as an indicator of dehydration (Simon et al., 1989). Levels of circulating ANGII which temporarily rose as high as 300 fmol/ml were observed in ducks during acclimation to maximum chronic salt stress (Gray and Simon, 1985) and in Japanese quail during 48 hr of dehydration (Takei et al., 1988). Conversely, extracellular volume expansion by intravenous loading with isosmotic saline lowered plasma ANGII in kelp gulls (Gray, 1987). Volume expansion in ducks with isosmotic and slightly hyperoncotic dextran, which remained confined to the intravascular compartment and substantially increased the plasma concentration of the notably blood volume sensitive atrial natriuretic factor (ANF), had little influence on the ANGII plasma concentration (Keil et al., 1991). Thus, in duck plasma, ANGII levels seem to be correlated more closely with the interstitial than the intravascular compartment, as indicated also by the observation that the gradual increase in ANGII plasma levels during physiological adaptation of ducks to chronic salt stress was associated with an extracellular volume reduction that was confined to the extravascular compartment whereas blood volume remained unchanged (Brummermann and Simon, 1990).
2. CONTROL OF CIRCULATING ANGIOTENSIN H IN lm~Ds
3. ANGIOTENSIN H SPECIFIC SYSTEMS IN THE ROSTRAL BRAIN'STEM OF BIRDS AS COMPARED TO ~ M M A L S
The active peptide in birds is 5vaI-ANGII, an analog to 5ile-ANGII found in most mammals, and both have comparable biological activities in birds and mammals (Nakayama et al., 1973; Evered and Fitzsimons, 1981a). Formation of ANGII as a circulating hormone seems to be basically identical in birds and mammals. By the action of the ubiquitous convetting enzyme the active octapeptide is ultimately cleaved from the decapeptide angiotensin I, whose
3. I. NEURONALSYSTEMSAND INTERCONNECTIONS Important neuronal structures involved in the control of salt and fluid balance are located in the most rostral extension of the brainstem. Compared to mammals, the anatomical evaluation of the brain of birds reveals multiple homologies in this region with a topography similar to that in mammals, if the
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FIG. 1. Schematic presentation o f a sagittal section (upper left) through a duck's hypothalamus according to the histological section (lower left). S F O = s u b f o r n i c a l organ, A C = a n t e r i o r commissure, OVLT = organum vasculosum laminae terminalis. AV3V = rostral and closely periventricular section of hypothalamus; VIII = third cerebral ventricle, M C = projection of the parasagittally located magnocellular portion of the paraventricular nucleus on the sagittal plane, PCh = choroid plexus. EM = median eminence. Schematic frontal sections (1-4, right) present coronal sections approximately along the planes that are indicated in the upper left schema (1-4). TSM = septomesencephalic tract.
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ANGIOTENSINII IN BIRDS
difference between mammals and birds in the stereotaxic position of the base of the brain, relative to the horizontal plane of the skull is taken into consideration (Karten and Hodos, 1967) (Fig. 1). As one of the notable quantitative differences, the supraoptic nucleus (SON) is less developed in birds, relative to the paraventricular nucleus (PVN) and, thus, the latter contributes more to the neurosecretory hypothalamo-neurohypophyseal system (Swanson and Sawchenko, 1983; Korf, 1984). As in mammals, two circumventricular organs (CVOs) are located in the rostral and dorsal border of the avian third ventricle which are considered as important target structures for ANGII: the organum vasculosum laminae terminalis (OVLT) occupies the most rostral and ventral extension of the ventricular wall; the subfornical organ (SFO) is located immediately dorsal to the anterior commissure (AC) in the roof of the third ventricle (Bosler, 1977; Takei et al., 1978; Kuenzel and Masson, 1988). Dorsal to the OVLT, a narrow band of neurones seems to represent a homolog to the median preoptic nucleus (MePO) of mammals (Kuenzel and Van Tienhoven, 1982) which is considered a major centre of integration in salt and fluid balance (McKinley et aL, 1989; Thrasher, 1989), receiving inputs from the OVLT (Camacho and Phillips, 1981) and SFO (Miselis, 1981). Periventricular clusters of neurones adjacent to the OVLT in the most rostral lateral parts of the third ventricular wall are present in birds and seem to correspond to the anteroventral third ventricle (AV3V) region in mammals which is also important as a site of neuronal integration in salt and fluid balance (Brody and Johnson, 1980). Taken together, a large degree of homology seems to exist between structures in the most rostral extension of the avian third ventricle, especially with regard to the arrangement of CVOs and hypothalamic nuclei (McKinley et al., 1990) that has been termed "forebrain receptor band for ANGII" (Plunkett et al., 1987) in mammals because of its target function for both circulating and brainintrinsic ANGII. 3.2. ANGII ASA BRAIN-INTRINSICPEPTIDE The presence of ANGII, together with all the components of a RAS, in brain tissue (Ganten et al., 1978) and of nerve fibers and neurones containing the peptide (Lind et aL, 1985; Imboden et al., 1987, 1989), have been amply confirmed for mammals. Taking the rostral hypothalamus of the rat as a well documented example, both immunoreactive nerve fibers and somata were found in the PVN, SON, and medial preoptic area. Immunoreactive terminals were also found in the region of the MePO, while immunereactive fiber tracts were particularly prominent in both the internal and external lamina of the median eminence. Among the rostral CVOs, the SFO was shown to contain both immunoreactive fibers and cells, whereas in the OVLT, ANGII-immunopositive staining was confined to nerve fiber varicosities. Synaptosomal endings were also found to contain renin as well as converting enzyme activity (Paul et al., 1985). The expression of the ANGII converting enzyme mRNA in the rat brain was reported just recently following the localization of the enzyme by
183
employing quantitative in vitro autoradiography (Chai et al., 1987; McKinley et al., 1990; Whiting et al., 1991). Both expression of specific mRNA and enzymatic activity were found in the SFO, the choroid plexus, the caudate putamen and the cerebel. lum. In birds, the ANGII-immunoreactive system of the brain has not yet been systematically mapped. A first immunocytochemical search was carried out in the hypothalamus of the duck (Ramieri et al., 1984) with an ANGII antibody that showed 10% cross reactivity with ANGIII in radioimmunological studies (Gray and Simon, 1985). In a subsequent study on the duck and quail hypothalamus, scattered ANGII positive somata of neurones were found in the SON and PVN. Positively staining fibers were sparsely distributed in the anterior hypothalamic region but formed a more distinct bundle in the third ventricular floor that extended throughout the inner layer of the median eminence (Ramieri, 1988) (Fig. 2). These preliminary data in two bird species suggest that the distribution of ANGII-immunoreactive cells and fibers does not basically differ in the mammalian and avian rostral brainstems. Peptide extracts obtained from chicken as well as duck brains and separated by reversed phase HPLC clearly revealed the presence of ANGII-like peptides co-eluting with bird-specific Sval-ANGII as proven by specific ILIA. With values of 50-80 fmol immunoreactive ANGII per g tissue wet weight, however, hypothalamic ANGII concentrations proved to be even lower than those reported for the rat central nervous system, suggestive of fast enzymatic degradation of the peptide (Hermann et al., 1984; Gray and Simon, 1985; Gerstberger, unpublished observation). Further evidence for a brain-intrinsic ANGIIsystem in birds has been provided by the comparative radioimmunological analysis of ANGII concentrations in the blood and cerebrospinal fluid (CSF) of conscious ducks (Gray and Simon, 1987). In euhydrated animals ANGII concentration in cisternal CSF was about 50% of that in blood plasma. In ducks deprived of water for 48 hr or chronically acclimated to hypertonic saline, ANGII concentrations were increased in each compartment. Interestingly, upon rehydration ANGII levels in the CSF had significantly decreased at a time when plasma ANGII levels had not yet changed significantly (Fig. 3). This observation was also made in dogs (Simon-Oppermann et al., 1986) and suggests for both mammals and birds that the generation of ANGII in the brain and in the circulation are controlled independently in accordance with the view that ANGII in the CSF is derived from the brain-intrinsic RAS and not from circulating ANGII for which the BBB is virtually impermeable (Ganong, 1984). To our knowledge, neither the central nervous distribution of renin- or cathepsinlike enzymes, nor of the converting enzyme cleaving the precursor angiotensin I (ANGI) to yield ANOII have been demonstrated in the brain of any avian species. Preliminary studies in the duck indicate processing of radiolabelled avian ANGI to ANGII using homogenized choroid plexus tissue and HPLC technology (Gerstberger, unpublished observation).
184
E. SIMONet al.
characterized pharmacologically by competitive displacement of radiolabelled lsar-Sile-ANGII from its target sites. The labelled ANGII antagonist bound to duck hypothalamic membrane fractions could be 200 fully displaced by both the unlabelled antagonist and mammalian as well as avian ANGII with Ka values of 0.9, 1.8 and 1.3 nu, respectively. Avian-specific 100 ANGIII and ANGI as well as the ANGII antagonist ~sar-Sala-ANGII exhibited low affinities with Ka I CSF values in the micromolar range, while peptides such 0 as angiotensinogen, Sarg-vasotocin, mesotocin or substance P could not compete with radioligand binding (Gerstberger et al., 1987b; Gerstberger, unpublished observation). This sequence of potencies for the ANGII-specific binding sites proved to be comparable with that obtained for duck adrenal .~, 310 1 tissue (Gray et al., 1989), but differed from reports using rat HTS tissue with regard to the rather high affinities of ANGIII and ~sar-Sala-ANGII for the 290 21 20 mammalian ANGII receptor (Mann et al., 1981; Mendelsohn et al., 1984). Avian ANGII receptor Ibefore I tafter I ,l$0minaftm'l molecules might therefore represent a new type of 24-48 h cl~ydratlon r~ydration ANGII-specific binding sites in the vertebrate kingdom in general. Fie. 3. Osmolality (lower ordinate) and ANGII conTo identify discrete neuronal entities in the central eentration (upper ordinate) in plasma (dots) and cerebrospinal fluid (CSF, circles) of conscious ducks in the state of nervous system bearing ANGII-specific binding sites, normal hydration, after 24--48hr of water deprivation, and autoradiography enabled the exact histological local150min after rehydration. Numerals indicate number of ization and spatial distribution of ANGII receptors measurements. Asterisks indicate mean values which were in the brain of various mammals such as the rat sJt,nit~antly different (*P < 0.01, **P < 0.005) from their (Mendelsohn et al., 1984; Gehlert et al., 1986a; preceding values. (Simon-Oppermann et al., 1988, Saavedra et al., 1986; Tsutsumi and Saavedra, 1991), modified.) rabbit (Mendelsohn et al., 1988), dog (Speth et al., 1985), sheep (McKinley et al., 1986) and human (McKinley et al., 1987; Allen et al., 1988). With 3.3. ANGII RECEPTORSIN DUCKBRAINWITHSPECIAL regard to lower vertebrates and birds in particular, the duck brain exclusively has been screened for REFERENCETO THE ROSTRALBRAINSTEM binding sites specific for ANGII (Gerstberger et al., 1987a, b) (Table 1). Neuronal structures outside the 3.3.1. A N G H receptor characterization and BBB, such as the SFO and OVLT, and therefore localization accessible to blood-borne ANGII (Fig. 4), were To act on central nervous structures, both blood- prominently labelled in all species investigated includborne ANGII and ANGII of neuronal/glial origin ing the duck, and the same holds true for the interact as "first messengers" with membrane-intrin- neurosecretory system of the median eminence with sic receptor proteins with subsequent activation or high receptor densities found in the duck median inhibition of intracellular signal transduction path- eminence for both its anterior and posterior section. ways. To identify central nervous ANGII receptive Autoradiographical Scatchard analysis of putative mechanisms, binding studies have been performed ANGII binding sites in consecutive tissue sections of almost exclusively in the rat brain with additional the rat SFO and median eminence resulted in high receptor characterization in the central nervous sys- receptor densities of 175 and 50 fmol/mg protein, tern of some rodents and calves using radioactively respectively (Plunkett et al., 1987), with comparative labelled ANGII of high specific activity (Bennett and quantitative data in avian species not being available. Snyder, 1976; Harding et aL, 1981). Enriched Similar to results obtained in the rat, competitive membrane fractions of the rat hypothalamus-- displacement studies carried out for the duck thalamus-svptum (HTS) region as a source for the SFO revealed the same potency of various ANGII specific ANGII binding proteins revealed a dis- analogs to displace radiolabelled lsar-Sile-ANGII as sociation constant (Ko) of 0.2-5.5 nM for the ligand- demonstrated for hypothalamic tissue preparations receptor compkx at receptor densities of 8-15 fmol/ (Gerstberger et al., 1987b). nag protein depeading on the study performed (Sirett Scattered specific labelling of the choroid plexus et al., 1977; Mann et al., 1981; Mendeisohn et al., (PCh) could be found in the duck brain, indicative of 1983, 1984; Leun8 et al., 1991). Comparable data the putative regulatory action of circulating ANGII could be obtained for the freshwater acclimated on trans-epithelial transport in the process of CSF Pekin duck with a hypothalamic ANGII receptor production by PCh epithelial cells. Through alterdensity of 4 fmol/mg protein at a dissociation con- ation of PCh blood flow or ion transport, marked stant of 1.2nM when using radiolabelled avian changes in the local environment of periventricular ANGII as ligand (Gentberjer et aL, 1987a, b). The neurones and glial cells might, thus, be provoked by duck hypothalamic ANGII receptor could further be ANGII as described for the rat (Maktabi et al., 1990). 300
301/ =
1
"
r
dt
B FtG. 4. Autoradiographic localization of ANGII-spccific binding sites in coronal sections of the adult duck brain using [125I] nsar-Sile-ANGII as radioligand. (A): Specific ANGII binding sites could be labelled in the subfornical organ (SFO), the AV3V region and the amygdala-analogous structure of the nucleus taeniae (TN). (B-D): Binding of the radioligand to the subfornical organ (SFO) of a saltwater-(B) and freshwater-acclimated (C) duck. Non-specific binding is demonstrated in (D) (Gerstberger et al., 1987b). Bars represent 1 ram. 185
Fro. 5. Autoradiographic localization of ANGII-specific binding sites in embryonic and juvenile duck brains using [~25I]-ANGII as radioligand. One day before hatching (A, B), ANGII-spexific binding sites can be located in the paraventricular nucleus (PVN), the amygdala-analogous structure of the nucleus taeniae (TN) and the ventromedial hypothalamic nucleus (VMN): Labelling of the subfornical organ (SFO) is demonstrated eight days (C) and one day (D) before, as well as 3 days (E) and 14 days (F) after hatching. The choroid plexus (ClaP) is labelled only in very early embryonic stages (C) and scattered binding only returns in adulthood. (Courtesy of Mr A. R. Mfiller). Bars represent 1 mm.
186
ANOIOTENSlN II is BraDS
187
TABLE I. DmTmmmoN oF ANGII BtNDINGSrrEs L~ V,~mOUSCENTRALNmtvotm STRUC1'tm~ OUTSIDE(UPPER SECTION)AND INSIDE(LOWERSECTION)THEBLOOD--BaAINB ~ OFT ~ RAT, R.~arr, DoG, SH~P, HUM~ ANDDUCK Rat AH AP
+++ ++
Rabbit
Dog +++ +++ ++ +++
OVLT
++
+ +++ ++
~h
++
+
ME
PI SFO AMYG ARC AV3V DMX IO LS MnPO NTS OB PVN SCN SON
+
0 +++
++ +
+++ ++ ++ ++ +++ +++ +++ +++ +++
0 +++ ++ + 0 ++ ++ +++ + ++
Sheep
Human
Duck
+++ +++
+ + ++ +
++
++ +++
++ +++
+
++ +++
0 +++
+++ ++ +++
+ +++ +++ ++
++ +++ +++
+++ +++ ++
+ ++
0 ++
+++ +++ + +++ +++ +++ +
+++ + + ++ ++ ++ + +
Abbreviations: AH = adenohypophysis, AMYG ffi amygdala complex, AP ffi area postrema, ARC -- arcuate nucleus, AV3V = anterio-ventral third ventricular region, DMX = dorsal vagal motor nucleus, IO = inferior olivary complex, LS = lateral septum, ME = median eminence, MnPO = median preoptic nucleus, NTS = nucleus of the solitari tract, OB = olfactory bulb, OVLT = organum vasculosum laminae terminalis, PCh •ffi choroid plexus, PI = pineal gland, PVN ffi paraventricular nucleus, SCN ffi suprachiasmatic nucleus, SFO = subfornical organ, SON--supraoptic nucleus. (For references see text.) (0,+,+ + , + + +) reflect optical semi-quantitative ratings.
Of other CVOs located in the ependymal lining of the third cerebral ventricle, the pineal gland was endowed with A N G I I receptors in the dog and duck, with negative results reported only for the rabbit and sheep, thus, reflecting possible species variations, while the subcommissural organ proved to be devoid of ANGII-specific binding sites. Periventricular areas within the BBB and possibly relayed to the OVLT and/or SFO such as the MePO and the AV3V region (McKinley et aL, 1990), expressed ANGII-specific binding sites in all species examined, suggestive of the important role that A N G I I may play as a brain-intrinsic modulator in hydromineral homeostasis. This view is supported by the presence of A N G I I binding sites in the A D H synthesizing nuclei, both the PVN and SON, of the duck as well as many mammalian species (Fig. 4). In addition, distinct periventricular sites containing mostly fibers and only few perikarya, and possibly representing fiber connections between the SFO and median eminence, were marked by labelled A N G I I in the avian brain, as were the ventromedial hypothalamic nucleus and components of the thalamic habenular complex. Neuroanatomical areas reciprocally connected to the autonomic centres of the duck hypothalamus such as the lateral septum or amygdala-analogous entities (nucleus taeniae) could be labelled with the radioligand to moderate and high degrees, respectively. With regard to the septum, this observation is comparable to findings in the brain of the rat, mouse, hamster, rabbit, dog and human (Harding et al., 1981; McKinley et al., 1987; Mendelsohn et al., 1988). In summary, A N G I I specific binding sites could be localized in hypothala-
mic nuclei and areas both inside and outside the BBB possibly involved in modulatory functions within the regulatory circuits of body fluid homeostasis in both birds and mammals. Among the A N G I I binding sites outside the hypothalamic and adjacent brain regions, those in the lower brainstem of mammals, especially in the locus coeruleus, area postrema, nucleus of the solitary tract and adjacent motor nuclei (Sirret et al., 1977; Mendelsohn et al., 1984; Heal), et al., 1986; Diz et al., 1987) have received attention as putative targets mediating part of the modulatory actions of A N G I I on circulatory control. This assumption rests on studies on dogs (Joy and Lowe, 1970; Gildenberg et aL, 1973; Atsuhiro et al., 1986; Averill et al., 1987) and rats (Casto and Phillips, 1984; Rettig et al., 1986; Unger et ai., 1988; Muratani et al., 1991). With special respect to the area postrema, sustained alterations of circulatory control were not observed in animals with chronic lesions (Zandberg et al., 1977; Haywood et al., 1980). Further, a less specific relationship cannot be excluded between circulatory responses mediated by the area postrema and the more general chemoreceptor properties of this structure which have been implicated in the generation of emesis (Carpenter et al., 1988). F o r birds, the only evidence for A N G I I receptors in the lower brainstem has been provided by studies on the duck (Gerstberger et al., 1987a, unpubfished observation) which demonstrated a distribution similar to that in mammals (Table 1). As a target for physiological actions of A N G I I , the lower brainstem of birds has not been studied, so far. However, considering that physiological changes in A N G I I plasma concentration did
188
E. SIMONet al.
not affect arterial blood pressure (Simon-Oppermann et al., 1984), possible target functions on the blood side of the BBB do not seem to be functionally relevant in cardiovascular control of birds. As demonstrated for most peptidergic and nonpeptidergic receptor proteins, binding hormones or neurotransmitters with high affinity, the presence of more than one subtype of ANGII-specific binding site has been postulated (Chiu et al., 1989). To pharmacologically differentiate between the ANGII receptor subtypes ATe, which is sensitive to sulfhydryl reducing agents, and AT2, non-peptidic imidazole ligands were used as A N G I I specific receptor antagonists (Chang and Lotti, 1989; Chiu et al., 1989) to displace radiolabelled ANGII or its antagonist ~sar-Sile-ANGII from rat central nervous binding sites. Regions consistent with known actions of angiotensin II such as the OVLT, SFO, PVN, PCh, median eminence or nucleus of the solitary tract contained AT~ receptor subtypes exclusively, while AT2-type receptors could be localized in the thalamus, lateral septum and medullary structures such as the locus coeruleus, medial geniculate nucleus and the inferior olive (Gehlert et al., 1990; Rowe et al., 1991; Song et al., 1991; Tsutsumi and Saavedra, 1991). Until now, a functional response cannot be attributed to the AT 2 subclass of A N G I I receptors. With values for the inhibitor constants of 10-500 nM in the case of the AT:specific antagonist and even higher values for the AT2-antagonist, further investigations seem necessary to specify imidazole ligands as valuable tools in central ANGII receptor research. Autoradiographical binding studies in the duck central nervous system revealed a marked displacement of both monoradioiodinated 5vaI-ANGII and lsar-Sile-ANGII from all hypothalamic and amygdala-complex binding sites in the presence of sulfhydryl reducing agents, indicative of AT~ type prevalence (Gerstberger, unpublished observation). With regard to second messenger systems possibly involved in signal transduction coupled to A N G I I receptors in the brain, only limited information is available. Using primary neuronal and astrocyte glial cultures prepared from 1-day-old rat hypothalami, ANGII-specific binding sites were characterized in both cell types with prevalence of the A T : t y p e in glial cells and the AT2-type in neuronal cells (Raizada et al., 1987; Sumners and Myers, 1991; Sumners et al., 1991). In the astrocyte glial cultures, ANGII increased inositol phospholipid hydrolysis, while in neuronal cultures neither the IP3/DAG system, nor the formation of cyclic AMP could be modulated by the presence of ANGII in the medium (Sumners et al., 1990). On the other hand, basal cellular cyclic GMP (cGMP) concentrations are decreased by A N G I I in a time- and concentration-dependent way in the neuronal, but not glial culture system (Sumners and Myers, 1991), while cGMP increased in a murine neuroblastoma cell line (Gilbert et al., 1984). For the avian central A N G I I receptive system, neither data concerning the presence of glial A N G I I binding sites nor the role of putative second messengers have been obtained so far.
3.3.2. A N G H
receptor regulation
In the rat, ANGII plays a role in the central control of salt intake within the first few weeks after birth, and the number of whole brain A N G I I receptors is maximal in two-week-old rat pups. Autoradiographical analysis revealed a marked increase in A N G I I binding sites in the various medullary nuclei of the pup's brain as compared to the adult stage, and the existence of additional cerebellar cortical binding sites no longer present in the adult animal (Leshem and Epstein, 1989; Tsutsumi and Saavedra, 1991). With regard to age-dependent expression of hypothalamic ANGII binding sites of the AT:type, ATt receptor densities proved to be higher in young as compared to adult rats in the SFO, while the suprachiasmatic nucleus and the PCh were endowed with lower AT~ receptor concentrations. Labelling was comparable in both groups of animals in the PVN and SON. In the Pekin duck, preliminary investigations were performed at the embryonic stages 8 and I day(s) before hatching as well as 3 and 14 days after hatching, using radiolabelled birdspecific 5val-ANGII as radioligand (Fig. 5). Both the ADH-synthesizing PVN and the amygdalaanalogous structure of the nucleus taeniae were endowed with A N G I I binding sites at day 1 before hatching, while at the early embryonic stage these structures could not be clearly identified histologically or through receptor autoradiography. In contrast, the PCh of the lateral ventricles were heavily stained at day 8 before hatching with progressively weaker labelling in later pre- and posthatching periods. The pineal gland revealed high binding capacity throughout all stages of development, whereas the median eminence appeared not to express receptor proteins before hatching. The SFO as the prime target organ of circulating ANGII showed slight labelling at day 1 before hatching with gradual increase in the binding signal up to adulthood (Fig. 5). These data might reflect the development of the hypothalamic ANGII receptive system in structures playing a role in the central control of body fluid homeostasis in the duck starting even before hatching. As mediator of the dipsogenic effects of circulating and possibly also central ANGII in birds and mammals, the SFO-intrinsic ANGII receptive system undergoes up- and down-regulation, with regard to receptor density primarily, depending on the status of the extracellular fluid volume (ECFV). In rats chronically dehydrated for 5 days, only the anterior pituitary and the SFO revealed a significant increase in ANGII receptor density with constant values for the PVN, MePO and OVLT. Chronic dietary sodium depletion, on the other hand, reduced the expression of functional SFO binding sites specific for ANGII (Hwang et al., 1986; Nazarali et al., 1987; Ray et al., 1990). In addition to these, experimentally induced alterations in ECFV, persistent high arterial pressure as found in the genetically hypertensive SHR rat or after repeated stress, increased the density of A N G I I binding sites in the SFO and components of the ADH-synthesizing neuroendocrine circuit (C~hlert et al., 1986b). Unlike experimental dehydration in mammals which can be maintained only for a limited
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FIG. 6. Dose dependent water intake (ordinate) of pigeons in response to intracranial and intraperitoneal injections of ANGII at doses between 100 fmol and 1 #mol (abscissa). Numerals in brackets indicate number of measurements. (Evered and Fitzsimons, 1981a, modified.) length of time, the Pekin duck can be adapted chronically to hypertonic saline as drinking fluid, due to the presence of their supraorbital salt glands (Simon, 1982), with a restricted degree of permanent dehydration (Gray et al., 1987). Acclimation to hypertonic sodium intake in these birds induced a stimulation of the peripheral and central RAS (Gray and Simon, 1987) associated with a marked up-regulation of ANGII binding sites in the SFO exclusively (Gerstberger et al., 1987a, b). Thus, saltwater-acclimated birds showed a three-fold rise in ANGII receptor density in the SFO with unchanged binding affinity, at elevated plasma and cerebrospinal fluid ANGII immunoreactivity (Fig. 4). This hypersensitivity of the central nervous ANGII system due to augmentation of both the hormonal/neuromodulatory signal and membrane-intrinsic receptive elements under conditions of ECFV depletion represents a rare example of signal transfer enhancement in the vertebrate kingdom.
4. CENTRALLY MEDIATED PHYSIOLOGICAL ACTIONS OF ANGIOTENSIN H IN BIRDS 4.1. DRINKING AS A BEHAVIOURAL ACTIVITY IN SALT AND FLUID BALANCE
As in mammals, ANGII-induced drinking has also been well studied in birds, and there can be little doubt that central targets are required for ANGII to induce this response. ANGII infused intravenously at sufficiently high rates or injected into the rostral brainstem or third ventricle was shown to stimulate drinking in the sparrow (Wada et aL, 1975), pigeon (Evered and Fitzsimons, 1976, 1981a; Kaufman and Peters, 1980; Barraco et al., 1984), quail (Takei, 1977a; Kobayashi and Takei, 1982), fowl (Snapir et al., 1976; Schwob and Johnson, 1977), duck (DeCaro et al., 1980), and turkey (Denbow, 1985). For each route of application the dose dependence of the amount of water drunk could be demonstrated (Fig. 6). Attempts were made by means of stereo-
189
taxicallycontrolledintracerebralANGII injectionsto localize the specific target structures involved. Data obtained in the pigeon (Evered and Fitzsimons, 1981a) and quail (Kobayashi and Takei, 1982) showed that periventricular sites in the ventral preoptic area (POA) close to the midline were particularly sensitive. Furthermore, injections directly into the SFO and the dorsal third ventricle near its junction with the lateral ventricles were particularly effective (Takei, 1977b). In all, the locations of these sites were shown to correspond to the distribution of ANGII receptors in the duck hypothalamus (Gerstberger et al., 1987a, b), including the SFO, the POA and the AV3V region. Catecholaminergie fiber tracts running from the quail POA towards the SFO appear important in the stimulation of water intake elicited by ANGII injection into the POA as proven by the ineffectiveness of ANGII to stimulate drinking after fiber transsection. Information relayed by ANGII and perceived by the POA might, thus, require catecholaminergic nerve fiber inputs in order to be transferred properly (Takei et aL, 1979). The presence of both tyrosine-hydroxylase immunoposirive fibers and ,q- as well as a2-specific adrenoceptors in the SFO of the duck also suggest catecholaminergic modulation at the SFO target site of central ANGII action (Gerstberger et aL, 1992). The results of pharmacological studies to test the specificity of ANGII in eliciting drinking in birds, though not fully consistent, have supported the function of ANGII as a natural, centrally acting dipsogen. ANGII-induced drinking in pigeons was inhibited by lsar:ile-ANGII and tsar-Sleu-ANGII (DeCaro et al., 1982), but lsar-Sala-ANGII was ineffective as an inhibitor, while the action of ANGIII as an agonist was only 1% of that of ANGII (Evered and Fitzsimons, 1981b). In turkeys, tsar-Sala-ANGII attenuated but did not completely abolish ANGII induced drinking (Denbow, 1985). The neurones of the SFO which are directly accessible to blood-borue agents were considered early as the most likely rostral brainstem target in both mammals and birds (Fitzsimons, 1980) where circulating ANGII acts to stimulate drinking and other effectors of salt and fluid balance. Similar to evidence in mammals (Thrasher et al., 1982), experiments in the pigeon showed that drinking in response to blood-borne ANGII was diminished after lesioning or isolating the SFO, which also attenuated the drinking response to acute hypovolemia, while water deprivation as a dipsogenic stimulus involving hypertonicity was not impaired (Massi et aL, 1986). Less clear is the role of the OVLT in mammals, and in birds this organ has not been systematically studied. The question whether or not exogenously induced increases in plasma ANGII within the physiological range may affect water intake has not been definitely settled for mammals (Andersson et al., 1984; Phillips 1987). As far as birds are concerned, studies in one pigeon (Evered and Fitzsimons, 1981a) showed that the threshold doses for the stimulation of water intake by intravenous ANGII infusions of 15 min duration were in the order of 3-15 pmol/min/kg body weight. When selecting intravenous infusions of about 0.3 ml/min of hypertonic (0.5 M) saline for 15 min, or of equally hypertonic sucrose or mannitol
E. SIMON et al.
190 40
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~ . [M]
FIG. 7. Drinking (ordinate) of pigeons in response to infusions into the third cerebral ventricle (abscissa) of hypertonic saline of increasing concentrations at a rate of 2/zl/min for 10min (circles) and to administration of ANGII (dots) together with the hypertonic infusions. (Fitzsimons et al., 1982, modified.) solutions, as a dipsogenic stimulus in normally hydrated pigeons, drinking was distinctly augmented when the hypertonic stimulus was combined with 3 nmol ANGII (Fitzsimons et ai., 1982). These data clearly indicate that the levels at which circulating ANGII was dipsogenic in pigeons, or capable of potentiating the effects of other dipsogenic stimuli, were well within the physiological range, considering the relationship between plasma ANGII concentrations and ANGII infusion rates determined in ducks (Gray and Simon, 1985) and gulls (Gray and Erasmus, 1989). Higher threshold infusion rates for ANGII were determined by other authors in pigeons (Kaufman and Peters, 1980) and in quail (Takei, 1977a). However, the minimum doses evaluated as dipsogenic appear to be more pertinent, because drinking, as a complex behavioural reaction, may be subject to impeding motivational and physiological influences that cannot be controlled by the experimenter. If one compares the dipsogenic potency of systemically and intracranially applied ANGII, the latter route requires, as a rule, much smaller amounts of ANGII to become effective in both mammals and birds (Fitzsimons, 1980) (Fig. 6). In the quail, a single dose of 5 pmol ANGII was sufficient to elicit drinking when injected directly into the preoptic area or into the SFO (Takei, 1977b, Kobayashi and Takei, 1982). In the pigeon, the threshold dose for drinking of ANGII administered into the third ventricle was between 10 and 100 fmol, as compared to 0.1-1.0 /~mol with single intraperitoneal ANGII injections, while with intravenous application the dipsogt~c threshold dose of ANGII was between 3 and 15 pmol/min/kg body w~isht ~ a i a t e r e d for 15 min (Evered and Fitzsimons, 1981a). Similar to the combination of ANGII with osmotic stimuli in systemic applications, the dose-dependent drinking r e -
sponse to intracranial 10rain infusions of 2/~l/min hypertonic saline with increasing NaCI concentrations was augmented in an approximately additive fashion, when 10 pmol ANGII were added to the hypertonic infusate (Fig. 7). Deducing from generally lower ANGII doses, greater physiological relevance of the intracranial as compared with the systemic route of ANGII action, however, does not seem to be justified. Intracranial doses of ANGII were usually delivered in both mammals and birds in small volumes (in the order of 1 #1) and, therefore, ANGII concentrations in the central infusates were usually in the order of 1-100 pmol/ml, i.e. much higher than in circulating blood or in the CSF. For this reason it is difficult to use dosage as a basis from which to draw conclusions concerning the physiological significance, if comparisons are made between putative ANGII receptors on the blood and brain side of the BBB. On the other hand, the high ANGII concentrations used for intracranial stimulations are no argument against the physiological relevance of the observed effects. According to histochemical evidence, ANGII is strongly compartmentalized in the brain, being stored at presumably very high concentrations in nerve fibers and synaptic varicosities. Therefore, high concentrations might well occur at localized sites, when brain-intrinsic ANGII is released, for instance, at synaptic junctions. Comparisons between the effects of ANGII, acting either from the blood or the brain side of the BBB, are further complicated by the possibility that permeation across the BBB may not be symmetrical for ANGII circulating in the blood or being released, and injected respectively, into the brain or CSF at high concentrations. Tanycytes, which are located in the ependyma but may reach the pial surface of the brain with their processes, have been implicated as carriers for ANGII from the CSF into the interstitial compartment of the brain and even into the CVOs (Andersson et al., 1984; Phillips 1987). Further speculations take into consideration so-called CSF-contacting neurones (Vigh and Vigh-Teichmann, 1973; Leonhardt, 1980; Bruni et al., 1985) which send dendrites across the ependyma and, within the CVOs, might be capable of sensing both circulating and intracerebral ANGII (Buranarugsa and Hubbard, 1979; Andersson et al., 1984). These speculations would imply that ANGII and various analogs, respectively, may penetrate the BBB more easily from the brain to the blood side than vice versa. Supportive evidence for this hypothesis can be drawn from the observation, that the intracranial application of the ANGII antagonist ~sar-Sala-ANGlI prevented the binding of blood-borne [125I]-ANGII to the CVOs (Van Houten et al., 1983). 4.2. BLOODPRESSURECONTROL As indicated in the introduction, a number of studies suggest that direct vasoconstrictor actions of ANGII are not physiologically relevant in birds. Slight increases in blood pressure by 5-10 mm Hg were observed in conscious pigeons when approximately 15 pmol/min/kg body weight ANGII was infused i.e. (Evered and Fitzsimons, 1981a). In anacsthetiz~ chickens bolus injections of 10-1000 pmol/kg
ANOIOTENSINII n~ BIRDS anti AVT I.v.
ANQ U i.c.v.
~
II i.c.v.
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FIG. 8. Mean arterial pressure (MABP), heart rate and respiratory frequency of ducks responding typically with arterial hypertension and tachycardia (left part) to intracvrebroventricular (i.c.v.) infusion of 2pmol/min/kg body weight over 10 rain. Preceding intravenous (i.e.) infusion of an AVT-antiserum (right part) attenuates the responses to i.c.v. ANGII infusion. (Gerstherger et al., 1984a). body weight ANGII produced biphasic blood pressure changes consisting of a short-lasting initial drop and a subsequent dose-dependent rise (Nishimura et al., 1982). In conscious chickens the primary depressor action of ANGII injections was more pronounced and the subsequent pressor response was observed only with doses of 0.5 and 1.0nmol ANGII (Nakamura et al., 1982). Continuous ANGII infusion at a rate of 200 pmol/min/kg body weight in conscious chickens caused an initial depressor response which was restored within 5 rain, but in the further course of the infusion arterial pressure tended to decrease continuously (Goto et al., 1986). Injection and infusion studies in conscious ducks showed that an estimated threshold plasma concentration of 2000 fmol/ml ANGII, which is clearly beyond the physiological range, had to be surpassed before measurable rises in blood pressure could bc detected (Simon-Oppermann et aI., 1984). The absence of a generalized vasoconstrictor response to A N G I I applies equally to 5vaI-ANGII and 5ile-ANGII (Brummermann and Simon, 1990). Apparently smooth muscle cellsdo not possess sufficient A N G I I binding sitesand/or intraccllularsecond messenger systems necessary for activation of constriction. N o constrictor effects were detected when avian aortic, sciatic and pulmonary arteries were tested/n vitro for the effectsof A N G I I (Somlyo et al., 1967; Moore et aL, 1981). This would conform to evidence in vivo according to which the pressor responses of birds to pharmacological doses of A N G I I are caused indirectly, as the result of the facilitatory action of A N G I I on catecholamine secretion, an action c o m m o n throughout vertebrate
191
phylogeny (Wilson, 1984b). This mode of action is suggested by the observation that in chickens and ducks doses of 1 nmol/kg body weight ANGII had to be administered in order to se¢ appreciable prcssor responses which were, however, associated with large rises in plasma norepinephrine keels (Wilson and West, 1986). Blockade of r,-receptors enhanced the early hypotensive and diminished the subsequent pressor actions of 200 and 500 pmol/kg body weight ANGII in anaesthetized chickens (Nishimura et al., 1982). The hypertensive component of the blood pressure responses to ANGII doses of I nmol/kg body weight was substantially diminished by reserpine pretreatment (Wilson and Butler, 1983). As a conclusion, the inability of physiological levels of circulating ANGII to trigger pressor responses by acting peripherally in both conscious and anaesthetized birds allows us to state with greater certainty than in mammals, that the circulating hormone does not trigger physiological pressor responses by a central action on any of the putative hypothalamic and lower brainstem ANGII receptors. Interestingly, the antidiuretic hormone, in both the avian form 8arg-vasotocin (AVT), and the mammalian form, 8arg-vasopressin (AVP), does not increase blood pressure in birds when administered peripherally. Large doses rather had a hypotensive effect in chickens (Ames et al., 1971; Wilson and West, 1986) and ducks (Wilson and West, 1986; Brummermann and Simon, 1990). For this response, as well as for the early hypotensive response to ANGII, a direct relaxing effect on the vascular walls has been taken into consideration (Wilson, 1989). This assumption would be in accordance with the surprising observation that progressive increases in both AVT and ANGII plasma concentration in the course of acclimation of ducks to severe salt stress were associated with a distinct decrease in arterial pressure (Brummermann and Simon, 1990). Blood pressure responses to centrally applied ANGII have been little studied in birds. Intracranial injections of ANGII in pigeons at sites where drinking could be elicited with doses of I pmol, did not increase arterial pressure, and a slight pressor response was seen only with a dose of I nmol (Evered and Fitzsimons, 1981a). On the other hand, circumscribed perfusions of the third ventricular lumen of conscious ducks in the state of diuresis with ANGII at a rate of 2 pmol/min/kg body weight for 10 min and at sites where antidiuretic responses could be elicited, increased arterial blood pressure by some 30 mmHg, and doubled heart rate (Gerstberger et al., 1984a) (Fig. 8). Since an overflow of ANGII into the circulation was unlikely and, moreover, would not explain the hypertensive response, these effects must have been elicited on the brain side of the BBB. The response pattern strongly suggests that cardiovascular sympathetic innervation was stimulated and possibly also cardio-inhibitory parasympathetic innervation inhibited during third ventricular ANGII perfusion. An interesting observation was that systemic application of an AVT antiserum not only abolished the antidiuretic effect of centrally administered ANGII but also reduced the hypertensive response (Fig. 8), despite the well-founded fact that systemic AVT produces arterial hypo- rather than
192
E. SIMON et al. 15
-3O
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[ml]
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18
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[fmol.m)-'I 10
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-15
-10
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16
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2 fmol
20 fmol
200 frnol
2 pmol
20 pmol
ANG II [10 min-l'kg-lbw]
FIG. 9. Perfusion of third cerebral ventricle (i.c.v.) at 5 #l/min for 10 min with ANGII at concentrations between 100 fmol/ml and 1 nmol/ml (2 fmol/10 min/kg body weight to 20 pmol/10min/kg body weight) in ducks made diuretic by continuous intravenous infusion of 1 ml/min hypotonic (200 mOsmol/l) saline: ANGII i.c.v, dose-dependently increased AVT plasma levels (AAVT) and amounts of urine retained during 30 min, relative to average steady state excretion rate (AUv) as an indicator of antidiure=s: (Gerstbcrger et al., 1984a.) hypertension in birds. This seems to suggest that intracranially acting A N G I I released AVT as a secondary mediator which acted on brain structures that were also accessible to blood-borne AVT-antiserum, i.e. most likely one of the CVOs. A further observation was that the effects of third ventricular A N G I I perfusion could be elicited only in the rostroventral part of the third ventricle. The critical importance of the site of perfusion might explain the discrepancy of presser responses in ducks (Gerstberger et al., 19Ma) and negative results in pigeons (Evered and Fitzsimons, 1981a). 4.3. CENTRAL CONTROL OF THE ANTIDIURETIC HORMONE
ANGII as a centrally acting stimulator for ADH release has been frequently studied in mammals. While antidiuretic responses to centrally applied A N G I I were a consistent response, divergent results have been obtained with systemic application and have precluded a clear answer to the question whether stimulation of A D H release by circulating A N G I I is physiologically relevant (Reid, 1984). Theoretically, A N G I I as a volume-controlled hormone would be a plausible mediator for volume influences on A D H release, in addition to inhibitory inputs from cardiovascular high and low pressure afferents which, as in mammals, are also relevant in avian volemic control of ADH (Simon-Oppermann et ai., 1980). However, where plasma A N G I I levels could be estimated m mammals, doses of A N G I I effective in eliciting antidiuresis were above the physiological range (Phillips, 1987). The same seems to apply for birds. In the quail the intraperitoneal A N G I I dose required to double resting AVT plasma concentration amounted to 100 nmol/kg body weight
(Kobayashi and Takei, 1982). In hydrated chickens receiving intravenous A N G I I infusions only the highest rate of 200 pmol/min/kg body weight raised plasma AVT concentration significantly (Gore et al., 1986). In conscious salt and fluid loaded ~ with a resting plasma A N G I I concentration of 50 fmol/ml, increasing the hormone concentration for 2 hr to levels of 700 fmol/ml by intravenous infusion did not influence plasma AVT concentration (Gray et al., 1986). In the kelp gull sustained increases in plasma A N G I I from a level of 60 fmol/ml to a level o f over 300 fmol/ml did not alter plasma AVT levels and, when the same A N G I I infusion was given together with hypertonic saline, the rise of plasma AVT was not larger than with the hypertonic stimulus alone (Gray and Erasmus, 1989). So far, effects of centrally administered A N G I I on AVT plasma concentration in birds have been determined in only one species, the duck. In conscious animals made diuretic by continuous infusion with isotonic fluid at a rate of I ml/min, the anterior third ventricle was locally push-pull perfused at a rate of 5/~l/min with artificial CSF to which different amounts of A N G I I were added, Taking the peffusion as an infusion, which clearly overestimated the amounts of A N G I I a d m i n : ~ ' e d , the threshold amount of ANGII to be infused intraventricutarly within 10rain In order to induce measurable antidiuresis was 20 fmol/kg body weight. In the dose range from 20 fmol/kg body weight to 20 pmol/kg body weight, both plasma AVT concentration and the amounts of urine retained, relative to the rate of fluid infusion increased dose-dependently in a strictly parallel fashion (Gerstbcrger et aL, 1984a) (Fig. 9). Interestingly, the efficiency of centrally ~ r e d A N G I I in eliciting antidiurcsis critically ~ on the site of local perfusion. Consistent r e s p o n m were
ANOIOTENSINII
IN
BIRDS
193
ANGII
in the cephalic circulation (Gcrstberger et aL, 1984c) was shown to control salt gland activity and to be 1-1 0.6 monitored at periventricular sites in the rostral extvnsion of the third cerebral ventricle (Gerstbergcr et al., ~ 0.5 1984b). Activation of salt gland secretion by ECFV 0.4 expansion (Hanwell et al., 1972; Hammel et al., 1980) 0.3 is of comparable importance, although differently expressed in other bird species (Hughes, 1987). ECFV control of salt gland activity seems to be mainly 0.1 mediated by afferent signals reflecting changes in the interstitial compartment (Simon, 1982). Fluid excretion by the kidneys and salt excretion by the salt I I I I I glands are closely matched, as demonstrated in ducks 0 60 120 180 210 exposed to various combinations of salt and fluid [min] loading (Simon and Gray, 1989). FIE;. 10. Salt gland activity (usmolal excretion) in conscious The closely interdependent excretory functions of ducks loaded by continuous intravenous infusion of the hormonally controlled kidneys and the neuraily 0.4 ml/min saline at 1000mOsmol/kg: Inhibitory effect of controlled salt glands have directed early attention ANGII infused into the third cerebral ventricle for 10 rain towards possible hormonal contributions, especially at a rate of 2 pmol/min/kg body weight (Gtrstberger et aL, by osmoregulatory hormones, to the control of salt 19s4a). gland activity (Holmes, 1975; Holmes and Phillips, 1985; Gerstberger, 1991). Among many hormones obtained only when the push-pull system was located tested ANGII could be identified as an inhibitory in the anterior third ventricle, whereas more posterior hormone (Hammel and Maggert, 1983; Butler, 1984; positions made peffusions ineffective. Taken together Wilson e t a / . , 1985). The observation of inhibitory the results in the duck agree with those of numerous actions of ANGII, when administered into the rostral studies in mammals which show stimulation of ADH third ventricle (Gerstberger et ai., 1984a), suggested release and antidiuresis as a consistent effect of the existence of central targets for ANGII, at least on intracranially infused ANGII (Reid, 1984; Phillips, the brain side of the BBB (Fig. I0). The idea that salt 1987). The strong dependence of the antidiuretic gland inhibition by circulating ANGII might be effect on the site of perfusion points to structures on centrally mediated as well, was suggested by the time the brain side of the BBB which are located in the course of salt gland secretion when ANGII was rostral extension of the third ventricle (Gerstberger intravenously infused in saline loaded ducks (Gray et al., 1987b). e t a / . , 1986), and was further supported by the absence of ANGII receptors in the salt gland tissue (Gerstberger et al., 1987a).. The ability of circulating 4.4. CONTROLOF SALT GLAND ACTIVITY ANGII to inhibit salt gland activity at plasma conThe salt secreting glands function as auxiliary centrations within the physiological range was clearly excretory organs in avian species living in marine or demonstrated in kelp gulls. When plasma ANGII estuarine habitats (Schmidt-Nielsen, 1960; Peaker concentration was increased from its control level of and Linz¢ll, 1975). No such system exists in mam- 60fmol/ml to 120, 270 and 840fmol/ml by intramals. Salt gland secretion in birds is efferently con- venous infusions of 5, 15 and 45pmol/min/kg trolled by the secretory portions of the cranial ANGII, salt gland output was dose-dependently parasympathetic nerves, with tonicity of the body reduced by 10, 40 and 60% (Gray and Erasmus, fluid and ECFV as the regulated variables. Tonicity 1989) (Fig. 11). 5 pmol.kg'l.mln
"1
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FIG. 11. Salt gland activity (osmolal excretion) in kelp gulls, induced and maintained by intravenous (i.v.) infusion of 0.3 ml/min saline at 1200mOsmol/kg. Dose-dependent inhibition of salt gland secretion by I hr i.v. infusions of ANGII at rates of 5, 15, and 45 pmol/min/kg body weight (Gray and Erasmus 1989).
194
E. SIMONet al.
Infuaion of 1000 mOsrn NaCI ( 0.98 ml/mln -1 i.v.) MCh (10 pglmin -1 i.v.)
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400 :3.
200
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FIG. 12. Na + secretion by the salt glands of a duck in response to continuous intravenous (i,v.) infusion of hypertonic saline. ANGII injected i.v. temporarily inhibits salt gland secretion stimulated by parasympathetic, cholinergic efferents. Subsequent ganglionic blockade by i.v. injection of mecamylamine produces a long-lasting suppression of natural salt gland innervation, but salt gland activity can be restored by i.v. infusion of a cholinergic agonist (methacholine bromide, MCh), during which, however, i.v. injection of ANGII no longer inhibits salt gland secretion. (Butler et al., 1989, modified.)
Central mediation of ANGII-induced salt gland inhibition was confirmed by studies on ducks in which an intravenous dose of 2 nmol ANGII transiently suppressed salt gland secretion induced by continuous saline loading, whereas the same dose was completely ineffective, when the natural parasympathetic activation of the glands was replaced by pharmacological stimulation with a cholinergic agonist (Butler et al., 1989) (Fig. 12). Modulation of parasympathetically controlled glandular activity by a circulating hormone that acts exclusively via a central target, appears rather unique as a physiological phenomenon. 4.5. PHYSIOLOGICALCONSEQUENCESOF CENTRAL
A N G I I ACTIONS The multiplicity of the centrally-mediated actions of A N G I I described above underscore the concept that this peptide plays a vital role in avian volume regulation. More specifically, these effects of A N G I I are consistent with the generally accepted idea that A N G I I functions as an agent to maintain ECFV by preventing or minimizing ECFV shrinkage. However, whereas in mammals the centrally-mediated actions of plasma-borne A N G I I and those of the brainintrinsic hormone are identical, in birds some divergence exists between the central actions of A N G I I on targets on the blood and brain side of the BBB The physiological effects of systemic ANGII, which are mediated via central target sites, are restricted to dipsogenesis and the inhibition of salt gland function
in birds which possess them. These actions of ANGII are designed to reduce salt and fluid loss and, at the same time, stimulate the intake o f both. When taken together with other physiological actions of circulating ANGII demonstrated in birds, inchatin8 the stimulation of sodium retaining aldosterone and a direct antinatriuretic/antidiuretic effect (Gray et al., 1989; Gray and Erasmus, 1989), then the sigl~Lfw,ance of systemic A N G I I in avian osmoregulation can be appreciated. Although centrally applied A N G I I also initiates dipsogenesis and salt gland inhibition counteracting hypovolaemia, ANGII as a neuropeptide has supplementary effects which exceed and reinforce those of the systemic hormone. A N G I I acting on the brain side of the BBB in addition increases renal water conservation by stimulating ADH release, and its hypertensive effect might contribute to the maintenance of proper cardiovascular filling under conditions of emergency by activating the autonomic vasoconstrictor system to reduce vascular compliance.
5. ANGIOTENSIN H RESPONSIVE NEUltONES Physiological analysis has shown that centrally mediated actions of A N G I I on either side of the BBB contribute in a co-ordinated manner to the control of salt and fluid balance in mammals and birds. In the two classes of vertebrates the distributions o f high alfmity binding sites for A N G I I I n the region of the "forebraln receptor band" (Plunkett et al., 1987)
ANGIOTENSlNII IN BraDS
195 ANG II 10"7 M
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FIo. 13. ExtraceUularly recorded activity of a SFO neurone in a tissue slice from duck hypothalamus showing dose-dependent activation when the slice was superfused with medium containing ANGII (horizontal bars) at three different concentrations (Matsumura and Simon, 1990a). seem to be largely homologous, although this subject has been much less studied in birds. Theories about the structural design of the rostral brainstem network controlling salt and fluid balance have been put forward repeatedly for mammals (McKinley et aL, 1989; Thrasher, 1989; Honda et al., 1990) but not for birds, partly because of the paucity of data and partly under the premise that the mammalian and avian integrative systems are largely homologous. Since data on neuronal ANGII responsiveness in birds have only recently been provided (Matsumura and Simon, 1990a, b), their interpretation needs to be related to corresponding data obtained in mammals. 5.1. DISTRmUTIONAND PROPERTIESOF ANGII RESPONSIVEROSTRALBRAINSTEMNEURONES Numerous studies in mammals have confirmed that the distribution of electrophysiologically identified neuronal ANGII responsiveness in the rostral brainstem is to a large extent congruent with the autoradiographically determined distribution of ANGII receptors. Most frequently demonstrated was the SFO as a site where exposure of neurones to ANGII consistently affected substantial fractions of neurones, with increases in activity as the prevailing response (Felix and Akert, 1974; Phillips and Felix, 1976; Felix and Schlegel, 1978; Okuya et al., 1987). ANGII responsive neurones were also found in the OVLT (Knowles and Phillips, 1980; Sayer et al., 1984). Structures on the brain side of the BBB exhibiting neuronal ANGII responsiveness were the neurosecretory nuclei, SON and PVN (Nicoll and Barker, 1971; Harding and Felix, 1987), and the AV3V region (Gronan and York, 1978; Okuya et al., 1987). Neuronal activation by ANGII and hypertonic stimulation applied to the third ventricle were shown to converge on neurosecretory cells (Akaishi et al., 1980), with ANGII being involved as a transmitter (Akaishi et al., 1981). ANGII responsive neurones demonstrated in the medial and lateral septal area (Huwyler and Felix, 1980) and lateral hypothalamus (Wayner et aL, 1973) were tentatively associated with the control of water intake. The specificity of ANGII as a mostly excitatory peptide is supported by the attenuating or suppressive effects of locally administered ANGII antagonists which were tested in several of the cited studies. Some uncertainty exists, as to whether ANGII or des-~asp-ANGII (ANGIII) is the biologically relevant compound in the stimulation of SFO neurones in cats and rats (Felix and Schlegel, 1978; Harding and Felix, 1987).
For the avian rostral brainstem, knowledge about neuronal ANGII responsiveness has been provided, so far, only by studies on ducks. The distribution of ANGII responsive neurones was systematically analyzed in ducks which had been raised on freshwater (freshwater ducks). In this condition the salt glands were not activated and plasma osmolalities and concentrations of osmoregulatory hormones corresponded to those of the commonly used laboratory mammals. Hypothalamic tissue slices were taken from these ducks and extracellular recordings were made in vitro in a perfusion chamber with subsequent histological examination of the topography of the recording sites (Matsumura and Simon, 1990a). Stimulations were made by adding ANGII in known amounts to the perfusion medium and, for control reasons, by altering its osmolality. In freshwater ducks, ANGII responsive neurones were encountered most frequently in the SFO in which 65% of the recorded neurones consistently responded with activation to 10-7~a ANGII added to the perfusion medium. In the anterior third ventricle region where scattered ANGII binding sites had been demonstrated, only 2 out of 22 neurones were activated by ANGII, however, with large increases in discharge rates similar to those of SFO neurones. In the dorsal periventricular region, where neurones had been found to be excitable by hypertonic stimulations (Kanosue et aL, 1990), and in the magnocellular portion of the PVN only 1 out of 37, and 4 out of 81 neurones, respectively, responded to ANGII, and the responses were distinctly weaker than those in the SFO and anterior third ventricle. For the SFO neurones, ANGII responsiveness was clearly dose-dependent with a threshold concentration in the perfusion chamber of 10-gM ANGII (Fig. 13), and responsive neurones were successively recruited when ANGII concentration in the perfusate was raised from 10 -9 to 10-7 M. The majority of neurones retained their ANGII responsiveness in a low-Ca2+/high-Mg2÷ perfusion medium which blocked synaptic transmission, as verified by the abofition of responses to remote electrostimulation. Responsiveness to ANGII was reversibly blocked by Isar-SileANGII, and neither ANGII-responsive nor -insensitive SFO neurones were influenced by bird-specific ANGIII (Fig. 14). This is in accordance with the competitive displacement of radiolabelled ANGII from its SFO target site by various ANGII analogs revealing high affinity for the antagonist ~sar-Sile-ANGII and low atfmity for ANGIII
196
E. SIMON et al. !
30
0
l ~ a r . 8 1 k a - AM('~. II t/~ "6 kA
A N G II 10 -7 M I
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1 min
FIG. 14. Traces of discharge rate recorded from a SFO neurone in a tissue slice from duck hypothalamus which was superfused with medium containing ANGII, ANGIII and the specific ANGII receptor antagonist ;sar-Sile-ANGII (SARILE). The neurone responds to ANGII with activation (first trace), is not responsive to ANGIII (second trace), without alteration of the subsequent response to ANGII (third trace), however, it loses responsivity to ANGII during co-infusion of SARILE, (fourth trace), which is subsequently restored (fifth trace) after superfusion with SARILE-free medium. (Matsumura and Simon, 1990b.) (Gerstberger et al., 1987b; Gerstberger, unpublished observation). 5.2. CORRELATIONBETWEENFUNCTIONALAND NEURONALRESPONSESTO CENTRALLYACTING A N G I I IN THE DUCK Despite the fact that knowledge about A N G I I responsive neurones in the brainstem of birds is currently limited to the duck, this species seems to offer particularly favourable conditions for the assessment of the specificity of the observed neuronal responses. First, the roles of tonicity and A N G I I in central control of the two independent osmoregulatory effector organs, the salt glands and kidneys, have been thoroughly analyzed in ducks (Simon and Gray, 1989; Simon-Oppermann and Gerstberger, 1989). Second, structural information about central interconnections relevant in the control of osmoregulatory effectors (Korf et al., 1982) and about the distribution of A N G I I receptors (Gerstberger e t a / . , 1987b) and sites of tonicity perception (Kanosue et al., 1990) have been provided for the duck rostral brainstem. In ducks with active salt glands, due to acclimation to hypertonic saline as their drinking fluid (saltwater ducks), hypertonic stimuli and A N G I I applied to either side of the BBB were shown to act oppositely to each other, in that secretion was activated by osmotic stimulation (Gcrsthergar eta/., 1984b, c) but inhibited by A N G I I (C~rstbergor et al., 1984a; Gray et al., 1986). However, in the control of antidiuresis
the actions of centrally applied A N G I I and of systemic or intraventricular increases in tonicity were concurrent, in that AVT release was enhanced by each stimulus (C_)¢rstherger et al., 1984a-c). The fact that the actions of hypertonicity and A N G I t were concurrent in the control of one ¢ffoctor but opposing in the control of another effcctor, excluded the possibility that the two stimuli wen) monitored by one set of neurones, but rather postulated that separate sets of neurones must exist which were responsive to either ANGII or hypertonic stimulation. Indeed, neurones in the duck's rostral brainstem respon~ng to A N G I I and hypertonic stimulations were found to be separate from each other (Matsmmura and Simon, 1990a). Among 18 A N G I I responsive SFO neurones exposed to 20 mosmol/kg rises in tonicity by adding NaCI to the perfusate, only 1 neurone was slightly activated and 1 neurone inhibited, whereas the incidence of responses to changes in tonicity was sim~ificantly larger among 65 ANGII-insens/tive neurones tested in the periventricular brain tissue 0 2 stimulations and 8 inhibitions). Especially in the dorsal periventricular region where mmmensitive neurones were found to be particularly ¢onetmtrated 0gdtaotue et al., 1990), A N G I I binding was little according to autoradiographic analysis (Gentberser et al., 1987a). As in mammals (De Bold et a/., 1981; Gene~ and Cantin, 1985; Laragh and Atlas, 1988), atrial natriuretic factor (ANF) is also relevant in birds as a hormone controlling salt and fluid balmme (CrreB and Wideman, 1986; Springate et al., 1987; Gray
ANG[OT~S]~II IN BIRDS 20
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197
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FIG. 15. Traces of discharge rate of an ANGII responsive neurone in the SFO of a duck (A) and a rat (B). (Courtesy of Dr H. Schmid.) (A) Response of a duck SFO neurone to superfusion with ANGII (10 -7 M) and to combined superfusion with chicken atrial natriuretic factor (chANF) and porcine brain natriuretic peptide (pBNP) at the same concentration. There was no effect of the natriuretic hormones on resting discharge rate or on the response to ANGII. (B) Response of a rat SFO neurone to superfusion with ANGII (10-7 M) and rat atrial natriuretic factor (rANF) at the same concentration. The neurone is activated by ANGII and inhibited by rANF.
et al., 1991a). A high density of A N F receptors could be demonstrated in the SFO of ducks (Schfitz et al., 1992). Unfike in mammals, however, where a high incidence of simultaneous responsiveness to A N G I I and A N F of SFO neurones is indicated by studies in rats (Hattori et ai., 1988), recent experiments on duck SFO neurones showed that responsiveness to A N F was not exhibited, as a rule, by neurones responsive to A N G I I (Schmid, personal communication). In accordance with a preceding study (Matsumura et al., 1990a), the majority of 56 neurones recorded extracellularly in the duck SFO in an in vitro preparation were activated by superfusion with 10-7M ANGII, but among 24 A N G I I responsive neurones tested for A N F responsiveness, none changed its activity during superfusion with either rat A N F (rANF) or chicken A N F (chANF), which most probably is the native A N F in ducks as well (Gray et al., 1991b), or porcine brain natriuretic peptide (pBNP) (Fig. 15). Rat SFO neurones recorded under identical experimental conditions also revealed A N G I I responsiveness, however, unlike in ducks 8 out of 10 A N G I I responsive rat SFO neurones decreased their spontaneous firing rate when supeffused with 10-7 M rANF (Fig. 15) and pBNP, as well as with chANF which had to be administered in some neurones at a slightly higher concentration of 3 x 1 0 - T M to be effective. This comparison strongly suggests that, similar to the relationship between osmoresponsiveness and A N G I I responsiveness, a more distinct functional separation exists in birds, as compared to mammals, also with regard to neuronal responsiveness to A N G I I on the one hand, and to A N F and related peptides on the other.
The question of whether A N G I I responsiveness and responsiveness to changes in tonicity in mammals are carried by separate sets of neurones has not yet been clarified. For the SFO the data are somewhat controversial, with either no evidence (Buranarugsa and Hubbard, 1979) or with positive evidence (Gutman et al., 1988) for combined neuronal osmotic and ANGII-responsivenc~s in rats being demonstrated. The possibility has been considered that synaptic interactions in the SFO of rats may result in combined responsiveness of neurones to A N G I I and osmotic stimulations (Buranarugsa and Hubbard, 1988). In the rat OVLT, responsiveness to A N G I I and to changes in tonicity seemed to be partially carried by the same neurones (Sayer et al., 1984). The neuronal network which has been proposed as necessary for the generation of osmoreceptive signals in mammals (Honda et al., 1990) comprises structures such as the SON and the AV3V region where A N G I I receptors, as well as A N G I I responsiveness, have been demonstrated. The distribution of A N G I I responsive neurones in the rostral bralnstem of the duck deviated to some extent from the distribution of receptors. Unlike in mammals, A N G I I responsive neurones were very scarcely found in the magnoceUular neurosecretory regions of the PVN (Matsumura et al., 1990a), although scattered A N G I I receptors could be demonstrated in both the SON and PVN of the duck (Gerstberger et al., 1987a, b). The function of the A N G I I receptors in the vicinity of the magnucellular neurones in the duck's PVN is currently n o t clear. On the other hand, the agreement between
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FIG. 16. Compamon of frac,tio~ of AN~H ~ n s i v e SFO neurones recorded in hypothalamic tissue from freshwater ~ : ~ saltwater ( $ W ) d ~ at 4 different ANGII concentrations in the perfusion medium. Numerals above columns indicate number of neurones investigated in each group and at each concentration. (Matsumura and Simon, 1990b).
electrophysiological and autoradiographical analysis was virtually perfect for the SFO, where a particularly high ANGII receptor density corresponded to a high fraction of ANGII responsive neurones. Moreover, the physiological significance of ANGII responsiveness in the SFO could be endorsed by the observation of concerted changes in circulating ANGII levels, density of ANGII receptors and neuronal ANGII responsiveness in ducks as the result of acclimation to high salt intake. Saltwater ducks acclimated to saline as their only water supply, that is two-fold higher in concentration (600 mosmol/kg) than normal body fluid osmolality (Brummermann and Simon, 1990), cope with this situation indefinitely. This degree of salt stress is associated with plasma hypertordcity, elevated levels of AVT and chronic elevations of ANGII plasma levels in the range of 50-200 fmol/ml that are most likely the result of a reduced interstitial fluid volume (Gray et al., 1987) at unchanged blood volume (Brummermann and Simon, 1990). Saltwater ducks exhibited a distinctly higher ANGII receptor density in the SFO than ducks on freshwater (Gerstberger et ai., 1987b) (Fig. 4). Upregulation of ANGII receptor density in the SFO of saltwater ducks seems to correspond to ANGII receptor upregulation in the SFO of rats subjected to severe water deprivation (Nazarali et al., !987) which, however, can be maintained only temporarily. When hypothalamic tissue slices from freshwater and saltwater ducks were compared with regard to their ANGII responsiveness in the SFO, the sensitivity of ANGII responsive neurones was increased 10-fold in the SFO of saltwater ducks and the fractions of neurones ~ n d i n g to ANGH at a given concentration were latser in compa~son to freshwater ducks (Matsumura u d Simon, 1990b) (Fig. 16). Thus, salt acclimation in ducks produ__c~_congraent into'eases in plasma A N G | I levels, enhanced ANGII receptor density in the SFO and enhanced responsiveness of SFO neurones to ANGII.
5.3. TOPOGRAPHYOF NEURONAL A N G I I RESPONSIVENESSPERTINENTTO SALT AND FLUID BALANCE
In both mammals and birds, the most plausible function of ANGII responsive neurones in the CVOs, i.e. on the blood side of the BBB, would be monitoring of the circulating hormone. At some depth in the brainstem tissue, neuronal ANGII responsiv~ss, e.g. in the neurosecretory nuclei, may reflect the function of ANGII as a synaptic tranmnitter. At the brain side of the BBB, ANGII responsive nenmn~, especially those located more closely to the w m ~ lar ependyma might also be naturally ~ b y ANGII as a neuromodulator, being either near the site of its action or transported with the interstitial and ventricular CSF. In mammals, putative functions as peptide receptors or interneurones have been assi~ed to A N ~ I responsive rostral brainstem structures a~ording to supplementary evidence derived from experiments and from tracing neuronal connections by labelling or with e i e c t r o p h y s i ~ means (McKinley et al., 1989; Thrasher, 1989;:]beutque and Renaud, 1990). Corresponding models of the neuronal circuitry controlting salt and fluid balance in. chide pathways from the SFO and OVLT to the neurosecretory nuclei which either pass throuah, or are relayed in, the median preoptic and AV3V regions and which contain angiotensinersic (Honda et:aL, 1990; Jhamandas et al., 1989) as well as A~qOIl responsive neurones. Experimental ~ ~ be obtained for the ability of circulafi~ ANOII to increase the excitability of SON and 1 ~ mmmm:s in the rat through action on the SFO with ~ t relay of information to hypothalam~ ~ o r y cells (Ferguson and Renaud, 1986; ~ eta/., 1989). On the other hand, mutual between the same regions have been ~ , z m m tial for the ~ t i o n of the o s m ~ v e ~ in mammals (Honda et al., 1990). The intricate of neurones subserving different functions w i t t ~ file
FIG. 17. (A) Retrogradely labelled neurones (*) in the subependymal periventricular layer @I) shown in a frontal section of the duck hypothalamus, with ventricular cavity (V III) to the right and the site of horseradish peroxidase (I-IRP) application (arrowhead) in the magnocellular centre (mc) of the paraventricular nucleus to the left. This site had previously been identified by antidiuresis evoked in the conscious animal by micro-electrostimulation at the site of subsequent iontophoretic application of HRP (Korf et al., 1982). (B) Golgi impregnation of a frontal section of the duck hypothalamus with ventricular cavity to the right. The lower part shows a magnocellular neurone (MCN) of the paraventricular nucleus, of which a dendrite is contacted by a neurite (arrows) originating from a conspicuous subependymal neurone (*). The same neurone is shown at larger magnification in the upper part to demonstrate its dendritic process (arrowheads) penetrating the ependymal layer. (Korf et al., 1983.)
ANOIOTENSINII IS BraDS
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Autonomic centres of the reticular formation: locus coerulaus superior and Inferior Imllvatory nuclei ventral tegn,4mtal area nucl. of the solitary tract spinal cord
FIo. 18. Upper part: Schematic presentation of afferent projections (double circles) to the neurosecretory magnocellular neurones of the paraventricular nucleus of the duck (PEN, fat circle with efferent projection to the posterior pituitary, PP), as evaluated by retrograde labelfing with horseradish peroxidase (HRP). Sofid lines represent neurones which were marked rctrogradely after application of minute amounts of HRP and presumably project monosynaptically. Interrupted lines represent neurones which were labelled only after more voluminous HRP deposits and presumably project polysynaptically. Note that there are monosyuaptic projections from the contralateral PVN (npv) and from the ipsilateral subependymal neurones (pl) shown in Fig. 17A. (Korf, 1984.) Lower Part: Schematic presentation of brain regions (double rectangles) to which the paraventricular nucleus (PVN) of the duck was found to project efferently. Connections were evaluated with anterograde tracing techniques after HRP injection into the PVN region and immunocytochemically by means of antibodies against vasotocin and neurophysin. (Korf, 1984.) neuronal network controlling ~ h and fluid balance in mammals has posed major problems in delineating specific receptive functions against integrative functions of the neurones involved. In mammals, interconnections between the hypothalamic antidiuretic system and medullary structures presumably pertinent in circulatory control were shown to involve both angiotensinergic neurones (Lind et al., 1985) and lower brainstem A N G I I binding sites (Mendelsohn et al., 1984), the latter being particularly prominent in the locus coeruleus and nucleus of the solitary tract regions and in the area postrema as a circumventricular organ, where JPN ~/2--F
receptors should at least in part be accessible to circulating ANGII. In mammals, A N G I I responsive neurones in these regions have been implicated in the mediation of central adjustments of cardiovascular innervation (Papas et al., 1990), apart from multimodel chemoreceptor functions of area postrema neurones (Carpenter et al., 1988). Comparable studies on birds do not exist. For birds electrophysiological evaluation of neuronal responsiveness to A N G I I and to hypertonic stimulation in hypothalamic tissue slices from ducks has revealed that, unlike in mammals, neurones in the magnocellular neuroendocrine portion of the duck
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PVN were only weakly responsive to each of the two stimuli. Responsiveness to hypertonic stimulation on the brain side of the BBB in the duck hypothalamus was confined to an identifiable group of parvocellular, periventricular neurones in the dorsal third ventricle (Kanosue et al., 1990), where ANGII responsiveness was virtually absent (Matsumura et al., 1990a). On the other hand, the frequently encountered A N G I I responsive neurones in the SFO were, as a rule, not osmosensitive. The more distinct separation of neuronal properties found in the brainstem of the duck, as compared to several mammals, seems to reflect the more distinct spatial separation of functionally diverse sets of neurones that is implicit in the cluster cytoarchitecture of the avian brainstem (Oksche, 1978). In contrast to the duck, no clear distinction can presently be made in mammals between the contributions to osmoresponsiveness provided by interneurones, putative receptors and the neurosecretory neurones themselves (Honda et al., 1990). 5.4. INTERCONNECTIONSOF THE AVIANPVN AS A MAJOR EFFECTORIN SALTAND FLUID BALANCE Taking the magnocellular portion of the PVN as a central neuroendocrine effector system, the afferent connections to this nucleus were retrogradely traced in conscious ducks as a first approach to the elucidation of the integrative neuronal network serving salt and fluid balance of birds (Korf et al., 1982), Antidiuresis in response to micro-electrostimulation within the PVN by means of a stereotaxically inserted microelectrode was used to identify the location of the magnocellular neurohormonal effector neurones of the PVN. Subsequently small amounts of horseradish peroxidase (HRP) were deposited electrophoretically at the site of stimulation. Histological examination by diaminobenzidine staining of the label in histological sections prepared 2-5 days after micromarking, disclosed monosynaptic projections of hypothalamic, as well as extrahypothalamic, origin to the magnocellular centre of the PVN (Fig. 17A). In particular, a distinct group of monosynaptically projecting neurones from the dorsomedially located subependymal region corresponded to the site where neurones had been shown to respond to local hypertonic stimulation (Kanosue et al., 1990). This laminar, subependymal cluster of cells fell into the category of CSF contacting neurones (Fig. 17B), as demonstrated by Golgi impregnation of neurones in the magnocellular and subependymal regions of the PVN (Korf et al., 1983; Panzica et al., 1986). With regard to further afferent projections to the PVN (Fig. 18, upper part), inputs from sites of neuronal A N G I I responsiveness, especially from the SFO, were marked only if the HRP deposits in the PVN region exceeded the border of the magnoceUular portion and, thus, had to be considered as polysynaptic (Kerr, 1984). Inputs from the AV3V region and OVLT as putative sites of neuronal A N G I I responsiveness were also found not to be monosynaptic. This arrangement corresponded well with functional and electrophysiological evidence according to which A N G I I responsiveness and perception of tonicity in the duck should reside in different
neurones, in order to permit their synergistic interaction in the control of AVT release and their antagonistic interaction in the control of salt gland activity. Since the lower brainstem of birds has not yet been probed for neuronal ANGII responsiveness, no information is currently available as to what extent A N G I I is an important mediator/modulator in the transfer of information from this region to the PVN. However, considering the general analogy between mammals and birds, the involvement of both angiotensinergic neurones and lower brainstem neurones endowed with ANGII receptors is a likely assumption. In the duck, retrograde labelling of lower brainstem projections to the PVN suggested multisynaptic inputs from the area postrema but monosynaptic inputs from the nucleus of the solitary tract region. When considering the efferent projections of the PVN in the duck (Fig. 18, lower part), it becomes clear that they mostly include brain regions from where neurones project to the PVN, mono- or polysynaptically, including those sites, where high-affinity binding of A N G I I had been demonstrated (Korf, 1984). Thus, most brain targets for ANGII seem to be connected reciprocally with the PVN as a major effector system in efferent osmoregulatory control (Fig. 18).
6. CONCLUSIONS The distribution of angiotensinergic systems and of targets for A N G I I in the central nervous system of birds was shown to be basically identical with that in mammals. The implication of A N G I I as a mediator/modulator in central control of salt and fluid balance, as suggested by the results of numerous studies on mammals, has received support with regard to osmoregulatory effector activities that are common to both classes of vertebrates, and by study, ing the control of secretion by the salt glands as an additional, bird-specific osmoregnlatory effector organ. The absence of peripheral vasomotor effects on physiological levels of circulating A N G I I in the avian class has strengthened the idea that mediation of physiological central actions of A N G I I on circulatory control is restricted to targets on the brain side of the BBB. Brain intrinsic angiotensinergic systems and their targets, thus, are important in the coordination of mechanisms controlling appropriate cardiovascular filling by adjusting intake and output of water and electrolytes, as well as the compliance of the cardiovascular system. With regard to the central neuronal mechanisms involved, the available evidence indicates that for birds, receptive functions for A N G I I on the one hand and for body fluid tonicity on the other are more distinctly separate, both functionally and spatially, than in mammals. In the SFO as an a u t o ~ ' a p h ically identified target for both circulating A N G I I (Gerstberger et al., 1987a) and A N F (Schiitz et al., 1992) at least a functional separation seems to e ~ t in as much as simultaneous neuronal r e s p o n s i v e ~ to A N G I I and A N F has n o t been observed, so far, in the duck (Schmid, personal communication),
ANGIO'EF.NSIN II IN BraDS
quite unlike the situation in the rat (Hattori et al., 1988). In all, these observations correspond to the view that the cluster organization of the avian rostral brainstem implies a more distinct separation of neuronal functions and, thus, might generally provide more favourable conditions in birds than in mammals for the independent characterization of the various receptive functions accomplished by brainstem neurones. Acknowledgements--The important contributions of Dr K. Kanosue, Dr H.-W. Korf, Dr K. Matsumura, Dr H. Sehmid, Dr H. Schiitz and Dr C. Simon-Oppermann to the experimental work carried out in the authors' laboratories are gratefully acknowledged. Part of the experimental work was supported by the Deutsche Forschungsgemeinschaft (Si 230/4-4,/4-5, /8-1).
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