Atria1 Natriuretic George

Athanassopoulos

HE MAIN FUNCTIONS of cardiac cells traditionally were thought to be excitation, conduction, and contraction. The finding that some cardiac cells possess a secretory function was unexpected. When this new function became evident, old studies demonstrating links between atria and the kidney could be reevaluated.’ The existence of a volume-controlling system has been speculated since 1935.’ Henry and Pearse in 19563 demonstrated that atria1 distention in experimental animals increased urinary flow. Linden4 suggested that atria1 stretch receptors were stimulated at atria1 distention, leading to increased afferent activity in the vagi, which was thought to possibly affect renal function. Carswell et al were the first to suggest a humoral factor linking the atria and the kidney.’ The first step in the isolation and purification of atria1 natriuretic peptide began with a morphologic study by Kisch of intracellular granules in atria1 cardiocytes.6 In 1976, Marie et al’ showed that the degree of atria1 granulation was related to water and sodium intake. The discovery by de Bold in 1981’ that the intravenous administration of atria1 extracts can produce a marked increase in urinary sodium excretion in rats led to a surge of research to identify this “atria1 natriuretic factor” (ANF).

T

SYNTHESIS

AND PRODUCTION

Much of our current understanding of ANF biosynthesis comes from biochemical and molecular biological studies.‘.l2 The primary structure of the ANF precursor was determined by nucleotide sequencing of cDNA clones obtained from atria1 tissue. These studies showed that atria1 mRNA encodes a 150-152 amino acid precursor, termed pre-pro-ANF. The first 23-25 amino (N-)terminal amino acids of pre-proANF contain a hydrophobic group of residues that are characteristic of peptide hormone signal sequences, which are common to most secreted proteins. They are believed to facilitate transduction of the elongating polypeptide chain across the microsomal membrane into the cisternae of the rough endoplasmic reticulum as the elongating peptide chain is being synthesized by Progress

in CardiovascularDiseases,

Vol XXXIII,

No 5 (March/April),

Factor

and Dennis V. Cokkinos

the ribosomes.” The remaining amino acid residues comprise a 15- to 17- kd peptide that is termed pro-ANF. It exhibits a high degree of homology among all species examined (humans, rats, dogs, rabbits, mice, and COWS).~ ANF is stored within the atria1 myocyte in specific granules that are morphologically similar to those found in polypeptide hormoneproducing cells.‘3-16 It has been demonstrated that the major molecular form of immunoreactive ANF stored in the atria is the large prohormone, pro-ANF, also called ANFl-126 (Fig 1A). Several studies have demonstrated that the circulating form of ANF in the plasma consists of smaller ( N 3 kd) C-terminal fragments of the prohormone.‘7.18 The primary form consists of 28 amino acids (ANF99-126), and its generation requires the cleavage of Arg-Ser peptide bonds in the prohormone (pro-ANF). The presence of additional noncleaved Arg-Ser peptide bonds within the pro-ANF suggests that the cleavage of pro-ANF to its circulating forms requires a highly specific enzyme’9z20(Fig 1B). The identification of this activating enzyme is an issue of major interest, because storage of ANF as the prohormone without intracellular cleavage appears to be unique compared with all other peptide hormonal systems, with the possible exception of the enkephalins.*l While circulating protease (thrombin, kallikrein) may possess specific proteolytic activity,22*23studies with perfused hearts suggest that pro-ANF is cleaved before it reaches the circulation;24 this is supported by catheterization studies showing that blood withdrawn from the coronary sinus contained exclusively the 3-kd form of ANF.Z5 The concentration of ANF is higher in blood from the right atrium and ventricle than the venae cavae, indicating that ANF enters the circulation from the right side of the heart. ANF From the Department of Cardiology, Tzanio State Hospital, Piraeus, Greece. Address reprint requests to Dennis I/ Cokkinos, MD, 5, Dolylaiou, I1521 Athens, Greece. Copynight o 1991 by W.B. Saunders Company 0033~0620191/3305-0003$5.00/O 1991:

pp 313-328

313

314

@

ATHANASSOPOULOS

Pre

..

H2N -

---___-------_------

Pro

ANF ANF

----____----------------

~~~~~~-~.~~~;

I I I I I I; I I

ANP

@

(1-28)

AND

COKKINOS

l-28

- CmH Asp-Am-Me-Gly-Ala

1

26

124

152

\

ML

Pro -------------H2N -:

/ Arg

ANF --------------------

--------------

--------------------

27

ANF (l-28)

01~

;~~~~~-~~~~~j

124

/

\

152

[A) Structure

of ANF

precursor

molecules.

(B) Amino

acid

levels in coronary sinus blood are much higher in blood from the right side of the heart,25*26 indicating that ANF is secreted by way of the coronary sinus into the right atrium from left or right atria1 myocytes or both. A decline in ANF concentration has been demonstrated between the pulmonary artery and veinF7 An increase occurs across the left side of the heart, suggesting Thebesian vein drainage from the left atrium.‘* Although both atria appear to secrete ANF, the relative contributions of the left and right atria to plasma level are unknown.29 The ventricles also synthesize and secrete pro-ANF.30 Ventricular ANF biosynthesis differs from atria1 synthesis in that the synthetic rate is lower and the peptide is not stored in secretory granules, but rather is constantly released.31 The question arises, therefore, as to the relative contribution of ventricular ANF versus atria1 ANF to circulating plasma levels of this hormone, given the large mass of ventricular tissue. Recently, it has been demonstrated that ANF expression in the ventricular myofibers is regulated developmentally, ie, ANF is abundantly expressed in fetal ventricular tissue, but can hardly be detected in normal adult myocardium. In ventricular tissues of patients with congestive heart failure, ANF is significantly present as estimated by radioimmunoassay.32 There is immunocytochemical evidence that ANF is also located in the salivary glands, gut mucosa, and pancreatic islets.34 The ANF gene and its mRNA transcripts also have been localized in the adventitia of the aortic arch.33 In the

sequence

/ Ser

LOU / 01~ / Cya \ Aen

Ars

Ser

Phe \

--

s--s

--

At-g

Phs

Leu

Arg

/ H2N-

Ser G 1~’

\ GlY

- COOH

Cye

Fig 1. of ANF.

Gln \

Ser'

\ i-jr

-

COOH

central nervous system, available evidence indicates multiple sites of localization of ANF in neurons.” N-terminal deleted peptides, like ANF (Arg 1OZTry 126), ANF (Ser 103-Tyr 126), and ANF (Ser 104-Tyr 126), are equipotent in terms of diuretic-natriuretic activity, but gradually lose potency in vascular smooth muscle relaxation assays.” Removal of C-terminal amino acids (Asn 122, Ser 123, Phe 124) drastically reduces the renal and vascular smooth muscle effects of ANF. Aldosterone inhibition is affected much more by C-terminal than N-terminal cleavage.” These studies suggest that the C-terminus modulates binding to receptors, since minor modification at this end greatly reduces biological activity. Long-acting peptide analogues of ANF have been synthesized by replacing glycine residues of the peptide by D-alanine. Replacement of other L-amino acids of the ANF(99-126) structure may result in more stable analogues without loss of potency.35 MECHANISM

OF RELEASE:

METABOLISM

Multiple studies have demonstrated a relationship between increases in atria1 pressure and circulating ANF. In animals, acute36 or graded37 isotonic volume expansion resulted in a significant increase in central venous-atria1 pressure and proportionally in circulating ANF levels. In man, plasma ANF increases during head-out water immersion38 and head-down suspension,39 conditions that increase atria1 pressure. During cardiac catheterization, a correla-

ATRIAL

NATRIURETIC

FACTOR

tion of plasma ANF to atria1 pressure was detected.@ During right ventricular or atria1 pacing, plasma ANF was observed to increase concordantly with right atria1 pressure, rather than heart rate.41.42The same mechanism may well underlie the increase of plasma ANF during exercise43 and with the assumption of supine posture.U In both an isolated heart mode145 and a clinical study,4” when right atria1 pressure was increased by 1 mm Hg above the level of 4 mm Hg, the concentration of ANF in plasma increased by 36% to 38%. A significant correlation between left atria1 volume and plasma levels of ANF seems to exist in humans,30,47 similar to that observed for the right atrium. ANF levels are elevated in patients with chronic left atria1 hypertension and normal or minimally elevated right atria1 pressure. Short-term decompression of the left atrium by mitral valvuloplasty is followed within 24 hours by a marked decrease in plasma ANF.30 Despite this apparent importance of atria1 pressure, a dissociation between ANF release and atria1 pressure elevations in the presence of tamponade supports the hypothesis that atria1 stretch is the primary stimulus for ANF secretion.48-“” Cardiac tamponade is a condition in which intra-atria1 pressure is elevated, but atria1 stretch is not increased. Clinical investigations demonstrated low ANF levels during tamponade as contrasted to high levels noted after pericardiocentesis. Presumably, this reflects some persistence of elevated intracardiac filling pressures, despite partial hemodynamic improvement after relief of tamponade.54 ANF levels also increased after surgical release of pericardial constriction in calcific constrictive pericarditis.55 Taken together, these findings strongly support the hypothesis that ANF secretion is causally related to atria1 stretch. Similarly, large amounts of ANF-containing electron-dense granules and ANF-mRNA were detected in the cytoplasm of overstretched cardiocytes in and around left ventricular aneurysms.56 In patients with congestive heart failure, ANF content estimated by radioimmunoassay is higher in the left than the right free ventricular wall, and the left ventricular subendocardium contained more ANF than the subepicardium. This strongly suggests that regional wall stress

315

plays a critical role in the expression and subsequent production of ANF.32 There is no evidence suggesting a direct role of plasma sodium concentration in the regulation of either ANF synthesis or release. In animals, ANF is reduced by chronic water deprivation,” but this correlation appears to define a parallel between atria1 pressure and not plasma sodium.58 In humans, a low sodium diet (10 mmol/d) decreased plasma ANF, in contrast to a high sodium diet ( > 300 mmol/d), which had the opposite effect.59 Rapid infusion of either sodium chloride solution or whole blood produced an increase in plasma levels of ANF. However, the peak hormone levels occurred much earlier when expansion was obtained with sodium chloride rather than whole blood.45z60In other studies, the shift in plasma ANF values induced by a given amount of dietary sodium varied significantly.6’ Dehydration in the human increases plasma osmolarity and plasma sodium, but does not change ANF levels.62 It is possible that atria1 pressure-stretch mechanisms override the effects of increased serum sodium concentration in the regulation of ANF. Plasma ANF levels were inversely correlated to plasma aldosterone concentrations and renin activity.” The secondary hyperaldosteronism induced by 2 hours of tamponade in dogs was not a potent stimulus for secretion of ANF.” There is no evidence that ANF release is mediated by endogenous neurotransmitters (noradrenaline, acetylcholine). The influence of resting tension on ANF release from atria1 secretory granules seems to be unrelated to direct neural contro1,5”.53although it has been postulated that there is such a relation.63 Interestingly, sympathetic denervation seems to inhibit the release of ANF.64 In contrast, in humans, the ANF increase noted during exercise seems to be unrelated to norepinephrine levels.65 Thus, the role for atria1 neurogenic reflexes as regulatory factors in the control of sodium excretion remains uncertain. The existence of ANF in the rat brain has been demonstrated@ and its distribution is similar to that of angiotensin II receptors. The latter may suggest possible involvement of the brain renin-angiotensin system in the regulation of ANF secretion from the heart.“’ ANF levels are in some manner modmated by

316

ATHANASSOPOULOSANDCOKKINOS

the type, as well as the extent, of cardiac disease. For identical right and left meridional atria1 wall stress, three to four times higher plasma ANF levels were obtained in patients with dilated cardiomyopathy than in patients with left-sided valvular heart disease.@’ The biological half-time of ANF(99-126) in blood is 0.5 to 1.5 minutes, while the N-terminal fragment(l-99) has a longer half-time, approximately 5 minutes. Approximately 50% of ANF(99-126) is cleared in the kidney, while the N-terminal fragment (l-99) is cleared completely during circulation through the kidney.69 The circulating form of ANF (28-residue peptide) contains a 17-residue disulfide-linked ring. The degradation of the molecule commences with hydrolysis of the Cys 7-Phe 8 bond within the ring. The enzyme that catalyzes this reaction during incubation with kidney microvillar membranes is endopeptidase -2411.” MECHANISMS

OF ACTION

Renal Effects

Although an increase in glomerular filtration rate in response to ANF has been reported in dogs,‘l there is no corroborating human data, either in healthy subjects or patients with heart in hufailure.72-74 During ANF administration mans, there is an inverse relation between urinary flow and renal vascular resistance.” This tendency toward lower renal vascular resistance suggests that ANF may preferentially relax afferent arterioles. This effect is qualitatively different from that produced by infusion of noradrenaline or angiotensin II, which increase filtration fraction by preferentially contracting efferent arterioles.76 The renal blood flow response to intrarenal infusion of ANF is unique. Infusion is characterized by a significant, but transient, increase in renal blood flow, despite continued ANF administration. The mechanism of his biphasic renal how response is unclear, but may reflect interaction of different intrarenal vasoconstrictor mechanisms.“,” The observed increase in glomerular filtration rate that occurs despite a decrease in renal blood flow may be related either to an increase in postglomerular arteriolar resistance or to an increase of the ultrafiltration coefficient.79.8’ ANF also effects the permeability and hydraulic properties of capillaries. The peptide may

effect the transcapillary efflux of endovascular fluid, either by altering capillary permeability or increasing intracapillary hydrostatic pressure, or both.” ANF decreases tubular reabsorption of sodium at one or more nephron segments. There is evidence consistent with either a proximal tubular” or collecting duct segments3 site of action. There is a strong evidence that the natriuretic-diuretic effect of ANF may be mediated in part by the renal dopaminergic system. Presynaptic D2 activation inhibits ANF-induced diuresis in rats.84 Interaction With Hormone Systems

The absence of any change in plasma renin activity despite a decrease in blood pressure and increased sodium excretion after ANF administration, suggests that ANF exerts an inhibitory effect on the juxtaglomerular apparatus.73 This contrasts with the stimulation of renin release after administration of loop diuretics. ANF does not inhibit renin secretion in a kidney in which there is no functional macula densa. Thus, it seems that renin inhibition is dependent on sodium delivery to the macula densa.” ANF inhibits corticotropin (ACTH), K+, and angiotensin II-stimulated aldosterone release, probably by different mechanisms.85x86Although there is controversy concerning the effects of ANF on vasopressin release and vice versa, it has been demonstrated that ANF inhibits vasopressin action on the collecting duct segment of the kidney.*’ Stimulation with triidothyronine increases ANF in a dose-dependent marine?’ (Fig 2). Vascular and Neural Effect: the Second Messenger

ANF stimulates the production of cyclic guanosine monophosphate (GMP) in a dosedependent manner in the adrenal gland, glomerulus, and renal collecting ducts.89.90Furthermore, cyclic GMP (cGMP) accumulation and cGMPdependent protein kinease activation precede subsequent vascular relaxation91 Despite this evidence, there is still controversy regarding the precise role of cGMP as the second-ANF messtudies have resenger.92 Autoradiographic vealed the presence of receptor sites in the kidney (glomerular mesangial cells, vasa recta), vascular smooth muscle cells, and platelets.11,93 Receptors presumably exist in large blood ves-

ATRIAL

NATRIURETIC

317

FACTOR

STRETCH

ATRIAL / PRESSURE

n

ANF

tion and

Fig 2. Schematic representaof interactions between ANE hormonal systems.

NEZHRON

-

/

T

RENIN

sels, since isoleucine (Ile) 125-ANF exhibits high-affinity binding to rabbit aortic membranes.32,33ANF induces a dose-dependent relaxant effect in aortic strips (rabbit and rat) contracted by angiotensin II, noradrenaline, serotonin, or histamine.y4 The effect is associated with increases of cGMP and is independent of the integrity of endothelium. In conscious animals, ANF may stimulate cardioinhibitory neurons and result in bradycardia, despite the induced hypotension.y5*y6 When administered directly into the forearm circulation in humans, ANF decreases forearm vascular resistance.97 In contrast, there is no effect when administered systemically. The localization of the ANF gene” and mRNA’* transcripts to the aortic arch may imply an interaction between ANF and aortic baroreflex mediators.99 The effects of ANF on the central nervous system are less well known. The histochemical localization of ANF neurons and fibers in the anterior part of the hypothalamus suggests ANF involvement in fluid and electrolyte homeostasis. The intracerebroventricular administration of ANF inhibits angiotensin II-induced vasopressin secretion,lm as well as the pressor response. Additionally, dopamine turnover is increased in the hypothalamic region and this may indicate that the central action is mediated, in part, via the dopaminergic system. ANF at Various Stagesof Life

ANF has been detected in human plasma at all stages of life, including umbilical cord blood at delivery.“’ Beyond the neonatal period through adolescence, no significant difference has been found among age groups.“‘* Beyond adolescence, plasma ANF increases steadily with agelo and is clearly higher in elderly men.

THYROID

HORMONE

HEART

secretion

‘““‘“i”“”1

ADRENALS

POSTvPITUITARY

4 ALDOSTERONE

$ ? VASOPRESSIN

Age-related increases may reflect subtle alterations of atria1 pressure, associated with an age-dependent decrease in ventricular compliance, and/or a normal, progressive impairment of sodium excretory function and peptide plasma clearance mechanisms. In pregnancy, a state in which bIood volume increases by 40%, modestly elevated ANF levels have been reported.‘04 A sharp increase 3 to 5 days after delivery has been detected, suggesting a correlation with redistribution of fluid volumes and diuresis. The negative correlation between plasma ANF and aldosterone normally seen was not found in pregnancy. This finding may partially explain the sodium retention state in normal pregnancy.“’ The relationship between the increased ANF plasma levels found in pregnancy-mediated hypertension and atria1 pressure or atria1 shape is not clear.‘* Other factors contributing to increased ANF in pregnancy may be a hypertensive-mediated ventricular production of ANF in response to left ventricular overload.‘” In untreated preeclampsia, right atria1 and pulmonary wedge pressures have usually been reported as lower than those found in normal pregnancy.“’ PATHOPHYSIOLOGICAL

IMPLICATIONS

CongestiveHeart Failure

The increased plasma ANF concentration noted in patients with heart failure is most likely due to increased atria1 secretion, although altered clearance may also contribute to the elevated plasma level.‘“’ Recent data have demonstrated that atria1 and ventricular ANF gene expression both may be maximally stimulated during experimental heart failure.‘oy.‘oo While the primary stimulus that enhances ANF secre-

318

tion in heart failure is probably increased atria1 and ventricular distension, direct stimulation of ANF release by plasma epinephrine, angiotensin II, or vasopressin cannot be discounted.“’ A role for the ventricle in addition to that of the atrium as a site of ANF secretion is emerging. During volume overload, recruitment of ANF-mRNA in animal ventricular myocardium has been detected.“’ Plasma ANF increases, and concentrations may exceed the upper limits of normal by 10 times in severe heart failure.lX3 The phenomenon occurs regardless of primary etiology, and the degree of ANF increase corresponds to the severity of symptoms and to the extent of hemodynamic impairment.‘14 The relative importance of left versus right atria1 contributions to circulatory ANF levels remains to be determined in both health and heart failure, although some claim that ANF plasma concentrations correlate closely with right atria1 pressures.“’ With treatment of heart failure, ANF values decrease in parallel with jugular venous pressure and body weight.l16 During upright posture, there is a marked increase in ANF levels, despite very high baseline (supine) levels. The correlation between increasing heart rate and plasma ANF suggests that tachycardia or increased sympathetic nervous activity may cause the increase in ANF.“’ While ANF is increased in chronic heart failure, it remains unclear whether ANF secretion is appropriate for the magnitude of increase in atria1 pressure. It is well known that as heart failure evolves, homeostatic mechanisms regulating plasma volume are reset and vasoconstriction, as well as fluid accumulation, occurs as if there were severe volume depletion.“’ The role of ANF in this adaptation is not clear. However, because infusion of ANF seems to improve the hemodynamic, renal, and endocrine derangements of heart failure,“’ there is a suggestion that atria1 secretion and thereby arterial levels may not be maintained at levels necessary to prevent fluid accumulation and vasoconstriction. This may reflect a primary atria1 process such as would be characteristic of atria1 cardiocyte secretory abnormalities or atria1 cell loss, or both. The latter could be due to atria1 fibrosis, as has been described in severe chronic congestive heart failure.“’ Exercise in patients with chronic heart failure

ATHANASSOPOULOS

AND

COKKINOS

resulted in a disproportionately small increase in ANF, in relation to a marked increase in atria1 pressure.“’ Also, data from animals (cardiomyopathetic hamsters) are consistent with the concept that the reduction in atria1 granularity and elevation of circulating ANF levels in congestive heart failure characterizes a stimulated system in which the atria1 peptide is synthesized and rapidly released with subsequent depletion of storage sites.‘*l Natriuretic and vasorelaxant properties of ANF have been observed in vivo only when pharmacologic doses are administered to humans.” Despite this observation, there is a positive correlation between plasma levels of vasoconstrictor hormones (renin, vasopressin) and vasodilator hormones (ANF, prostaglandin) in heart failure.1”*‘23 It has been suggested that a primary mechanism for sodium retention in heart failure is a combined renal hyporesponsiveness to ANF, associated with cardiac hypersecretion of ANF in response to chronic pressure and/or volume overload.lz4 In chronic heart failure, plasma ANF concentration varies with acute changes in atria1 pressure, although plasma norepinephrine, renin activity, and vasopressin responses are blunted. After successful treatment with captopril, ANF returns to control levels.1z Plasma renin and ANF values are weakly, but positively, correlated in patients with chronic heart failure, in contrast to the normal inverse relation. This presumably reflects both abnormal atria1 distention and decreased renal perfusion, the basis of renin secretion in heart failure.126 In a model of severe chronic ventricular pacing-induced heart failure in dogs, plasma ANF increases and peaks early during the development of heart failure, declines and then reaches a plateau as severe heart failure ensues.“’ Thus, it seems that in the early stage of heart failure, release of ANF may modulate the effects of the sympathetic nervous system and the renin-angiotensin system. In advanced heart failure, the effects of the vasoconstrictor forces become dominant and exceed the ability of ANF to modulate them. There is a recent evidence that in humans with asymptomatic left ventricular dysfunction (ejection fraction slightly less than 45%), ANF

ATRIAL

NATRIURETIC

319

FACTOR

is increased in association with the increased cardiac filling pressures and/or volumes.‘25 In chronic heart failure, ANF secretion is not mediated by baroreflex mechanisms. It may function as an ideal counterregulatory hormone, opposing the vasopressor and volume retentive effects of vasoconstrictor systems (sympathetic nervous activity/secretion of renin and vasopressin), which are tonically activated because of baroreceptor dysfunction in congestive heart failure. However, recent studies suggest that ANF has only a weak role as a counterregulatory hormone in chronic heart failure, and only blunts forearm splanchnic and renal vasoconstriction mediated by the sympathetic nervous system, renin-angiotensin system, and vasopressin”’ (Table 1). In subjects who have undergone cardiac transplantation, ANF remains (despite the reversal of cardiac failure) chronically increased.lz9 The presence of atria1 granules in the transplanted human heart has been reported and underscores the preservation of atria1 endocrine function following denervation.13” In human recipients of the Jarvik-artificial heart, ANF is present in plasma and secretion can be stimulated by increasing right atria1 pressure.‘31 Valve Disease

In patients with mitral stenosis and sinus rhythm, ANF plasma levels are elevated commensurate to left atria1 pressure. ANF levels are also high in mitral stenosis with atria1 fibrillation, but levels do not directly correspond to changes in left atria1 pressure. Moreover, cGMP production in the lungs is related to ANF in patients with sinus rhythm, whereas it seems to be independent in those with atria1 fibrillation.‘32 The increase of ANF and subsequently of cGMP in the pulmonary circulation may play a role in the control of pulmonary resistance.‘3z After mitral valvuloplasty, despite a decrease in intracardiac pressures, ANF levels remain abTable 1. ANF is increased dysfunction. 2. ANF is present

1. ANF in Congestive even

in early

in the ventricle

Heart

asymptomatic of the failing

Failure

low dose.

Coronary Heart Disease

ANF is a potent direct coronary vasodilator with hemodynamic actions similar to nitroglycerine.‘36 Severe ischemia in patients undergoing angioplasty produced a fourfold to fivefold increase in arterial ANF levels, similar to those elicited by low-dose infusion of ANF (0.1 kg/kg/ min). ANF mediates dose-dependent coronary vasodilation and it is possible that during severe ischemia ANF may contribute to the modulation of coronary vasomotor tone.13’ Because of considerable individual variation in the ANF response during angioplasty, it may be that ventricular failure, induced after the acute occlusion of a major coronary artery, and not myocardial ischemia itself, stimulates ANF secretion.138 Increased production was demonstrated with “stepwise” incremental atria1 pacing in human subjects.‘39 In acute myocardial infarction, ANF is increased 10 hours after the onset of symptoms. The ANF levels were more closely related to pulmonary capillary wedge pressure than to right atria1 pressure. This emphasizes the influence of the increase in left atria1 pressure during acute left cardiac failure.lW Patients treated with intravenous streptokinase seem to have normal concentrations of plasma ANF, which are significantly lower than those in patients not given streptokinase.‘41 ANF is also a part of the neurohormonal response to right ventricular infarction. In inferior myocardial infarction without right ventricular involvement, ANF is markedly less increased.‘42 Arrhythmias

left ventricular heart.

3. Natriuretic response to ANF is attenuated (offsetting of antinatriuretic systems and/or receptor-downregulation) 4. ANF can cause renin inhibition and renal vasodilation

normal for up to 6 months.‘33 The mitral valve prolapse syndrome has been related to abnormal secretion of ANF.‘34 The very high levels of ANF in patients with aortic stenosis tend to decline following balloon valvuloplasty. An increase of ANF of more than 10% after valvuloplasty appears to be a strong predictor of poor early clinical outcome (return or persistence of symptoms).135

action at a

It is well known that a polyuric response may occur during or immediately after atria1 tachyarrythmias, as well as supraventricular tachycardia.143The characteristics of this renal response include an increase in urine flow, sodium excretion, and free water clearance, with a decrease

ATHANASSOPOULOS

in urine osmolarity. While the mechanism of this renal excretory response to tachycardia may be mediated in part by activation of atria1 neurogenic reflexes, recent reports support a role for ANF. Supraventricular tachycardia was associated with increased ANF levels.13g~144 The mechanism of the increase in ANF during tachycardia remains controversial. While supraventricular tachydysrhythmias and supraventricular tachycardia may increase atria1 pressure, an increase in the frequency of atria1 contraction may also be a stimulus for modulating ANF secretion.‘” In contrast to this situation, ANF levels in atria1 fibrillation are not higher than those in atria1 flutter, despite the fact that fibrillation is characterized by more atria1 electrical impulses per unit time than is flutter.146 Plasma levels of ANF decreased significantly in the first hour after cardioversion of atria1 fibrillation to sinus rhythm.139V’46It remained stable for a 30-day follow-up period.14’ Induced sustained ventricular tachycardia is associated with a marked and rapid, but variable, elevation of plasma ANF. The mechanism for such elevations have been suggested to be the elevation of right atria1 pressure,14’ although controversy exists concerning the significance of right atria1 pressures in the condition.‘49 During VVI pacing (ventricular pacing, ventricular sensing, inhibitory mode), ANF increases and it may again diminish with DDD pacing (dual chamber pacing, dual chamber sensing, atria1 triggered and/or inhibited).“’ Congenital Heart Disease

High plasma concentrations of ANF are present in a variety of congenital heart and pulmonary diseases known to be associated with high atria1 pressures and atria1 distention. These include ventricular septal defects, bronchopulmonary dysplasia, and Fallot’s tetralogy.151 Right atria1 area determined by two-dimensional echocardiography and indexed for body surface area is an important predictor of both central and peripheral concentrations of ANF in children with congenital heart disease.152 In patent ductus arteriosus, the levels of ANF may serve as an index of severity of left atrial wall strain in persistent ductus and may reflect the successof the therapeutic closure.“’ In patients with systemic hypertension following repair of coarctation of the

AND

COKKINOS

aorta, ANF levels are too low to oppose the effects of increased levels of vasopressinE3 Hypertension

In hypertension, plasma ANF is correlated positively with arterial pressure, with the most extreme values having been reported in the malignant phase.ls4 ANF levels decrease with effective treatment of hypertension. It must be emphasized that peptide levels in hypertensives display a broad overlap with those observed in normal subjects.79 Patients with evidence of left ventricular hypertrophy appear to have a greater increase in ANF levels for a given degree of hypertension.155,‘56 An abnormal venous capacitance and/or a decreased ventricular compliance secondary to left ventricular hypertrophy may result in an increase in atria1 pressures and hence an increase in ANF. A substantial proportion of patients (40%) with essential hypertension has raised ANF levels and these levels can be altered by changes in sodium intake.157g160*161 The significance of this observation is problematic because of evidence that plasma ANF levels are not significantly increased in patients with mild essential hypertension.158 In view of the greater pressures and distention in both atria in mild and moderate essential hypertension,‘59 an atria1 hyporesponsiveness to ANF release is postulated.1s6 Other Conditions

In patients with end-stage renal failure on maintenance hemodialysis, ANF values are elevated and decrease with dialysis.162 It has been suggested that this may be a result of “priming” of atria1 secretory mechanisms and therefore an exaggerated peptide response to acute fluid volume changes.163 In cirrhosis, although it seems likely that ANF values are raised, the effect appears variable and subtle. It seems unlikely that an absolute deficiency of ANF exists in cirrhotic edema as characterized by an absolute deficiency of ANF. Bartter’s syndrome is associated with normotension, renal sodium wasting, hypovolemia, hyperreninemia, and hyperaldosteronism. Gordon’s syndrome is a hypertensive state that is the mirror image of Bartter’s syndrome with respect to the other features listed. Primary ANF excess and deficiency have been consid-

ATRIAL

NATRIURETIC

321

FACTOR

ered possible pathogenic mechanisms in these two rare syndromes, respectively.165*‘66 Raised ANF levels have been reported in the syndrome of inappropriate antidiuretic hormone secretion.16’ Diabetes mellitus with its associated tendencies to low renin activity and increased filtration rate is a disorder of interest for students of ANF. In insulin-dependent diabetics, although all patients who exhibited ANF levels above normal had autonomic system neuropathy, there was no relationship between the level of autonomic deficit and plasma ANF values.16* Thyroid function may well influence ANF synthesis and/or release. ANF values are decreased in hypothyroid patients and increase markedly after therapy.‘69 INFLUENCE

OF PHARMACOLOGICAL ON ANF

AGENTS

Bay-K-8644, a voltage-sensitive calcium channel activator, induces a sustained increase in the secretory rate of atria1 natriuretic factor. It has been shown that free intracellular calcium often appears to play a key role in triggering the secretion of other peptide hormones.“’ In humans, voltage-sensitive calcium blockers impair stimulated secretion of ANF.“’ B-Blocking therapy in patients with hypertension has been found to be associated with increased levels of plasma ANF.‘72 In contrast, the use of angiotensin converting-enzyme inhibitors decreases ANF plasma levels and may also rapidly counteract the action of B-blockers on ANF.‘73 EXOGENOUS

ANF ADMINISTRATION

In normal subjects, bolus injection and/or short infusions of human ANF(99-126) (15 pmol/kg/min) lasting 30 to 60 minutes, resulted in increased natriuresis with a transient diuresis. Urinary calcium, magnesium, and chloride excretion also increased significantIy.‘74 Potassium excretion (in most instances) was not affected. With prolonged infusion (4 to 6 hours), a peak effect during the first 2 hours with a subsequent progressive reduction of an ANF effect on urinary solute excretion was found.“’ After short-term infusions, blood pressure decreased in a dose-dependent manner, probably due to the direct vasodilating effect of ANF.‘@ The reduction in blood pressure is usually small and occurs simultaneously with an increase in

heart rate.176 When much smaller doses of ANF were infused for a longer period, the blood pressure reduction was greatly delayed and occurred mostly during the third and fourth hour of infusion, long after steady-state plasma levels of ANF had been achieved.“’ Episodes of severe hypotension developed in some volunteers at the same time and were accompanied by a transient bradycardia, rather than by tachycardia. An increase in hematocrit levels of approximately 10% resulted, probably as a consequence of some shift of fluid out of the circulation, possibly from the capillary bed. In addition, ANF exerts a relaxant effect on the venous vasculature.“* The lack of a sustained vasodilating effect may be related to reflex activation of the sympathetic nervous system, although ANF seems to be less prone to trigger such a reaction other than vasodilators.‘79 During infusion, ANF suppressed the expected increase in aldosterone and renin, which otherwise would be triggered by its natriuretic and hypotensive effects.‘75 Although it was assumed that ANF acted as an arteriolar vasodilator and the blood pressure lowering effect was primarily due to a decrease in total peripheral resistance,74 a more multifactorial explanation for the hypotensive action of ANF was recently postuIated.*‘o Reduction of cardiac output may be due to increased vagal activity,‘*l decreased venous return due to venodilation, or a reduction in intravascular volume secondary to diuresis.‘*’ A negative or positive inotropic effect of ANF does not appear to be invo1ved.183~184 When an infusion rate of 50 ngJkg/min for 2 hours was preceded by a 50-ug bolus, ANF appeared to act primarily on the venous bed without increasing sympathetic activity. Plasma vasopressin levels do not seem to be affected.185.1*6In hypertensive patients administration of ANF as a bolus injection resulted in a brisk increase in urine volume and urine sodium, calcium, magnesium, and phosphorous excretion. However, ANF induced no decrease in blood pressure.‘” When ANF was administered by infusion for 4 or more hours, blood pressure decreased in a dose-dependent manner.l*’ It appears that in hyperactive patients, ANF can induce an increase in natriuresis, at least transiently, and it might reduce blood pressure when infused for a

322

certain period of time. In hypertensive patients, as in normal volunteers, there is a very slim margin between controlled blood pressure reduction and severe hypotensive episodes. In patients with New York Heart Association (NYHA) class III or IV heart failure due to ischemic or dilated cardiomyopathy, 2- to 4-hour ANF infusions resulted in a significant decrease of pulmonary capillary wedge pressure, while cardiac index decreased slightly but not significantly. A small increase in urinary sodium excretion and a decrease in peripheral vascular resistance was observed. The increase in cardiac output was most pronounced during the first hour and by the fourth hour it had returned to baseline. During 24-hour infusions (at a rate of 0.08 kg/kg/min) the hemodynamic effects are also diminished over time. The use of ANF for long-term intravenous administration might be hampered by the development of partial tolerance and adverse events noted during withdrawal (increased heart rate, mean arterial pressure, and pulmonary wedge pressure).‘*’ Although the exact mechanism responsible for the beneficial effects of ANF is not clear yet, this may in part be explained by the large distribution volume of ANF. The large distribution volume would raise the possibility that ANF receptors are not saturated in patients with congestive heart failure, even if they are downregulated.“’ Studies using autoradiography with ‘*‘Ilabeled ANF have indicated limited numbers of binding sites for ANF in ventricular myocardium.“’ It is then unlikely that ANF acts on the myocardium directly and changes contractility. There is a strong suggestion that ANF alters loading conditions of the heart by dilating both arterioles and veins and thereby improves left ventricular function in the same manner as conventional balanced vasodilators.‘92~‘93 Among patients with heart failure, the renal response to ANF may differ. There are studies in which either bolus or continuous infusions of low doses have failed to show any renal effect,n while others have shown a doubling of urinary flow and sodium excretion.“’ Interpatient variability, different baseline hemodynamic, renal, and endocrine status, or differences in the bioavailability of the peptide may contribute to this discrepancy.

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In patients with heart failure, a blunted renal response to exogenous administration of ANF may be due to the maximal ceiling effect that can be exerted on the kidney, to receptor downregulation at the kidney level, overwhelming effects of vasoconstrictor, or sodium-retaining hormones. Plasma renin activity, plasma aldosterone, noradrenaline, and vasopressin were not altered by ANF administration. Plasma ANF levels before infusion were markedly elevated, but were not predictive of the subsequent hemodynamic response to exogenous ANF.‘93 In patients with cirrhosis, an inverse doseresponse relationship was noted, with the lowest dose of ANF inducing the highest natriuresis and the least reduction in blood pressure. But, as in heart failure, the magnitude of the natriuresis was rather small and clinically insignificant. In addition, there occurred episodes of marked hypotension with ANF infusion (but not with bolus injection).194 ADMINISTRATION

OF ATRIOPEPTIDASE INHIBITORS

UK-69578 is a potent selective inhibitor of atriopeptidase (EC 3.4.24.1 l), the rate-limiting enzyme in the breakdown of ANF by renal homogeneates. It has been shown both in animals19’ and normal human volunteers’” to cause diuresis and natriuresis. In mild heart failure,19’ as well as in hypertension,‘86 the intravenous administration of UK-69578 induces diuresis and natriuresis without stimulation of the reninangiotensin system. ANF AND EXERCISE

A general increase in plasma ANF occurs during graded dynamic exercise. Despite this, there is evidence that heart rate is an independent predictor of right ventricular plasma ANF concentrations and a heart rate greater than 120 beats per minute is necessary for ANF to be released.198*199It has been suggested that heart rate during dynamic exercise may itself be an independent stimulus for ANF release. It is not clear, therefore, whether tachycardia per se, or increased preload, constitutes the triggering mechanism of ANF release during exercise. There is recent evidence that during intense dynamic exercise, left atria1 pressure seems to be an important mediator of ANF release.‘*

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Increments of ANF release correlate to pulmanic wedge pressure during exercise.*O” In essential hypertension, ANF increases with moderate exercise and correlates positively with both left atria1 and mean arterial blood pressure.zo’ In valvular heart disease, ANF increased significantly at the 75workload on a bicycle ergometer. Greater increments of ANF increase were observed in patients with mitral stenosis than those with aortic regurgitation.*‘* In congestive heart failure, right atria1 ANF levels increased soon after dynamic exercise.203,*" Even in severe heart failure with markedly elevated basal ANF levels, there is a further increase in plasma ANF in response to the stress of maximal exercise.‘04 In orthotopic cardiac transplants, ANF increases with exercise, being correlated to the pulmonary wedge pressure, indicating that despite denervation, ANF secretory function is well preserved.*” In patients with a recent myocardial infarction, ANF Ievels increase significantly at moderate exercise workloads (50 to 75 W) in a similar way as seen in valvular heart disease and hypertension206 Pulmonary wedge pressure was also closely related with ANF levels. Thus, ANF during exercise may be an indicator of the severity of myocardial dysfunction resulting from infarction.

CONCLUSION

Insight into cardiac endocrine function has increased our appreciation of the intricate and diverse mechanisms that modulate functional performance of the heart. The heart seems to participate both as a sensor and effector organ in the reflex mechanisms that contribute to control of the circulation. ANF is a hormonal system that plays an important role in volumearterial pressure regulation. ANF produces significant atria1 and venous vasodilation in association with a mild natriuresis. These effects appear to be unique, because ANF inhibits the neuroendocrine compensatory mechanisms that characterize vasodilator therapy. Further investigation of ANF in the pathophysiologic syndrome of congestive heart failure should provide continuing insight into both the mechanism of action of ANF, as well as a clearer understanding of the pathogenesis of the syndrome. The existence of a cardiac hormone with volume-regulating effects underlines the elegant but multifactorial design of the cardiovascular system. Its discovery offers the possibility of adding an endogenous substance to the pharmacologic armamentarium used for the treatment of heart failure.

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AND

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