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The Renin-Angiotensin-Aldosterone System and The 36 Heart (Supplement 3) 1996;76:36-44 The renin-angiotensin-aldosterone system and the cardiac natriuretic peptides Heart: first published as 10.1136/hrt.76.3_Suppl_3.36 on 1 November 1996. Downloaded from A Mark Richards Natriuretic peptides and the renin- functions as a "clearance receptor", removing angiotensin-aldosterone system (RAAS) have natriuretic peptides from the circulation.5 reciprocal effects at multiple sites and in varied ANF and BNP stimulate cGMP production situations. They interact in health and cardio- through the NPR-A receptor. The NPR-B vascular disease to influence renal, endocrine, receptor is selective for CNP.6 The NPR-C and haemodynamic function and cardiovascu- (clearance receptor) binds all three of the lar cell growth. The atrial natriuretic peptide natriuretic peptides. Natriuretic peptides are (atrial natriuretic factor, ANF) discovered by also subject to clearance by enzymatic degra- De Bold in 19811 was cloned and sequenced dation. The neutral endopeptidase EC by molecular biological techniques in 1984.2 3A4'24'11 contributes to ANF clearance (and The related peptides, brain natriuretic peptide to a lesser extent BNP clearance) in humans.7 (BNP) and C-type natriuretic peptide (CNP), The biochemistry of natriuretic peptides is fur- were sequenced in 1988 and 1990, respec- ther detailed in a recent review.8 tively.34 The mature forms of the peptides The focus of the present review is the inter- share a common core structure consisting of a action of the cardiac natriuretic peptides with 17-amino acid ring with some conservation of the RAAS. Studies in humans will be amino acid residues between peptides (fig reviewed, with additional information from in 1).24 ANF is present at high concentrations in vitro or intact animal experiments where atrial tissue, and in lesser amounts in the cen- appropriate. tral nervous system and plasma. BNP was originally identified in the porcine brain, but subsequent work showed that it is primarily a Reciprocal responses of natriuretic cardiac hormone. CNP, the most recently dis- peptides and RAAS covered member of the natriuretic peptide Secretion of ANF from the atria and BNP family, has no carboxy terminal extension (fig from cardiac ventricles is regulated by atrial 1). It is widespread in vascular endothelium distension and intraventricular pressures, http://heart.bmj.com/ and is the most prevalent of the three peptides respectively. The RAAS is activated with con- within the central nervous system, while little traction of plasma volume and fall in renal is present in the heart. perfusion. Renin secretion is stimulated The natriuretic peptides exert their biological through effects on the afferent arterial baro- activity through specific cell receptors. Three receptor system, shifts in the filtered load of Department of Medicine, natriuretic peptide receptors (NPR) have been sodium presented to the macula densa, and by Christchurch Hospital, characterised. NPR-A and NPR-B have changes in renal sympathetic traffic. Renin Christchurch, New guanylate cyclase activity and mediate biologi- stimulates production of circulating angio- on September 24, 2021 by guest. Protected copyright. Zealand cal activity through the second messenger tensin II, a major secretagogue for A M Richards aldosterone. The natriuretic peptides enhance Correspondence to: cyclic guanosine monophosphate (cGMP). Dr A M Richards. NPR-C is not guanylate cyclase linked, and natriuresis, lower blood pressure, and promote ANP BNP CNP Figure 1 Mature forms ofpeptides belonging to the human atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) families. Filled circles are amino acids common to all three peptides. The mature forms shown are ANF, BNP-32, and CNP-22. Reproduced with permission from Yandle et al.8 The renin-angiotensin-aldosterone system and the cardiac natriuretic peptides 37 a contraction of plasma volume by shifting Normal fluid volume from the intravascular to the Infusion extravascular space.9 In contrast, the RAAS 60 K promotes maintenance of circulating volume 50 Heart: first published as 10.1136/hrt.76.3_Suppl_3.36 on 1 November 1996. Downloaded from and arterial pressure through both renal A Urine sodium 40 sodium reabsorption and vasoconstrictor (%) 30 effects. 20 - In view of these differing stimuli for secre- 10 K_ tion and opposed end organ biological effects, it is not surprising that plasma natriuretic pep- -20 tide concentrations and circulating RAAS 15 - A cGMP 10 _ activity alter in reciprocal fashion in the face of (pmol = 10) 5 _- a variety of physiological and experimental stimuli. For example, intravenous saline chal- 1. lenge increases plasma concentrations of ANF 8- (although not BNP) while suppressing the A Plasma ANP 6 RAAS.'0 Similarly, administration of diuretics, (pmol/l) 4 or conversely, expansion of central blood vol- 2- ume by means of lower body immersion, pro- duces clear reciprocal changes in natriuretic 4L- peptide and RAAS activity." Dietary changes A Systolic ° I pressure -4- I leading to shifts in cumulative sodium balance I induce a direct parallel shift in plasma natri- (mm Hg) -8 4-Ki uretic peptides but a reciprocal change in -12- renin.10 These observations do not allow dis- A Plasma 0 L tinction between the possibilities of indepen- noradrenaline 50 dent reciprocal responses of natriuretic (pg/mI) -1°0 peptides and the RAAS to a given stimulus 0.2- and potential direct effects of one circulating A PRA 0H factor on the other. (nmol/l/h) -0 -04L-4 100 Natriuretic peptide infusions in normal 50 man A Plasma 0 Administration of high doses of ANF, with aldosterone -50 associated substantial falls in arterial pressure, (pmol/l) -100 has no effect on plasma renin activity.'2 13 -150 !'sI X During an early experiment in which high 0 60 120 180 240 doses of ANF caused a pronounced fall in Time (min) http://heart.bmj.com/ blood pressure, plasma renin activity increased Figure 2 Response to intravenous infusions ofhuman while aldosterone secretion was suppressed.'3 atrial natriureticfactor (ANP) (0 75 pmollkg/min for 180 Therefore, in addition to any effect of ANF on min) in six normal subjects equilibrated on a daily sodium aldosterone through the renin-angiotensin sys- intake of 150 mmol. Values (mean with SEM) are plotted is as change (A) from time matched levels on the control day tem, there also a direct inhibitory effect of for urinary excretion ofsodium and cyclic guanosine natriuretic peptides on the adrenal zona monophosphate (cGMP), plasma ANP, systolic pressure, glomerulosa. Physiological doses of ANF con- plasma noradrenaline, plasma renin activity (PRA) and sistently suppress both plasma renin activity plasma aldosterone (bottom panel). Reproduced with on September 24, 2021 by guest. Protected copyright. and aldosterone concentrations.9 14'15 Low dose permission from Espiner et al. 81 ANF infusions inducing small increments in plasma ANF confined to the mid-portion of the normal resting range briskly suppressed in plasma BNP to levels similar to those plasma renin activity and aldosterone concen- observed in mild heart failure. Natriuresis trations by one third to one half below occurred, together with rapid suppression of matched placebo values (fig 2). ' ANF inhibits renin activity and aldosterone concentrations the renin response in man to head up tilt, loop to 50% ofplacebo values.'7 Little information is diuretic, isoprenaline, prostaglandin, and available comparing the effects of ANF and angiotensin converting enzyme (ACE) inhibi- BNP on the renin-angiotensin-aldosterone tion.'5 Age, arterial blood pressure, sodium system. Cargill et al'8 studied normal volun- status, and posture all affect responses to teers in a three way crossover study with natriuretic peptides, and conflicting reports administration of 10 pmol/kg/min of ANF, are largely due to inadequate control of these BNP, or vehicle, with concomitant infusion of potentially confounding variables. 16 Overall, in angiotensin II (6 ng/kg/min). ANF and BNP the absence of major haemodynamic distur- had similar vasodilator effects. However, ANF bance with its consequent neurosympathetic was twice as potent as BNP in suppressing the activation, secretion of both renin and aldos- aldosterone response to angiotensin II. We terone is readily inhibited by small changes in have confirmed this finding in a similar experi- plasma ANF. ment incorporating stepped infusions of angio- BNP has comparable ability to suppress the tensin II on a background of lower dose (2 RAAS. In normal volunteers, low dose BNP pmol/kg/min) infusions of ANF and BNP (2 pmol/kg/min over 3 h) induced an increase (Hunt PJ et al, unpublished data). 38 Richards CNP infused in normal men19 at a dose of 5 renin and aldosterone secretion, and a direct pmol/kg/min over a period of 2 h in placebo vasodilator effect. Interaction between natri- controlled studies increased plasma immuno- uretic peptides and the RAAS may also occur reactive CNP levels to 60 pmol/l. Plasma ANF in some blood vessels. In isolated vascular Heart: first published as 10.1136/hrt.76.3_Suppl_3.36 on 1 November 1996. Downloaded from rose (approximately 2 pmol/l), as did plasma preparations, ANF shows a pronounced cGMP (approximately 1 nmol/l). Aldosterone antagonism of angiotensin II induced vasocon- concentrations fell, whereas plasma angio- striction in large conduit arteries such as tensin II levels were not altered. CNP had no preparations of isolated aorta.29 In contrast, significant effect on the aldosterone or pressor peripheral vessels (cerebral and mesenteric responses to angiotensin II infusions. The vessels in the rat and glomerular arterioles in observed effects on aldosterone and plasma the rabbit) preconstricted with noradrenaline cGMP may have been due to competitive dis- or angiotensin II are insensitive to ANFs. placement by CNP of ANF in common Early human studies do not suggest preferen- degradative pathways. In view of the likely role tial antagonism by natriuretic peptides of the of CNP as a paracrine rather than endocrine net pressor effects of angiotensin II over that hormone, the physiological or pathophysiolog- of noradrenaline.
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