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36 (Supplement 3) 1996;76:36-44 The renin-- system and the

cardiac natriuretic 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 " 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 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 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- 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 . 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 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 presented to the , 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 , 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 sodium 40 sodium 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 .'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, , and available comparing the effects of ANF and angiotensin converting (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 such as tensin II levels were not altered. CNP had no preparations of isolated .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 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. ANF and angiotensin II ical significance of these findings is uncertain. both constrict renal efferent arterioles,30 sug- The mechanisms underlying natriuretic gesting a common mechanism whereby both peptide inhibition of renin secretion are not peptides preserve intraglomerular pressure fully defined."5 Peptide-induced dilatation of and . the afferent glomerular may stimulate Natriuretic peptides and angiotensin II may involved in the control of renin exert counterbalancing effects upon vascular release from the juxtaglomerular apparatus. cell growth and hypertrophy. Angiotensin II is a Enhanced delivery of sodium to the macula promoter of vascular cell densa induced by natriuretic peptides will also growth.31 ANF inhibits vascular smooth mus- inhibit renin release. The possibility that natri- cle cell proliferation32 and attenuates the uretic peptides also act directly on juxta- action of angiotensin II on vascular hyper- glomerular cells to inhibit renin release has trophy33 independently of its induction of been addressed by in vitro experiments, but proto-oncogenes. Natriuretic peptides antago- the data are conflicting. nise growth factor dependent DNA synthesis and cell proliferation of cardiac fibroblasts.34 These counterpoised effects of natriuretic pep- Natriuretic peptides and angiotensin II tides and angiotensin II on cardiovascular cell bioactivity growth suggest that the combination of ACE Natriuretic peptides oppose most of the inhibition with natriuretic peptide enhance- known biological effects of angiotensin II. ment (for example, with neutral endopepti- They antagonise angiotensin II induced aldos- dase inhibition) may oppose vascular and terone production.'8 20 Natriuretic peptide cardiac hypertrophy in human cardiovascular

induced natriuresis is partly due to antagonism disease. http://heart.bmj.com/ of the effects of angiotensin II on glomerular Angiotensin II and natriuretic peptide inter- permeability and proximal tubular sodium actions may influence cardiac conduction and reabsorption, as well as aldosterone secretion rhythm. Angiotensin II has a direct toxic effect into the distal .5 21 22 Recently, Garcia upon cardiac cells,35 and in the setting of car- and Garvin23 have published evidence suggest- diac ischaemia angiotensin II may be pro- ing that the two peptides interact in the proxi- arrhythmic. Little is known of the effect of mal straight tubule of the nephron through a natriuretic peptide on cardiac conduction and mechanism requiring medi- rhythm. Crozier et al36 infused exogenous on September 24, 2021 by guest. Protected copyright. ated by cGMP dependent kinase. In ANF during cardiac electrophysiological stud- normal man, McMurray and Struthers have ies in man. ANF induced falls in intra- shown that ANF inhibits angiotensin II atrial conduction time, PR interval, right atrial induced antinatriuresis, and that angiotensin effective refractory period, and ventriculoatrial II inhibits ANF induced natriuresis at doses refractory period. In the isolated perfused which do not disturb systemic haemodynam- heart (rat), angiotensin II exacerbated ics.24 ischaemia induced ventricular fibrillation, Sodium depletion enhances the aldosterone impaired cardiodynamics, and increased the response to angiotensin II.25 Some data sug- release of creatine kinase. These effects were gest that concomitant shifts in natriuretic pep- abolished by ANF,37 which increased myocar- tides may contribute to the sodium related dial glycogen, ATP, and creatine phosphate, changes in the dose-response relation between and decreased lactate levels. Angiotensin II angiotensin II and aldosterone secretion. In induced deterioration in these metabolic vari- sodium depleted dogs receiving a background ables. Hence, natriuretic peptides may offer infusion ofANF calculated to cause restitution protection against the metabolic and arrhyth- of plasma ANF concentrations to salt replete mic consequences of cardiac ischaemia and values, the enhanced aldosterone response to reperfusion. Functional antagonism of angio- angiotensin II was significantly attenuated.26 tensin II may underlie this beneficial effect. However, data in humans from Tuchelt et a127 and Clinkingbeard et al28 are inconclusive. Natriuretic peptides alter blood pressure Natriuretic peptides and angiotensin II in through a range of mechanisms which include the central nervous system contraction of plasma volume, inhibition of Angiotensin II given into the cerebral ventri- The renin-angiotensin-aldosterone system and the cardiac natriuretic peptides 39

cles raises blood pressure, stimulates drinking, showed that vasopressor infusions of angio- salt preference and adrenocorticotropic hor- tensin II also enhanced plasma ANF levels. mone release, and inhibits renal renin release. Volpe et a142 found that subpressor doses of

These central nervous system actions of angio- angiotensin II administered to dogs during Heart: first published as 10.1136/hrt.76.3_Suppl_3.36 on 1 November 1996. Downloaded from tensin II are similar to those observed with saline loading (with and without converting peripheral administration. In contrast, central enzyme inhibition) significantly increased nervous system angiotensin II induces natri- plasma ANF levels without change in atrial uresis while peripheral angiotensin II pro- pressure. In isolated atrial appendages and in motes sodium retention. Intracerebro- crude rat atrial tissue preparations, angio- ventricular ANF antagonises all of the central tensin II stimulates ANF release consistent nervous system effects of angiotensin II.15 with a direct effect of angiotensin II indepen- The brain renin-angiotensin system may dent of haemodynamic changes."5 influence ANF secretion. Itoh et al'8 showed that intracerebroventricular angiotensin II did not alter basal plasma ANF, but the natri- ACE and natriuretic peptides uretic peptide response to systemic volume Early in vitro studies suggesting that convert- loading was enhanced. However, the angio- ing enzyme inhibition slowed the metabolism tensin II AT-1 receptor blocker given of ANF have not been reproduced.43 In man, intracerebroventricularly in normal sheep and conflicting reports appeared as to whether sheep with heart failure raised peripheral ACE inhibition raised or lowered endogenous renin, angiotensin II, and aldosterone concen- plasma ANF.'5 Reduced ANF induced natri- trations in both states without significant uresis during ACE inhibition has been a con- effects on plasma natriuretic peptides sistent finding. This effect may simply reflect (Rademaker MT, et al unpublished data). falls in renal perfusion pressures reducing the There is little information about BNP or renal response to ANF. Richards et al studied CNP given into the cerebral ventricles. In con- supine, salt loaded, normal volunteers. In this scious sheep, intracerebroventricular ANF setting, ACE inhibition caused little change in produced little change in basal and blood pressure and did not alter metabolic haemodynamics, whereas CNP induced a clearance or bioactivity of infused exogenous prompt fall in mean arterial pressure with an ANF.44 abrupt early increase in both plasma A sole report from Kawaguchi et al45 indi- and aldosterone, followed by a decline to val- cated that ANF was able to inhibit ACE activ- ues equal to or below control levels.39 The data ity in a dose dependent manner in cultured indicate that central nervous system CNP pulmonary endothelial cells. reduces arterial pressure (without a reflex tachycardia) and suppresses the adrenocortical response (fig 3). Inhibition of natriuretic peptide Systemic angiotensin II enhances natri- metabolism

uretic peptide secretion by haemodynamic and Blockade of natriuretic peptide metabolism http://heart.bmj.com/ direct mechanisms. Pressor doses of angio- provides further information on the action of tensin II increased ANF secretion in the rat natriuretic peptides on the RAAS. Maack et proportionally to concomitant changes in right al5 discovered non-guanylyl-cyclase-linked atrial pressure.40 In humans, Schenker et al4 "clearance" receptors by using an ANF ana-

Figure 3 Schemative diagram showing the on September 24, 2021 by guest. Protected copyright. regulation and actions of natriuretic peptides. Reproduced with permission from Espiner et al.82

VOLUME CONTROL - STRETCH t feedback Negativet Plasma volume ; BP (E- .0 ; Aldo 4& ; Renin t FF(Na) 40 Richards

logue, ANPC 4-23, which had no direct activ- in plasma aldosterone. In rats, HS142 abol- ity in vitro but which elicited a natriuresis ished the natriuretic response to ANF and when given to intact rats. The modified ligand BNP.54 Similar effects were observed in anaes-

displaced biologically active natriuretic pep- thetised dogs, in which HS 142 decreased basal Heart: first published as 10.1136/hrt.76.3_Suppl_3.36 on 1 November 1996. Downloaded from tide from C receptors. While many reports sodium excretion in association with a dou- confirm the diuretic and vasodepressor effects bling of plasma renin activity. Together, these of giving a variety of NPR-C ligands, few data indicate an important role for endoge- describe the concomitant effects on the RAAS. nous natriuretic peptides in regulating basal Wegner et a146 found a minor suppression of and stimulated plasma renin activity and renin below time matched placebo values with aldosterone concentrations. administration of the clearance receptor ligand AP8 11 in anaesthetised dogs. No data are available concerning the effects of such ligands on RAAS activity in humans. Plasma natriuretic peptide concentrations rise The neutral endopeptidase EC 3-4-24- 11 is progressively with increasing severity of hyper- pivotal in the initial enzymatic degradation of tension,55 and plasma ANF and BNP are cor- ANF7 and also contributes to clearance of related with left ventricular mass. Plasma ANF BNP. In man and in animals, administration and the RAAS may both be disturbed in of neutral endopeptidase inhibitors results in hypertensive disorders. In Gordon's syn- modest rises in plasma ANF together with a drome55 (hypertension, hyperkalaemia, vol- transient natriuresis above time matched ume expansion, and low renin), plasma ANF placebo values.4748 Single doses of neutral is low and has a subnormal response to saline endopeptidase inhibitors initially suppress lev- challenge. Deficient ANF responses may be els of plasma renin and aldosterone in associa- attenuated in Gordon's syndrome and may tion with the initial stimulus to plasma therefore contribute to volume expansion and natriuretic peptide concentrations,47 but with hypertension in this state. sustained dosing in normal volunteers activa- Luparini et al56 investigated the effect of tion of the RAAS occurs.49 Presumably changes in sodium status on the ANF decreased blood pressure and negative sodium response to angiotensin II infusions in patients balance override the primary inhibitory effect with "non-modulating"57 essential hyperten- of enhanced tissue natriuretic peptide on renin sion with blunted renal and RAAS responses secretion. In addition, in man, neutral to shifts in sodium status. In contrast to modu- endopeptidase inhibition interferes with clear- lators, non-modulators show no increase in ance of angiotensin II.50 plasma ANF in response to infusions of angio- tensin II at either low or high sodium intakes. In patients with Natriuretic peptide blockade (divided into "renin responsive" and "renin Clarification of the role of natriuretic peptides unresponsive" subgroups on the basis of their with respect to the RAAS has been handi- plasma renin response to challenge with capped by the absence of a specific, potent, frusemide and upright posture), renin unre- http://heart.bmj.com/ and safe antagonist to natriuretic peptides sponsive patients showed an enhanced plasma suitable for administration to humans. Such ANF response to hypertonic saline challenge.58 an agent would offer important complemen- Natriuretic peptide levels may be an important tary evidence to that presented above. Several codeterminant of the RAAS response to studies have already shown that physiological change in sodium status and of natriuretic increments in plasma or tissue natriuretic pep- responses to sodium challenge.

tides significantly inhibit the RAAS.9 1415 17 18 If it In , plasma ANF is on September 24, 2021 by guest. Protected copyright. could also be shown that a specific blockade of appropriately raised and falls with excision of endogenous natriuretic peptide produced the the adrenal adenoma or during treatment with opposite effect, that is, activation of the aldosterone antagonists.55 Renovascular hyper- RAAS, then the evidence that endogenous tension and hypertension associated with natriuretic peptides play a "tonic" role in regu- chronic renal impairment are also associated lation of RAAS activity would be compelling. with increased plasma natriuretic peptide con- Although such data are not available from centrations. human experiments, their near equivalent can be gleaned from animal data documenting the effect of monoclonal antibodies to ANF, and CNP also from the use of the polysaccharide natri- Plasma concentrations of CNP are far lower uretic peptide antagonist HS142-1 which than concomitant levels of ANF or BNP. This selectively inhibits the binding of ANF and is consistent with the putative paracrine role BNP to guanylyl cyclase linked natriuretic for this peptide. Plasma CNP concentrations peptide receptors.51 are not altered in human hypertension and the Stasch and colleagues have reported that values do not correlate with concurrent levels the expected suppression of plasma renin of BNP.59 Sited in vascular and central ner- activity and plasma aldosterone concentrations vous system tissues, CNP has the potential to by acute hypervolaemia is abolished by pre- influence arterial pressure and RAAS activity. treatment with monoclonal antibody directed Central nervous system CNP lowered blood against ANF.52 Rudd53 and colleagues, pressure and adrenocortical secretion in nor- employing this monoclonal antibody in rats, motensive sheep.39 CNP inhibits growth of rat showed falls in basal natriuresis and a 50% rise vascular smooth muscle cells. It also inhibits The renzn-angzotenszn-aldosterone system andt the cardiac natriuretic peptides 41

arterial intimal thickening after vascular injury Lazzeri et al66 induced a comparable increase in rat carotid arteries.60 These vascular in plasma BNP concentrations in association antitrophic actions are the opposite of those with a similar increase in sodium excretion

expected for angiotensin II, suggesting a possi- and a trend towards suppression of plasma Heart: first published as 10.1136/hrt.76.3_Suppl_3.36 on 1 November 1996. Downloaded from ble functional antagonism between CNP and renin activity (- 30%) which did reach signifi- angiotensin II with respect to cardiovascular cance. This may be because the number of cell growth. sampling points (only two per study phase) was limited. Natriuretic peptide infusions in human hypertension Inhibition of neutral endopeptidase Early studies confirmed the natriuretic and 3*4*24*11 in hypertension hypotensive effects of ANF in human hyper- Single doses or limited doses of neutral tension, but the large doses of ANF used in endopeptidase inhibitors have produced an these studies induced compensatory reflex increase in plasma ANF and BNP together responses that tended to disguise the primary with natriuresis, increases in plasma and urine inhibitory effect of ANF on the RAAS which cGMP, and suppression of the RAAS. These became apparent in later work. In essential doses had little effect on blood pressure.47 hypertension, ANF doses of 1 and 2 In contrast, chronic dosing with neutral pmol/kg/min increased plasma ANF to con- endopeptidase inhibitors produces transient centrations which remained within the range natriuresis, sustained elevation of cGMP, observed in hypertension. Despite a clear, and a significant fall in arterial pressure in dose related fall in arterial pressure and a sig- association with a delayed activation of the nificant natriuresis, RAAS activity was not RAAS.47 67 68 stimulated.6' ANF infusions (0 75 pmol/kg/ min) inducing a shift in plasma peptide con- centrations, entirely within the normal resting Heart failure range, produced a natriuresis together with Plasma natriuretic peptide levels are increased consistent suppression of plasma renin activity in heart failure in proportion to the severity of and aldosterone to less than 50% of time cardiac dysfunction.69 Positive correlations matched placebo values.62 exist between circulating ANF and BNP levels Recently Ferri et a!63 have compared the and cardiac filling pressures, while natriuretic effects of ANF infused into low renin and nor- peptide concentrations are inversely related to mal renin essential hypertensives. Basal indices of left ventricular function. In cardiac plasma ANF was higher in low renin than in failure, the normal inverse relation between normal renin hypertensives. ANF (0 7 pmol/ plasma natriuretic peptide concentrations and kg/min for 3 h) induced a more rapid and pro- RAAS activity is replaced with a positive cor- nounced decrement in the plasma aldosterone relation,70 presumably reflecting simultaneous of low renin patients. stimulation of both natriuretic peptide (sec- http://heart.bmj.com/ With respect to secondary hypertension, ondary to cardiac chamber distension) and there are at least four reports of ANF given in renin release (in response to decreased renal primary aldosteronism55 at doses ranging 1 6 perfusion). The latter effect probably over- to 32 pmollkg/min. Blood pressure lowering comes the inhibitory action of raised circulat- and natriuretic effects were substantial and ing natriuretic peptide on renin release. similar to those observed in essential hyperten- In the absence of a specific antagonist to sion. Unsurprisingly, plasma aldosterone lev- natriuretic peptides, we cannot conclusively

els were not altered by ANF. Hirata et a!64 define their place in the pathophysiology of on September 24, 2021 by guest. Protected copyright. infused ANF (8 pmollkg/min for 40 min) into heart failure in man. Nevertheless, data are renal parenchymal hypertensive, renovascular available from elegant animal experiments. hypertensive, and normotensive control sub- Lee et a!7' examined two canine models of jects. Blood pressure (-5%) and plasma reduced cardiac output. Ligation of the tho- aldosterone (-40%) decreased by a similar racic inferior vena cava caused reductions in proportion in the three groups. Interestingly, cardiac output, reduced systemic arterial pres- plasma renin activity was not significantly sure, increased peripheral vascular resistance, affected in any group. and decreased renal blood flow and activation Overall, the inhibitory effects of natriuretic of the RAAS. However, in contrast to the pac- peptides on the RAAS are observed in both ing induced model of heart failure in the dog, primary and secondary human hypertension, ventricular filling pressures are not raised and but may be modified by baseline RAAS activity. consequently plasma natriuretic peptides are Human BNP (2 pmol/kg/min) infused not increased. In the inferior vena cava ligation intravenously in controlled studies of model, sodium excretion is curtailed and untreated patients with essential hypertension RAAS activity is enhanced when compared increased plasma BNP to values (20-30 with the pacing model. When ANF is given in pmol/l) similar to those previously observed in the inferior vena cava ligation experiments to other patients suffering from mild heart fail- produce matching levels of plasma ANF to ure. Plasma aldosterone was significantly sup- those observed in the paced model, sodium pressed to 50% of placebo values, in retention is ameliorated in association with association with the 2-5-fold increase in suppression of the RAAS. In canine pacing sodium excretion.65 Plasma renin activity was induced heart failure, HS142 reduced plasma also inhibited. A later, similar study from and urinary cGMP in a dose dependent fash- 42 Richards

ion and inhibited natriuresis.7' Plasma renin (a) V V activity and plasma aldosterone levels 160 - increased rapidly to double the control values. 140 -

Endogenous natriuretic peptides attenuate 120 - Heart: first published as 10.1136/hrt.76.3_Suppl_3.36 on 1 November 1996. Downloaded from 3, 100- activation of the RAAS and sodium retention I 80- in evolving heart failure. E (b) In human heart failure, ANF consistently E 160- induces falls in cardiac preload and afterload, (D 140 - with transient increases in cardiac output and 0,, 120- little change in heart rate.69 The inhibitory XD 100- effects of ANF on the RAAS are attenuated in X 80- O (c) heart failure. However, the absence of change o 160- in plasma levels of renin, angiotensin II, and 140 - aldosterone, despite haemodynamic effects, 120 - presumably indicates some persisting 100 - inhibitory effect of ANF on the RAAS.69 80 - In the only full report available73 on human heart failure (New York Heart Association 7 9 11 13 15 17 19 21 23 1 3 5 7 classes II-IV), BNP given at a high dose (33 Time (h) reduced left ventricular filling pmol/kg/min) Figure 4 Serial integrated 1 h values ofsystolic and pressure and systemic vascular resistance diastolic bloodpressures obtained by ambulatory blood while increasing cardiac output. In this study, pressure recording on (N) placebo or (0) active BNP had no effect on heart rate or arterial treatment. In (a) the effect of25 mg ofcaptoprd twice per day is compared with placebo; in (b) the effects of 100 mg pressure. Plasma aldosterone was suppressed ofsinorphan twice per day are compared with placebo; and while plasma renin activity was unchanged. In in (c) the combined treatment and the mean of the two striking contrast to the attenuated natriuretic placebo phases are compared. Arrows indicate dose times. Values are expressed as means, error bars = SEM. response to ANF usually observed in heart Reproduced with permission from Favrat et al.79 failure, these researchers reported an enhanced natriuretic response to BNP in com- parison to that observed in normal controls. the natriuretic response to volume expan- These findings require confirmation. sion.78 Taken together, these animal data sug- Endopeptidase inhibition in single and gest that the combination of ACE and neutral chronic dose studies has shown a beneficial endopeptidase inhibition produces comple- effect in human heart failure, with reduction in mentary biological effects, resulting in effec- left ventricular pressures and systemic arterial tive antihypertensive action across a range of pressure and preservation of cardiac output in forms of hypertension. The only available association with inhibition of renin activity.7476 report in human hypertension showed that the combination of an neutral endopeptidase

inhibitor (sinorphan) with an ACE inhibitor http://heart.bmj.com/ Combined inhibition ofACE and neutral () resulted in significant falls in arterial endopeptidase pressure (fig 4), whereas (at the doses ACE inhibitors are an established treatment in employed) neither agent given alone produced hypertension and heart failure. ACE inhibition a clinically important antihypertensive effect.79 has the greatest haemodynamic effect when In heart failure, currently published data baseline activity of the RAAS is increased. As concerning combined ACE and neutral yet, neutral endopeptidase inhibition has no endopeptidase inhibition are confined entirely defined therapeutic application, although pre- to animal experiments. Co-administration of on September 24, 2021 by guest. Protected copyright. liminary data suggest beneficial effects in captopril and an neutral endopeptidase hypertension and heart failure. However, effi- inhibitor (SQ 28603) in canine pacing cacy may be curtailed by secondary activation induced heart failure lowered arterial pressure of the RAAS. Hence combining these two and systemic and renal vascular resistance, modes of enzyme inhibition may augment the while enhancing cardiac output and renal beneficial effects of either approach alone. blood flow.80 This combination therapy war- Pham et aF77 reported that in three rat models rants further trials in human hypertension and of hypertension neutral endopeptidase inhibi- heart failure. tion consistently enhanced natriuresis and lev- els of cGMP, ANF, and bradykinin. Blood pressure fell only in DOC-Na rats and was not Conclusion altered in either SHR or renovascular hyper- An intricate web of incompletely understood tensive (two , one clip) rats. ACE inhi- interactions has been found between the natri- bition alone reduced blood pressure effectively uretic peptides and the RAAS in health and in both SHR and renovascular animals, but disease. These interactions influence cardio- not in the DOC-Na model. The two inhibitors vascular structure and function and combined augmented the diuresis and natri- pressure/volume , and may be uresis observed in DOC-Na and SHR models manipulated to cause a beneficial effect in and the fall in blood pressure in the SHR. hypertension and heart failure. Glucoprilat and alatrioprilat (which have com- bined in low Original work from the author's group was supported by the enzyme inhibitory activity) given National Heart Foundation and the Health Research Council dose to rodents prevented hypertension sec- of New Zealand. Expert secretarial assistance was provided by ondary to infused angiotensin I and enhanced Barbara Griffin. The renin-angiotensin-aldosterone system and the cardiac natriuretic peptides 43

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