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Heart (Supplement 3) 1996;76:36-44

The renin-angiotensin-aldosterone system and thecardiac natriuretic peptides

A Mark Richards

Natriuretic peptides and the renin-angiotensin-aldosterone system (RAAS) havereciprocal effects at multiple sites and in variedsituations. They interact in health and cardio-vascular disease to influence renal, endocrine,and haemodynamic function and cardiovascu-lar cell growth. The atrial natriuretic peptide(atrial natriuretic factor, ANF) discovered byDe Bold in 19811 was cloned and sequencedby molecular biological techniques in 1984.2The related peptides, brain natriuretic peptide(BNP) and C-type natriuretic peptide (CNP),were sequenced in 1988 and 1990, respec-tively.34 The mature forms of the peptidesshare a common core structure consisting of a17-amino acid ring with some conservation ofamino acid residues between peptides (fig1).24 ANF is present at high concentrations inatrial tissue, and in lesser amounts in the cen-tral nervous system and plasma. BNP wasoriginally identified in the porcine brain, butsubsequent work showed that it is primarily acardiac hormone. CNP, the most recently dis-covered member of the natriuretic peptidefamily, has no carboxy terminal extension (fig1). It is widespread in vascular endotheliumand is the most prevalent of the three peptideswithin the central nervous system, while littleis present in the heart.The natriuretic peptides exert their biological

activity through specific cell receptors. Threenatriuretic peptide receptors (NPR) have beencharacterised. NPR-A and NPR-B haveguanylate cyclase activity and mediate biologi-cal activity through the second messengercyclic guanosine monophosphate (cGMP).NPR-C is not guanylate cyclase linked, and

functions as a "clearance receptor", removingnatriuretic peptides from the circulation.5ANF and BNP stimulate cGMP productionthrough the NPR-A receptor. The NPR-Breceptor is selective for CNP.6 The NPR-C(clearance receptor) binds all three of thenatriuretic peptides. Natriuretic peptides arealso subject to clearance by enzymatic degra-dation. The neutral endopeptidase EC3A4'24'11 contributes to ANF clearance (andto a lesser extent BNP clearance) in humans.7The biochemistry of natriuretic peptides is fur-ther detailed in a recent review.8The focus of the present review is the inter-

action of the cardiac natriuretic peptides withthe RAAS. Studies in humans will bereviewed, with additional information from invitro or intact animal experiments whereappropriate.

Reciprocal responses of natriureticpeptides and RAASSecretion of ANF from the atria and BNPfrom cardiac ventricles is regulated by atrialdistension and intraventricular pressures,respectively. The RAAS is activated with con-traction of plasma volume and fall in renalperfusion. Renin secretion is stimulatedthrough effects on the afferent arterial baro-receptor system, shifts in the filtered load ofsodium presented to the macula densa, and bychanges in renal sympathetic traffic. Reninstimulates production of circulating angio-tensin II, a major secretagogue foraldosterone. The natriuretic peptides enhancenatriuresis, lower blood pressure, and promote

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

Department ofMedicine,Christchurch Hospital,Christchurch, NewZealandAM RichardsCorrespondence to:Dr A M Richards.

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The renin-angiotensin-aldosterone system and the cardiac natriuretic peptides

a contraction of plasma volume by shiftingfluid volume from the intravascular to theextravascular space.9 In contrast, the RAASpromotes maintenance of circulating volumeand arterial pressure through both renalsodium reabsorption and vasoconstrictoreffects.

In view of these differing stimuli for secre-tion and opposed end organ biological effects, itis not surprising that plasma natriuretic pep-tide concentrations and circulating RAASactivity alter in reciprocal fashion in the face ofa variety of physiological and experimentalstimuli. For example, intravenous saline chal-lenge increases plasma concentrations ofANF(although not BNP) while suppressing theRAAS.'0 Similarly, administration of diuretics,or conversely, expansion of central blood vol-ume by means of lower body immersion, pro-duces clear reciprocal changes in natriureticpeptide and RAAS activity." Dietary changesleading to shifts in cumulative sodium balanceinduce a direct parallel shift in plasma natri-uretic peptides but a reciprocal change inrenin.10 These observations do not allow dis-tinction between the possibilities of indepen-dent reciprocal responses of natriureticpeptides and the RAAS to a given stimulusand potential direct effects of one circulatingfactor on the other.

Natriuretic peptide infusions in normalmanAdministration of high doses of ANF, withassociated substantial falls in arterial pressure,has no effect on plasma renin activity.'2 13During an early experiment in which highdoses of ANF caused a pronounced fall inblood pressure, plasma renin activity increasedwhile aldosterone secretion was suppressed.'3Therefore, in addition to any effect ofANF onaldosterone through the renin-angiotensin sys-tem, there is also a direct inhibitory effect ofnatriuretic peptides on the adrenal zonaglomerulosa. Physiological doses of ANF con-sistently suppress both plasma renin activityand aldosterone concentrations.9 14'15 Low doseANF infusions inducing small increments inplasma ANF confined to the mid-portion ofthe normal resting range briskly suppressedplasma renin activity and aldosterone concen-trations by one third to one half belowmatched placebo values (fig 2). ' ANF inhibitsthe renin response in man to head up tilt, loopdiuretic, isoprenaline, prostaglandin, andangiotensin converting enzyme (ACE) inhibi-tion.'5 Age, arterial blood pressure, sodiumstatus, and posture all affect responses tonatriuretic peptides, and conflicting reportsare largely due to inadequate control of thesepotentially confounding variables. 16 Overall, inthe absence of major haemodynamic distur-bance with its consequent neurosympatheticactivation, secretion of both renin and aldos-terone is readily inhibited by small changes inplasma ANF.BNP has comparable ability to suppress the

RAAS. In normal volunteers, low dose BNP(2 pmol/kg/min over 3 h) induced an increase

A Urine sodium(%)

A cGMP(pmol = 10)

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Figure 2 Response to intravenous infusions ofhumanatrial natriuretic factor (ANP) (0 75 pmollkg/min for 180min) in six normal subjects equilibrated on a daily sodiumintake of 150 mmol. Values (mean with SEM) are plottedas change (A) from time matched levels on the control dayfor urinary excretion ofsodium and cyclic guanosinemonophosphate (cGMP), plasma ANP, systolic pressure,plasma noradrenaline, plasma renin activity (PRA) andplasma aldosterone (bottom panel). Reproduced withpermission from Espiner et al. 81

in plasma BNP to levels similar to thoseobserved in mild heart failure. Natriuresisoccurred, together with rapid suppression ofrenin activity and aldosterone concentrationsto 50% of placebo values.'7 Little information isavailable comparing the effects of ANF andBNP on the renin-angiotensin-aldosteronesystem. Cargill et al'8 studied normal volun-teers in a three way crossover study withadministration of 10 pmol/kg/min of ANF,BNP, or vehicle, with concomitant infusion ofangiotensin II (6 ng/kg/min). ANF and BNPhad similar vasodilator effects. However, ANFwas twice as potent as BNP in suppressing thealdosterone response to angiotensin II. Wehave confirmed this finding in a similar experi-ment incorporating stepped infusions of angio-tensin II on a background of lower dose (2pmol/kg/min) infusions of ANF and BNP(Hunt PJ et al, unpublished data).

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CNP infused in normal men19 at a dose of 5pmol/kg/min over a period of 2 h in placebocontrolled studies increased plasma immuno-reactive CNP levels to 60 pmol/l. Plasma ANFrose (approximately 2 pmol/l), as did plasmacGMP (approximately 1 nmol/l). Aldosteroneconcentrations fell, whereas plasma angio-tensin II levels were not altered. CNP had nosignificant effect on the aldosterone or pressorresponses to angiotensin II infusions. Theobserved effects on aldosterone and plasmacGMP may have been due to competitive dis-placement by CNP of ANF in commondegradative pathways. In view of the likely roleof CNP as a paracrine rather than endocrinehormone, the physiological or pathophysiolog-ical significance of these findings is uncertain.The mechanisms underlying natriuretic

peptide inhibition of renin secretion are notfully defined."5 Peptide-induced dilatation ofthe afferent glomerular arteriole may stimulatebaroreceptors involved in the control of reninrelease from the juxtaglomerular apparatus.Enhanced delivery of sodium to the maculadensa induced by natriuretic peptides will alsoinhibit renin release. The possibility that natri-uretic peptides also act directly on juxta-glomerular cells to inhibit renin release hasbeen addressed by in vitro experiments, butthe data are conflicting.

Natriuretic peptides and angiotensin IIbioactivityNatriuretic peptides oppose most of theknown biological effects of angiotensin II.They antagonise angiotensin II induced aldos-terone production.'8 20 Natriuretic peptideinduced natriuresis is partly due to antagonismof the effects of angiotensin II on glomerularpermeability and proximal tubular sodiumreabsorption, as well as aldosterone secretioninto the distal nephron.5 21 22 Recently, Garciaand Garvin23 have published evidence suggest-ing that the two peptides interact in the proxi-mal straight tubule of the nephron through amechanism requiring phosphorylation medi-ated by cGMP dependent protein kinase. Innormal man, McMurray and Struthers haveshown that ANF inhibits angiotensin IIinduced antinatriuresis, and that angiotensinII inhibits ANF induced natriuresis at doseswhich do not disturb systemic haemodynam-ics.24

Sodium depletion enhances the aldosteroneresponse to angiotensin II.25 Some data sug-gest that concomitant shifts in natriuretic pep-tides may contribute to the sodium relatedchanges in the dose-response relation betweenangiotensin II and aldosterone secretion. Insodium depleted dogs receiving a backgroundinfusion ofANF calculated to cause restitutionof plasma ANF concentrations to salt repletevalues, the enhanced aldosterone response toangiotensin II was significantly attenuated.26However, data in humans from Tuchelt et a127and Clinkingbeard et al 28 are inconclusive.

Natriuretic peptides alter blood pressurethrough a range of mechanisms which includecontraction of plasma volume, inhibition of

renin and aldosterone secretion, and a directvasodilator effect. Interaction between natri-uretic peptides and the RAAS may also occurin some blood vessels. In isolated vascularpreparations, ANF shows a pronouncedantagonism of angiotensin II induced vasocon-striction in large conduit arteries such aspreparations of isolated aorta.29 In contrast,peripheral vessels (cerebral and mesentericvessels in the rat and glomerular arterioles inthe rabbit) preconstricted with noradrenalineor angiotensin II are insensitive to ANFs.Early human studies do not suggest preferen-tial antagonism by natriuretic peptides of thenet pressor effects of angiotensin II over thatof noradrenaline. ANF and angiotensin IIboth constrict renal efferent arterioles,30 sug-gesting a common mechanism whereby bothpeptides preserve intraglomerular pressureand filtration.

Natriuretic peptides and angiotensin II mayexert counterbalancing effects upon vascularcell growth and hypertrophy. Angiotensin II is apromoter of vascular smooth muscle cellgrowth.31 ANF inhibits vascular smooth mus-cle cell proliferation32 and attenuates theaction of angiotensin II on vascular hyper-trophy33 independently of its induction ofproto-oncogenes. Natriuretic peptides antago-nise growth factor dependent DNA synthesisand cell proliferation of cardiac fibroblasts.34These counterpoised effects of natriuretic pep-tides and angiotensin II on cardiovascular cellgrowth suggest that the combination of ACEinhibition with natriuretic peptide enhance-ment (for example, with neutral endopepti-dase inhibition) may oppose vascular andcardiac hypertrophy in human cardiovasculardisease.

Angiotensin II and natriuretic peptide inter-actions may influence cardiac conduction andrhythm. Angiotensin II has a direct toxic effectupon cardiac cells,35 and in the setting of car-diac ischaemia angiotensin II may be pro-arrhythmic. Little is known of the effect ofnatriuretic peptide on cardiac conduction andrhythm. Crozier et al 36 infused exogenousANF during cardiac electrophysiological stud-ies in man. ANF induced falls in intra-atrial conduction time, PR interval, right atrialeffective refractory period, and ventriculoatrialrefractory period. In the isolated perfusedheart (rat), angiotensin II exacerbatedischaemia induced ventricular fibrillation,impaired cardiodynamics, and increased therelease of creatine kinase. These effects wereabolished by ANF,37 which increased myocar-dial glycogen, ATP, and creatine phosphate,and decreased lactate levels. Angiotensin IIinduced deterioration in these metabolic vari-ables. Hence, natriuretic peptides may offerprotection against the metabolic and arrhyth-mic consequences of cardiac ischaemia andreperfusion. Functional antagonism of angio-tensin II may underlie this beneficial effect.

Natriuretic peptides and angiotensin II inthe central nervous systemAngiotensin II given into the cerebral ventri-

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cles raises blood pressure, stimulates drinking,salt preference and adrenocorticotropic hor-mone release, and inhibits renal renin release.These central nervous system actions of angio-tensin II are similar to those observed withperipheral administration. In contrast, centralnervous system angiotensin II induces natri-uresis while peripheral angiotensin II pro-motes sodium retention. Intracerebro-ventricular ANF antagonises all of the centralnervous system effects of angiotensin II.15The brain renin-angiotensin system may

influence ANF secretion. Itoh et al'8 showedthat intracerebroventricular angiotensin II didnot alter basal plasma ANF, but the natri-uretic peptide response to systemic volumeloading was enhanced. However, the angio-tensin II AT-1 receptor blocker losartan givenintracerebroventricularly in normal sheep andsheep with heart failure raised peripheralrenin, angiotensin II, and aldosterone concen-trations in both states without significanteffects on plasma natriuretic peptides(Rademaker MT, et al unpublished data).There is little information about BNP or

CNP given into the cerebral ventricles. In con-scious sheep, intracerebroventricular ANFproduced little change in basal hormones andhaemodynamics, whereas CNP induced aprompt fall in mean arterial pressure with anabrupt early increase in both plasma cortisoland aldosterone, followed by a decline to val-ues equal to or below control levels.39 The dataindicate that central nervous system CNPreduces arterial pressure (without a reflextachycardia) and suppresses the adrenocorticalresponse (fig 3).

Systemic angiotensin II enhances natri-uretic peptide secretion by haemodynamic anddirect mechanisms. Pressor doses of angio-tensin II increased ANF secretion in the ratproportionally to concomitant changes in rightatrial pressure.40 In humans, Schenker et al4

showed that vasopressor infusions of angio-tensin II also enhanced plasma ANF levels.Volpe et a142 found that subpressor doses ofangiotensin II administered to dogs duringsaline loading (with and without convertingenzyme inhibition) significantly increasedplasma ANF levels without change in atrialpressure. In isolated atrial appendages and incrude rat atrial tissue preparations, angio-tensin II stimulates ANF release consistentwith a direct effect of angiotensin II indepen-dent of haemodynamic changes."5

ACE and natriuretic peptidesEarly in vitro studies suggesting that convert-ing enzyme inhibition slowed the metabolismof ANF have not been reproduced.43 In man,conflicting reports appeared as to whetherACE inhibition raised or lowered endogenousplasma ANF.'5 Reduced ANF induced natri-uresis during ACE inhibition has been a con-sistent finding. This effect may simply reflectfalls in renal perfusion pressures reducing therenal response to ANF. Richards et al studiedsupine, salt loaded, normal volunteers. In thissetting, ACE inhibition caused little change inblood pressure and did not alter metabolicclearance or bioactivity of infused exogenousANF.44A sole report from Kawaguchi et al45 indi-

cated that ANF was able to inhibit ACE activ-ity in a dose dependent manner in culturedpulmonary endothelial cells.

Inhibition of natriuretic peptidemetabolismBlockade of natriuretic peptide metabolismprovides further information on the action ofnatriuretic peptides on the RAAS. Maack etal 5 discovered non-guanylyl-cyclase-linked"clearance" receptors by using an ANF ana-

Figure 3 Schemativediagram showing theregulation and actions ofnatriuretic peptides.Reproduced withpermission from Espiner etal.82

VOLUME CONTROL - STRETCH

tNegative feedback

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; BP (E-.0

; Aldo 4&; Renin

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logue, ANPC 4-23, which had no direct activ-ity in vitro but which elicited a natriuresiswhen given to intact rats. The modified liganddisplaced biologically active natriuretic pep-tide from C receptors. While many reportsconfirm the diuretic and vasodepressor effectsof giving a variety of NPR-C ligands, fewdescribe the concomitant effects on the RAAS.Wegner et a146 found a minor suppression ofrenin below time matched placebo values withadministration of the clearance receptor ligandAP8 11 in anaesthetised dogs. No data areavailable concerning the effects of such ligandson RAAS activity in humans.The neutral endopeptidase EC 3-4-24- 11 is

pivotal in the initial enzymatic degradation ofANF7 and also contributes to clearance ofBNP. In man and in animals, administrationof neutral endopeptidase inhibitors results inmodest rises in plasma ANF together with atransient natriuresis above time matchedplacebo values.4748 Single doses of neutralendopeptidase inhibitors initially suppress lev-els of plasma renin and aldosterone in associa-tion with the initial stimulus to plasmanatriuretic peptide concentrations,47 but withsustained dosing in normal volunteers activa-tion of the RAAS occurs.49 Presumablydecreased blood pressure and negative sodiumbalance override the primary inhibitory effectof enhanced tissue natriuretic peptide on reninsecretion. In addition, in man, neutralendopeptidase inhibition interferes with clear-ance of angiotensin II.50

Natriuretic peptide blockadeClarification of the role of natriuretic peptideswith respect to the RAAS has been handi-capped by the absence of a specific, potent,and safe antagonist to natriuretic peptidessuitable for administration to humans. Suchan agent would offer important complemen-tary evidence to that presented above. Severalstudies have already shown that physiologicalincrements in plasma or tissue natriuretic pep-tides significantly inhibit the RAAS.9 1415 17 18 If itcould also be shown that a specific blockade ofendogenous natriuretic peptide produced theopposite effect, that is, activation of theRAAS, then the evidence that endogenousnatriuretic peptides play a "tonic" role in regu-lation of RAAS activity would be compelling.Although such data are not available fromhuman experiments, their near equivalent canbe gleaned from animal data documenting theeffect of monoclonal antibodies to ANF, andalso from the use of the polysaccharide natri-uretic peptide antagonist HS142-1 whichselectively inhibits the binding of ANF andBNP to guanylyl cyclase linked natriureticpeptide receptors.51

Stasch and colleagues have reported thatthe expected suppression of plasma reninactivity and plasma aldosterone concentrationsby acute hypervolaemia is abolished by pre-treatment with monoclonal antibody directedagainst ANF.52 Rudd53 and colleagues,employing this monoclonal antibody in rats,showed falls in basal natriuresis and a 50% rise

in plasma aldosterone. In rats, HS142 abol-ished the natriuretic response to ANF andBNP.54 Similar effects were observed in anaes-thetised dogs, in which HS142 decreased basalsodium excretion in association with a dou-bling of plasma renin activity. Together, thesedata indicate an important role for endoge-nous natriuretic peptides in regulating basaland stimulated plasma renin activity andaldosterone concentrations.

HypertensionPlasma natriuretic peptide concentrations riseprogressively with increasing severity of hyper-tension,55 and plasma ANF and BNP are cor-related with left ventricular mass. Plasma ANFand the RAAS may both be disturbed inhypertensive disorders. In Gordon's syn-drome55 (hypertension, hyperkalaemia, vol-ume expansion, and low renin), plasma ANFis low and has a subnormal response to salinechallenge. Deficient ANF responses may beattenuated in Gordon's syndrome and maytherefore contribute to volume expansion andhypertension in this state.

Luparini et al56 investigated the effect ofchanges in sodium status on the ANFresponse to angiotensin II infusions in patientswith "non-modulating"57 essential hyperten-sion with blunted renal and RAAS responsesto shifts in sodium status. In contrast to modu-lators, non-modulators show no increase inplasma ANF in response to infusions of angio-tensin II at either low or high sodium intakes.In patients with essential hypertension(divided into "renin responsive" and "reninunresponsive" subgroups on the basis of theirplasma renin response to challenge withfrusemide and upright posture), renin unre-sponsive patients showed an enhanced plasmaANF response to hypertonic saline challenge.58Natriuretic peptide levels may be an importantcodeterminant of the RAAS response tochange in sodium status and of natriureticresponses to sodium challenge.

In primary aldosteronism, plasma ANF isappropriately raised and falls with excision ofthe adrenal adenoma or during treatment withaldosterone antagonists.55 Renovascular hyper-tension and hypertension associated withchronic renal impairment are also associatedwith increased plasma natriuretic peptide con-centrations.

CNPPlasma concentrations of CNP are far lowerthan concomitant levels ofANF or BNP. Thisis consistent with the putative paracrine rolefor this peptide. Plasma CNP concentrationsare not altered in human hypertension and thevalues do not correlate with concurrent levelsof BNP.59 Sited in vascular and central ner-vous system tissues, CNP has the potential toinfluence arterial pressure and RAAS activity.Central nervous system CNP lowered bloodpressure and adrenocortical secretion in nor-motensive sheep.39 CNP inhibits growth of ratvascular smooth muscle cells. It also inhibits

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arterial intimal thickening after vascular injuryin rat carotid arteries.60 These vascularantitrophic actions are the opposite of thoseexpected for angiotensin II, suggesting a possi-ble functional antagonism between CNP andangiotensin II with respect to cardiovascularcell growth.

Natriuretic peptide infusions in humanhypertensionEarly studies confirmed the natriuretic andhypotensive effects of ANF in human hyper-tension, but the large doses of ANF used inthese studies induced compensatory reflexresponses that tended to disguise the primaryinhibitory effect of ANF on the RAAS whichbecame apparent in later work. In essentialhypertension, ANF doses of 1 and 2pmol/kg/min increased plasma ANF to con-centrations which remained within the rangeobserved in hypertension. Despite a clear,dose related fall in arterial pressure and a sig-nificant natriuresis, RAAS activity was notstimulated.6' ANF infusions (0 75 pmol/kg/min) inducing a shift in plasma peptide con-centrations, entirely within the normal restingrange, produced a natriuresis together withconsistent suppression of plasma renin activityand aldosterone to less than 50% of timematched placebo values.62

Recently Ferri et a!63 have compared theeffects ofANF infused into low renin and nor-mal renin essential hypertensives. Basalplasma ANF was higher in low renin than innormal renin hypertensives. ANF (0 7 pmol/kg/min for 3 h) induced a more rapid and pro-nounced decrement in the plasma aldosteroneof low renin patients.With respect to secondary hypertension,

there are at least four reports of ANF given inprimary aldosteronism55 at doses ranging 1 6to 32 pmollkg/min. Blood pressure loweringand natriuretic effects were substantial andsimilar to those observed in essential hyperten-sion. Unsurprisingly, plasma aldosterone lev-els were not altered by ANF. Hirata et a!64infused ANF (8 pmollkg/min for 40 min) intorenal parenchymal hypertensive, renovascularhypertensive, and normotensive control sub-jects. Blood pressure (-5%) and plasmaaldosterone (-40%) decreased by a similarproportion in the three groups. Interestingly,plasma renin activity was not significantlyaffected in any group.

Overall, the inhibitory effects of natriureticpeptides on the RAAS are observed in bothprimary and secondary human hypertension,but may be modified by baseline RAAS activity.Human BNP (2 pmol/kg/min) infused

intravenously in controlled studies ofuntreated patients with essential hypertensionincreased plasma BNP to values (20-30pmol/l) similar to those previously observed inother patients suffering from mild heart fail-ure. Plasma aldosterone was significantly sup-pressed to 50% of placebo values, inassociation with the 2-5-fold increase insodium excretion.65 Plasma renin activity wasalso inhibited. A later, similar study from

Lazzeri et al66 induced a comparable increasein plasma BNP concentrations in associationwith a similar increase in sodium excretionand a trend towards suppression of plasmarenin activity (- 30%) which did reach signifi-cance. This may be because the number ofsampling points (only two per study phase)was limited.

Inhibition of neutral endopeptidase3*4*24*11 in hypertensionSingle doses or limited doses of neutralendopeptidase inhibitors have produced anincrease in plasma ANF and BNP togetherwith natriuresis, increases in plasma and urinecGMP, and suppression of the RAAS. Thesedoses had little effect on blood pressure.47In contrast, chronic dosing with neutralendopeptidase inhibitors produces transientnatriuresis, sustained elevation of cGMP,and a significant fall in arterial pressure inassociation with a delayed activation of theRAAS.47 67 68

Heart failurePlasma natriuretic peptide levels are increasedin heart failure in proportion to the severity ofcardiac dysfunction.69 Positive correlationsexist between circulating ANF and BNP levelsand cardiac filling pressures, while natriureticpeptide concentrations are inversely related toindices of left ventricular function. In cardiacfailure, the normal inverse relation betweenplasma natriuretic peptide concentrations andRAAS activity is replaced with a positive cor-relation,70 presumably reflecting simultaneousstimulation of both natriuretic peptide (sec-ondary to cardiac chamber distension) andrenin release (in response to decreased renalperfusion). The latter effect probably over-comes the inhibitory action of raised circulat-ing natriuretic peptide on renin release.

In the absence of a specific antagonist tonatriuretic peptides, we cannot conclusivelydefine their place in the pathophysiology ofheart failure in man. Nevertheless, data areavailable from elegant animal experiments.Lee et a!7' examined two canine models ofreduced cardiac output. Ligation of the tho-racic inferior vena cava caused reductions incardiac output, reduced systemic arterial pres-sure, increased peripheral vascular resistance,and decreased renal blood flow and activationof the RAAS. However, in contrast to the pac-ing induced model of heart failure in the dog,ventricular filling pressures are not raised andconsequently plasma natriuretic peptides arenot increased. In the inferior vena cava ligationmodel, sodium excretion is curtailed andRAAS activity is enhanced when comparedwith the pacing model. When ANF is given inthe inferior vena cava ligation experiments toproduce matching levels of plasma ANF tothose observed in the paced model, sodiumretention is ameliorated in association withsuppression of the RAAS. In canine pacinginduced heart failure, HS142 reduced plasmaand urinary cGMP in a dose dependent fash-

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ion and inhibited natriuresis.7' Plasma reninactivity and plasma aldosterone levelsincreased rapidly to double the control values.Endogenous natriuretic peptides attenuateactivation of the RAAS and sodium retentionin evolving heart failure.

In human heart failure, ANF consistentlyinduces falls in cardiac preload and afterload,with transient increases in cardiac output andlittle change in heart rate.69 The inhibitoryeffects ofANF on the RAAS are attenuated inheart failure. However, the absence of changein plasma levels of renin, angiotensin II, andaldosterone, despite haemodynamic effects,presumably indicates some persistinginhibitory effect ofANF on the RAAS.69

In the only full report available73 on humanheart failure (New York Heart Associationclasses II-IV), BNP given at a high dose (33pmol/kg/min) reduced left ventricular fillingpressure and systemic vascular resistancewhile increasing cardiac output. In this study,BNP had no effect on heart rate or arterialpressure. Plasma aldosterone was suppressedwhile plasma renin activity was unchanged. Instriking contrast to the attenuated natriureticresponse to ANF usually observed in heartfailure, these researchers reported anenhanced natriuretic response to BNP in com-parison to that observed in normal controls.These findings require confirmation.

Endopeptidase inhibition in single andchronic dose studies has shown a beneficialeffect in human heart failure, with reduction inleft ventricular pressures and systemic arterialpressure and preservation of cardiac output inassociation with inhibition of renin activity.7476

Combined inhibition ofACE and neutralendopeptidaseACE inhibitors are an established treatment inhypertension and heart failure. ACE inhibitionhas the greatest haemodynamic effect whenbaseline activity of the RAAS is increased. Asyet, neutral endopeptidase inhibition has nodefined therapeutic application, although pre-liminary data suggest beneficial effects inhypertension and heart failure. However, effi-cacy may be curtailed by secondary activationof the RAAS. Hence combining these twomodes of enzyme inhibition may augment thebeneficial effects of either approach alone.Pham et aF77 reported that in three rat modelsof hypertension neutral endopeptidase inhibi-tion consistently enhanced natriuresis and lev-els of cGMP, ANF, and bradykinin. Bloodpressure fell only in DOC-Na rats and was notaltered in either SHR or renovascular hyper-tensive (two kidney, one clip) rats. ACE inhi-bition alone reduced blood pressure effectivelyin both SHR and renovascular animals, butnot in the DOC-Na model. The two inhibitorscombined augmented the diuresis and natri-uresis observed in DOC-Na and SHR modelsand the fall in blood pressure in the SHR.Glucoprilat and alatrioprilat (which have com-bined enzyme inhibitory activity) given in lowdose to rodents prevented hypertension sec-ondary to infused angiotensin I and enhanced

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Figure 4 Serial integrated 1 h values of systolic anddiastolic blood pressures obtained by ambulatory bloodpressure recording on (N) placebo or (0) activetreatment. In (a) the effect of 25 mg of captoprd twice perday is compared with placebo; in (b) the effects of 100 mgofsinorphan twice per day are compared with placebo; andin (c) the combined treatment and the mean of the twoplacebo phases are compared. Arrows indicate dose times.Values are expressed as means, error bars = SEM.Reproduced with permission from Favrat et al.79

the natriuretic response to volume expan-sion.78 Taken together, these animal data sug-gest that the combination of ACE and neutralendopeptidase inhibition produces comple-mentary biological effects, resulting in effec-tive antihypertensive action across a range offorms of hypertension. The only availablereport in human hypertension showed that thecombination of an neutral endopeptidaseinhibitor (sinorphan) with an ACE inhibitor(captopril) resulted in significant falls in arterialpressure (fig 4), whereas (at the dosesemployed) neither agent given alone produceda clinically important antihypertensive effect.79

In heart failure, currently published dataconcerning combined ACE and neutralendopeptidase inhibition are confined entirelyto animal experiments. Co-administration ofcaptopril and an neutral endopeptidaseinhibitor (SQ 28603) in canine pacinginduced heart failure lowered arterial pressureand systemic and renal vascular resistance,while enhancing cardiac output and renalblood flow.80 This combination therapy war-rants further trials in human hypertension andheart failure.

ConclusionAn intricate web of incompletely understoodinteractions has been found between the natri-uretic peptides and the RAAS in health anddisease. These interactions influence cardio-vascular structure and function andpressure/volume homeostasis, and may bemanipulated to cause a beneficial effect inhypertension and heart failure.

Original work from the author's group was supported by theNational Heart Foundation and the Health Research Councilof New Zealand. Expert secretarial assistance was provided byBarbara Griffin.

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1 de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H. A

rapid and potent natriuretic response to intravenous

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