vasopeptidase inhibition: effective blood pressure control for vascular protection

Vasopeptidase Inhibition: Effective Blood Pressure Control

for Vascular ProtectionThomas Quaschning, MD*, Frank Ruschitzka, MD, and Thomas F. Lüscher, MD

Address*Department of Medicine, Division of Nephrology, University Hospital of Würzburg, Josef Schneider Strasse 2, D-97080 Würzburg, Germany. E-mail: [email protected] Hypertension Reports 2002, 4:78–84Current Science Inc. ISSN 1522-6417Copyright © 2002 by Current Science Inc.

IntroductionThe importance of the renin-angiotensin-aldosterone sys-tem (RAS) in the pathophysiology of various forms ofhypertension is illustrated by numerous clinical trials thatdemonstrate a reduction of clinical endpoints using agentsto interrupt this system. The RAS plays a crucial role in car-

diovascular regulation both as a circulating and paracrinelocal vascular system. The endothelium is a source ofpotent paracrine mediators such as nitric oxide (NO),angiotensin II, and endothelin-1 (ET-1) (Fig. 1). The differ-ent circulating and local systems show important syner-gisms and interactions. They may either have synergisticeffects or may be the functional counterpart of another sys-tem in a subtle multivariate balance. As such, atrial natri-uretic peptides (ANP) counteract the effects of angiotensinII (Fig. 2). Since effects of endothelium-derived substancesare not limited to vasoconstriction or vasodilatation butalso may include regulation of mitogenesis (Fig. 2), endo-thelial dysfunction does not only affect the function of thecardiovascular system, but also its structure. In fact, someendothelial substances stimulate the production of cyto-kines and growth factors leading to vascular smooth mus-cle cell proliferation. All these regulatory systems areresponsible for circulatory homeostasis and for the integ-rity of vascular function and structure.

Angiotensin Converting Enzyme Inhibition and Neutral Endopeptidase Inhibition: the Components of Vasopeptidase InhibitionThe beneficial effect of angiotensin converting enzyme(ACE) inhibition has been documented in many large ran-domized trials for the treatment of hypertension [1,2],after myocardial infarction [3–6], and in heart failure [7].The Heart Outcomes Prevention Evaluation (HOPE) studyconfirmed that ACE inhibitors are vascular protective inde-pendent of their effects on blood pressure and remodeling[8]. The mechanisms involved may be related to theirinhibitory effects on angiotensin formation and/or on acti-vation of bradykinin-related effects [9]. ACE inhibitors notonly prevent the formation of a potent vasoconstrictorwith proliferative properties, but also increase the localconcentration of bradykinin and, in turn, the productionof NO [10] and prostacyclin [11], which may contribute tothe vascular protective effects of the ACE inhibitors byimproving local blood flow and preventing platelet activa-tion. In the principle of vasopeptidase inhibition, benefi-cial effects of ACE inhibition are combined with theadditional inhibition of the neutral endopeptidase (NEP).

Angiotensin converting enzyme (ACE) inhibition is a well-established principle in the treatment of hypertension, and numerous large scale clinical studies have clearly demon-strated the beneficial effects of inhibiting the renin-angio-tensin-aldosterone system (RAS) in hypertension. The clinical success of ACE inhibitors encouraged attempts to inhibit other key enzymes in the regulation of vascular tone, such as the neutral endopeptidase (NEP). Similar to ACE, NEP is an endothelial cell surface metalloproteinase, which is involved in the degradation of several regulatory peptides including the natriuretic peptides, and augments vasodilatation and natriuresis through increased levels of atrial natriuretic peptide. By inhibiting the RAS and potenti-ating the natriuretic peptide system at the same time, com-bined NEP/ACE inhibitors, the so-called “vasopeptidase inhibitors,” reduce vasoconstriction and enhance vasodila-tation, and in turn decrease peripheral vascular resistance and blood pressure. Within the vessel wall this may lead to a reduction of vasoconstrictor and proliferative mediators such as angiotensin II and endothelin-1, and may increase local levels of bradykinin as well as natriuretic peptides. Based on these considerations, numerous preclinicial stud-ies with vasopeptidase inhibitors have been performed and reveal promising results in experimental hypertension. Cor-respondingly, large-scale clinical studies in patients with hypertension are on the way, to transfer the principle of vasopeptidase inhibition from bench to bedside.

Vasopeptidase Inhibition: Effective Blood Pressure Control for Vascular Protection • Quaschning et al. 79

Selective NEP inhibition prevents the degradation ofvasoactive peptides such as ANP, brain natriuretic peptide,C-type natriuretic peptide, substance P, and bradykinin[12], and increases their biologic activity. In addition todegrading vasoactive peptides to inactive breakdown prod-ucts, NEP is also involved in the enzymatic conversion ofbig ET-1 to its active form, the vasoconstrictor peptide ET-1. Hence, the balance of effects of NEP inhibition on vascu-lar tone will depend on whether the predominantsubstrates degraded by NEP are vasodilators or vasocon-strictors, and on the extent of NEP involvement in the pro-cessing of big ET-1 [13]. Interestingly, the treatment ofhypertensive patients with the selective NEP inhibitor can-

doxatril led only to a minimal reduction of the blood pres-sure, whereas its combination with an ACE inhibitorcaused a marked reduction [14].

This implicates that simultaneous inhibition of ACEand NEP may exceed the effects of inhibiting either sys-tem alone. Therefore, compounds with the capability ofinhibiting ACE and NEP at the same time may offer thepossibility of inhibiting the RAS and potentiating thenatriuretic peptide system by the use of one single mole-cule, and thus simultaneously reducing vasoconstrictionand enhancing vasodilatation. Therefore, a number ofsubstances with affinities for both ACE and NEP areunder current development.

Figure 1. Influence of angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) on production and degradation of vasoactive peptides. ANP—atrial natriuretic peptide; Arg—arginine; CNP—C-type natriuretic peptide; EC—endothelial cell; ECE—endothelin convert-ing enzyme; ET-1—endothelin-1; GC—guanylate cyclase; PLC—phospholipase C; NOS—nitric oxide synthase; VSMC—vascular smooth muscle cell.

Figure 2. Balance of vasoactive substances. The regulation of enzymatic production and degradation of vasoactive peptides maintains the fragile balance between vasoconstriction and vasodilatation. ANP—atrial natriuretic peptide; BNP—brain natriuretic peptide; CNP—C-type natriuretic peptide.

80 Vascular Mechanisms

Vasopeptidase Inhibitors in Experimental HypertensionThe synergistic effect of combined NEP and ACE inhibi-tion is based on the simultaneous blockade of angio-tensin II synthesis and the degradation of severalvasoactive peptides (Fig. 1), including bradykinin andnatriuretic peptides, which contribute to vasodilatation,diuresis, and improvement of myocardial function.Thus, the development of combined vasopeptidaseinhibitors represents an attractive therapeutic strategyfor the treatment of cardiovascular disease, such ashypertension [15–18].

Vasopeptidase inhibition has been shown to lowerblood pressure under various experimental conditionsincluding renovascular hypertension [19], spontaneoushypertension [20,21•], deoxycorticosterone acetate-induced hypertension [21•], as well as salt-sensitive hyper-tension [22•]. Therefore, its beneficial effects seem to beindependent of the activity of the RAS or the degree of saltretention [15,23]. In spontaneously hypertensive rats,vasopeptidase inhibition significantly lowered blood pres-sure even when combined with experimental diabetes [20].Correspondingly, significant reduction of blood pressurein low-, normal-, and high-renin models of hypertensionwas seen with treatment with omapatrilat, the vasopepti-dase inhibitor with most preclinical and clinical data avail-able at present [21•]. Since antihypertensive effects ofcombined ACE/NEP inhibition exceeded those of ACEinhibition alone [24–27], vasopeptidase inhibition may

advance as a promising novel option for the treatment ofvarious forms of hypertension .

In salt-sensitive Dahl rats, omapatrilat compared withequipotent doses of the ACE inhibitor captopril restoredthe impaired NO system by increasing protein levels ofendothelial NO synthase and vascular nitrate levels (Fig.3), and normalized endothelium-dependent relaxations[22•]. Since endothelial dysfunction is not only the resultbut also a promoter of cardiovascular disease, vasopepti-dase inhibition may be beneficial in interrupting thevicious cycle of altered endothelial function. Correspond-ingly, in spontaneously hypertensive rats, omapatrilat notonly lowered blood pressure, but also improved systemichemodynamic parameters [28].

Even though certain NEP inhibitors are capable ofinhibiting the endothelin converting enzyme (ECE) [29],the vasopeptidase inhibitor omapatrilat reduced vascularECE levels in a model of salt-sensitive hypertension [30](Fig, 4), leading to normalization of ECE activity in thismodel. This suggests that the beneficial effects ofvasopeptidase inhibition—exceeding the improvement ofisolated parameters—may reflect a resetting of cardiovas-cular control systems.

Vasopeptidase inhibition not only improves the func-tion, but also the structure of the cardiovascular system. Insalt-sensitive hypertension, omapatrilat improved vascularremodeling of resistance arteries [31,32] and was capableof preventing vascular hypertrophy [33] (Fig. 5). Vasopep-tidase inhibition, therefore, may be beneficial in the treat-ment of hypertension and other vascular diseasesassociated with structural alteration of the vessel wall, suchas heart failure.

Vasopeptidase Inhibitors in the Treatment of HypertensionVasopeptidase inhibitors have been shown to be well toler-ated and effective in clinical trials in hypertensive patientsunder several conditions. The vasopeptidase inhibitor sam-patrilat demonstrated efficacy in the treatment of essentialhypertension [34]. Omapatrilat significantly loweredblood pressure and increased urinary ANP secretion in twostudies in elderly patients [35,36].

In 57 patients with salt-sensitive hypertension, 40 mg/domapatrilat revealed a greater reduction in systolic, diastolic,and mean arterial pressure compared with 20 mg/d lisinopril[37]. Omapatrilat exhibited long-lasting antihypertensiveeffects in 83 patients even 2 weeks after withdrawal of long-term (2 months) treatment [38], and was even more effectivewhen combined with diuretics [39].

It appears as if blood pressure lowering by vasopeptidaseinhibitors is even more pronounced in systolic rather than indiastolic blood pressure. This was demonstrated in 429patients with isolated systolic hypertension in a 9-week pla-cebo-controlled trial [40], and was confirmed in a 10-weekdouble-blind trial of omapatrilat (20–80 mg/d) versus lisi-

Figure 3. Aortic nitrite and nitrate levels in salt-sensitive Dahl rats after 8 weeks of treatment with different regimens. Results are shown as mean ± SEM. *P < 0.05 versus control rats and versus treatment groups. Salt feeding reduced levels of nitrite and nitrate, the stable endproducts of the nitric oxide metabolism, in rat aorta. Nitrite and nitrate levels were normalized by treatment with either omapatrilat (O, 36 ± 4 mg/kg/d) or captopril (C, 94 ± 2 mg/kg/d). (Adapted from Quaschning et al. [22•].)


nopril (10–40 mg/d) [35], as well as in a double-blind trialin 430 patients receiving either omapatrilat (20–80 mg/d) oramlodipine (5–10 mg/d) [41]. Furthermore, in a study of 690patients with mild to moderate hypertension, omapatrilat(5–40 mg/d) lowered systolic blood pressure to a signifi-cantly greater extent than lisinopril (20–40 mg/d) [42]. Inpatients with renal impairment, there was no need for dosereduction of omapatrilat [43,44], independent of the degreeof impaired renal function [45].

Compared with studies of other antihypertensive drugssuch as ACE inhibitors, the number of patients treated withvasopeptidase inhibitors at present is rather small.

Therefore, a large-scale clinical trial with 12,600patients—Omapatrilat in Persons with Enhanced Risk ofAtherosclerosis (OPERA)—has been initiated to evaluatethe impact of vasopeptidase inhibition in isolated systolichypertension [46]. Patients older than 65 years of age withsystolic blood pressure between 140 and 160 mm Hg willbe randomized in 900 centers to receive either 40 mg/domapatrilat or placebo, and cardiovascular morbidity andmortality will be followed up for 3 to 5 years. Another clin-ical trial with 25,000 hypertensive patients—OmapatrilatCardiovascular Treatment Assessment versus Enalapril(OCTAVE)—to assess the efficacy and safety of low doses(10 mg/d) of omapatrilat versus 5 mg/d of enalapril hasrecently been completed.

Vasopeptidase Inhibitors and the KidneySince inhibition of ANP degradation seems to be one ofthe most important features of vasopeptidase inhibitors

[47,48], and elevation of plasma ANP levels by vasopepti-dase inhibition has been demonstrated in several preclini-cal [22•,49] and clinical [50] studies, there is a strong linkto renal involvement in the regulatory processes inducedby vasopeptidase inhibition.

Since renal protection, such as in diabetic nephropa-thy, is one of the favorable effects of ACE inhibitors [51],the influence of vasopeptidase inhibitors on renal func-tion is of major interest. In experimental diabetes,vasopeptidase inhibition reduced albuminuria and leadto improvement of renal function [20]. In obese Zuckerrats with unilateral nephrectomy, vasopeptidase inhibi-tion revealed greater renal protection in terms of reducedproteinuria compared with ACE inhibition [52]. Thesefavorable renal effects could be confirmed in Wistar ratsafter subtotal nephrectomy [53,54]. In 89 patients withimpaired renal function (creatinine clearance < 60 mL/min), 12 weeks treatment with omapatrilat reduced pro-teinuria about 20% and increased serum creatinineabout 15% [44], thus indicating improvement of renalfunction by vasopeptidase inhibition.

Since renal impairment is a frequent condition amongpatients with advanced cardiovascular disease, safety ofpharmacotherapy in these patients is an important issue.The plasma concentrations of omapatrilat administered to29 patients with moderate to severe renal impairment, andeven on hemodialysis treatment, did not differ from con-trols with normal renal function [45]. Therefore, no doseadjustment of omapatrilat will be required in patients withrenal impairment, independent of its severity. In addition,even in patients with impaired renal function, omapatrilat

Figure 4. Functional endothelin converting enzyme (ECE) activity (given as contraction to big endothelin-1 [big ET-1] 10-7 mol/L divided by contraction to ET-1 10-7-mol/L) in renal artery segments of salt-sen-sitive Dahl rats. Eight-week of treatment with omapatrilat (O), but not with captopril (C) restored functional ECE activity. *P < 0.05 versus controls. (Adapted from Quaschning et al. [30].)

Figure 5. Standardized aortic weight in salt-sensitive Dahl rats after 8 weeks of treatment with omapatrilat (O) or captopril (C), respectively. In contrast to angiotensin converting enzyme inhibition by captopril, the vasopeptidase inhibitor omapatrilat prevented vascular hypertro-phy completely. *P < 0.05 versus rats on salt diet. †P < 0.05 versus rats on omapatrilat treatment. (Adapted from Quaschning et al. [33].)


increased urinary ANP excretion [43,55], indicating thepresence of its beneficial properties irrespective of thedegree of renal impairment.

Safety of Vasopeptidase InhibitorsVasopeptidase inhibitors are characterized by safe adminis-tration over a broad range of dosages [40], even in case ofrenal impairment [44], but the number of patients treatedand documented at present is rather low. In clinical stud-ies, side effects were comparable with those of ACE inhibi-tors: cough and flush in 573 patients in the Inhibition ofMetalloproteinase in a Randomized Exercise and Symp-toms Study in Heart Failure (IMPRESS) trial were reportedto occur equally as often as in ACE inhibitor-treatedpatients [56••]. Nevertheless, in data submitted for thenew drug application of omapatrilat at the US Food andDrug Administration, 44 instances of angioedema werereported among more than 6600 patients [57•]. Therefore,incidence of angioedema was about twice as high (0.7%)in omapatrilat-treated patients as in patients treated withramipril reported in the HOPE study [8]. Since patients inthe IMPRESS trial were pretreated with ACE inhibitors, ele-vated incidence of angioedema after the onset of vasopep-tidase inhibition requires even more careful evaluation inlarge scale, randomized, double-blind clinical trials. TheOCTAVE study was especially designed to evaluate the riskof adverse effects on omapatrilat treatment in low doses.Preliminary data from the OCTAVE study indicate that inthe treatment of hypertension, omapatrilat indeed is safe,and documented adverse effects do not exceed those ofother commonly used antihypertensive compounds. Nev-ertheless, until extensive data about adverse effects onlong-term treatment are available, safety of vasopeptidaseinhibitors remains a matter of debate.

ConclusionsIn all preclinical and clinical trials completed so far,vasopeptidase inhibition has proven highly effective in var-ious forms of hypertension. To replace or extend tradi-tional treatment concepts, novel cardiovascular drugs willhave to come up with an excellent profile of beneficialeffects and/or minimized side effects. Vasopeptidase inhi-bition has been demonstrated to be beneficial in diabetes[20], endothelial dysfunction [22•], and renal failure [44],which are common conditions among cardiovascularpatients. The encouraging experimental and limited clini-cal results obtained with this broad-spectrum and potentcardiovascular active agent warrant further clinical investi-gation. Since clinical trials on vasopeptidase inhibition inhypertension have been performed with rather small num-bers of patients, evidence concerning efficacy and safetywill have to be extended by large-scale clinical studies(OPERA, OCTAVE). Their future results will help to better

assess the place of vasopeptidase inhibition in the treat-ment of cardiovascular disease.

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angio-oedema. Lancet 2000, 356:608–609.This editiorial comment discusses the adverse effects of vasopeptidase inhibitors.

vasopeptidase inhibition: effective blood pressure control for vascular protection

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