Journal of Human Hypertension (2000) 14, 537–539  2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh COMMENTARY Vasopeptidase inhibition: cardiovascular therapy for the new millennium?

M Walters and J Reid Department of Medicine and Therapeutics, University of Glasgow, Glasgow, Scotland, UK

Keywords: vasopeptidase inhibition; cardiovascular therapy

In most developed societies hypertension is a lead- marked structural similarities between the active ing risk factor for the development of cardiovascular sites of ACE and those of NEP; in addition both disease, renal disease and stroke.1 Despite combined enzymes tend to co-localise on the cell surface. In efforts of clinicians and researchers, high blood experimental models, inhibition of NEP alone leads pressure and its consequences continue to represent to potentiation of natriuretic peptides, causing vaso- a significant burden of disease. A substantial pro- dilatation and natriuresis but only a temporary portion of hypertensive patients fail to achieve rec- reduction in arterial pressure. Long-term inhibition ommended levels of pressure and there remains a of NEP in experimental models does not cause sus- need for well-tolerated new therapies which will tained blood pressure reduction, probably due to improve blood pressure control, facilitate manage- compensatory activation of the RAAS, leading to ment and improve outcome.2 salt retention and a reflex increase in blood press- Advances in our knowledge of the pathophysiol- ure.3 In hypertensive humans, NEP inhibition leads ogy of hypertension have led to interest in a number to natiuretic peptide-mediated increases in urinary of neurohumoral systems as potential therapeutic excretion of sodium, water, atrial natiuretic peptide targets in the treatment of hypertension.3 The natriu- (ANP) and cyclic guanosine monophosphate retic peptide system (NPS), the -- (cGMP). In hypertensive patients NEP inhibition aldosterone system (RAAS) and the kallikrein-kinin does not usually lead to a significant fall in arterial (KK) system are all involved in the regulation of pressure, again probably due to compensatory both blood pressure and sodium balance. Pharmaco- increase in RAAS activity.3 logical interference with the RAAS using inhibitors The structural similarity of ACE and NEP has of angiotensin II (AII) receptors or inhibitors of angi- enabled development of vasopeptidase inhibitors, a otensin-converting enzyme (ACE) are established new class of drugs in which a single chemical entity therapies both in hypertension and cardiac failure. inhibits both enzymes.5 Simultaneous inhibition of The most significant mechanistic difference between ACE and NEP may augment the beneficial effects of ACE inhibitors and AII antagonists is that the former isolated ACE inhibition and potentiate the vasodilat- are potentiators of whereas the latter are atory and natriuretic effects of NEP inhibition, lead- not. Endogenous bradykinin potentiation through ing to a shift in the balance of humoral factors in interference with the KK system may be responsible favour of vasodilatation (Figure 1). By inhibiting for the pharmacodynamic differences seen between these agents in clinical practice, and may confer additional benefit in certain populations.4 The dif- fering effects of AII antagonists (which affect the RAAS selectively) and ACE inhibitors (which affect both the RAAS and the KK systems), together with advances in our knowledge of the complex interplay between these neurohumoral systems have provided a rationale for the investigation of more extensive pharmacological modulation. Neutral endopeptidases (NEP) are enzymes which degrade endogenous natriuretic peptides. There are

Correspondence: Dr Matthew Walters MD, Department of Medi- cine and Therapeutics, University of Glasgow, Glasgow, Scot- land, UK Received 22 May 2000; accepted 26 May 2000 Figure 1 Neurohumoral effect of vasopeptidase inhibition. Vasopeptidase inhibition M Walters and J Reid 538 both enzymes, vasopeptidase inhibitors will modu- neurohumoral systems mediated by drugs such as late many vasoregulatory neurohumoral cascades, omapatrilat offer the opportunity to more effectively potentiating natiuretic peptides, bradykinin and lowers blood pressure in mild to moderate hyperten- other vasodilatory peptides (such as sion. Omapatrilat however an ACE inhibitor and adrenomedullin) while diminishing the vasocon- side effects of cough and will occur strictor effect of angiotensin II. Such agents may be more frequently than with non-ACEI based regi- useful in the management of both hypertension and mens. Further clinical experience will indicate other conditions characterised by disturbances of whether these side effects will occur with more or neurohumoral function such as cardiac failure. The less or similar frequency compared to other ACE most useful agent will provide clinically significant inhibitors. The crucial issue is whether vasopeptid- blockade of both ACE and NEP within the thera- ase inhibitors, with their extended effects on vasoac- peutic dose range. tive neurohumoral modulation, offer real clinical Several such agents are currently in clinical devel- benefit over existing ACE inhibitors and angiotensin opment. The most advanced is the heterocyclic II receptor antagonists. The potential superiority of dipeptide mimetic omapatrilat, a vasopeptidase vasopeptidase inhibitors is based upon their potenti- inhibitor which inhibits both ACE and NEP in a ation of vasodilatory natriuretic peptides and competitive fashion, having similar potency against enhanced clinical efficacy, however it remains to be each enzyme. Preclinical studies of omapatrilat have seen whether this mechanistic difference will lead revealed a sustained antihypertensive effect in both to clinically relevant improvement in outcome. high and low renin models of hypertension.6 It has Long-term prospective clinical trials designed to been postulated that omapatrilat-mediated NEP compare vasopeptidase inhibitors with established inhibition is predominantly responsible for the therapies will be required before the role of vaso- observed fall in blood pressure in the low-renin peptidase inhibition in the management of cardio- models, and ACE inhibition contributes relatively vascular disease can be fully defined. more to the drug’s antihypertensive effect in high- renin models. As may be predicted from the drug’s References mechanism of action, other potentially beneficial cardiovascular effects such as reduction in both per- 1 Joint National Committee on prevention, detection, ipheral vascular resistance and left ventricular end- evaluation and treatment of high blood pressure. The diastolic pressure were observed in animal studies.7 sixth report of the Joint National Committee on pre- vention, detection, evaluation and treatment of high Studies comparing omapatrilat with in blood pressure. Arch Int Med 1997; 157: 2413–2446. animal models of have suggested that 2 Berlowitz DR et al. Inadequate management of high the combination of ACE and NEP inhibition confers blood pressure in a hypertensive population. N Engl J significant benefit in survival and left ventricular Med 1998; 339: 1957–1963. remodelling over ACE inhibition alone.8 3 Robl JA, Trippodo NC, Petrillo EW. Neutral endopepti- Early clinical studies of omapatrilat9,10 have con- dase inhibitors and combined inhibitors of neutral firmed potent and sustained inhibition of NEP and endopeptidase and angiotensin converting enzyme. In: ACE activity. In normotensive volunteers increased van Zwieten PA, Greenlee WJ (eds). Antihypertensive urinary ANP and cGMP excretion were reported. Drugs. Harwood Academic Publishers: Australia, 1997, There was a dose-dependent reduction in both sys- pp 113–211. 4 Gavras I. Bradykinin-mediated effects of ACE inhi- tolic and diastolic blood pressure, the duration of bition. Kidney Int 1992; 42: 1020–1029. the antihypertensive effect exceeding 24 h. Omapa- 5 Robl JA et al. Dual metalloproteinase inhibitors. Mer- trilat was reported to be safe and well-tolerated in captoacetyl-based fused heterocyclic dipeptide minet- these studies, and trials of the compound in hyper- ics as inhibitors of angiotensin converting enzyme and tensive patients are underway. The possibility of a neutral endopeptidase. J Med Chem 1997; 40: 1570– favourable therapeutic profile in the treatment of 1577. mild to moderate hypertension compared to amlodi- 6 French JF, Anderson BA, Downs TR, Dage RC. Dual pine and has been suggested by three inhibition of angiotensin converting enzyme and neu- dose-ranging comparative studies involving 1800 tral endopeptidase in rats with hypertension. J Car- patients.11 Omapatrilat (80 mg) in those studies diovasc Pharmacol 1995; 26: 107–113. 7 Trippodo NC et al. Cardiovascular effects of the novel caused significantly greater falls in systolic and dias- dual inhibitor of neutral endopeptidase and angioten- tolic blood pressure compared to amlodipine 10 mg sin converting enzyme BMS-182657 in experimental or lisinopril 40 mg. Further comparative work in hypertension and heart failure. J Pharmacol Exp Ther hypertensive subjects is needed, particularly studies 1995; 275: 745–752. designed to compare monotherapy with vasopep- 8 Thomas C et al. Dual metalloproteinase inhibition dur- tidase inhibitors with rational combinations of ing the development of left ventricular failure: effects established antihypertensive therapy such as ACE on LV and myocyte function and geometry. Circulation inhibitor plus low dose diuretic, as well as combi- 1997; 98: I–524. nations of vasopeptidase inhibitors with other 9 Liao W et al. Supine mean arterial blood pressure low- classes of drugs. ering and oral tolerance of BMS-186716, a new dual metalloproteinase inhibitor of angiotensin converting Inhibition of both ACE and NEP represents a new enzyme and neutral endopeptidase in healthy male and exciting concept in cardiovascular therapy, with subjects. Clin Pharmacol Ther 1997; 61: 229. the potential to be widely applied in the manage- 10 Vesterqvist O et al. Effects of BMS-1867, a new dual ment of both hypertension and cardiac failure. The metalloproteinase inhibitor on pharmacodynamic synergistic regulation of a number of vasoactive markers of angiotensin converting enzyme and neutral

Journal of Human Hypertension Vasopeptidase inhibition M Walters and J Reid 539 endopeptidase activity in healthy men. Clin Pharm omapatrilat compared with lisinopril and amlodipine Ther 1997; 61: 230. in mild to moderate hypertension. Am J Hypertens 11 Black HR et al. Monotherapy treatment success rate of 1999; 12: 26A.

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