Research update
Vasopeptidase inhibitors: an emerging class of cardiovascular drugs

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Abstract

Vasopeptidase inhibitors (VPIs) inhibit both angiotensin-converting enzyme (ACE) and neprilysin (NEP) and can thus reduce the activity of the renin–angiotensin system and potentiate the vasodilatory, natriuretic and antiproliferative effects of bradykinin and natriuretic peptides. In preclinical studies, VPIs display a large profile being effective in all tested models of hypertension and in heart failure, and ongoing clinical studies suggest that VPIs possess advantages over other therapies.

Section snippets

ACE, NEP and metabolism of hormonal peptides

Because ACE and NEP are involved in the regulation of the cardiovascular and renal systems, simultaneous inhibition of the two enzymes has the potential to reduce the activity of the renin–angiotensin system and to potentiate the vasodilatory, natriuretic and antiproliferative effects of bradykinin, natriuretic peptides and adrenomedullin (Fig. 2).

Demonstration of enhanced plasma atrial natriuretic peptide (ANP) immunoreactivity and natriuresis 7 following administration of a pure NEP inhibitor

Effects of VPIs in hypertension

VPIs have been tested on various rodent models of hypertension known to be susceptible to either ACE inhibitors or NEP inhibitors and to have different levels of plasma renin activity: models with normal renin [e.g. spontaneously hypertensive rats (SHR)] or high renin (e.g. two-kidney, one-clip Goldblatt model and sodium-depleted SHR) in which ACE inhibitors are effective, and a volume-dependent model with low renin (e.g. desoxycorticosterone acetate-sodium hypertensive rats) in which NEP (but

Effects of VPIs in heart failure

The therapeutic potential of VPIs could be even greater in heart failure 13 than in hypertension. Thus, acute administration of fasidotrilat to infarcted rats 14 or of omapatrilat to cardiomyopathic hamsters 15 lowered left ventricular end-diastolic pressure to a greater extent than pure ACE or NEP inhibitors. The effects of a four-week treatment with fasidotril on the morphological, hormonal and hemodynamic responses to myocardial infarction in rats were evaluated 14 in comparison with

Beneficial and possible detrimental effects resulting from simultaneous ACE and NEP inhibition

Globally, the rationale for simultaneous ACE and NEP inhibition is that the renin–angiotensin system and the natriuretic peptides and kallikrein–kinin system exert opposite actions on vascular tone, Na+ excretion and cell growth. However, other synergistic effects might arise from simultaneous inhibition of ACE and NEP. In a pilot study 19, administration of a NEP inhibitor in heart failure patients receiving ACE inhibitors was well tolerated, paving the way to the clinical use of VPIs.

Concluding remarks

VPIs represent a new and promising approach to the treatment of hypertension and heart failure, and preclinical studies indicate that they offer advantages over ACE inhibitors. In patients with mild to moderate hypertension, VPIs are characterized by a high response rate and seem to be particularly effective in decreasing SBP, which is now recognized to be a greater risk factor than is DBP. Organ-protective properties, related to local cGMP and nitric oxide production and possibly independent

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      Combined with the data obtained in vivo in rodents using potent and selective NEP inhibitors, such as phosphoramidon and thiorphan (Roques et al., 1980), key roles were established for NEP in the central nervous system. Subsequently, renal NEP was shown to be the principal enzyme inactivating the vasodilator, atrial natriuretic peptide (Kenny and Stephenson, 1988), which has led to much investment in the development of NEP inhibitors, either alone or in combination with ACE inhibitors (vasopeptidase inhibitors), as drugs in the treatment of hypertension, congestive heart failure, and renal disease (Bralet and Schwartz, 2001), although concerns over their safety have been raised (Quaschning, 2005). NEP also plays important roles in other peripheral tissues such as in chemoreception and in potentiation of the response of the carotid body to hypoxia via degradation of its preferred substrate, SP (Kumar et al., 1990, 2000).

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