Novel neurohormonal modulators in cardiovascular disorders. The therapeutic potential of endopeptidase inhibitors.

Abstract

Since angiotensin II is an established target of pharmacological interventions, there is an increasing interest in the biological effects and metabolism of other vasoactive peptides like atrial natriuretic factor (ANF) and endothelin (ET). Exogenous administration of the vasodilatory and natriuretic ANF and of its analogues improved haemodynamics and renal function in cardiovascular disease, including congestive heart failure (CHF). Effects of natriuretic peptides appeared to be attenuated during prolonged infusion and in more severe disease. Promising results were obtained in animal experiments and initial patient studies concerning haemodynamics and kidney function with inhibition of ANF metabolism by inhibitors of the neutral endopeptidase 24.11 (NEP). With further clinical studies, moderately relevant effects of acute intravenous or oral NEP inhibition were observed, but these effects were blunted with prolonged drug administration. There is increasing evidence that NEP inhibitors such as candoxatril, expected to exhibit vasodilatory activity at least at certain doses and in certain clinical settings, even induce vasoconstriction. As well as natriuretic peptides, NEP also metabolises the vasoactive peptides ET, angiotensin II and bradykinin. It now appears to be evident, especially from human experiments on forearm blood flow after intra-arterial infusion of agents, that NEP inhibitor--induced vasoconstriction is mediated by increased ET-1 rather than by angiotensin II. The hypothesis that concurrent ACE inhibition would unmask the benefits of NEP inhibitors was not supported by a recent 10-week study in CHF; with ecadotril given to ACE inhibitor-pretreated patients, there were no clear hints towards improvement of symptoms but troublesome aspects on mortality. Future clinical studies on dual inhibitors of NEP and ACE will have to reveal the place of NEP inhibition in cardiovascular disease in the presence of established therapeutic standards. Remarkable haemodynamic and cardioprotective effects have been obtained with antagonists of the ET receptor. Specific inhibitors of the endothelin converting enzyme (ECE) have only recently been introduced, inhibiting ET generation from its precursor, big ET. If the results previously obtained with ET receptor antagonists can be reproduced with ECE inhibitors, and transferred to clinical medicine, endopeptidase inhibition might open new horizons in cardiovascular treatment strategies.