Vasodilator effects of endothelin-converting enzyme inhibition and endothelin ETA receptor blockade in chronic heart failure patients treated with ACE inhibitors
Love, M.P.; Haynes, W.G.; Gray, G.A.; Webb, D.J.; McMurray, J.J.
Circulation 94(9): 2131-2137
Background: The importance of endothelin-1 in chronic heart failure (CHF) is unclear. We therefore investigated the effects of endothelin-converting enzyme (ECE) inhibition and endothelin ET-A receptor blockade in CHF patients treated with ACE inhibitors. We also compared the function of ET-A and ET-B receptors in healthy subjects and patients with CHF. Methods and Results: Locally active doses of study drugs were infused into the nondominant brachial artery while forearm blood flow (FBF) was measured by venous occlusion plethysmography. In CHF patients (n=10), phosphoramidon (a combined ECE and neutral endopeptidase inhibitor) and BQ-123 (an ET-A receptor antagonist) increased FBF by 52-10% (P=.0006) and 31-6% (P=.002), respectively, and thiorphan (a selective neutral endopeptidase inhibitor) reduced FBF by 15+-5% (P=.0007). Forearm vasoconstriction to endothelin-1 (an ET-A and ET-B receptor agonist) was significantly blunted in CHF patients compared with control subjects (both n=10; CHF versus control subjects, P lt .001), whereas vasoconstriction to sarafotoxin S6c (an ET-B receptor agonist) was significantly enhanced in CHF patients compared with control subjects (both n=10; CHF versus control subjects, P lt .05). Conclusions: ECE inhibitors and ET-A receptor antagonists may be useful as vasodilator agents in CHF patients already receiving treatment with an ACE inhibitor. Both ET-A and ET-B receptors can mediate agonist-induced vasoconstriction in healthy subjects and patients with CHF, but further studies are required to clarify the contribution of each receptor subtype in mediating the effects of endogenous endothelin-1.