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(Hypertension. 2007;49:1134.)
© 2007 American Heart Association, Inc.

Original Articles

Endogenous Endothelin in Human Coronary Vascular Function

Differential Contribution of Endothelin Receptor Types A and B

Julian P.J. Halcox; Khaled R.A. Nour; Gloria Zalos; Arshed A. Quyyumi

From the Institute of Child Health (J.P.J.H.), University College London, London, United Kingdom; the Division of Cardiovascular Medicine (K.R.A.N.), Henry Ford Hospital, Detroit, Mich; Cardiology Branch (G.Z.), National Heart Lung and Blood Institute, Bethesda, Md; and the Division of Cardiology (A.A.Q.), Emory University School of Medicine, Atlanta, Ga.

Correspondence to Julian P. J. Halcox, Vascular Physiology Unit, Institute of Child Health, 30 Guildford St, London WC1N 1EH, United Kingdom. E-mail j.halcox{at}ich.ucl.ac.uk

Endothelin 1 mediates coronary vasoconstriction and endothelial dysfunction via endothelin receptor type A (ET_A) activation. However, the effects of selective endothelin receptor type B (ET_B) and combined ET_A+B receptor blockade on coronary vasomotion are unknown. We measured coronary vascular tone and endothelium-dependent and -independent vasomotor function before and after selective infusion of BQ-788 (an ET_B receptor antagonist) or combined infusion of BQ-788+BQ-123 (an ET_A antagonist) into unobstructed coronary arteries of 39 patients with coronary atherosclerosis or risk factors undergoing cardiac catheterization. BQ-788 did not affect epicardial diameter but constricted the microcirculation (P<0.0001), increased coronary sinus endothelin, and reduced nitrogen oxide levels. In contrast, BQ-123+BQ-788 dilated epicardial (P<0.0001) and resistance (P=0.022) arteries. Responses to acetylcholine and sodium nitroprusside were unaffected by BQ-788 alone. Epicardial endothelial dysfunction improved after BQ-123+BQ-788 (P=0.007). Coronary microvascular responses to acetylcholine and sodium nitroprusside were unaffected by BQ-123+BQ-788. We conclude that selective ET_B receptor antagonism causes coronary microvascular constriction, without affecting epicardial tone or endothelial function, via reduced endothelin clearance and NO availability. Combined ET_A+B blockade dilates coronary conduit and resistance vessels and improves endothelial dysfunction of the epicardial coronary arteries. Thus, endogenous endothelin, predominantly via ET_A receptor stimulation, contributes to basal constrictor tone and endothelial dysfunction, whereas ET_B activation mediates vasodilation in human coronaries. Our data suggest that selective ET_A blockade may have greater therapeutic potential than nonselective agents, particularly for treatment of endothelial dysfunction in atherosclerosis.

Key Words: clinical science • blood flow regulation • endothelin • endothelium • atherosclerosis