Endothelin-A Receptor Antagonist–Mediated Vasodilatation Is Attenuated by Inhibition of Nitric Oxide Synthesis and by Endothelin-B Receptor Blockade

Abstract

Background —The role of endothelin (ET)-1 in maintenance of basal vascular tone has been demonstrated by local and systemic vasodilatation to endothelin receptor antagonists in humans. Although the constrictor effects mediated by the vascular smooth muscle ET A receptors are clear, the contribution from endothelial and vascular smooth muscle ET B receptors remains to be defined. The present study, in human forearm resistance vessels in vivo, was designed to further investigate the physiological function of ET A and ET B receptor subtypes in human blood vessels and determine the mechanism underlying the vasodilatation to the ET A -selective receptor antagonist BQ-123. Methods and Results —Two studies were performed, each in groups of eight healthy subjects. Brachial artery infusion of BQ-123 caused significant forearm vasodilatation in both studies. This vasodilatation was reduced by 95% ( P =.006) with inhibition of the endogenous generation of nitric oxide and by 38% ( P <.001) with coinfusion of the ET B receptor antagonist BQ-788. In contrast, inhibition of prostanoid generation did not affect the response to BQ-123. Infusion of BQ-788 alone produced a 20% reduction in forearm blood flow ( P <.001). Conclusions —Selective ET A receptor antagonism causes vasodilatation of human forearm resistance vessels in vivo. This response appears to result in major part from an increase in nitric oxide generation. ET B receptor antagonism either alone or on a background of ET A antagonism causes local vasoconstriction, indicating that ET B receptors in blood vessels respond to ET-1 predominantly by causing vasodilatation.