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

• Published in: Circulation (New York, N.Y.) Vol. 97; no. 8; pp. 752 - 756
• Main Authors: Verhaar, Marianne C., Strachan, Fiona E., Newby, David E., Cruden, Nicholas L., Koomans, Hein A., Rabelink, Ton J., Webb, David J.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 03.03.1998
• Subjects: Adult; Biological and medical sciences; Endothelin Receptor Antagonists; Female; Forearm - blood supply; Fundamental and applied biological sciences. Psychology; Hemodynamics. Rheology; Humans; Male; Nitric Oxide - biosynthesis; Nitric Oxide Synthase - antagonists & inhibitors; Oligopeptides - pharmacology; Peptides, Cyclic - pharmacology; Piperidines - pharmacology; Prostaglandins - biosynthesis; Receptor, Endothelin A; Receptor, Endothelin B; Regional Blood Flow - drug effects; Vasodilation - drug effects; Vasodilator Agents - pharmacology; Vertebrates: cardiovascular system; Human; Endothelin; Nitric oxide; Brachial artery; Blocking; Exploration; Circulatory system; Hemodynamics; Vasodilation; Blood flow; Biological receptor
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.97.8.752

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.