POTENT VASOCONSTRICTION MEDIATED BY ENDOTHELIN ET(B) RECEPTORS IN CANINE CORONARY-ARTERIES

Endothelin (ET) 1 is a powerful vasoconstrictor of coronary arteries and may play a role in coronary spasm, atherosclerosis, and myocardial infarction. Previous studies have demonstrated that intracoronary ET caused marked vasoconstriction of the coronary circulation; however, it remains unclear which ET receptor types are present and which of these receptors mediate this vasoconstriction. To characterize the ET receptors present in dog coronary arteries, competition binding assays with radiolabeled ET-1 using ET-1, ET-3, ET(A) receptor antagonist BQ-123, and sarafotoxin S6c were performed. Three binding sites were apparent in the left circumflex coronary artery: an ET(A) receptor, a high-affinity ET(B) receptor, and a lower-affinity ET(B) receptor. To investigate the in vivo effects of ET(B) receptor stimulation, intracoronary sarafotoxin S6c, a highly selective ET(B) agonist, was administered in anesthetized open-chest dogs in a constant-pressure coronary artery perfusion model. Sarafotoxin S6c doses of 0.1 and 0.3 mu g caused a transient pronounced decrease in coronary resistance. Doses of 1.0 and 3.0 mu g caused marked decreases in coronary diameter and blood flow, as well as myocardial segmental shortening. These effects of sarafotoxin S6c were not inhibited by constant infusion of BQ-123. The present study demonstrates the presence of ET(B) receptors in the canine coronary circulation that can mediate both vasodilation and vasoconstriction. These findings have important implications for an understanding of the pathophysiological function of ET in the coronary vasculature and for the development of therapeutically effective ET antagonists.