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

Endothelin (ET) 1 is a powerful vasoconstrictor of coronary arteries a nd may play a role in coronary spasm, atherosclerosis, and myocardial infarction. Previous studies have demonstrated that intracoronary ET c aused marked vasoconstriction of the coronary circulation; however, it remains unclear which ET receptor types are present and which of thes e receptors mediate this vasoconstriction. To characterize the ET rece ptors present in dog coronary arteries, competition binding assays wit h radiolabeled ET-1 using ET-1, ET-3, ET(A) receptor antagonist BQ-123 , and sarafotoxin S6c were performed. Three binding sites were apparen t in the left circumflex coronary artery: an ET(A) receptor, a high-af finity ET(B) receptor, and a lower-affinity ET(B) receptor. To investi gate 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 p erfusion model. Sarafotoxin S6c doses of 0.1 and 0.3 mu g caused a tra nsient 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 st udy demonstrates the presence of ET(B) receptors in the canine coronar y circulation that can mediate both vasodilation and vasoconstriction. These findings have important implications for an understanding of th e pathophysiological function of ET in the coronary vasculature and fo r the development of therapeutically effective ET antagonists.