EFFECTS OF BQ-485, A SELECTIVE ET(A) ANTAGONIST, ON ENDOTHELIN-MEDIATED VASOMOTION IN RAT CORONARY VASCULAR BEDS

The effects of BQ-485, a selective endothelin (ET)-A receptor antagoni st, on the vasomotion induced by a low dose of ET were investigated. I n the isolated rat heart perfused with Krebs-Henseleit solution at a c onstant flow, intracoronary bolus injection of ET-1 or ET-3 (10 pmol) elicited a rapid transient decrease, followed by a slight sustained in crease, in the coronary perfusion pressure (CPP). The decrease in CPP induced by ET-I was similar in magnitude to (similar to 30%) but short er in duration than that induced by ET-3. Pretreatment of the heart wi th saponin (30 mu g/ml) to denude the coronary endothelium abolished t he decrease and markedly enhanced the increase in CPP induced by ETs, indicating that the vasorelaxing action of ETs is endothelium-dependen t. The selective ET(A) receptor antagonist BQ-485 (1 mu M) significant ly prolonged the duration of the ET-1-induced decrease in CPP, made th e vasodilatation by ET-1 indistinguishable from that by ET-3, and elim inated the subsequent increase in CPP. In the saponin-treated heart, B Q-485 also eliminated the ET-1-mediated increase in CPP. These finding s suggest that, in rat coronary vascular beds, a low dose of ET-1 elic its vasoconstriction and endothelium-dependent vasodilatation through the ET(A) receptor on the vascular smooth muscle and presumably the ET (B) receptor on the endothelium, respectively. Furthermore, it is expe cted that selective ET(A) receptor antagonists, including BQ-485, may be able to protect the heart against ET-1-induced coronary spasm in si tuations, such as hyperlipidemia or atherosclerosis, in which the rele ase and/or function of endothelium-derived vasorelaxing substances is impaired.