Coronary vasoconstriction by endothelin-1 in anesthetized goats: Role of endothelin receptors, nitric oxide and prostanoids

The role of endothelin ET(A) and ET(B) receptors as well as of nitric oxide (NO) and prostanoids in the effects of endothelin-l on the coronary circulation was studied in anesthetized goats, where blood flow in the left circumflex coronary artery (coronary blood flow) (electromagnetically measured), systemic arterial pressure, left ventricle pressure and dP/dt, and heart rate were recorded. Endothelin-l (0.01-0.3 nmol), intracoronarily injected, produced marked, dose-dependent reductions in basal coronary blood flow, ranging from 5% for 0.01 nmol to 75% for 0.3 nmol; 0.1 and 0.3 nmol endothelin-l also reduced systolic ventricle pressure and dP/dt. The effects of endothelin-1 on coronary blood flow were diminished during intracoronary infusion of BQ-123 (cyclo-(D-Asp-Pro-D-Val-Leu-D-Trp), specific antagonist for endothelin ET(A) receptors, 2-16 nmol/min) in a dose-dependent way, but not during the infusion of BQ-788 (N-[N-[N-[(2,6-dimethyl-1-piperidinyl)carbonyl]-4-methyl-L-leucyl]-1-(methoxycarbonyl)-D-tryptophyl]-D-norleucine monosodium, specific antagonist for endothelin ET(B) receptors, 2-4 nmol/min). IRL 1620 (Suc-[Glu(9), Ala(11,15)]endothelin-1-(8-21), specific agonist for endothelin ET(B) receptors, 0.01-0.3 nmol), intracoronarily injected, slightly reduced basal coronary blood flow only when 0.1 and 0.3 nmol were applied (maximal reduction about 25%); 0.3 nmol IRL 1620 also reduced systolic ventricle pressure and dP/dt. The effects of IRL 1620 were not modified by BQ-123 or BQ-788. N-G-nitro-L-arginine methyl ester (L-NAME, inhibitor of NO synthesis, 47 mg/kg by i.v. route) reduced resting coronary blood flow by 10% and increased mean systemic arterial pressure and systolic ventricle pressure by 22 and 20%, respectively, without changing systolic ventricle dP/dt and heart rate. With L-NAME, the reductions of coronary blood flow by endothelin-l were potentiated (P < 0.05), and those by IRL 1620 were not changed (P > 0.05). Meclofenamate (cyclooxygenase inhibitor, 4-6 mg/kg by i.v. route) modified neither the basal values of hemodynamic variables nor the coronary effects of endothelin-l and IRL 1620. Therefore, endothelin-l produces marked coronary vasoconstriction, which may be mediated by endothelin ET(A) receptors, with no participation of endothelin ET(B) receptors. NO, but not prostanoids, may produce a basal coronary vasodilator tone and may inhibit endothelin-l-induced coronary vasoconstriction. Also, it is suggested that the coronary vasoconstriction by endothelin-l may impair cardiac performance due to heart ischemia.