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 coron ary circulation was studied in anesthetized goats, where blood flow in the left circumflex coronary artery (coronary blood flow) (electromag netically measured), systemic arterial pressure, left ventricle pressu re and dP/dt, and heart rate were recorded. Endothelin-l (0.01-0.3 nmo l), intracoronarily injected, produced marked, dose-dependent reductio ns 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 vent ricle pressure and dP/dt. The effects of endothelin-1 on coronary bloo d 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 yl]-1-(methoxycarbonyl)-D-tryptophyl]-D-norleucine monosodium, specific antagonist for endothelin ET(B) receptors, 2-4 nm ol/min). IRL 1620 (Suc-[Glu(9), Ala(11,15)]endothelin-1-(8-21), specif ic agonist for endothelin ET(B) receptors, 0.01-0.3 nmol), intracorona rily injected, slightly reduced basal coronary blood flow only when 0. 1 and 0.3 nmol were applied (maximal reduction about 25%); 0.3 nmol IR L 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-argini ne methyl ester (L-NAME, inhibitor of NO synthesis, 47 mg/kg by i.v. r oute) reduced resting coronary blood flow by 10% and increased mean sy stemic arterial pressure and systolic ventricle pressure by 22 and 20% , respectively, without changing systolic ventricle dP/dt and heart ra te. 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, endothel in-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 va sodilator tone and may inhibit endothelin-l-induced coronary vasoconst riction. Also, it is suggested that the coronary vasoconstriction by e ndothelin-l may impair cardiac performance due to heart ischemia.