DIFFERENTIAL RESPONSIVENESS OF CONDUIT AND RESISTANCE CORONARY-ARTERIES TO ENDOTHELIN-A AND ENDOTHELIN-B RECEPTOR STIMULATION IN ANESTHETIZED DOGS

The effects of endothelin-I (ET-1), an ET(A)/ET(B)-receptor agonist, and IRL 1620, a potent and selective ET(B)-receptor agonist, were assessed on left circumflex coronary artery diameter (sonomicrometry) and flow (electromagnetic flow probe) in pentobarbital-anesthetized dogs. Intracoronary (i.c.) bolus injections of ET-1 (80 pmol/dose) caused large, sustained coronary diameter decreases (281 +/- 39 mum) and transient flow increases (5.6 +/- 2.6 ml/min), followed by transient (10.0 +/- 1.9 ml/min) and then sustained flow reductions (6.6 +/- 2.5 ml/min) before terminating in ventricular fibrillation after two to five doses (max DELTAs; n = 4 dogs). IRL 1620 boluses (5-2,000 pmol/dose i.c.; max DELTAs; n = 3) also dose-dependently and transiently increased (16.8 +/- 1.4 ml/min; 200 pmol), then transiently decreased (12.8 +/- 1.5 ml/min; 1,600 pmol) flow but had minimal effects on diameter (A = - 23 +/- 4 mum; 2,000 pmol). Doses of IRL 1620 beyond 400 pmol were accompanied by a slowly responding, sustained decrease in baseline flow (- 9.2 +/- 2.7 ml/min) and baseline diameter (232 +/- 150 mum). In a separate group of dogs (n = 5), IRL 1620 (400 pmol i.c.) was evaluated before and after sequential inhibition of cyclooxygenase (indomethacin; 10 mg/kg i.v.) and then nitric oxide synthase (Nomega-nitro-L-arginine methyl ester, L-NAME; 50 mg/kg i.v.). Indomethacin alone did not affect the flow increase to IRL 1620 (11.0 +/- 2.0 versus 11.8 +/- 1.8 ml/min) but blunted the flow decrease by 30 +/- 6% (10.6 +/- 1.4 versus 7.1 +/- 0.7 ml/min). Combined indomethacin plus L-NAME reduced the IRL 1620-mediated flow increment by 66 +/- 8% (3.4 +/- 0.8 ml/min), returned the flow decrement to control (11.0 +/- 1.5 ml/min), and markedly prolonged the time for the flow decrement to recover by 80% (172 +/- 27 versus 406 +/- 50 s), but did not unmask a transient conduit coronary diameter decrease (- 26 +/- 13 versus - 21 +/- 13 mum). IRL 1620 was rarely arrhythmogenic and never induced ventricular fibrillation. Our results suggest that conduit coronary constriction and proarrhythmic activity of ET-1 in dogs are mediated predominantly by ET(A) receptors, whereas resistance vessel constriction may at least in part be generated by ET(B) receptors. ET(B) vasoconstriction is opposed by an ET(B)-mediated release of nitric oxide.