REVERSAL OF ENDOTHELIN-INDUCED VASOCONSTRICTION BY ENDOTHELIUM-DEPENDENT AND ENDOTHELIUM-INDEPENDENT VASODILATORS IN ISOLATED HEARTS AND VASCULAR RINGS

Endothelin (ET-1) is a potent endogenous vasoconstrictor. Several fact ors increase ET-1 release in vitro and ET-1 levels increase in vivo in situations that damage blood vessels. The aim of this study was to te st the activity of several differently acting vasodilator drugs on rev ersing or attenuating the vasoconstrictor effects of exogenously admin istered ET-1 in isolated guinea-pig hearts, in isolated rings with int act endothelium from canine middle cerebral and basilar arteries, and from guinea-pig aortas. Vasodilator drugs tested up to maximal concent rations were adenosine (ADE), nitroprusside (NP), acetylcholine (ACH), nifedipine (NIF), and butanedione monoxime (BDM), an excitation-uncou pling agent. Variables measured in isolated hearts included coronary f low, percentage oxygen extraction (% O2E), left ventricular pressure ( LVP), and myocardial oxygen consumption. It was found that ADE, NP, AC H, and BDM each attenuated the 60% decrease in coronary flow and 20% i ncrease in % O2E elicited by 0.5 nM ET-1 in isolated hearts, but only BDM restored coronary flow, whereas BDM and ADE both restored % O2E. I n isolated rings constricted with 20 nM ET-1, BDM restored tone equiva lent to that by papaverine, whereas NP and NIF only attenuated the vas oconstriction elicited by ET-1. Ring experiments also demonstrated tha t the vasodilatory effect of BDM was independent of nitric oxide-depen dent pathways and that BDM attenuated vasoconstriction resulting from increased bath KCl. The study suggests that drugs affecting intracellu lar Ca2+ with a mechanism of action downstream from cell-membrane rece ptors or intracellular messengers may be more effective for reversing the constrictor effect of ET-1. NP, however, would be a better clinica l choice for reversing ET-1-induced vasoconstriction.