Reversal of endothelin-induced vasoconstriction by endothelium-dependent and -independent vasodilators in isolated hearts and vascular rings.
Endothelin (ET-1) is a potent endogenous vasoconstrictor. Several factors 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 test the activity of several differently acting vasodilator drugs on reversing or attenuating the vasoconstrictor effects of exogenously administered ET-1 in isolated guinea-pig hearts, in isolated rings with intact endothelium from canine middle cerebral and basilar arteries, and from guinea-pig aortas. Vasodilator drugs tested up to maximal concentrations were adenosine (ADE), nitroprusside (NP), acetylcholine (ACH), nifedipine (NIF), and butanedione monoxime (BDM), an excitation-uncoupling agent. Variables measured in isolated hearts included coronary flow, percentage oxygen extraction (% O2E), left ventricular pressure (LVP), and myocardial oxygen consumption. It was found that ADE, NP, ACH, and BDM each attenuated the 60% decrease in coronary flow and 20% increase 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. In isolated rings constricted with 20 nM ET-1, BDM restored tone equivalent to that by papaverine, whereas NP and NIF only attenuated the vasoconstriction elicited by ET-1. Ring experiments also demonstrated that the vasodilatory effect of BDM was independent of nitric oxide-dependent pathways and that BDM attenuated vasoconstriction resulting from increased bath KCl. The study suggests that drugs affecting intracellular Ca2+ with a mechanism of action downstream from cell-membrane receptors or intracellular messengers may be more effective for reversing the constrictor effect of ET-1. NP, however, would be a better clinical choice for reversing ET-1-induced vasoconstriction.
Stowe
D F
DF
Department of Anesthesiology, Medical College of Wisconsin, and Veterans Affairs Medical Center, Milwaukee 53226, USA.
O'Brien
W C
WC
Chang
D
D
Knop
C S
CS
Kampine
J P
JP
D000109:Acetylcholine / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001488:Basilar Artery / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects*; D002536:Cerebral Arteries / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D003931:Diacetyl / Q000031:analogs & derivatives / Q000494:pharmacology; D004285:Dogs; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009599:Nitroprusside / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D019332:Endothelin-1; D014665:Vasodilator Agents; D009599:Nitroprusside; C004717:diacetylmonoxime; D003931:Diacetyl; D000241:Adenosine; D000109:Acetylcholine