Endothelium-dependent tolerance to ethanol-induced contraction of rat aorta: effect of inhibition of EDRF action and nitric oxide synthesis.
In vitro ethanol induces a dose-dependent contraction of the aorta. Tolerance to this effect of ethanol is expressed by a rightward shift of the dose-response curve in aorta from animals intoxicated with ethanol for 2 days. The expression of tolerance in the aorta is dependent upon the presence of functional endothelial cells which suggests that tolerance is mediated, in part, by endothelium-derived relaxing factor (EDRF). To test this hypothesis, three inhibitors of EDRF action and an inhibitor of nitric oxide synthesis were studied for their ability to alter tolerance to ethanol-induced contraction of the aorta. In vitro pretreatment of aortic rings with gossypol (10(-6)-10(-5) M), pyrogallol (10(-5) M), hemoglobin (10(-6) M), and NG-nitro-L-arginine (NOARG, 10(-4) M) inhibited endothelium-dependent relaxation induced by carbachol. The inhibition of carbachol-induced relaxation produced by pyrogallol was reversed by superoxide dismutase (SOD, 45 units/ml). In vitro pretreatment of rings obtained from ethanol-treated rats with gossypol, pyrogallol, hemoglobin, or NOARG inhibited the expression of ethanol tolerance, shifting the ethanol dose-response curve to control values. SOD reversed the effect of pyrogallol pretreatment. None of the antagonists significantly altered the ethanol dose-response curve of aortic rings obtained from control animals. These data support the hypothesis that tolerance to ethanol-induced contraction of the aorta is mediated by the release of EDRF from endothelial cells.
Knych
E T
ET
Department of Pharmacology, University of Minnesota, School of Medicine, Duluth 55812.
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D000431:Ethanol / Q000494:pharmacology*; D006072:Gossypol / Q000494:pharmacology; D006454:Hemoglobins / Q000502:physiology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*; D019335:Nitroarginine; D011748:Pyrogallol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
D006454:Hemoglobins; D011748:Pyrogallol; D019335:Nitroarginine; D009569:Nitric Oxide; D000431:Ethanol; D002217:Carbachol; D001120:Arginine; D006072:Gossypol