Changes in the venous compliance by bradykinin and angiotensin II and its significance for the vascular effects of cyclosporine-A.
Local infusion of both bradykinin and enalaprilic acid, the active metabolite of the converting enzyme inhibitor enalapril, elicited dose-dependent reduction of the compliance of the saphenous vein in conscious dogs. The competitive bradykinin B1-receptor antagonist, des-Arg9-Leu8-bradykinin antagonized venous responses to both bradykinin and enalaprilic acid effectively and with similar potency whereas the bradykinin B2-receptor antagonist Thi5,8,D-Phe7-bradykinin was about 100 times less potent when tested against bradykinin. Under control conditions local infusion of angiotensin II had no contractile activity but it elicited considerable venodilation after blockade of endogenous thromboxane A2 synthesis by dazoxiben. Blockade of the converting enzyme by enalapril (3 mg/kg i.v.) enhanced the maximal responses to bradykinin. Under these conditions concomitant local infusion of angiotensin II attenuated the venoconstrictor effects of bradykinin. Venous responses to bradykinin were inhibited after oral treatment of the dogs with the thromboxane A2 receptor antagonist BM 13,177 and nearly completely abolished after i.v. administration of the thromboxane synthesis inhibitor dazoxiben. In contrast, venous responses to enalaprilic acid were unchanged by thromboxane A2 receptor blockade and enhanced after dazoxiben. Following oral administration of cyclosporine-A (10 and 30 mg/kg), venous responses to bradykinin were attenuated while those to enalaprilic acid remained unchanged. Concomitant local infusion of the angiotensin II receptor antagonist saralasin (1 microgram/min) reversed completely the cyclosporine-A-induced reduction of the venoconstrictor effects of bradykinin.(ABSTRACT TRUNCATED AT 250 WORDS)
Müller-Schweinitzer
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Preclinical Research, SANDOZ Ltd., Basel, Switzerland.
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology*; D004285:Dogs; D004656:Enalapril / Q000494:pharmacology; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D012504:Saralasin / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology
D003524:Cyclosporins; D000804:Angiotensin II; D012701:Serotonin; D004656:Enalapril; D012504:Saralasin; D001920:Bradykinin; D009638:Norepinephrine