Interaction of cyclosporine-A with the renin-angiotensin system in canine veins.
Responses of canine saphenous veins to bradykinin and angiotensin and the effect of cyclosporine-A were investigated both in conscious dogs in vivo and on ring preparations from canine saphenous veins in vitro. In vivo local infusion of bradykinin into the saphenous vein elicited dose-dependent reduction in compliance, i.e., venoconstriction, whereas local infusion of angiotensin elicited dose-dependent venodilatation, which was markedly enhanced during blockade of endogenous thromboxane A2 synthesis by dazoxiben (2.5 mg/kg i.v.). The venoconstrictor response to bradykinin was attenuated after oral administration of both the thiazide-like diuretic clopamide (0.5 mg/kg) or cyclosporine-A (30 mg/kg), and by concomitant local infusion of cyclosporine-A (1-10 micrograms/min). Systemic i.v. infusion of the renin inhibitor H-77 (0.1 mg/kg/h) reversed the inhibition of bradykinin by both clopamide and cyclosporine-A. In vitro bradykinin elicited relaxation at low (0.1-10 nmol/l) but constriction at higher concentrations. The venoconstrictor response to bradykinin was resistant to blockade of thromboxane A2 synthesis and only partially attenuated after selective blockade of cyclooxygenase or lipoxygenase. Concomitant blockade of both lipoxygenase and cyclooxygenase activity by nordihydroguaiaretic acid (NDGA 10-30 mumol/l) nearly abolished the contractile response thereby enhancing the relaxant component of the bradykinin effect. Angiotensin II also elicited biphasic responses of partially contracted venous rings. Concomitant blockade of both lipoxygenase and cyclooxygenase by NDGA (10 mumol/l) again attenuated the contractile component of the angiotensin effect thereby unmasking the venodilator activity which could be inhibited by the angiotensin II receptor blocker saralasin (0.01-1 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)
Müller-Schweinitzer
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Preclinical Research, Sandoz Ltd., Basle, Switzerland.
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D003005:Clopamide / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology; D012083:Renin / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012501:Saphenous Vein / Q000187:drug effects / Q000378:metabolism; D014665:Vasodilator Agents
D003524:Cyclosporins; D009842:Oligopeptides; D014665:Vasodilator Agents; D000804:Angiotensin II; D003005:Clopamide; C034503:H 77; D012083:Renin; D001920:Bradykinin