Interaction of cyclosporine-A with the renin-angiotensin system in canine veins

Summary

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 venodilation, 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 μg/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 μmol/l) nearly abolished the contractile response thereby enhancing the relaxant component of the bradykinin effect. Angiotensin 11 also elicited biphasic responses of partially contracted venous rings. Concomitant blockade of both lipoxygenase and cyclooxygenase by NDGA (10 μmol/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 μmol/l). Blockade of converting enzyme by enalaprilic acid, the active metabolite of the converting enzyme inhibitor enalapril, attenuated responses to angiotensin I but shifted the concentration-response curve to bradykinin to the left. Compared to angiotensin I or angiotensin II, angiotensinogen was about ten times less potent in relaxing venous rings, but its potency was enhanced by a factor 10 in the presence of the serine protease kallikrein. Neither in the absence nor in the presence of kallikrein did the renin inhibitor H-77 modify the venodilator responses to angiotensinogen in vitro. Furthermore, venous responses to both bradykinin and angiotensinogen were unchanged in rings incubated for 1 h with 1 μmol/l cyclosporine-A.

It is suggested, that the venoconstrictor response to bradykinin is mediated through enhanced formation and/or release of both prostaglandins and leukotrienes and that the bradykinin effect is modulated by endogenous angiotensin. Furthermore, the present data suggest (1) that the canine saphenous vein possesses a local renin-angiotensin system with activatable angiotensin forming enzyme(s) and (2) that activation of circulating prorenin rather than of tissue renin contributes to the vascular effect of cyclosporine-A.