PREVENTIVE EFFECTS OF DILTIAZEM ON CYCLOSPORINE-A-INDUCED VASCULAR SMOOTH-MUSCLE DYSFUNCTION

Cyclosporin A may cause vascular smooth muscle dysfunction due to calc ium overload as a consequence of chronically augmented calcium influx. In the present study, the responsiveness to vasoconstrictors was inve stigated in rats after chronic treatment for 6 weeks with placebo, cyc losporin A (30 mg/kg per day), diltiazem (60 mg/kg per day), or cyclos porin A plus diltiazem. Twenty-four hours after the last oral treatmen t the animals were sacrified and rings of the thoracic aorta were susp ended in organ chambers under isometric conditions in the absence of c yclosporin A or diltiazem. Chronic treatment with cyclosporin A signif icantly augmented contractions to angiotensin II (10 10(-5) M). This e ffect was prevented by cotreatment with diltiazem. Diltiazem did not a ffect the cyclosporin A-induced reduction in the response to potassium chloride (10-80 mM) The contractions to phenylephrine (10(-9)-10(-6) M) and endothelin-1 (10(-9)-10(-7) M) were not significantly different in the four groups. The preventive effect of diltiazem against the cy closporin A-induced hypersensitivity to angiotensin II supports the hy pothesis of increased calcium influx during cyclosporin A therapy. The results may provide an additional rationale for the use of calcium an tagonists in the treatment of the vascular side effects of cyclosporin A.