Preventive effects of diltiazem on cyclosporin A-induced vascular smooth muscle dysfunction

Cyclosporin A may cause vascular smooth muscle dysfunction due to calcium overload as a consequence of chronically augmented calcium influx. In the present study, the responsiveness to vasocontrictors was investigated in rats after chronic treatment for 6 weeks with placebo, cyclosporin A (30 mg/kg per day), diltiazem (60 mg/kg per day), or cyclosporin A plus diltiazem. Twenty-four hours after the last oral treatment the animals were sacrificed and rings of the thoracic aorta were suspended in organ chambers under isometric conditions in the absence of cyclosporin A or diltiazem. Chronic treatment with cyclosporin A significantly augmented contractions to angiotensin II (10(-9)-10(-5) M). This effect was prevented by cotreatment with diltiazem. Diltiazem did not affect 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 cyclosporin A-induced hypersensitivity to angiotensin II supports the hypothesis of increased calcium influx during cyclosporin A therapy. The results may provide an additional rationale for the use of calcium antagonists in the treatment of the vascular side effects of cyclosporin A.