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.
Götze
S
S
Department of Internal Medicine, German Heart Institute Berlin, Berlin.
Auch-Schwelk
W
W
Bossaller
C
C
Thelen
J
J
Fleck
E
E
D000818:Animals; D001794:Blood Pressure; D003251:Constriction, Pathologic / Q000517:prevention & control; D016572:Cyclosporine / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology*; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D014662:Vasoconstrictor Agents; D016572:Cyclosporine; D004110:Diltiazem