Calcium entry blockade may prevent cyclosporin A-induced hypersensitivity to angiotensin II and endothelial dysfunction in the rat aorta.
Vascular smooth muscle dysfunction after chronic treatment with cyclosporin A was in part explained by chronically augmented calcium influx leading to calcium overload. The potential protective effect of calcium antagonism with diltiazem as regards endothelial and vascular smooth muscle reactivity was investigated during chronic treatment with cyclosporin A. Male Wistar rats were orally treated for 6 weeks with either cyclosporin A (30 mg.kg-1 x day-1 in 1 ml, n = 8), with the vehicle alone (n = 10), with diltiazem (60 mg.kg-1 x day-1, n = 10) or with a combination of cyclosporin A and diltiazem (30 mg.kg-1 x day-1 and 60 mg.kg-1 x day-1, n = 8), respectively. Rings of the isolated thoracic aorta were mounted in organ chambers to measure isometric force. Chronic treatment with diltiazem alone did not affect the responsiveness to any of the drugs tested, but the augmentation of contractions to angiotensin II (10(-9) to 10(-6) M) after treatment with cyclosporin, was prevented by co-treatment with diltiazem. Co-treatment with diltiazem, however, did not affect the response to potassium chloride (20-80 mM), endothelin-1 (10(-9) to 10(-7) M) or phenylephrine (10(-9) to 10(-6) M). Endothelium-dependent relaxations to calcitonin gene-related peptide (CGRP, 10(-10) to 10(-7) M) and acetylcholine (10(-8) to 10(-5) M) were reduced in cyclosporin A treated rats. Co-treatment with diltiazem normalized the response to CGRP. The response to acetylcholine was not significantly affected.(ABSTRACT TRUNCATED AT 250 WORDS)
Götze
S
S
German Heart Institute Berlin, Department of Internal Medicine and Cardiology, Germany.
Auch-Schwelk
W
W
Bossaller
C
C
Thelen
J
J
Fleck
E
E
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects
D000804:Angiotensin II; D016572:Cyclosporine; D004110:Diltiazem