Attenuation of vascular relaxation and cyclic GMP responses by cyclosporin A

The effect of Cyclosporin A (CsA) on vascular vasomotor responses was determined in two isolated tissue preparations. The first preparation was the rat mesenteric vascular bed which was constricted by phenylephrine (EC80) and perfused with CsA (8.32 x 10(-8) to 8.32 x 10(-6) M). Vasodilation responses to acetylcholine, bradykinin and the calcium ionophore, A23187, were impaired, as was the response to sodium nitroprusside at high CsA concentrations. Indomethacin had no effect suggesting that the CsA effect is unrelated to the synthesis of cyclooxygenase products. In the second preparation, thoracic aortic rings from rats treated with CsA (5-10 and 20-50 mg/kg/daily for 3 and 1 weeks, respectively) were used. Aorta rings precontracted by phenylephrine (EC80) also showed impaired responses to both endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) vasodilators. Furthermore, a marked decrease of the guanosine 3',5'-cyclic monophosphate (cGMP) content in aortic preparations was found to accompany the in vivo effect of CsA on relaxation. In addition, exposure of aortic rings to CsA (8.32 x 10(-8) to 8.32 x 10(-6) M) in vitro, also inhibited markedly the cGMP response induced by acetylcholine or sodium nitroprusside. This effect of CsA was not modified by isobutyl methylxanthine, a phosphodiesterase inhibitor. We conclude that CsA acts directly on the vascular smooth muscle; and speculate that CsA may compromise the response to vasodilators by inhibiting cGMP formation.