CYCLOSPORINE, BUT NOT FK506, SELECTIVELY INDUCES RENAL AND CORONARY-ARTERY SMOOTH-MUSCLE CONTRACTION

Background. Cyclosporine immunosuppression for organ transplantation i s associated with hypertension and nephrotoxicity. Because the effects of cyclosporine as an immunosuppressant are mediated by the effect of cyclosporine as a phosphatase inhibitor, and phosphatase inhibitors a re potent vascular smooth muscle contractile agents, we hypothesized t hat cyclosporine might induce contraction of the renal artery vascular smooth muscle directly. Methods. Strips of bovine renal, carotid, sup erior mesenteric or coronary arteries were obtained fresh from an abat toir. The strips were equilibrated in a muscle bath, and the contracti le responses to cyclosporine and FK506 were determined. Results. Cyclo sporine (50 to 5000 mu g/ml), but not FK506, induced rapidly developin g, sustained contractions of renal and coronary artery smooth muscle. The magnitude of the cyclosporine-induced contractions of carotid and superior mesenteric artery smooth muscles was significantly less. The magnitude of renal artery smooth muscle contractions induced by cyclos porine was enhanced in the presence of an intact endothelium. Conclusi ons. Although these effects occurred in vitro to relatively high doses of cyclosporine, these data suggest that cyclosporine may selectifely induce renal artery smooth muscle contraction through activation of t he Ca2+-dependent phosphatase (calcineurin) in the smooth muscle, and these contractions may be enhanced by the release of endothelial-deriv ed contracting factors.