Cyclosporine, but not FK506, selectively induces renal and coronary artery smooth muscle contraction.
BACKGROUND
Cyclosporine immunosuppression for organ transplantation is 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 are potent vascular smooth muscle contractile agents, we hypothesized that cyclosporine might induce contraction of the renal artery vascular smooth muscle directly.


METHODS
Strips of bovine renal, carotid, superior mesenteric, or coronary arteries were obtained fresh from an abattoir. The strips were equilibrated in a muscle bath, and the contractile responses to cyclosporine and FK506 were determined.


RESULTS
Cyclosporine (50 to 5000 micrograms/ml), but not FK506, induced rapidly developing, 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 cyclosporine was enhanced in the presence of an intact endothelium.


CONCLUSIONS
Although these effects occurred in vitro to relatively high doses of cyclosporine, these data suggest that cyclosporine may selectively induce renal artery smooth muscle contraction through activation of the Ca(2+)-dependent phosphatase (calcineurin) in the smooth muscle, and these contractions may be enhanced by the release of endothelial-derived contracting factors.
Epstein
A
A
Department of Surgery, Medical College of Georgia, Augusta 30912, USA.
Beall
A
A
Wynn
J
J
Mulloy
L
L
Brophy
C M
CM
D000818:Animals; D002417:Cattle; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D016572:Cyclosporine / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D066298:In Vitro Techniques; D008855:Microscopy, Electron, Scanning; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D012077:Renal Artery / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D016559:Tacrolimus / Q000494:pharmacology*; D013997:Time Factors
D016572:Cyclosporine; D016559:Tacrolimus