MECHANISMS OF THE ENDOTHELIAL TOXICITY OF CYCLOSPORINE-A ROLE OF NITRIC-OXIDE, CGMP, AND CA2+

Cyclosporin A (CyA) is an efficient immunosuppressive agent, which, however, causes functional and struc tural alterations in endothelial cells. The aim of the present study was to examine the mechanisms of CyA-induced endothelial disfunction. CyA administration (Wistar rats, 25 mg/kg per day for 15 days) induced a significant inhibition of endothelium-dependent relaxation to acetylcholine on isolated femoral arteries. No changes with CyA were detected in the relaxation response to the endothelium-independent agent (sodium nitroprusside) or the endothelium-dependent receptor-independent agent (Ca2+ ionophore). The addition of L-arginine (10(-5) mol/L) shifted to the left the acetylcholine-mediated vasorelaxing response in CyA-treated segments, an effect that was accompanied by a marked increase of cGMP. Ca-45(2+) uptake was higher in CyA-treated segments with respect to control segments but became normalized after incubation with L-arginine or sodium nitroprusside. Deendothelization or incubation with the L-arginine competitive analogue N Omega-nitro-L-arginine (NwNLA) increased Ca-45(2+) uptake in control segments but not in CyA-treated segments. In conclusion, in isolated rat arteries, chronic CYA therapy affects endothelial function by uncoupling the acetylcholine-mediated relaxation and interfering with an endothelium-mediated pathway that regulates Ca-45(2+) uptake by a mechanism reversed by an L-arginine-dependent cGMP generation. (Circ Res.1994;74:477-484.)