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Circulation Research. 1994;74:477-484

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Circulation Research, Vol 74, 477-484, Copyright © 1994 by American Heart Association

ARTICLES

Mechanisms of the endothelial toxicity of cyclosporin A. Role of nitric oxide, cGMP, and Ca2+

MJ Gallego, AL Garcia Villalon, AJ Lopez Farre, JL Garcia, MP Garron, S Casado, L Hernando and CA Caramelo
Instituto de Investigaciones Medicas, Fundacion Jimenez Diaz, Madrid, Spain.

Cyclosporin A (CyA) is an efficient immunosuppressive agent, which, however, causes functional and structural 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. 45Ca2+ uptake was higher in CyA-treated segments with respect to control segments but became normalized after incubation with L-arginine or sodium nitroprusside. De-endothelialization or incubation with the L- arginine competitive analogue N omega-nitro-L-arginine (NwNLA) increased 45Ca2+ 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 45Ca2+ uptake by a mechanism reversed by an L-arginine- dependent cGMP generation.


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