Mechanisms of the endothelial toxicity of cyclosporin A. Role of nitric oxide, cGMP, and Ca2+.
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.
Gallego
M J
MJ
Instituto de Investigaciones Médicas, Fundación Jiménez Díaz, Madrid, Spain.
García Villalón
A L
AL
López Farre
A J
AJ
García
J L
JL
Garrón
M P
MP
Casado
S
S
Hernando
L
L
Caramelo
C A
CA
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001120:Arginine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects*; D005263:Femoral Artery / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects
D009569:Nitric Oxide; D016572:Cyclosporine; D001120:Arginine; D006152:Cyclic GMP; D002118:Calcium