Testosterone depletion contributes to cyclosporine-induced chronic impairment of acetylcholine renovascular relaxations

Abstract The immunosuppressant drug cyclosporine causes nephrotoxicity mainly via alterations of renovascular reactivity. This study investigated whether this effect of cyclosporine is modulated by the male gonadal hormone testosterone. The endothelium-dependent and -independent relaxations evoked by acetylcholine and sodium nitroprusside, respectively, were evaluated in phenylephrine-preconstricted isolated perfused kidneys obtained from sham-operated, castrated, and testosterone-replaced castrated (CAS+T) male rats in the absence and presence of cyclosporine. Compared with sham-operated values, short-term (10 days) castration or cyclosporine treatment caused significant and equivalent reductions in plasma testosterone levels and vasorelaxant responses to acetylcholine. Treatment of castrated rats with cyclosporine caused no further attenuation of acetylcholine relaxations. Testosterone replacement of castrated (CAS+T) or cyclosporine-treated castrated (CAS+CyA+T) rats restored plasma testosterone and acetylcholine relaxations to near-sham-operated levels. On the other hand, castration caused significant increases in nitroprusside relaxations versus no effect for cyclosporine. The relaxant responses to nitroprusside in castrated rats were restored to sham-operated levels after testosterone replacement. Plasma urea and creatinine were not affected by castration but were significantly increased by cyclosporine. These findings suggest that testosterone exerts directionally opposite modulatory effects on endothelium-dependent and -independent renal relaxations. Further, the results demonstrate that testosterone depletion may contribute, at least partly, to the inhibitory effect of cyclosporine on renovascular endothelial function. These data are clinically important because endothelial dysfunction contributes to vascular abnormalities associating cyclosporine therapy.