The therapeutical use of cyclosporine A (CsA) is hampered by the development of nephrotoxicity characterized by a marked increase in renal vascular resistance (RVR). We investigated vascular functions in kidneys of rats treated with CsA. The ex vivo vascular reactivity of kidneys from control rats and animals treated subacutely with CsA [50 mg/kg/day subcutaneously (s.c.) for 16-21 days] or an olive oil vehicle (1 ml/kg) was analyzed in male Wistar rats. The right kidney was isolated and perfused with Tyrode's or Krebs solution in an open circuit. The effects of acetylcholine (Ach), fenoldopam (FEN), and sodium nitroprusside (SNP) on norepinephrine (NE) preconstricted kidneys were studied. In control kidneys (untreated or vehicle-treated), Ach induced a relaxation (EC 50 = 0.56 ± 0.05 x 10 -9 M ; E max = 88.2 ± 2.1% decrease in the vascular tone restored by NE) which was endothelium-dependent [near-complete abolition after treatment with a detergent, 3-[(3-cholamidopropyl)-dimethyl-ammonio]-1-propane-sulfonate (CHAPS) treatment] but only partially inhibited by indomethacin (EC 5O = 1.71 ± 0.39 x 10 -9 M, p < 0.05 ; E max = 87.1 ± 4.9%, NS) or indomethacin with N G -nitro-L-arginine methyl ester (L-NAME : EC 50 = 1.04 ± 0.38 x 10 -9 M, NS ; E max = 63.8 ± 2.5%, p < 0.01). CsA treatment induced a marked decrease in creatinine clearance and natriuresis measured in vivo but had no effect on systolic blood pressure (SBP). In CsA-treated rats, Ach-induced renal relaxation was partly blunted (EC 50 = 1.88 ± 0.34 x 10 -9 M, p < 0.01 ; E max = 82.8 ± 4.6%, NS), with both a defect in prostaglandin (PG) and nitric oxide (NO)-related responses. CsA treatment had no effect on endothelium-independent relaxations induced by FEN and SNP. These results show that subacute CsA treatment selectively impairs renal endothelium-dependent relaxation related to PGs and NO release.
