MODIFICATION OF ENDOTHELIUM-DEPENDENT REN AL VASCULAR REACTIVITY BY CYCLOSPORINE-A

Clinical use of the immunosuppressant cyclosporine A (CSA) is hampered by its nephrotoxicity. The renal vascular resistance is increased, ma y be as a consequence of a deleterious effect of the drug on the vascu lar endothelial cell function. The renal effects of a subchronic treat ment with CSA (50 mg/kg/d, sc, 18 days), or olive oil vehicule (1 ml/k g), were studied in normotensive male Wistar rats. Creatinine clearanc e was measured on 24 h urine collection before the right kidney of the animals was isolated and perfused in an open circuit at 6 ml/min with Tyrode's solution. Renal vasodilator responses to acetylcholine (ACH, 10(-10) to 10(-7) M) and sodium nitroprusside (NP, 3 x 10(-9) to 3 x 10(-6) M) were studied after reestablishment of a renal vascular tone by a continuous perfusion of noradrenaline (NA, 10(-7) M). ACH was mor e potent than NP to induce renal vasodilation (EC50 = 0.57 +/- 0.05 x 10(-9) M, n = 8, vs 3.42 +/- 0.29 x 10(-8) M, n = 5), but both drugs r eversed the NA-induced vasoconstriction by near 90 %. L-NAME (3 x 10(- 5) M) had no effect on NP-induced renal relaxation but suppressed resp onses to low concentrations of ACH and decreased by half its Emax (47 +/- 17 %). CSA treatment lowered creatinine clearance (0.284 +/- 0.041 vs 0.410 +/- 0.031 ml/min/100 g BW; p < 0.05) and blunted the vasodil ator response to ACH (EC50 = 1.92 +/- 0.46 x 10(-9) M, p < 0.05; n = 5 ) without alteration of the response to NP (EC50 = 5.19 +/- 0.20 X 10( -8) M; n = 6). These results show that subacute CSA treatment impairs endothelium-dependent relaxation of the renal vascular bed. This may c ontribute to the renovascular constriction observed with CSA treatment .