Clinically relevant doses and blood levels produce experimental cyclosporine nephrotoxicity when combined with nitric oxide inhibition.

摘要: Cyclosporine (CsA) administration and nitric oxide (NO) blockade promote similar chronic renal hemodynamic alterations in rats. We evaluated various clinical CsA doses under conditions of NO using L-NAME (N-nitro L-arginine methyl ester). Groups Sprague-Dawley rats kept on a normal salt (+NaCl) or low-salt (-NaCl) diet were given 7.5 mg/kg, 2.5 vehicle (VH) for 21 days. VH treatment was preceded by one week continued three weeks. Inulin clearance, blood level, weekly pressure change assessed at 28 Marked dose dependent reductions GFR -NaCl animals (P < 0.01 versus + L-NAME) +NaCl 0.05 L-NAME, +NaCl) as well elevations days) occurred groups concurrently treated with L-NAME. In addition, impaired function morphologic lesions (CsA mg/kg) receiving alone demonstrated levels within the therapeutic range human transplant patients. produced but spared functional morphological alterations. Primary included proximal tubule collapse vacuolization and, less frequently, interstitial edema cells. Unique to simultaneously vascular abnormalities consisting endothelial arteriolar medial hyperplasia occasional acute necrosis. conclusion, nephrotoxicity can be enhanced simultaneous blockade, suggesting has protective effect CsA-induced nephropathy. These results achieved drug exposure profile that correlates therapy.