Effect of nifedipine in cyclosporine-induced nephrotoxicity in rats: rolesof the thromboxane and endothelin systems

Cyclosporine (CsA) (45 mg/kg/day for 7 days) administration in female Wista r rats induced significant decrease in creatinine clearance (Ccr) and body weight loss (BWL). Urine volume (V) was not altered and proteinuria (PU) no t provoked. These changes were associated with increased urinary endothelin 1 (ET-1) and thromboxane B-2 (TXB2) concentrations, and decreased urinary ratios of prostaglandin (6ketoPGF(1 alpha) and PGE(2)) to TXB2 excretions. Nifedipine (NFD) (0.1 mg/kg/day for 7 days), a calcium channel blocker, adm inistrated in addition to CsA, to another group of animals, significantly a ugmented Ccr and urineV but did not prevent BWL in comparison to CsA-only t reated rats. The urinary ET-1 and TXB2 concentrations displayed significant and non-significant decrease respectively, while the urinary excretion rat ios of 6ketoPGF(1 alpha)./TXB2 and PGE(2)/TXB2 were significantly enhanced. These observations indicate that the partial protection of NFD in CsA-induc ed nephrotoxicity could be attributed to augmented urinary prostanoid ratio s of renal vasodilators (6ketoPGF(1 alpha) and PGE(2)) to vasoconstrictor ( TXB2) excretions, and also to reduced release of rather renal origin ET-1, the most potent mamalian vasoconstrictor peptide known to date. In a previo us study, we found that NFD only slightly prevented structural renal damage , induced by CsA. So, the NFD protection refers only to functional toxicity and not to structural damage, mediated at least in part by the preservatio n of relatively high renal TXB2 levels. However, other nephrotoxic factors and additional mechanisms could also be implicated in this CsA-induced synd rome. (C) 2000 Harcourt Publishers Ltd.