Effect of nifedipine in cyclosporine-induced nephrotoxicity in rats: roles of the thromboxane and endothelin systems.
Cyclosporine (CsA) (45 mg/kg/day for 7 days) administration in female Wistar rats induced significant decrease in creatinine clearance (Ccr) and body weight loss (BWL). Urine volume (V) was not altered and proteinuria (PU) not provoked. These changes were associated with increased urinary endothelin 1 (ET-1) and thromboxane B(2)(TXB(2)) concentrations, and decreased urinary ratios of prostaglandin (6ketoPGF(1 alpha)and PGE(2)) to TXB(2)excretions. Nifedipine (NFD) (0.1 mg/kg/day for 7 days), a calcium channel blocker, administrated in addition to CsA, to another group of animals, significantly augmented Ccr and urine V but did not prevent BWL in comparison to CsA-only treated rats. The urinary ET-1 and TXB(2)concentrations displayed significant and non-significant decrease respectively, while the urinary excretion ratios of 6ketoPGF(1 alpha)/TXB(2)and PGE(2)/TXB(2)were significantly enhanced.These observations indicate that the partial protection of NFD in CsA-induced nephrotoxicity could be attributed to augmented urinary prostanoid ratios of renal vasodilators (6ketoPGF(1 alpha)and PGE(2)) to vasoconstrictor (TXB(2)) excretions, and also to reduced release of rather renal origin ET-1, the most potent mamalian vasoconstrictor peptide known to date. In a previous 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 preservation of relatively high renal TXB(2)levels. However, other nephrotoxic factors and additional mechanisms could also be implicated in this CsA-induced syndrome.
Darlametsos
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IE
Centre Franco-Hellénique de Recherches Biomédicales, General Hospital of Agrinion, 30100 Agrinion, Greece.
Papanikolaou
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EN
Varonos
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DD
D015121:6-Ketoprostaglandin F1 alpha / Q000652:urine; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003404:Creatinine / Q000652:urine; D016572:Cyclosporine / Q000494:pharmacology*; D015232:Dinoprostone / Q000652:urine; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000652:urine; D016232:Endothelins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D007118:Immunoassay; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology*; D011507:Proteinuria; D051381:Rats; D017208:Rats, Wistar; D013053:Spectrophotometry; D013929:Thromboxane B2 / Q000378:metabolism* / Q000652:urine; D014556:Urine
D002121:Calcium Channel Blockers; D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D016572:Cyclosporine; D003404:Creatinine; D009543:Nifedipine; D015232:Dinoprostone