Preventive effect of platelet-activating factor antagonist, Y-24180, against cyclosporine-induced acute nephrotoxicity.
To evaluate the effect of Y-24180, a potent and long-acting antagonist to platelet-activating factor (PAF) receptors, on cyclosporine A (CsA)-induced acute renal failure, the influence of its pretreatment on the CsA-induced alterations in renal hemodynamics was examined in male Wistar rats under anesthesia. CsA decreased the clearances of inulin and p-aminohippuric acid (PAH) in a dose-dependent manner. Y-24180 (3 mg/kg, i.v.) tended to attenuate the CsA-induced reduction in inulin clearance. Y-24180 (0.3 and 3 mg/kg) significantly prevented the reductions in PAH clearance and the increase in calculated renal vascular resistance (RVR) in a dose-dependent manner. Serum endothelin-1 (Et) concentration in the CsA-treated group was higher than that in the vehicle-treated group. Y-24180 did not influence such the elevated Et concentration. Serum thromboxane B2 (TxB2) concentration did not increase by treatment with CsA. A significant correlation was observed between RVR and Et, but not TxB2 concentration. The present study showed that a PAF receptor antagonist, Y-24180, has the preventive effect against CsA-induced acute renal failure, which indicates that PAF may partly be involved in the mechanism of renal vasoconstriction induced by CsA. The present findings also support the idea that Et contributes to the CsA-induced acute nephrotoxicity.
Kawaguchi
A
A
Department of Clinical Pharmacology, Jichi Medical School, Kawachi-gun, Tochigi, Japan.
Sugimoto
K
K
Fujimura
A
A
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D016572:Cyclosporine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000097:blood; D006439:Hemodynamics / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects*; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D013929:Thromboxane B2 / Q000097:blood; D014230:Triazoles / Q000494:pharmacology*
D001381:Azepines; D019332:Endothelin-1; D007166:Immunosuppressive Agents; D010972:Platelet Activating Factor; D014230:Triazoles; C068035:4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-6,9-dimethyl-6H-thieno(3,2-f)(1,2,4)triazolo(4,3-a)(1,4)diazepine; D013929:Thromboxane B2; D016572:Cyclosporine