Background  

Cyclosporine is a potent immunosuppressant with nephrotoxic effects. The decreased effective renal blood flow caused by vasoconstriction of afferent arterioles is now considered the main mechanism of cyclosporine-induced nephrotoxicity. It has been suggested that endothelin (ET) receptor antagonists might have beneficial effects against cyclosporine-induced vasoconstriction. We studied the acute effect of a nonpeptide selective ET-A receptor antagonist, S-0139, against cyclosporine-induced reduction of renal cortical blood flow (RCBF).

Methods  

Male Wistar rats were divided into 3 groups (10 rats each). Both cyclosporine and S-0139 were dissolved in normal saline solution and infused into the femoral vein. Group 1 received cyclosporine at a dose of 0.1 mg/kg per minute. Group 2 received cyclosporine at the same dose and S-0139 at 0.2 mg/kg per minute. Group 3 received the medium as a control. RCBF was measured every 30 minutes for 4 hours by the hydrogen gas clearance method under urethane anesthesia. Serum creatinine, serum potassium, plasma endothelin 1 (ET1) concentrations and plasma renin activity were then measured.

Results  

Group 1 showed a significant decrease in RCBF, while groups 2 and 3 showed no change. Serum creatinine and serum potassium were significantly higher in group 1 than in groups 2 and 3. Plasma ET1 levels were both significantly higher in groups 1 and 2 than in group 3. There were no significant differences among the 3 groups in plasma renin activity.

Conclusion  

We conclude that S-0139 has an acute preventive effect against cyclosporine-induced RCBF reduction.