A preventive effect of a selective endothelin-A receptor antagonist, S-0139, on the erythropoietin-induced reduction of the renal cortical blood flow.
We have confirmed that renal cortical blood flow (RCBF) is significantly decreased by recombinant human erythropoietin (EPO). Endothelin-1 (ET(1)) is thought to be a mediator because its level increased significantly when EPO was administered. The present study was performed to clarify the effect of a selective ET-A receptor antagonist, S-0139, on EPO-induced RCBF reduction. Ten-week-old male Wistar rats, weighing about 250 g, were divided into five groups. Group 1 (n = 5), a control group, received normal saline solution (NSS). Group 2 (n = 5) received 200 U/kg body weight (BW) per hour of EPO. Group 3 (n = 5) received 400 U/kg BW per hour of EPO. Group 4 (n = 5) received both 200 U/kg BW per hour of EPO and 4 mg/kg BW per hour of S-0139. Group 5 (n = 5) received both 200 U/kg BW per hour of EPO and 40 mg/kg BW per hour of S-0139. Drugs were administered intravenously via the right femoral vein using a microinfusion pump for 4 h under urethane anesthesia. The RCBF was measured every 30 min by the hydrogen gas clearance method. When the 4 h had elapsed, the concentrations of plasma creatinine (Cr), ET1 and renin activity (RA) were measured. Compared with group 1, groups 2 and 3 showed significant (P < 0.001) decreases of RCBF, while the ET1 levels of these two groups increased significantly (P < 0.03). The ET1 of groups 4 and 5 also increased significantly (P < 0.03), however, the RCBF of these two groups did not decrease. No significant differences were observed in either Cr or RA between the five groups. EPO induces ET(1) secretion. The reduction of RCBF is due to ET(1)-derived vasoconstriction. S-0139 has potential for preventing EPO-induced and ET(1)-mediated RCBF reduction.
Ishikawa
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Department of Urology, Hamamatsu University School of Medicine, 3600 Handa-cho, Hamamatsu 431-31, Japan. ishikawa@hama-med.ac.jp
Suzuki
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K
Fujita
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D000818:Animals; D002109:Caffeic Acids / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D004921:Erythropoietin / Q000494:pharmacology*; D006801:Humans; D007672:Kidney Cortex / Q000098:blood supply*; D008297:Male; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D011994:Recombinant Proteins / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects
D002109:Caffeic Acids; D065128:Endothelin Receptor Antagonists; D044022:Receptor, Endothelin A; D011994:Recombinant Proteins; C086421:S 0139; D004921:Erythropoietin; D009828:Oleanolic Acid