Renal protective effect of YM598, a selective endothelin ET(A) receptor antagonist, against diabetic nephropathy in OLETF rats.
We have investigated the effect of potassium (E)-N-[6-methoxy-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl) pyrimidin-4-yl]-2-phenylenthenesulfonamidate (YM598), a selective endothelin ET(A) receptor antagonist, on renal function in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type II diabetes. YM598 (0.1 or 1 mg kg(-1)), enalapril (5 mg kg(-1)), an angiotensin-converting enzyme inhibitor, or vehicle was administered once daily by gastric gavage to 22-week-old male Otsuka Long-Evans Tokushima Fatty rats for 32 weeks. Enalapril but not YM598 mildly lowered blood pressure in the diabetic rats. YM598 blunted the development of albuminuria in a dose-dependent manner. High dose of YM598 reduced albuminuria comparable to enalapril. Urinary endothelin-1 excretion was greater in the diabetic than in the control rats, and was not substantially influenced by the agents. These data suggest that endothelin is involved in the progression of diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty rats, and an endothelin ET(A) receptor antagonist may be useful for the treatment of diabetic nephropathy.
Department of Clinical Pharmacology, Jichi Medical School, 3311-1 Minamikawachi, Tochigi 329-0498, Japan. ksugi@jichi.ac.jp
Koh-ichi
K
Sugimoto
Shuichi
S
Tsuruoka
Akio
A
Fujimura
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism / Q000652:urine; D016232:Endothelins / Q000378:metabolism*; D007677:Kidney Function Tests; D008297:Male; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D020334:Rats, Inbred OLETF; D044022:Receptor, Endothelin A; D013449:Sulfonamides / Q000494:pharmacology*
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; C449179:N-(6-methoxy-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl)-2-phenylethenesulfonamide; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D013449:Sulfonamides