Effects of KW-3902, a novel adenosine A1-receptor antagonist, on cephaloridine-induced acute renal failure in rats.
We investigated the possible renal protective effects of KW-3902 (8-(noradamantan-3-yl)-1,3-dipropylxanthine), a selective and potent adenosine A1-receptor antagonist, against cephaloridine (CER)-induced acute renal failure (ARF) in rats. ARF was induced by intravenous injection of CER at a dose of 600 mg/kg body weight. KW-3902 at doses higher than 0.01 mg/kg (p.o.) dose-dependently attenuated the decrease of creatinine clearance and the increase of proteinuria in rats with CER-induced ARF. In contrast, furosemide and trichlormethiazide (TCM) increased urinary protein and aggravated the serum parameters. These results suggest that KW-3902 has some advantages over furosemide and TCM when used in combination with CER. In the diuretic study in the rats with established ARF induced by CER, KW-3902, furosemide and TCM caused a significant increase in sodium excretion, whereas acetazolamide was ineffective. These results suggest that the proximal tubule is functionally damaged in rats with CER-induced ARF, in accord with the histological observation demonstrating the degeneration of the proximal tubule. From the fact that KW-3902 induces diuretic action even in CER-induced ARF, it is suggested that KW-3902 acts, directly or indirectly, on the proximal tubule or other tubular sites in the kidney, resulting in the diuretic effect.
Nagashima
K
K
Department of Pharmacology, Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Kusaka
H
H
Sato
K
K
Karasawa
A
A
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D002509:Cephaloridine / Q000633:toxicity; D004232:Diuretics / Q000494:pharmacology*; D004573:Electrolytes / Q000652:urine; D005665:Furosemide / Q000494:pharmacology; D008297:Male; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D014237:Trichlormethiazide / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology*
D004232:Diuretics; D004573:Electrolytes; D058915:Purinergic P1 Receptor Antagonists; D014970:Xanthines; C073525:rolofylline; D005665:Furosemide; D002509:Cephaloridine; D014237:Trichlormethiazide