PROTECTIVE EFFECTS OF FK453, A POTENT NONXANTHINE ADENOSINE A(1) RECEPTOR ANTAGONIST, ON GLYCEROL-INDUCED ACUTE-RENAL-FAILURE IN RATS

The purpose of the present study was to examine the protective effect of FK453, (+)-(R)-1-[(E)-3-(2-phenylpyrazolo [1,5-a] pyridin-3-yl) acr yloyl]-2-piperidine ethanol, a potent nonxanthine adenosine A(1) recep tor antagonist, on glycerol-induced acute renal failure (ARF) in rat i n comparison with the effects of FR113452 (S-(-) enantiomer of FK453), 1,3-dipropyl-8-cyclopentylxanthine (adenosine A(1) receptor antagonis t), theophylline (nonselective adenosine receptor antagonist), CGS1594 3 ([1,2,4] triazolo [1,5-C] quinazolone, adenosine A(2A) receptor anta gonist), and typical diuretics (hydrochlorothiazide and furosemide). F K453 (1 and 10 mg/kg orally) significantly reduced serum creatinine an d urea concentrations in 25% glycerol (10 ml/kg intramuscularly)-induc ed ARF by protective treatment. The effect was similar to that of 1,3- dipropyl-8-cyclopentylxanthine and theophylline. FR113452 and CGS15943 had little effect on serum creatinine and urea concentrations. In con trast, hydrochlorothiazide and furosemide increased serum creatinine a nd urea concentrations. FK453, hydrochlorothiazide, and furosemide did not have any effect on either serum creatinine or urea concentration in 25% glycerol-induced ARF by therapeutic treatment. In 50% glycerol (10 ml/kg im)-induced ARF, FK453 reduced serum creatinine and urea con centrations, and increased urine volume and creatinine clearance. The results of the present study showed that FK453, a potent nonxanthine a denosine A(1) receptor antagonist, ameliorated glycerol-induced ARF in the rat. The findings support the idea that adenosine is an important factor in the development of glycerol-induced ARF in the rat and that the protective effect of adenosine receptor antagonist is mediated vi a the adenosine A(1) receptor. (C) 1997 Wiley-Liss, Inc.