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Abstract
A potent adenosine A, receptor antagonist, FR-113453, was tested for its preventive effect on glycerol-induced acute renal failure in rats. First, the optimum timing of FR-113453 administration was studied. Oral FR-113453 (100 mg/kg) given 1 h before or 5–10 min after glycerol injection produced a significant reduction of the serum creatinine at 24 h (4.3 ± 0.8 mg/dL [vehicle] vs. 1.4 ± 0.4 mg/dL [FR-113453], and 4.7 ± 1.1 mg/dL vs. 1.3 ± 0.6 mg/dL, respectively, p < 0.001). However, when FR-113453 was given 2 h after glycerol injection, the serum creatinine did not improve. Creatinine clearance at 24 h after the induction of acute renal failure was significantly better in rats given FR-113453 (100 mg/kg) 1 h before glycerol than in rats given vehicle alone (0.08 ± 0.08 mL/min vs. 0.01 ± 0.02 mL/min), (p < 0.01). The kidney weight was lower and less severe histologic changes were observed at 24 h in the FR-113453-treated group. Renal blood flow (measured using 85Sr microspheres) did not change at 24 h after glycerol injection (3.0 ± 0.9 mL/min/g [vehicle] vs. 3.6 ± 0.9 mL/minig [FR-113453]), but renal vascular resistance was significantly reduced by FR-113453 (47.9 ± 37.9 vs. 26.4 ± 5.2 mm Hg/mL/min/g, p < 0.05). Beta-ATP levels (measured by 3IP-magnetic resonance spectroscopy) were reduced in glycerol-induced acute renal failure, with no difference between the vehicle and FR-113453-treated groups. These results demonstrate that FR-113453 ameliorates glycerol-induced acute renal failure when administered before or just after glycerol injection, indicating that adenosine has a very important role in the induction of acute renal failure by glycerol.
