fk-453 and Acute-Kidney-Injury

Topics: Acute Kidney Injury; Adenosine; Animals; Endothelins; Epidermal Growth Factor; Heat-Shock Proteins; Hepatocyte Growth Factor; Humans; Male; Oxygen; Purinergic Antagonists; Pyrazoles; Pyridines; Rats; Rats, Sprague-Dawley

The adenosine A1 receptor antagonist (FR113453) prevents glycerol- but not mercury-induced acute renal failure. To clarify this mechanism, adenosine concentration in the renal vein was measured serially. Plasma adenosine in the renal vein increased from the preinjection value of 120.6 +/- 15.4 (mean +/- SEM) pmol/ml to 426.9 +/- 107.5, 407.0 +/- 70.1 and 283.9 +/- 22.9 pmol/ml at 1, 5 and 60 min after intramuscular injection of 10 mg/kg of 50% glycerol into Sprague-Dawley rats. On the other hand, intramuscular vehicle (0.9% NaCl) injection and subcutaneous administration of 10 mg/kg of HgCl2 did not change or caused mild elevation of adenosine concentration in the renal vein. Furthermore, simultaneous blood collection from the carotid artery, renal vein and inferior vena cava revealed a greater increase in adenosine concentration in the inferior vena cava than in the artery or renal vein. These findings were not affected by the administration of FR113453 or vehicle (methylcellulose). The increase in adenosine in the inferior vena cava was derived from the release from the acutely damaged muscles due to glycerol injection. These findings suggest that the effect of adenosine A1 antagonist to prevent glycerol-induced acute renal failure is due to the inhibition of adenosine A1 receptor in the kidneys during the release of adenosine through the inferior vena cava. Therefore, the release of adenosine from the muscle and hemolysis plays an important role to induce acute renal failure in the glycerol-injected rat.

Topics: Acute Kidney Injury; Adenosine; Animals; Carotid Arteries; Glycerol; Mercuric Chloride; Purinergic Antagonists; Pyrazoles; Pyridines; Rats; Rats, Sprague-Dawley; Renal Veins; Time Factors; Vena Cava, Inferior

A potent adenosine A1 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/min/g [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 31P-magnetic resonance spectroscopy) were reduced in glycerol-induced acute renal failure, with no difference between the vehicle and FR-113453-treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Kidney Injury; Adenosine; Adenosine Triphosphate; Animals; Creatinine; Glycerol; Kidney; Magnetic Resonance Spectroscopy; Purinergic Antagonists; Pyrazoles; Pyridines; Rats; Rats, Sprague-Dawley; Renal Circulation; Time Factors