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Adenosine A1-receptor antagonists have been previously shown to possess protective effects in several nephrotoxic models of acute renal failure. To investigate the mechanism of protective effects of adenosine A1-receptor antagonists, we determined effects of 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902), a selective adenosine A1-receptor antagonist, on the accumulation of gentamicin (GM) into proximal renal tubules in rats. GM was intravenously administered at a dose of 10 mg/kg in anesthetized rats. KW-3902 (0.1 mg/kg) or its vehicle was given as a bolus injection 6 min before the GM injection. Administration of GM and KW-3902 did not affect the systemic blood pressure, heart rate, renal blood flow and glomerular filtration rate. KW-3902 did not affect the plasma concentration of GM. GM was accumulated in the proximal tubules 4 h after the GM injection. Treatment with KW-3902 significantly decreased the accumulation of GM into the proximal tubules. These results suggest that endogenous adenosine may accelerate the uptake of GM at the proximal tubules, and that the renoprotective effects of the adenosine A1-receptor antagonist may result from inhibiting this action of endogenous adenosine, leading to the suppression of intrarenal accumulation of GM.

Effect of KW-3902, a Selective Adenosine A1-Receptor Antagonist, on Accumulation of Gentamicin in the Proximal Renal Tubules in Rats