1. The effect of the selective
adenosine A1-receptor antagonist,
8-cyclopentyl-1,3-dipropylxanthine (CPX), on the development of
cisplatin-induced
acute renal failure was investigated in the rat. 2. CPX at doses of 0.03, 0.1 and 0.3 mg kg-1, i.v. caused increasing degrees of antagonism of
adenosine-induced
bradycardia in anaesthetized rats. The magnitude of antagonism was not directly proportional to the increment in dose, but for each dose, it was similar in rats injected with either saline or
cisplatin. CPX at a dose of 0.03 mg kg-1 significantly antagonized
adenosine-induced
bradycardia for up to 2.5 h, while doses of 0.1 and 0.3 mg kg-1 produced significant blockade for periods longer than 5 h. 3. Administration of
cisplatin (6 mg kg-1, i.v.) caused
acute renal failure characterized by decreased
inulin and
p-aminohippurate clearances, increased urine volume but decreased excretion of Na+, K+ and Cl-
ions and by increased plasma levels of
urea and
creatinine. Kidney weight was increased in
cisplatin-treated rats and
renal tubule necrosis occurred. 4. Administration of CPX (0.03 mg kg-1, i.v.; twice daily for two days) to rats given
cisplatin did not reduce the severity of the resultant
renal failure. However, treatment with 0.1 mg kg-1 CPX attenuated the increases in plasma
creatinine/
urea levels observed in rats on days 3 and 7 after induction of
renal failure. In addition, this dose significantly reduced renal tubule damage and increased
inulin and
p-aminohippurate clearances. A similar pattern of protection was noted with CPX at a dose of 0.3 mg kg-1 although the increase in
inulin clearance was not statistically significant. However, this higher dose of CPX significantly increased Na+ and K+ excretion compared to vehicle-treated rats. 5 CPX at doses of 0.03, 0.1 and 0.3 mgkg- produced blockade of an A1-receptor mediated response i.e.
adenosine-induced
bradycardia, but only treatment with the higher doses of CPX (0.1 and 0.3mgkg-1) ameliorated nephrotoxicity produced by
cisplatin. The lack of any protective effect afforded by the lowest dose of CPX could be a result of its shorter duration of action.6. This study indicates that
adenosine plays a significant role in the pathophysiology of
cisplatin-induced
acute renal failure.