Amelioration of cisplatin-induced acute renal failure with 8-cyclopentyl-1,3-dipropylxanthine.
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.
Knight
R J
RJ
Department of Pharmacology, The University, Leeds.
Collis
M G
MG
Yates
M S
MS
Bowmer
C J
CJ
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D000241:Adenosine / Q000037:antagonists & inhibitors; D000818:Animals; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004573:Electrolytes / Q000652:urine; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007668:Kidney / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D014508:Urea / Q000097:blood; D014970:Xanthines / Q000494:pharmacology*; D010130:p-Aminohippuric Acid / Q000652:urine
D004573:Electrolytes; D014970:Xanthines; D014508:Urea; C051360:1,3-dipropyl-8-cyclopentylxanthine; D003404:Creatinine; D000241:Adenosine; D002945:Cisplatin; D010130:p-Aminohippuric Acid