Amelioration of glycerol-induced acute renal failure in the rat with 8-cyclopentyl-1,3-dipropylxanthine.
1. Previous studies have shown that 8-phenyltheophylline (8-PT), a non-selective antagonist at adenosine A1- and A2-receptors, can ameliorate the severity of glycerol-induced acute renal failure (ARF) in the rat. In the present study we have examined the effects of an antagonist with selectivity for adenosine A1-receptors (8-cyclopentyl-1,3-dipropylxanthine, CPX) on the development of ARF. 2. In the anaesthetised rat 8-PT (4 mg kg-1, i.v.) and CPX (0.1 mg kg-1, i.v.) antagonised adenosine-evoked responses which are thought to be mediated via A1-receptors (bradycardia and decrease in renal blood flow). The agonist dose-ratio produced by CPX was equal to or greater than that found with 8-PT (heart rate and renal blood flow respectively). The hypotensive response to adenosine which is predominantly due to A2-receptor activation was also antagonised by 8-PT, whereas CPX was a much less effective antagonist of this response. 3. Administration of CPX (0.1 mg kg-1, i.v.; twice daily for two days) significantly attenuated the increase in plasma levels of urea and creatinine, the increased kidney weight and the renal tubule damage observed in rats 2 days following induction of ARF with intramuscular glycerol injection. In addition treatment with CPX significantly enhanced the clearances of inulin and p-aminohippurate. 4. After glycerol injection, the mortality rate over 7 days in untreated and vehicle-treated rats was 43% and 21% respectively. In contrast, all animals treated with CPX survived over the 7 day observation period. 5. These results support the suggestion that adenosine is an important factor in the development of ARF and indicate that this effect of the purine is likely to be mediated via an adenosine A1-receptor.
Kellett
R
R
Department of Pharmacology, University of Leeds.
Bowmer
C J
CJ
Collis
M G
MG
Yates
M S
MS
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D005990:Glycerol / Q000633:toxicity*; D006339:Heart Rate / Q000187:drug effects; D007444:Inulin / Q000097:blood; D007668:Kidney / Q000473:pathology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012039:Regional Blood Flow / Q000187:drug effects; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology; D010130:p-Aminohippuric Acid / Q000097:blood
C053907:8-cyclopentyl-1,3-dimethylxanthine; D007444:Inulin; D003404:Creatinine; D013806:Theophylline; D005990:Glycerol; D010130:p-Aminohippuric Acid