Effects of xanthine oxidase inhibition on ischemic acute renal failure in the rat.
To assess the effects of xanthine oxidase (XO) inhibition on ischemic injury, rats were pretreated with oxypurinol (OXY, 5 mg/kg) and subjected to 30 min of bilateral renal artery occlusion. OXY's effect on adenine nucleotide-nucleoside-purine base concentrations was determined at 10 and 30 min of ischemia and during reperfusion (5 and 30 min). To assess whether XO-mediated oxidant stress influences the severity of ischemic acute renal failure (IARF), the effects of 1) OXY pretreatment and 2) hypoxanthine infusion were assessed. During ischemia OXY inhibited XO activity (more than fourfold rise in hypoxanthine-xanthine ratios) and induced quantitatively trivial but significant increases in ATP and total adenine nucleotide concentrations (by 30 min). Increased OXY dosage (15 mg/kg) or allopurinol (40 mg/kg) had no greater effects. At 5 min of reflow, OXY maintained XO inhibition but did not influence adenine nucleotide levels. By 30 min of reflow, 17-20% increments in ATP-total adenine nucleotides resulted. Nevertheless, OXY did not lessen the severity of IARF (assessed by azotemia-histology at 24 h). Hypoxanthine infusion increased end-ischemic hypoxanthine concentrations by 47%, but it did not change the severity of renal damage. Conclusions include 1) OXY-allopurinol induces intrarenal XO inhibition; 2) XO inhibitors slightly increase late ischemic-reperfusion adenine nucleotide concentrations; and 3) neither XO inhibition nor intrarenal hypoxanthine loading alters the severity of IARF, suggesting that XO-mediated oxidant stress is not a critical, consistent mediator of ischemic renal injury.
Zager
R A
RA
Department of Medicine, University of Washington, Seattle.
Gmur
D J
DJ
D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism*; D000227:Adenine Nucleotides / Q000378:metabolism*; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D005260:Female; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000378:metabolism; D007288:Inosine / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D010117:Oxypurinol / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012077:Renal Artery / Q000502:physiology; D012079:Renal Circulation; D015424:Reperfusion; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
D000227:Adenine Nucleotides; D007042:Hypoxanthines; D011743:Pyrimidines; D019271:Hypoxanthine; D007288:Inosine; D000493:Allopurinol; D014969:Xanthine Oxidase; D010117:Oxypurinol