Xanthine oxidase inhibition does not limit canine infarct size.
BACKGROUND
Evidence supporting the role of xanthine oxidase in myocardial reperfusion injury is based on studies with pharmacological interventions used to inhibit enzyme function. Controversy exists, however, regarding the true role of xanthine oxidase in reperfusion injury. This study was performed to determine whether xanthine oxidase inhibition limits myocardial injury due to coronary artery occlusion and reperfusion.


RESULTS
Anesthetized dogs underwent coronary artery occlusion (90 minutes) and reperfusion (6 hours). Oxypurinol (28 mg/kg) or amflutizole (30 mg/kg), chemically unrelated inhibitors of xanthine oxidase, or vehicle was infused intravenously 15 minutes before and 3 hours after reperfusion. Regional myocardial blood flow was determined with radiolabeled microspheres. Infarct size was determined with the tetrazolium method. Myocardial infarct size (percent of risk region) was less in oxypurinol-treated dogs, 32 +/- 16%, compared with that of the control group, 46 +/- 15%. Infarct size for the amflutizole-treated dogs, 40 +/- 21%, was not significantly different from that of the control group. There were no differences in rate-pressure product or collateral blood flow to account for differences in infarct size. Uric acid concentration in the coronary venous plasma increased after reperfusion in the dogs treated with vehicle but not in the drug-treated dogs. Xanthine oxidase inhibition was demonstrated in each of the drug treatment groups, but only oxypurinol limited the extent of myocardial injury.


CONCLUSIONS
Previously reported cardioprotective effects of allopurinol, noted to occur only when the drug was administered chronically, may be related to a property of oxypurinol, a major metabolite of allopurinol. The beneficial effect of oxypurinol is unrelated to inhibition of superoxide formation during xanthine oxidase-catalyzed oxidation of xanthine and hypoxanthine.
Werns
S W
SW
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0010.
Grum
C M
CM
Ventura
A
A
Hahn
R A
RA
Ho
P P
PP
Towner
R D
RD
Fantone
J C
JC
Schork
M A
MA
Lucchesi
B R
BR
D000818:Animals; D004285:Dogs; D005609:Free Radicals; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D010117:Oxypurinol / Q000627:therapeutic use*; D013844:Thiazoles / Q000627:therapeutic use*; D013997:Time Factors; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000502:physiology
D005609:Free Radicals; D013844:Thiazoles; C046749:amflutizole; D014969:Xanthine Oxidase; D010117:Oxypurinol