Role of xanthine oxidase inhibitor as free radical scavenger: a novel mechanism of action of allopurinol and oxypurinol in myocardial salvage.
Xanthine oxidase (XO) has been hypothesized to be a potential source of oxygen-derived free radicals during reperfusion of ischemic myocardium based on the fact that allopurinol, a XO-inhibitor, can reduce reperfusion injury. In this communication we report that both allopurinol and oxypurinol, the principle metabolite of allopurinol, prevent the reperfusion injury in isolated pig heart. However, we found that neither pig heart nor pig blood contain any XO activity. Our study showed a direct free radical scavenging action of these XO-inhibitors during ischemia and reperfusion, as judged by the reduction of free radical signals when compared using an Electron Paramagnetic Resonance Spectrometer. Using a Luminometer, we also confirmed that both allopurinol and oxypurinol can scavenge ClO2, HOCl, and significantly inhibit free radical signals generated by activated neutrophils. These XO-inhibitors, however, failed to scavenge O2. and OH. radicals. Our results suggest that these XO-inhibitors salvaged the ischemic-reperfused myocardium by scavenging free radicals, and not by inhibiting XO in the pig heart.
Das
D K
DK
University of Connecticut School of Medicine, Farmington 06032.
Engelman
R M
RM
Clement
R
R
Otani
H
H
Prasad
M R
MR
Rao
P S
PS
D000255:Adenosine Triphosphate / Q000378:metabolism; D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D003327:Coronary Disease / Q000378:metabolism; D005260:Female; D005609:Free Radicals; D006321:Heart / Q000187:drug effects; D006878:Hydroxides; D017665:Hydroxyl Radical; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010117:Oxypurinol / Q000494:pharmacology*; D010725:Phosphocreatine / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D013552:Swine; D019820:Xanthine; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*; D014970:Xanthines / Q000378:metabolism
D005609:Free Radicals; D006878:Hydroxides; D007042:Hypoxanthines; D011743:Pyrimidines; D014970:Xanthines; D010725:Phosphocreatine; D019820:Xanthine; D019271:Hypoxanthine; D017665:Hydroxyl Radical; D000493:Allopurinol; D000255:Adenosine Triphosphate; D014969:Xanthine Oxidase; D010117:Oxypurinol