Role of xanthine oxidase in reperfusion injury of ischemic skeletal muscles in the pig and human.
We investigated whether xanthine oxidase (XO) is a major source of oxygen-derived free radicals (oxy-radicals) in the pig and human skeletal muscles. It was observed that xanthine dehydrogenase and XO activities in nonischemic pig latissimus dorsi (LD) and gracilis muscles and human LD and rectus abdominis (RA) muscles were < 0.5 mU/g wet wt. The pig LD muscle hypoxanthine content increased significantly from 0.33 +/- 0.02 to 2.33 +/- 0.44 mumol/g dry wt after 5 h of warm ischemia, but the muscle uric acid content remained unchanged up to 2 h of reperfusion. Similarly, the hypoxanthine content in the human LD and RA muscles increased from 0.33 +/- 0.03 to 0.84 +/- 0.23 mumol/g dry wt after 2.0-3.5 h of warm ischemia, and the muscle uric acid content remained unchanged at the end of 15-90 min of reperfusion. Furthermore, 5 days of allopurinol treatment (25 mg/kg iv twice daily) starting 2 days before ischemia or 3 days of oxypurinol treatment (25 mg/kg iv twice daily) starting 15 min before reperfusion did not attenuate the extent of skeletal muscle necrosis in pig LD muscles subjected to 5 h of ischemia and 48 h of reperfusion. However, deferoxamine treatment (250 mg/kg iv twice daily) starting before or after ischemia, as described above, significantly reduced the extent of pig LD muscle necrosis. Finally, at 2 and 48 h of reperfusion significantly higher muscle neutrophil contents were seen in ischemic than in nonischemic control pig LD muscles. Neutrophil depletion with mechlorethamine (0.75 mg/kg iv) significantly reduced the extent of necrosis in pig LD muscles. These observations indicate that XO is not a major source of oxy-radicals in ischemia/reperfusion injury in the pig gracilis and LD muscles and human RA and LD muscles.
Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
D
D
Dorion
A
A
Zhong
C
C
Chiu
C R
CR
Forrest
B
B
Boyd
C Y
CY
Pang
D000328:Adult; D000493:Allopurinol / Q000097:blood / Q000494:pharmacology; D000818:Animals; D001772:Blood Cell Count; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D007042:Hypoxanthines / Q000378:metabolism; D008297:Male; D008466:Mechlorethamine / Q000494:pharmacology; D009132:Muscles / Q000201:enzymology* / Q000473:pathology; D009336:Necrosis; D009504:Neutrophils / Q000201:enzymology / Q000502:physiology; D009919:Orchiectomy; D010117:Oxypurinol / Q000097:blood / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology*; D013552:Swine; D014527:Uric Acid / Q000378:metabolism; D014968:Xanthine Dehydrogenase / Q000378:metabolism; D014969:Xanthine Oxidase / Q000502:physiology*; D014970:Xanthines / Q000378:metabolism
D007042:Hypoxanthines; D017382:Reactive Oxygen Species; D014970:Xanthines; D014527:Uric Acid; D008466:Mechlorethamine; D000493:Allopurinol; D009195:Peroxidase; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase; D010117:Oxypurinol