Xanthine oxidase: its role in the no-reflow phenomenon.
This study was designed to probe the hypothesis that oxygen-derived free radicals are involved in initiation of the no-reflow phenomenon. We developed a reproducible model of no reflow in the rat hind limb. Laser Doppler studies confirmed that the hind limbs perfused well after 2 or 4 hours of ischemia, but perfusion ceased in the first 10 minutes after 6 hours of ischemia. Venous blood samples and biopsy specimens of skin and muscle were taken after 2 and 4 hours of ischemia to study tissue injury. Blood samples were evaluated for xanthine oxidase (XO), xanthine dehydrogenase, and creatine phosphokinase (CPK) activities. Conjugated dienes and iodine 125-labeled albumin extravasation were quantified in tissue samples. Groups of animals were treated with inhibitors of XO (allopurinol), antioxidant enzymes (superoxide dismutase plus catalase), and free radical scavengers (dimethyl sulfoxide and dimethyl thiourea) to assess the roles of free radicals in ischemia-reperfusion injury in the hind limbs. After 4 hours of ischemia followed by reperfusion, plasma XO activity rose threefold over preischemia levels (p less than 0.05). Xanthine dehydrogenase activity did not change; conjugated diene levels in muscle rose twofold; CPK levels rose sixfold, and 125I albumin extravasation rose twofold (p less than 0.05). Pretreatment with the XO inhibitor allopurinol reduced XO activity to negligible levels and significantly attenuated conjugated diene levels, CPK levels, and albumin extravasation. Albumin extravasation was also significantly attenuated by pretreating animals with superoxide dismutase together with catalase, dimethyl thiourea, and dimethyl sulfoxide. In all animals pretreated with allopurinol or superoxide dismutase and catalase, reperfusion persisted after 6 hours of ischemia. These data suggest that, in ischemia followed by reperfusion, tissue injury is related to oxygen products derived from XO activity.
Punch
J
J
Section of Plastic and Reconstructive Surgery, University of Michigan, Ann Arbor.
Rees
R
R
Cashmer
B
B
Wilkins
E
E
Smith
D J
DJ
Till
G O
GO
D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D016166:Free Radical Scavengers; D005609:Free Radicals; D006614:Hindlimb / Q000098:blood supply*; D006632:Histamine / Q000097:blood; D007511:Ischemia / Q000503:physiopathology*; D051381:Rats; D011919:Rats, Inbred Strains; D012039:Regional Blood Flow / Q000187:drug effects; D015424:Reperfusion; D012710:Serum Albumin, Bovine / Q000493:pharmacokinetics; D014968:Xanthine Dehydrogenase / Q000097:blood; D014969:Xanthine Oxidase / Q000097:blood / Q000502:physiology*
D000975:Antioxidants; D016166:Free Radical Scavengers; D005609:Free Radicals; D012710:Serum Albumin, Bovine; D000493:Allopurinol; D006632:Histamine; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase; D003402:Creatine Kinase