Superoxide dismutases and anti-oxidants protected mice from no-reflow and necrotic damage induced by ischemia.
A simple method in mice was established to screen anti-ischemic compounds. Thirteen times binding of rubber ring (1 x 1 mm, d = 42 mm) for 4.5 hrs, swelled the paws of 60% mice applied and 14 times binding swelled only of 5% mice. Critically reversible limit lay between these conditions. "All or none" rule dominated the paw swelling perhaps due to different endogenous anti-oxidants' levels of individual mice. Determination of paw reversibility at 90 min of recirculation, was proved to be suitable. Swollen paws at this time returned normal and the paws with no-reflow dropped out by muscle necrosis after several days. Intravenous (i.v.) bovine Cu, Zn-SOD and bacterial Mn-SOD (3-10 x 10(4) U/kg) or liposomal Cu, Zn-SOD (0.3-3 x 10(4) U/kg) were protective (35-50%) by 14 times binding. Allopurinol (10-100 mg/kg) and D-mannitol (3-30 mg/kg) was effective (25-55%). Catalase (i.v., up to 10(5) U/kg) showed little protection, but local injection of 100 U/kg resulted in 50% protection. Glutathione (30 mg/kg) was suppressive only by local injection suggesting the importance of administration route. Desferal, heparin and nitric oxide synthesis inhibitor showed some protection, but indomethacin, mepyramine, ascorbate, vitamin E and dexamethasone were without effect. Excess dosing of all anti-oxidants tested, dramatically decreased their effects demanding caution for therapeutic trials.
Oyanagui
Y
Y
Pharmacology Section 2, Fujisawa Pharmacentical Co. Ltd., Osaka, Japan.
Sato
S
S
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005528:Foot / Q000098:blood supply; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009336:Necrosis; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D013482:Superoxide Dismutase / Q000494:pharmacology* / Q000627:therapeutic use
D000975:Antioxidants; D013482:Superoxide Dismutase