The cardioprotective effect of Mn-superoxide dismutase is lost at high doses in the postischemic isolated rabbit heart.
The loss of protection by human recombinant (hr) Cu.Zn-superoxide dismutase (SOD) at higher doses reported previously may have been due to the weak peroxidase activity of this enzyme. To test this possibility we studied the dose-response relationship of hrMn-SOD, which lacks peroxidase activity. Isolated, buffer perfused rabbit hearts were subjected to 1 h of global ischemia followed by 1 h of reperfusion, and the percent recovery of developed tension (relative to preischemic) was measured via a left ventricular balloon connected through a pressure transducer to a polygraph recorder. The coronary effluent was assayed for lactate dehydrogenase (LDH) release. While hrMn-SOD almost completely protected against loss of function and LDH release at 2 and 5 mg/L (p less than 0.01), it exacerbated the damage at 50 mg/L concentration (p less than 0.05 against controls), thus giving an even sharper bell-shaped curve than seen with the hrCu,Zn-SOD. Therefore we conclude that, first, while the hrMn-SOD protects the reperfused heart at lower doses, it may exacerbate the damage at higher doses. Second, that the lack of protection seen at higher doses of hr-Cu,Zn-SOD is unlikely to be due only to its peroxidase activity.
Omar
B A
BA
Webb-Warning Lung Institute, University of Colorado, Denver 80262.
McCord
J M
JM
D000818:Animals; D003327:Coronary Disease / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000008:administration & dosage / Q000494:pharmacology*
D011994:Recombinant Proteins; D007770:L-Lactate Dehydrogenase; D013482:Superoxide Dismutase