Can superoxide dismutase alter myocardial infarct size?

Abstract

superoxide was xanthine oxidase.17 Supportive evidence from other laboratories19-23 led to experimental attempts to reduce ischemic and reperfusion injury in animal models of myocardial infarction. In several studies, the addition of catalase was not felt to be necessary in vivo because of the presence of significant amounts in erythrocytes. Myocardial Infarct Size: Independent VariablesTo test the hypothesis that SOD will reduce infarct size in an animal model, all other significant independent variables must be known and measured. The Animal Models for Protecting Ischemic Myocardium (AMPIM) cooperative study in dogs found that the anatomic area at risk, collateral blood flow, and hemodynamic determinants of myocardial oxygen demand (measured as the ratepressure product) could explain most of the variance in infarct size with the protocol used.24 However, indexes of contractility were not measured. There were small, unexplained differences in infarct size between participating laboratories, and there was lower collateral blood flow in anesthetized than in conscious dogs. The unexplained differences in infarct size and collateral flow suggest the existence of other unmeasured independent variables that may alter collateral flow and thereby explain some of the residual variance. Also, the preparatory surgery may have induced collateral development in the conscious model, in which 80% of the variability could be explained by the measured indexes (including collateral blood flow). The AMPIM study concluded that a 10% (in unconscious animals) to 13% (in conscious animals) reduction in infarct size (p<0.05) would be detected only 50% of the time with 15 animals each in the control and treatment groups. Statistical ConsiderationsThe AMPIM study clearly shows that in the dog model considerable variation exists in area at risk, collateral flow, and hemodynamic indexes (rate pressure product); thus, any intervention trial should measure and include these variables in the analysis of the results. Several published SOD trials involving animals did not measure collateral blood flow,2,3 whereas in pigs5 and rabbits,13 flow measurements

Reperfusion injury and its pharmacologic modification.

“…72 Neutrophils may be a source of free radicals during reperfusion injury. Lucchesi and colleagues73 have suggested that leukocytes influence infarct size by the production of free radicals.…”

Reperfusion injury induces apoptosis in rabbit cardiomyocytes.

“…Reperfusion is associated with polymorphonuclear leukocyte (PMN) accumulation, a burst of oxygen free radical production, activation of inflammation, excessive calcium entry, and possibly late cell death; however, the exact mechanisms whereby free radicals, calcium entry, or inflammation might result in lethal injury are not well defined (5)(6)(7)(8)(9)(10)(11)(12). Studies using superoxide dismutase and other antioxidants have provided interesting leads, suggesting that the oxidative stress and burst of free radical production associated with reperfusion are important mediators of myocardial damage; however, no clear answers have emerged (13). In animal models the net benefit of timely flow restoration outweighs the combination of ischemic and reperfusion injury.…”

Influence of postischemic administration of oxyradical antagonists on ischemic injury to rabbit skeletal muscle

“…20 The biochemical parameters measured were chosen to reflect different aspects of IRI: GSH as an important tissue antioxidant, which is depleted when free radical production increases; MPO as an index of neutrophil infiltration, neutrophils (MPO) being one of the sources of free radicals in postischemic tissue; and ATP as an index of the energetic state of the tissue.…”

“…11 However, chemotactic factors are released continuously during reperfusion and stimulate neutrophils to enter the injured tissue and act as a source of superoxide for much longer than the tissue halflife of SOD (<30 min). 20,35 In support of this hypothesis, Ricci et al, 32 examining the effects of SOD administration in a canine compartment syndrome model, demonstrated decreased technetium pyrophosphate uptake after 1 hr of reperfusion, but found no effect on muscle function after 17 hr reperfusion.…”

“…33,34 However, studies with cardiac muscle suggest that changes observed in the early stages of reperfusion may not be an accurate guide to the protective effect of SOD and CAT on muscle injury 24 hr or more later. 20 SOD and CAT may merely delay the injury by ablating the initial burst of superoxide production that provokes early neutrophil immigration. 11 However, chemotactic factors are released continuously during reperfusion and stimulate neutrophils to enter the injured tissue and act as a source of superoxide for much longer than the tissue halflife of SOD (<30 min).…”