Laboratory Investigation Myocardial Infarction

Reactive oxygen species such as the superoxide anion (-O2-) have recently been implicated as important agents involved in causing cell death in the setting of myocardial ischemia and reperfusion. When superoxide anion is involved in ischemic injury the administration of superoxide dismutase (SOD) may limit infarct size by reducing the level of superoxide anions in the myocardium. The study described herein was done to determine whether SOD could limit myocardial infarct size when infarcts were produced in dogs by a 40 min occlusion of the circumflex coronary artery followed by 4 days of reperfusion. The animals in the SOD treatment group received a 1 hr intra-atrial infusion of SOD, at a rate of 250 U/kg/min starting 15 min after occlusion and ending 35 min after reperfusion; control dogs received a saline infusion over the same time frame. Infarct size was determined histologically and expressed as a percentage of the anatomic area at risk (AAR). Infarct size was similar in the two groups, averaging 26.2 + 2.5% in the control group (n = 10) and 21.1 4.8% in the SOD group (n = 11) (p = .40). Hemodynamic variables were not statistically different in the two groups during the occlusion. The transmural mean collateral blood flow at 10 min into the 40 min occlusion was 0.13 + 0.02 ml/min/g in the controls and 0.17 + 0.03 ml/min/g in the SOD group (p = NS); moreover, SOD did not alter collateral blood flow. In control dogs, infarct size was inversely related to collateral blood flow; analysis of covariance showed that SOD did not shift this relationship. Thus, SOD did not limit infarct size in this study. The results of the current study are consistent with our previous study in which allopurinol, a xanthine oxidase inhibitor, did not limit infarct size in this same experimental preparation. The results suggest that superoxide anions that are accessible to the infused SOD are not a major cause of myocyte death caused by 40 min of severe ischemia followed by reperfusion. Circulation 75, No. 6, 1237-1248, 1987. REACTIVE OXYGEN SPECIES, including the superoxide anion (O20-), the hydroxyl radical (-OH), and hydrogen peroxide (H202) have been implicated as agents of cellular damage in several disease processes, including ischemia and reperfusion of the heart.1 Although the total amount and quantitatively most important sources of reactive oxygen metabolites in ischemic myocardium are not known, several sources have been proposed, including (1) the NADPH oxidase reaction of activated neutrophils, (2) the xanthine oxidase reaction (where hypoxanthine is oxidized to xanthine and From the Department of Pathology, Duke University Medical Center, Durham, NC. Supported in part by grants 27416 and 23138. Address for correspondence: Keith A. Reimer, M.D., PhD., Department of Pathology, Box 3712, Duke University Medical Center, Durham, NC 27710. Received July 27, 1986; revision accepted March 13, 1987. Vol. 75, No. 6, June 1987 uric acid concomitant with formation of 02 -, (3) "leaky" mitochondrial respiration, (4) enzymatic steps in arachidonic acid metabolism, and (5) autooxidation of catecholamines."s 3 5-12 Some oxygen-centered free radicals may be produced during ischemia from oxygen delivered via collateral blood flow. However, it is thought that most free radicals are likely to be produced upon reperfusion, when reactive hyperemia provides abundant supplies of oxygen to myocardium that has been "primed" by ischemia. In addition, the concentration of antioxidants, such as reduced glutathione and superoxide dismutase (SOD), may be reduced by ischemia. 13, 14 The concept of a burst of free radical production upon reperfusion has led to the hypothesis that some myocytes that are still viable after an episode of ischemia may be killed by free radical-mediated dam1237 by gest on A ril 5, 2017 http://ciajournals.org/ D ow nladed from