Effect of Intravenous Administration of Antioxidants Alone and in Combination on Myocardial Reperfusion Injury in an Experimental Pig Model

BACKGROUND: Several antioxidants have been found to have conflicting results in attenuating myocardial reperfusion injury. These Studies were done primarily in experimental protocols that did not approximate clinical situations. OBJECTIVE: The aim of this study was to test the efficacy of 3 different antioxidants (ascorbic acid [AA], desferrioxamine, and N-acetylcysteine [NAC]) administered IV alone and in combination in a closed-chest pig model. METHODS: Farm-raised domestic male pigs (aged 3-5 months, weight of 3035 kg) were assigned to I of 5 groups to receive treatment as follows: group A, AA 100 mg/kg; group B, desferrioxamine 60 mg/kg; group C, a loading dose of NAC 100 mg/kg for 20 minutes and a 20-mg/kg maintenance dose; group D, all 3 drugs in combination; and group E, normal saline (control group). The infusion of all drugs was started 15 minutes before and completed 5 minutes after reperfusion, except for the administration of NAC, which was terminated 60 minutes postreperfusion. Myocardial ischemia (45 minutes) and reperfusion (2 10 minutes) were achieved percutaneously by circumflex artery balloon occlusion. Ejection fraction, left ventricular end-diastolic pressure (LVEDP), flow in the infarcted artery, and all ventricular arrhythmias were recorded. Oxidative stress was estimated by serial measurements of thiobarbituric acid reactive substance (TBARS) concentration in coronary sinus blood. Infarct size was assessed as a percentage of the area at risk (I/R ratio) using the tetrazolium red staining method. RESULTS: The 25 pigs were divided into 5 groups of 5 pigs each. No significant between-group differences were found in I/R ratio or in oxidative stress (as measured by TBARS concentration). Group C developed significantly more ventricular arrhythmias than the control group (80% vs 0%, P = 0.02). No other differences among groups were found. LVEDP was significantly elevated in all treatment groups (mean LVEDP difference [SD] for group A, 6.0 [1.6] mm Hg; group B, 17.6 [1.9] mm Hg; group C, 3.6 [1.7] mm Hg; group D, 6.8 [3.2] and group E, 5.4 [3.4] mm Hg). LVEDP elevation was found to be significantly higher in group B compared with all the other groups (all, P < 0.001). No significant between-group differences were found in the other parameters measured. CONCLUSION: In this experimental pig model, the antioxidants AA, desferrioxamine, and NAC administered alone or in combination did nor reduce the deleterious effects of reperfusion injury and specifically the extent of myocardial necrosis. (Curr Ther Res Clin Exp. 2008-169:423-439) (c) 2008 Excerpta Medica Inc.