Limitation of myocardial infarct size in pigs with a dual lipoxygenase-cyclooxygenase blocking agent by inhibition of neutrophil activity without reduction of neutrophil migration

Department of Internal Medicine, University of California, Davis 95616.

OBJECTIVES. The purpose of this study was to assess the effect of the dual cyclooxygenase-lipoxygenase blocking agent BW755C on the extent of myocardial infarction in the pig and to identify the mechanisms of any cardioprotective action of this drug. BACKGROUND. Activated neutrophils contribute to reperfusion injury after myocardial infarction and inhibition of neutrophil function can limit infarct size. METHODS. In 9 control and 10 study pigs pretreated with intravenous BW755C (10 mg/kg body weight) 30 min before coronary occlusion, ischemia was induced by a 50-min occlusion of the mid-left anterior descending coronary artery, followed by 3 h of reperfusion. Heart rate, arterial pressure, left ventricular end-diastolic pressure, the first derivative of left ventricular pressure (dP/dt) and regional myocardial blood flow were measured during control, occlusion and reperfusion periods. Infarct size was determined by histochemical staining; and myeloperoxidase activity, a marker for tissue neutrophil content, was assessed in normal and infarcted myocardium. The effect of BW755C on the function of isolated neutrophils stimulated with zymosan-activated serum was evaluated by measuring neutrophil degranulation, leukotriene B4 production, superoxide generation and chemotaxis. RESULTS. Hemodynamic function and regional myocardial blood flow were similar in control and BW755C-treated animals. BW755C significantly reduced myocardial infarct size compared with that in control animals, as measured by infarct/risk areas by histochemical staining (39 +/- 5% vs. 63 +/- 7%, p < 0.05). Myocardial myeloperoxidase activity was similar in normal, salvaged and infarcted areas in the control and treated groups, indicating that neutrophil accumulation in injured myocardium was unaltered by BW755C. However, this agent attenuated function of isolated, stimulated (zymosan-activated serum) neutrophils. At a concentration of 0.03 mg/ml, BW755C inhibited degranulation (-46%), leukotriene B4 production (-48%) and superoxide generation (-74%), but there was minimal inhibition of chemotaxis in vitro. CONCLUSIONS. These findings demonstrate that myocardial infarct size can be reduced by selective inhibition of neutrophil cytotoxic activity without affecting neutrophil migration into injured myocardium.

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