LIMITATION OF MYOCARDIAL INFARCT SIZE IN PIGS WITH A DUAL LIPOXYGENASE-CYCLOOXYGENASE BLOCKING-AGENT BY INHIBITION OF NEUTROPHIL ACTIVITY WITHOUT REDUCTION OF NEUTROPHIL MIGRATION

Objectives. The purpose of this study was to assess the effect of the dual cyclooxygenase-lipoxygenase blocking agent BW755C on the extent o f myocardial infarction in the pig and to identify the mechanisms of a ny cardioprotective action of this drug. Background. Activated neutrop hils 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/k g body weight) 30 min before coronary occlusion, ischemia was induced by a 50-min occlusion of the mid left anterior descending coronary art ery, followed by 3 h of reperfusion. Heart rate, arterial pressure, le ft ventricular end diastolic pressure, the first derivative of left ve ntricular pressure (dP/dt) and regional myocardial blood flow were mea sured 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 i nfarcted myocardium. The effect of BW755C on the function of isolated neutrophils stimulated with zymosan-activated serum was evaluated by m easuring neutrophil degranulation, leukotriene B-4 production, superox ide generation and chemotaxis. Results. Hemodynamic function and regio nal myocardial blood Bow were similar in control and BW755C-treated an imals. BW755C significantly reduced myocardial infarct size compared w ith that in control animals, as measured by infarct/risk areas by hist ochemical staining (39 +/- 5% vs. 63 +/- 7%, p < 0.05). Myocardial mye loperoxidase activity was similar in normal, salvaged and infarcted ar eas in the control and treated groups, indicating that neutrophil accu mulation in injured myocardium was unaltered by BW755C. How ever, this agent attenuated function of isolated, stimulated (zymosan-activated serum) neutrophils. At a concentration of 0.03 mg/ml, BW755C inhibited degranulation (-46%), leukotriene B-4 production (-48%) and superoxid e generation (-74%), but there was minimal inhibition of chemotaxis in vitro. Conclusions. These findings demonstrate that myocardial infarc t size can be reduced by selective inhibition of neutrophil cytotoxic activity without affecting neutrophil migration into injured myocardiu m.