Protective action of a thromboxane synthetase inhibitor in preventing extension of infarct size in acute myocardial infarction.

ABSTRACT

U-63,557A, a new selective thromboxane synthetase inhibitor, was evaluated for its ability to prevent the extension of myocardial infarct size. Left coronary arteries of male Sprague-Dawley rats (230 - 270 g) were acutely ligated, producing a consistent model of myocardial infarction (MI) in rats analyzed 48 hours later. Left ventricular free wall (LVFW), creatine kinase (CK) activity, and amino-nitrogen concentrations were assayed as indices of infarct size. U-63,557A was administered intravenously in two doses (4 and 8 mg/kg) with a split schedule (2 min post-ischemia and either 4 or 24 hrs later). Administration of the thromboxane synthetase inhibitor significantly reduced both myocardial CK and amino-nitrogen loss at a dose of 8 mg/kg, but it was only slightly effective at 4 mg/kg. Drug treatment significantly increased the percent LVFW spared; 27 +/- 3% (vehicle) vs 43 +/- 7% and 52 +/- 7% (8 mg/kg). U-63,557A is an effective agent in myocardial ischemia for limiting the extension of infarct size after acute coronary artery ligation. Previous studies of other thromboxane synthetase inhibitors showed effectiveness in the early stages of MI. This study shows an effect on true infarct size 48 hours post-ligation, and suggests that inhibition of thromboxane A2 plays an important role in the pathogenesis of ischemic damage in the myocardium.