The thromboxane receptor antagonist SQ 30,741 reduces myocardial infarct size in monkeys when given during reperfusion at a threshold dose for improving reflow during thrombolysis

Abstract

The threshold dose of the selective thromboxane receptor antagonist SQ 30,741 for increasing reflow during thrombolysis was identified and then evaluated in a model of myocardial ischemia with reperfusion. In anesthetized cynomolgus monkeys, stenotic carotid arteries were occluded with a platelet-rich thrombus by electrical stimulation and recanalized with streptokinase (680 U/min intraarterially for 1 h) and heparin (200 U/kg + 120 U/h intravenously for 3 h). Concurrent administration of SQ 30,741 (2.1 mg/kg + 0.5 mg/kg per h intravenously for 3 h; n = 4) enhanced the extent of reflow 174% compared with saline solution (n = 4; p < 0.05) during the third hour, when lower doses were ineffective.This threshold dose was tested in anesthetized African green monkeys subjected to 90 min of left circumflex coronary artery occlusion and 5 h of reperfusion. SQ 30,741 (n = 8) or saline solution (n = 11) was administered 2 min before reperfusion and continued throughout reperfusion. The heart was removed on termination of reperfusion and perfused in vitro with Evans blue and triphenyltetrazolium chloride dyes to stain tissue at risk and infarcted tissue, respectively. The percent of left ventricle at risk did not differ between saline- (37 ± 4%) and SQ 30,741-treated (35 ± 3%) monkeys. In contrast, infarcted tissue expressed as percent of the left ventricle at risk was less (p < 0.01) in monkeys receiving SQ 30,741 (31 ± 2%) than in those receiving saline solution (49 ± 5%).This 36% reduction in infarct size occurred without significant differences between treatments in hemodynamic variables and myocardial blood flows (as assessed by radioactive microspheres) measured during control, occlusion and reperfusion intervals. Thus, a dose of SQ 30,741 that stabilizes reflow after thrombolysis also possesses antiischemic activity when administered only during coronary reperfusion in monkeys.