MYOCARDIAL SALVAGE EFFICACY OF A THROMBOXANE RECEPTOR ANTAGONIST, SQ-30,741, IN RELATION TO INHIBITION EX-VIVO OF PLATELET-FUNCTION IN THE FERRET

The myocardial salvage efficacy of a thromboxane A2 / prostaglandin en doperoxide (TP) receptor antagonist has not been previously determined in a ferret model of ischemia and reperfusion. Assessments of the rep roducibility of infarct size resulting from a 90 min period of occlusi on followed by 5 hr of reperfusion of the left anterior descending cor onary artery in saline-treated control ferrets revealed a consistent m ean level of tissue damage representing 23.1 +/- 1.4% of the left vent ricle. In subsequent studies, ferrets were given the thromboxane recep tor antagonist SQ 30,741 (1 mg/kg bolus and 1 mg/kg/hr infusion, i.v.) or vehicle. At this dose, SQ 30,741 significantly reduced infarct siz e from that measured in control ferrets by 44%. Concurrently, the drug produced a 97% inhibition of platelet TP receptors as measured by inh ibition of the ex vivo platelet shape change response to U-46,619. Dru g administration was not associated with measurable alterations in mea n blood pressure, heart rate or the rate-pressure-product. The importa nce of this finding to clinical utility and the mechanism of the obser ved cardioprotective action, however, remain unclear. These data indic ate that the ferret represents a useful model for the assessment of th e myocardial salvage efficacy of TP receptor antagonists and are consi stent with attenuation of ischemic myocardial damage by doses of these agents which produce >96% TP receptor blockade.