MYOCARDIAL SALVAGE EFFICACY OF THE THROMBOXANE RECEPTOR ANTAGONIST IFETROBAN IN FERRETS AND DOGS

The effect of the thromboxane A(2) (TXA(2))/ prostaglandin endoperoxid e (TP) receptor antagonist ifetroban (EMS-180291) on infarct size (IS) resulting from coronary occlusion/reperfusion was determined in anest hetized dogs and ferrets. In dogs, ifetroban (1 + 1 mg/ kg/h, intraven ously, i.v.) or vehicle administration was initiated 10 min before lef t circumflex coronary artery (LCX) occlusion. In ferrets, the left ant erior descending coronary artery (LAD) was occluded; after 75 min, a c ontinuous infusion of ifetroban (0.3 + 0.3 mg/kg/h i.v.) or vehicle wa s started. After 90-min ischemia in both species, the LCX or LAD occlu sion was released; reperfusion was continued for 5 h, at which time IS was determined. Regional myocardial blood flow (RMBF) before and duri ng occlusion and during reperfusion were measured with radioactive mic rospheres. Ifetroban significantly decreased the extent of infarction to 39 +/- 5% of the area at risk (AAR) from 64 +/- 5% in dogs and to 1 5 +/- 2% of the left ventricle as compared with a control of 22 +/- 2% in ferrets. The protective effect of ifetroban in both species occurr ed with no increase in collateral BF or treatment-related alterations in peripheral hemodynamic status. Ifetroban, at the doses that reduced IS in ferrets, inhibited 99% of platelet TP receptors throughout the experiment, as measured by inhibition of the ex vivo platelet shape ch ange response to U-46,619, a TP receptor agonist. Thus, doses of ifetr oban causing profound TP receptor blockade also salvaged jeopardized m yocardium in dogs and ferrets without changing collateral BF or periph eral hemodynamics.