DOSE-RELATED CARDIOPROTECTION BY IFETROBAN IN RELATION TO INHIBITION OF THROMBOSIS AND EX-VIVO PLATELET-FUNCTION

The dose-related cardioprotective efficacy of the thromboxane A(2)/pro staglandin endoperoxide (TP) receptor antagonist, ifetroban (BMS-18029 1), was investigated in an anesthetized ferret model of myocardial isc hemia (90 min) followed by reperfusion (5 h). Treatment was begun at e ither the 75th minute of ischemia or 5 min after initiating reperfusio n. The magnitude of TP receptor blockade was evaluated by ex vivo plat elet function. Additional experiments in ferrets tested the antithromb otic potency of ifetroban as an inhibitor of thrombotic cyclic flow re duction (CFR) in the stenosed abdominal aorta (Felts model). Continuou s ifetroban infusions of 0.03, 0.1 and 0.3 mg/kg/h reduced myocardial infarct size from 22% of the left ventricle in vehicle-control ferrets to 20, 12 and 9%, respectively. These represented reductions in infar ct size of 8, 43 and 56%. Delaying initiation of treatment with high-d ose ifetroban until 5 min into reperfusion also significantly reduced infarct size by 45%. High-dose ifetroban treatment did not prevent neu trophil (PMNL) accumulation measured as tissue myeloperoxidase activit y in infarcted tissue. At the end of the 5-hour reperfusion period, th e low, medium and high doses produced 90, 98 and 98% blockade of plate let TP receptors, respectively, measured as inhibition of ex vivo plat elet shape change responses to U-46,619. Ifetroban inhibited thromboti c CFR at a threshold dose of 0.03 +/- 0.004 mg/kg, which antagonized 9 2% of ferret platelet TP receptors. Thus, ifetroban exhibited cardiopr otective and antithrombotic activities and was effective at doses prod ucing > 90% TP receptor blockade. Cardioprotective activity was not as sociated with any reductions of PMNL accumulation in infarcted tissue and was demonstrable even when treatment was delayed until 5 min after initiation of reperfusion.