The dose-related cardioprotective efficacy of the
thromboxane A2/
prostaglandin endoperoxide (
TP) receptor antagonist,
ifetroban (BMS-180291), was investigated in an anesthetized ferret model of
myocardial ischemia (90 min) followed by reperfusion (5 h). Treatment was begun at either the 75th minute of
ischemia or 5 min after initiating reperfusion. The magnitude of
TP receptor blockade was evaluated by ex vivo platelet function. Additional experiments in ferrets tested the antithrombotic potency of
ifetroban as an inhibitor of thrombotic cyclic flow reduction (CFR) in the stenosed abdominal aorta (Folts model). Continuous
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
infarct size of 8, 43 and 56%. Delaying initiation of treatment with high-dose
ifetroban until 5 min into reperfusion also significantly reduced
infarct size by 45%. High-dose
ifetroban treatment did not prevent neutrophil (PMNL) accumulation measured as tissue
myeloperoxidase activity in infarcted tissue. At the end of the 5-hour reperfusion period, the low, medium and high doses produced 90, 98 and 98% blockade of platelet
TP receptors, respectively, measured as inhibition of ex vivo platelet shape change responses to U-46,619.
Ifetroban inhibited thrombotic CFR at a threshold dose of 0.03 +/- 0.004 mg/kg, which antagonized 92% of ferret platelet
TP receptors. Thus,
ifetroban exhibited cardioprotective and antithrombotic activities and was effective at doses producing > 90%
TP receptor blockade. Cardioprotective activity was not associated with any reductions of PMNL accumulation in infarcted tissue and was demonstrable even when treatment was delayed until 5 min after initiation of reperfusion.