FAILURE OF ASPIRIN TO INTERFERE WITH THE CARDIOPROTECTIVE EFFECTS OF IFETROBAN

The thromboxane receptor antagonist ifetroban ([1S-(1 alpha,2 alpha,3 alpha,4 ntylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2. .1]hept-2-y l]methyl]benzenepropanoic acid) and aspirin were evaluated for direct and combined effects on myocardial infarct size in anesthetized ferret s subjected to coronary artery occlusion (90 min) and reperfusion (5 h ). Aspirin (10 mg/kg) or vehicle was administered as an i.v. bolus dos e at the 45th min of occlusion in an initial assessment of its cardiop rotective potential in this species. In interaction studies, aspirin w as injected i.v. 10 min prior to occlusion (10 mg/kg) and at the 45th min of ischemia (5 mg/kg) both with and without subsequent administrat ion of ifetroban (0.3 mg/kg + 0.3 mg/kg per h) beginning at the 75th m in of occlusion. Aspirin administration alone caused non-significant ( P > 0.05) 5-7% reductions in tissue damage (19.8-21.8% of left ventric le) from that observed in vehicle-controls (20.4-22.9% of left ventric le). Ifetroban alone significantly (P < 0.05) reduced infarct size com pared to vehicle treatment (13 +/- 1% vs. 23 + 2% of left ventricle), and this was not prevented by combination with aspirin (12 +/- 2% vs. 22 +/- 3% of left ventricle). In the absence and presence of aspirin, ifetroban reduced infarct size by 42% and 43%, respectively. Concurren tly, thromboxane A(2)-generating capacity in blood (measured as thromb oxane B-2, in clotted serum) was decreased ca. 99% by aspirin treatmen t. Thus, virtually complete platelet cyclooxygenase inhibition by aspi rin afforded no cardioprotective action in the ferret and, more import antly, this inhibition did not interfere with the myocardial salvage e fficacy of ifetroban. Failure of aspirin treatment to attenuate the ca rdioprotective effect of ifetroban is relevant for clinical investigat ions with ifetroban, because increasing numbers of patients with heart disease routinely take aspirin. Furthermore, these findings suggest t hat ifetroban and aspirin could be used together for enhanced cardiopr otective efficacy over aspirin alone.