Failure of aspirin to interfere with the cardioprotective effects of ifetroban

• Published in: European journal of pharmacology Vol. 271; no. 2; pp. 471 - 479
• Main Authors: Gomoll, Allen W., Ogletree, Martin L.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 27.12.1994; Elsevier
• Subjects: Animals; Aspirin; Aspirin - pharmacology; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Bridged Bicyclo Compounds, Heterocyclic; Drug Interactions; Ferrets; Heart - drug effects; Hemodynamics - drug effects; Male; Medical sciences; Myocardial ischemia; Myocardial Reperfusion Injury - prevention & control; Oxazoles - pharmacology; Pharmacology. Drug treatments; Propionates - pharmacology; Receptors, Thromboxane - antagonists & inhibitors; Reperfusion injury; Thromboxane A2 - biosynthesis; Thromboxane receptor antagonist; Thromboxane receptor antagonist; Myocardial ischemia; Aspirin; Reperfusion injury; Fissipedia; Carnivora; Drug combination; Intravenous administration; Infarct; Thromboxane A2; Cardiovascular disease; Coronary heart disease; Myocardial disease; Prevention; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Ischemia; Animal; Ferret; Myocardium; Drug interaction; Antagonist; Salicylates; Biological receptor
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/0014-2999(94)90808-7

The thromboxane receptor antagonist ifetroban ([1 S-(1α,2α,3α,4α)]-2-[[3-[4-[(pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1] hept-2-yl]methyl]benzenepropanoic acid) and aspirin were evaluated for direct and combined effects on myocardial infarct size in anesthetized ferrets subjected to coronary occlusion (90 min) and reperfusion (5 h). Aspirin (10 mg/kg) or vehicle was administered as an i.v. bolus dose at the 45th min of occlusion in an intial assessment of its cardioprotective potential in this species. In interaction studies, aspirin was 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 administration of ifetroban (0.3 mg/kg + 0.3 mg/kg per h) beginning at the 75th min of occlusion. Aspirin administration alone caused non-significant ( P > 0.05) 5–7% reductions in tissue damage (19.8–21.8% of left ventricle) from that observed in vehicle-controls (20.4–22.9% of left vetricle). Ifetroban alone significantly ( P < 0.05) reduced infarct size compared 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%, respectively. Concurrently, thromboxane A 2-generating capacity in blood (measured as thromboxane B 2 in clotted serum) was decreased ca. 99% by aspirin treatment. Thus, virtually complete platelet cyclooxygenase inhibition by aspirin afforded no cardioprotective action in the ferret and, more importantly, this inhibition did not interfere with the myocardial salvage efficacy of ifetroban. Failure of aspirin treatment to attenuate the cardioprotective effect of ifetroban is relevant for clinical investigations with ifetroban, because increasing numbers of patients with heart disease routinely take aspirin. Furthermore, these findings suggest that ifetroban and aspirin could be used together for enhances cardioprotective efficacy over aspirin alone.