Failure of aspirin to interfere with the cardioprotective effects of ifetroban.
The thromboxane receptor antagonist ifetroban ([1S-(1 alpha,2 alpha,3 alpha, 4 alpha)]-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 artery 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 initial 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 ventricle). 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% and 43%, respectively. Concurrently, thromboxane A2-generating capacity in blood (measured as thromboxane B2 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Gomoll
A W
AW
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543.
Ogletree
M L
ML
D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004347:Drug Interactions; D005289:Ferrets; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D010080:Oxazoles / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013928:Thromboxane A2 / Q000096:biosynthesis
D019086:Bridged Bicyclo Compounds, Heterocyclic; D010080:Oxazoles; D011422:Propionates; D017482:Receptors, Thromboxane; D013928:Thromboxane A2; C078904:ifetroban; D001241:Aspirin