Endogenous prostaglandin endoperoxides may alter infarct size in the presence of thromboxane synthase inhibition: Studies in a rabbit model of coronary artery occlusion-reperfusion

Abstract

Objectives. The aim of this study was to assess whether prostaglandia endoperoxides, which continue to be formed in the setting of thromboxane A2synthase inhibition, might influence the fate of ischemic myocardium in a model of coronary occlusion and reperfusion.Background. It was recently demonstrated that thromboxane A2synthase inhibitors reduce ischemic myocardial injury through a redirection of prostaglandin (PG) endoperoxides toward the synthesis of “cardioprotective” prostaglandins, such as PGI2, PGE2and PGD2. However, part of these prostaglandin endoperoxides may also stimulate a receptor, shared with thromboxane A2, mediating piutelet aggregation and vasoconstriction.Methods. New Zealand White rabbits were subjected to 30 min of coronary occlusion, followed by 5.5 h of reperfusion. Fifteen minutes before reperfusion, the animals were randomized to receive 1) saline solution (control animals, n = 8); 2) SQ 29548, a potent and selective thromboxane A2/PGH2receptor antagonist (n = 8); 3) dazoxiben, a selective thromboxane A2synthase inhibitor (n = 8); 4) R 68070 (Ridogrel), a drug with dual thromboxane A2synthase-inhibiting and thromboxane A2/PGH2receptor-blocking properties (n = 8); or 5) aspirin + R 68070 (n = 8).Results. Dazoxiben and R 68070, but not SQ 29548, significantly reduced thromboxane B2formation and increased plasma levels of 6-keto-PGF10, PGE2and PGF2a. Ex vivo platelet aggregation induced by U46619 (a thromboxane A2mimetic) was inhibited by SQ 29548 and R 68070 but not by dazoxiben. In control animals, infarct size determined at the end of the experiment by triphenyltetrazolium chloride staining averaged 57.7 ± 3.2% of the area at risk of infarction. The administration of SQ 29548 did not significantly reduce infract size compared with that in control animals, whereas dazosxiben and R 68070 significantly reduced infarct size to 36.7 ± 2.8% and 16.6 ± 3.6% of area at risk of infarction, respectively (p < 0.001 vs. control values). In rabbits treated with R 68070, infract size was also significantly smaller than that of dazoxiben-treated rabbits (p < 0.01). This protective effect of R 68070 was completely abolished when the drug was administered with aspirin, infarct size in this group averaging 59.7 ± 1.6% (p = NS vs. control values). No differences in regional myocardial blood flow, systemic blood pressure, heart rate or extent of area at risk were observed among groups.Conclusions. Thus, prostaglandin endoperoxides play an important role in modulating the cardioprotective effects of thromboxane A2synthase inhibitors. The simultaneous inhibition of thromboxane A2synthase and blockade of thromboxane A2/PGH2receptors by R 68070 identify a pharmacologic interaction of potential therapeutic importance.