Objectives: The aim of this study was to assess whether prostaglandin endoperoxides, which continue to be formed in the setting of thromboxane A2 synthase inhibition, might influence the fate of ischemic myocardium in a model of coronary occlusion and reperfusion.
Background: It was recently demonstrated that thromboxane A2 synthase inhibitors reduce ischemic myocardial injury through a redirection of prostaglandin (PG) endoperoxides toward the synthesis of "cardioprotective" prostaglandins, such as PGI2, PGE2 and PGD2. However, part of these prostaglandin endoperoxides may also stimulate a receptor, shared with thromboxane A2, mediating platelet 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/PGH2 receptor antagonist (n = 8); 3) dazoxiben, a selective thromboxane A2 synthase inhibitor (n = 8); 4) R 68070 (Ridogrel), a drug with dual thromboxane A2 synthase-inhibiting and thromboxane A2/PGH2 receptor-blocking properties (n = 8); or 5) aspirin + R 68070 (n = 8).
Results: Dazoxiben and R 68070, but not SQ 29548, significantly reduced thromboxane B2 formation and increased plasma levels of 6-keto-PGF1 alpha, PGE2 and PGF2 alpha. Ex vivo platelet aggregation induced by U46619 (a thromboxane A2 mimetic) 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 infarct size compared with that in control animals, whereas dazoxiben 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, infarct 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 A2 synthase inhibitors. The simultaneous inhibition of thromboxane A2 synthase and blockade of thromboxane A2/PGH2 receptors by R 68070 identify a pharmacologic interaction of potential therapeutic importance.