Comparison of cardioprotective efficacy of two thromboxane A2 receptor antagonists

The purpose of the current study was to compare the efficacy of two structurally unrelated thromboxane A(2) (TXA(2)) receptor antagonists, KT2-962 and daltroban (BM 13.505), in a dog model of myocardial ischemia/reperfusion injury. Pentobarbital-anesthetized dogs were subjected to left circumflex coronary artery occlusion for 90 minutes followed by 5 hours of reperfusion. Vehicle, KT2-962(10 mg/kg), or daltroban (10 mg/kg) were administered as intravenous boluses 10 minutes before coronary occlusion. Systemic hemodynamics were measured throughout the experiments and regional myocardial blood flow was measured by the radioactive microsphere technique. At the end of the reperfusion period; myocardial infarct size was quantified by staining with triphenyltetrazolium chloride. Neither KT2-962 nor daltroban significantly altered heart rate, mean arterial blood pressure, or regional myocardial blood flow. The content of myeloperoxidase activity in the ischemic/reperfused tissue, an index of neutrophil infiltration, was not significantly different among the three treatment groups. However, administration of KT2-962, but not daltroban, significantly reduced the incidence of ventricular fibrillation during the ischemic period and significantly reduced myocardial infarct size expressed as a percentage of the risk region (approximately 40%). Subsequent in-vitro assays using electron spin resonance spectroscopy demonstrated that KT2-962 inhibited the formation of hydroxyl radicals, whereas daltroban had no effect. These results suggest that the beneficial effects of KT2-962 may be due to its direct free radical scavenging properties rather than its ability to block TXA(2) receptors.