The purpose of the current study was to compare the efficacy of two structurally unrelated
thromboxane A (TXA ) 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 receptors.(2) (2) (2)