Myocardial protection by F 15845, a persistent sodium current blocker, in an ischemia-reperfusion model in the pig

Abstract

The specific persistent sodium current blocker F 15845 was tested in two myocardial ischemia-reperfusion models in the pig in order to evaluate its cardioprotective effects. In the first protocol, the left circumflex coronary artery was ligated for 60-min and then reperfused for 48-h. F 15845 (2.5 + 2.5 and 5 + 5 mg/kg) was administered by i.v. infusion, starting before ischemia to the beginning of reperfusion. The second protocol attempted to evaluate F 15845 (5 + 5 mg/kg) response in a more pathological state of the heart. To this end, a non necrotic ligation of the left circumflex coronary artery was applied for 15 min one week before the actual 60 min occlusion. For both protocols, infarct size was determined at the end of the reperfusion period and was assessed by histochemistry (tetrazolium staining). Plasma levels of biochemical markers (myoglobin and troponin I) were also evaluated. In protocol 1, F 15845 significantly reduced the infarct size by 27 ± 3 and 43 ± 5% at 2.5 + 2.5 and 5 + 5 mg/kg, respectively. At 5 + 5 mg/kg, F 15845 decreased plasma levels of myoglobin and cardiac troponin I. In protocol 2, F 15845 (5 + 5 mg/kg) significantly reduced myocardial infarct size by 54 ± 15% and lowered the plasma myoglobin and troponin I levels relative to vehicle-treated animals. In conclusion, the highly effective persistent sodium current blocker F 15845 exerts remarkable cardioprotective activities. It reduces both myocardial infarct size and the release of biochemical markers in healthy pigs as well in pigs previously exposed to an ischemic episode.