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

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+5mg/kg) was administered by i.v. infusion, starting before ischemia to the beginning of reperfusion. The second protocol attempted to evaluate F 15845 (5+5mg/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+5mg/kg, respectively. At 5+5mg/kg, F 15845 decreased plasma levels of myoglobin and cardiac troponin I. In protocol 2, F 15845 (5+5mg/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.

Cardioprotection of cariporide evaluated by plasma myoglobin and troponin I in myocardial infarction in pigs.

The cardioprotective effects of cariporide were investigated against myoglobin and troponin I elevation in a model of myocardial infarction in pig, and the possible relationship between these markers and myocardial infarct size. The left circumflex coronary artery was ligated for 60-min and then reperfused for 48-h. Plasma levels of myoglobin and troponin I were quantified during reperfusion. Vehicle or cariporide (2.5 mg/kg) were administered i.v. before ischaemia and infused throughout ischaemia and for the beginning of reperfusion. In vehicle-treated pigs, the infarct size represented 26% +/- 3% of the area at risk. Cariporide significantly decreased the infarct size by 66% +/- 9%, and significantly reduced plasma levels of myoglobin and troponin I. A strongly correlated linear relationship between myocardial necrosis and plasma levels of myoglobin (R = 0.966, P < 0.0001) or troponin I (R = 0.855, P < 0.0001) was clearly identified. In conclusion, in our porcine model of myocardial infarction, even with small infarcts (in the presence of cariporide), plasma levels of myoglobin and troponin I are predictive of the presence of necrosis and its extent.