Background:
Despite advances in early reperfusion therapy for acute ST elevation myocardial infarction (MI), mortality rates and prevention of heart failure after the MI are not optimal. There have been many attempts to further reduce the size of acute MI and to limit the no reflow phenomenon after reperfusion, with mixed results. One promising approach may be to target the mitochondria. The purpose of the present study was to determine whether OP2113 and its active principle ATT (Anethol-TriThione, named also 5-(4-Methoxyphenyl)-3H-1,2-dithiole-3-thione; CAS 532-11-6 ), a pharmaceutical that has been shown to decrease mitochondrial reactive species production from complex I of the mitochondrial respiratory chain, could limit MI size and the no reflow phenomenon in a standardized rat model of 30 minutes of proximal coronary artery occlusion and reperfusion.
Methods and Results:
Anesthetized rats were exposed to MI and received OP2113 as an intravenous infusion starting either 5 minutes prior to coronary artery occlusion (preventive), or 5 minutes prior to reperfusion (curative), or received vehicle starting 5 minutes prior to coronary artery occlusion. Infusions continued until the end of the study (3 hours of reperfusion). MI size ( triphenyl tetrazolium chloride staining technique) , expressed as a percentage of the ischemic risk zone ( blue dye technique) was significantly lower in the OP2113 treated preventive group at 44.5 ± 2.9% versus 57.0 ± 3.6% ( p<0.05) in the vehicle group, with a nonsignificant trend toward a smaller infarct size in the curative group ( 50.8 ± 3.9%). Area of no reflow ( thioflavin S technique) as a percentage of the risk zone was significantly smaller in both the OP2113 treated preventive (28.8 ± 2.4%; p =0.026 vs vehicle) and curative groups ( 30.1 ± 2.3%; p=0.04 vs vehicle) compared to the vehicle group ( 38.9 ± 3.1%). OP2113 was not associated with any hemodynamic changes.
Conclusions:
These results suggest that OP2113 is a promising agent to reduce no-reflow as well as to reduce MI size, especially if it is on board early in the course of the MI. It appears to have benefit on no-reflow even when administered relatively late in the course of ischemia.
A novel adenylyl cyclase type 5 inhibitor that reduces myocardial infarct size even when administered after coronary artery reperfusion