Caspase inhibitor zVAD.fmk reduces infarct size after myocardial ischaemia and reperfusion in rats but not in mice.

Objective: Apoptosis of cardiomyocytes has been suggested to contribute to outcome following myocardial ischaemia and reperfusion (MI/R). Caspase inhibitors were developed as potential therapeutics for MI/R. However, various reports using the broad-spectrum caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) in the latter setting present conflicting results. Therefore, it is still unclear whether inhibition of apoptosis by caspase inhibitors promotes cardioprotection.

Materials And Methods: This study evaluated whether zVAD.fmk or novel caspase inhibitor quinoline-Val-Asp(Ome)-CH2-O-phenoxy (Q-VD-OPh) reduce myocardial infarct size in mice. Secondly, we tested zVAD.fmk's potential infarct-sparing effects in rats and whether these are accompanied by improved left ventricular function.

Results: In mice neither zVAD.fmk nor Q-VD-OPh reduced infarct size. In rats, however, zVAD.fmk reduced infarct size following ischaemia (25min) and reperfusion (7 days) by approximately 53%. This was, however, accompanied by an increase in left ventricular end-diastolic pressure.

Conclusion: This study provides further evidence that abrogation of apoptosis via caspase inhibition might not be sufficient to effectively limit infarct size following MI/R.