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

SummaryObjectiveApoptosis 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 methodsThis 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.ResultsIn mice neither zVAD.fmk nor Q–VD–OPh reduced infarct size. In rats, however, zVAD.fmk reduced infarct size following ischaemia (25 min) and reperfusion (7 days) by ∼53%. This was, however, accompanied by an increase in left ventricular end-diastolic pressure.ConclusionThis study provides further evidence that abrogation of apoptosis via caspase inhibition might not be sufficient to effectively limit infarct size following MI/R.