mdl-201053 and Myocardial-Infarction

The efficacy of a novel, nonpeptidic, caspase 3/7-selective inhibitor, (S)-(+)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin (MMPSI) for reducing ischemic injury in isolated rabbit hearts or cardiomyocytes was evaluated. MMPSI (0.1-10 microM) evoked a concentration-dependent reduction in infarct size (up to 56% vs. control; IC(50)=0.2 microM). Furthermore, apoptosis (DNA laddering, soluble nucleosomes) was reduced in the ischemic area-at-risk. MMPSI inhibited recombinant human caspase-3 with an IC(50)=1.7 microM. Apoptosis in H9c2 cells after 16-h simulated ischemia and 2-h simulated reperfusion was significantly reduced by MMPSI in a concentration-dependent manner (IC(50)=0.5 microM); similar effects were observed in isolated adult rabbit cardiomyocytes (IC(50)=1.5 microM). These data support an important role for caspase-3/7 in mediating myocardial ischemic injury. Furthermore, these data indicate that cardioprotection via caspase-3/7 inhibition is attainable via a small molecule (nonpeptidic) inhibitor, a necessary step in making this approach therapeutically viable.

Topics: Amino Acid Chloromethyl Ketones; Animals; Apoptosis; Caspase 3; Caspase 7; Caspase Inhibitors; Caspases; Cell Line; Cells, Cultured; Coronary Circulation; Cysteine Proteinase Inhibitors; Dipeptides; Dose-Response Relationship, Drug; Heart Rate; In Situ Nick-End Labeling; Isatin; Ketones; Male; Microscopy, Electron; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Pyrrolidines; Rabbits