Calpains, a family of Ca2+-dependent cysteine proteases, are activated during myocardial ischemia and reperfusion. This study investigates the cardioprotective effects of calpain inhibition on infarct size and global hemodynamics in an ischemia/reperfusion model in pigs, using the calpain inhibitor A-705253. The left anterior descending coronary artery was occluded for 45 min and reperfused for 6 h. A bolus of 1.0 mg/kg A-705253 or distilled water was given intravenously 15 min prior to induction of ischemia and a constant plasma level of A-705253 was maintained by continuous infusion of 1.0 mg/kg A-705253 during reperfusion. Infarct size was assessed histochemically using triphenyltetrazolium chloride staining. Macromorphometric findings were verified by light microscopy on hematoxylin-eosin- and Tunel-stained serial sections. Global hemodynamics, including the first derivate of the left ventricular pressure (dP / dtmax), were measured continuously throughout the experiment. A-705253 reduced the infarct size by 35% compared to controls (P < 0.05). Hemodynamic alterations, including heart rate, aortic blood pressure, central venous pressure and left atrial pressure, were attenuated mainly during ischemia and the first 2 h during reperfusion by A-705253. Cardiac function improved, as determined by dP / dtmax, after 6 h of reperfusion (P < 0.003). Our results demonstrate that myocardial protection can be achieved by calpain inhibition, which decreases infarct size and improves left ventricular contractility and global hemodynamic function. Hence, the calpain-calpastatin system might play an important pathophysiological role in porcine myocardial ischemia and reperfusion damage and A-705253 could be a promising cardioprotective agent.