title: Calpain inhibition reduces infarct size and improves global hemodynamics and left ventricular contractility in a porcine myocardial ischemia/reperfusion model.
abstract: 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.
authors.affiliation: Department of Surgery, Downtown Medical Centre, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Philipe N
authors.initials: PN
authors.lastname: Khalil
authors.forename: Christiane
authors.initials: C
authors.lastname: Neuhof
authors.forename: Ralf
authors.initials: R
authors.lastname: Huss
authors.forename: Matthias
authors.initials: M
authors.lastname: Pollhammer
authors.forename: Maurice N
authors.initials: MN
authors.lastname: Khalil
authors.forename: Heinz
authors.initials: H
authors.lastname: Neuhof
authors.forename: Hans
authors.initials: H
authors.lastname: Fritz
authors.forename: Matthias
authors.initials: M
authors.lastname: Siebeck
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D034421:Sus scrofa; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000517:prevention & control*
chemical_list: C500488:A-705253; D001549:Benzamides; D002316:Cardiotonic Agents; D002154:Calpain