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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.
AuthorsPhilipe N Khalil, Christiane Neuhof, Ralf Huss, Matthias Pollhammer, Maurice N Khalil, Heinz Neuhof, Hans Fritz, Matthias Siebeck
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 528 Issue 1-3 Pg. 124-31 (Dec 28 2005) ISSN: 0014-2999 [Print] Netherlands
PMID16324693 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • A-705253
  • Benzamides
  • Cardiotonic Agents
  • Calpain
Topics
  • Animals
  • Benzamides (administration & dosage, pharmacology)
  • Blood Pressure (drug effects)
  • Calpain (antagonists & inhibitors, metabolism)
  • Cardiotonic Agents (pharmacology)
  • Disease Models, Animal
  • Heart Rate (drug effects)
  • Hemodynamics (drug effects)
  • Infusions, Intravenous
  • Injections, Intravenous
  • Myocardial Contraction (drug effects)
  • Myocardial Infarction (enzymology, pathology, prevention & control)
  • Myocardial Reperfusion Injury (enzymology, pathology, prevention & control)
  • Sus scrofa
  • Ventricular Dysfunction, Left (enzymology, prevention & control)

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