Myocardial infarction remains a major cause of mortality and morbidity globally and infarct size is a major determinant of prognosis. Early and successful restoration of myocardial reperfusion is effective to reduce final infarct size and improve clinical outcomes. However, reperfusion induces further damage to the myocardium, hence the need for adjunctive therapy. Cardioprotective therapies to limit myocardial hypercontracture that occurs during prolonged ischemia and is associated with ischemia-reperfusion (I/R) injury are an important clinical goal. Previously, naltrindole (NTI, 5µM), when given prior to ischemia, exerted cardioprotective effects in ex-vivo, rat myocardial I/R, in part, by attenuating ischemic hypercontracture that occurred 20 min into global ischemia. The aim of this study was to determine the concentration-dependent relationship of NTI on infarct size and cardiac function in rat myocardial I/R.

Male Sprague Dawley rats (~300g) were anesthetized with heparin (1000U), xylazine (30mg/kg), and ketamine solution (90mg/kg). Hearts were excised and placed in a Langendorff apparatus. A pressure transducer was placed into the left ventricle (LV) to measure LV end diastolic pressure (LVEDP) during infusion prior to ischemia, ischemia (ischemic peak pressure; IPP) and reperfusion. Global ischemia was induced by stopping Krebs buffer infusion for 30 min, followed by reperfusion (45min). Hearts were treated with NTI at concentrations of 1.25µM (n=5), 2.5µM (n=6), 5.0µM (n=5), or Krebs buffer (i.e. control; n=7) at a rate of 1 mL/min for 5 min prior to ischemia (preconditioning; PC) and during the first 5 min of reperfusion. After reperfusion, hearts were frozen, sectioned (2mm), and stained with 1% triphenyltetrazolium chloride. Infarct size was determined (weight of infarcted vs. total tissue at risk). All data were evaluated using ANOVA Student Newman Keuls post-hoc analysis.

NTI 5µM (4.8±1%) and 2.5µM (6.8±0.8%), but not NTI 1.25 µM (12.2±3%), significantly reduced infarct size compared to control (14.1±1%, p

Only NTI 2.5µM reduced infarct size without a negative inotropic effect (e.g. increased LVEDP during pretreatment administration). Collectively, NTI concentration-dependently decreased infarct size by 66% (5μM), 52%, (2.5µM), 13% (1.25 μM). Data suggest that NTI (2.5μM) can be given prophylactically to high-risk MI patients. Future studies will investigate the effect of NTI on cardiac hypercontracture and intracellular calcium content during ischemia.