Naltrindole exerts robust concentration-dependent cardioprotection in rat myocardial ischemia reperfusion injury
Authors: Boakye Tanoh Desmond , Clair Logan , Ramsarran James , Talukder Zinya , Maricic Nikola , Kalu Ukoha , Melnik Juliet , Dean Tameka , Chen Qian , Barsotti Robert , Young Lindon 
Published: May 2023

Myocardial infarction remains a major cause of mortality and morbidity globally and infarct size is a major determinant of prognosis. Early restoration of myocardial reperfusion is effective to reduce final infarct size and improve clinical outcomes. However, reperfusion induces further damage to the myocardium. Cardioprotective therapies to limit myocardial damage associated with ischemia reperfusion (I/R) injury are an important clinical goal. Previously, naltrindole (NTI, 5μM) exerted cardioprotective effects in ex-vivo rat hearts when given prior to ischemia. The aim of this study was to determine the concentration-dependent relationship of NTI on infarct size and cardiac function in a rat myocardial I/R model. Male Sprague Dawley rats (~300g) were anesthetized with heparin (1000U), xylazine (30mg/kg), and ketamine solution (90mg/kg). Excised hearts were placed in a Langendorff apparatus with a pressure transducer in 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 as weight of infarcted vs. total tissue at risk. 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<0.05). LVEDP at PC was significantly increased for NTI 5μM (15±2 mmHg) compared to all other treatment groups (p<0.05): NTI 2.5μM (7.8±1 mmHg), NTI 1.25μM (9.6±1 mmHg), and control (9.7±0.7 mmHg). During global ischemia, IPP was significantly reduced by NTI 5μM (18.6±6 mmHg) compared to control (45.2±7 mmHg, p<0.05). LVEDP during reperfusion was significantly reduced by NTI 5μM from 30-45 min compared to control (p<0.05). Only NTI 2.5μM reduced infarct size without a negative inotropic effect (i.e., increased LVEDP during PC). Collectively, NTI reduction of infarct size by 66% (5μM), 52%, (2.5μM), 13% (1.25 μM) was concentration-dependent. 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. Division of Research, Department of Biomedical Sciences, Center for Chronic Disorders of Aging at Philadelphia College of Osteopathic Medicine, and Young Therapeutics, LLC. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.