Naltrindole Offers Potent Cardioprotection From Ischemia Reperfusion Injury; Opioid Antagonism Or Calcium Handling?

Coronary Artery Disease accounts for approximately 25% of deaths annually, and remains theleading cause of mortality inthe United States. Myocardial ischemic (MI) damage is the initialinjury, characterized by irreversible hyper-contracture of cardiac muscle. Currently, there is nopharmacologic treatment tomitigate MI damage that may occur inthe 250,000CABGs,215,000percutaneous coronary interventions (PCI), and heart transplantation. We havepreviously reported that naltrindole (NTI) dosedependently reduces infarct size upto82% ininvivomyocardial ischemia-reperfusion(MI/R) studies whengivenprior toregional ischemia. Werecently have shownthat NTI elicits this robust infarct size reducing effect by anovelmechanism since NTI alsoreduces polymorphonuclear leukocyte (PMNs) superoxide (SO)release at concentrations corresponding tothe blood concentrationinthe invivoMI/R study(8mg/kg = ∼200uM; 4mg/kg = ∼100uM). PMNs donot express opioid receptors, and NTI isknowntobe adeltaopioid receptor antagonist.Inour ex vivoLangendorff rat MI/R model, male SD rats (∼300g) were anesthetized, heartswere removed, perfused with 37°C Krebs' buffer and apressure transducer was placed intheleft ventricle (LV). Baseline recordings were made during the first 10minand the hearts werepretreated with NTI (5uM, n=8), naloxone (NX; panopioid receptor antagonist; 10uM, n=6)and binaltorphimine (BNI; kappaopioid receptor antagonist, 5uM, n=7) or controls (n=12) for 5mins prior toglobal I(30min)/R(45min).Ischemic PeakPressure (IPP) in control I/R hearts was39±3mmHg compared to pre-ischemic LVEDP of 9±1 mmHg at baseline(n=12,p<0.01),resulting in substantialinfarct at the end of 45min R (32±4%).IPP was reduced by NTI (18±3mmHg/s)compared to all groups(p<0.05).Final dP/dt max and infarct size were most improved with NTI (1830±90mmHg/s, 7±2%)compared to control(777±142mmHg/s, 32±4%,p<0.01).Cardiac function and infarctsize did not improve with BNI orNX. The results suggested that NTI exerted robust cardioprotection with significant reduction in infarct size independent of delta or kappaopioid receptor which led to investigating its possible underlying mechanism of action.