Abstract 17814: Naltrindole Mitigates Rigor During Myocardial Ischemia by a Novel Mechanism and Shows Translational Cardioprotection in Myocardial Ischemia-Reperfusion Injury Models

Introduction: Naltrindole (NTI) was cardioprotective in both ex-vivo (5μM) and in-vivo (7.5mg/kg) rat myocardial ischemia-reperfusion (MIR) models. Recently, we showed that NTI 50-200μM (~2-7.5mg/kg, in-vivo) attenuated phorbol ester-induced PMN superoxide release by a novel mechanism devoid of opioid receptors. We hypothesize that NTI exerts its cardioprotective effects (and therefore, its effects on the infarct size) in a dose-dependent manner.

Methods: Ex-vivo studies were done with Sprague Dawley male rats using a Langendorff apparatus. Excised hearts were pretreated with Krebs buffer (controls), NTI 1.25μM, NTI 2.5μM, or NTI 5μM for 5 min, followed by 30 min of global ischemia (I) and a 45 min reperfusion (R) period. In-vivo studies were performed with Sprague Dawley female rats which received infusions (NTI 0.2-1.0 mg/kg, 3.75 mg/kg, or 7.5 mg/kg) through the jugular vein (0.4mL/min) over 5 mins before regional I was induced by occluding the LAD artery for 30 min followed by a 3 hr R period. Cardiac function was measured in both studies through a pressure transducer placed into the left ventricle.

Results: Ex-vivo: NTI 5μM, 2.5μM and 1.25μM reduced infarct size by 66% (4.8±1%, n=5, p<0.05), 52% (6.8±0.8%, n=6, p<0.05), and 13% (12.2±3%, n=5) respectively compared to control (14.1±1%, n=7). NTI 5μM (1358±300 mmHg) had significantly improved dP/dt max at the end of R compared to untreated controls (576±163, p<0.05). In-vivo: High Dose (7.5 mg/kg x 5 min = 37.5 mg/kg [total dose]), Intermediate Dose (3.75 mg/kg x 5 min = 18.75 mg/kg [total dose]), and Low Dose (0.2-1.0 mg/kg x 5 min = 1.0-5.0 mg/kg [total dose]) NTI reduced infarct size by 81% (11±4%, n=5, p<0.05), 55% (26±7%, n=5, p<0.05), and 4% (55±4%, n=18) respectively compared to untreated controls (57±2%, n=15). DP/dt max was similar among all study groups at the end of R.

Conclusions: Both ex-vivo and in-vivo MIR models showed a dose-dependent effect on reducing infarct size. This effect is most likely correlated with a reduction in rigor during myocardial ischemia. Future in-vivo studies will test 2 mg/kg and 7.5 mg/kg in rat and porcine MIR respectively. The infarct reducing effect of NTI might benefit patients who will opt for elective PCI, CABG, and transplant.