Pretreatment with Naltrindole Generates Dose Dependent Effects on Reduction of Infarct Size During Myocardial Ischemia Reperfusion in An In-Vivo Model

Philadelphia, PA

Over one million individuals experience a myocardial infarction (MI) every year. Currently, no therapeutic is available to salvage necrotic cardiac tissue following an MI. The use of a prophylactic agent to reduce infarct size in patients at high risk for an MI would attenuate the development of heart failure. Interventional cardiologists state that a 25% reduction in infarct size is clinically meaningful to reduce heart failure. Previously, a 5 min pretreatment with high dose (HD) naltrindole (NTI) (7.5 mg/kg x 5 min = 37.5 mg/kg, n=3) resulted in a robust 74% (15±6%) reduction in infarct size compared to control in an in-vivo model of ischemia reperfusion injury (IRI). This effect was accompanied by a reduction in irreversible hypercontracture known as rigor. However, it caused a transient reduction in cardiac function during the infusion period. In this study, we aim to determine the effect of intermediate (ID; 3.75 mg/kg x 5 min = 18.75 mg/kg) and low dose (LD; 0.2-1.0 mg/kg x 5 min = 1.0-5.0 mg/kg) NTI pretreatment on infarct size and cardiac function in a rat in vivo model of IRI.

Female Sprague-Dawley rats (~250g) were divided into four cohorts: non-treated control (n=15), LD (n=18), ID (n=5), and HD (n=5) NTI groups. All cohorts were anesthetized with Ketamine-xylazine (90 mg/kg, 9 mg/kg). Control rats received normal saline (0.9% NaCl), while treatment groups received either HD, ID, or LD NTI infused through the jugular vein (0.4mL/min) over 5 mins before inducing regional ischemia by occluding the left descending coronary artery for 30 min followed by 3 hr reperfusion. Cardiac function was measured through a pressure transducer catheter placed into the left ventricle (LV) in NTI treated groups. Planimetered photographs of heart slices were used to determine infarct size. Data were analyzed via ANOVA, Bonferroni-Dunn, and post-hoc analysis. Probability values <0.05 were considered statistically significant.

HD, ID, and LD NTI reduced infarct size by 81% (11±4%) p<0.05, 55% (26±7%) p<0.05, and 4% (55±4%) respectively compared to control (57±2%). Cardiac function parameters such as dP/dt min, the maximal rate of LV pressure relaxation, was not significantly affected by ID NTI compared to LD NTI in contrast to the cardiac depression elicited by HD NTI. These results indicate that the cardiac depressive effects of NTI are dose dependent and the infarct reducing effects of NTI can be achieved through doses that spare cardiac function. Therefore, ID NTI prophylaxis may be an effective strategy to limit cardiac tissue death in populations at high risk of an MI. Future studies will be conducted on porcine cardiac IRI models.