Abstract 18789: Pharmacologically Induced Hypothermia with Cannabinoid Receptor Agonist WIN55,212-2 vs Mild Therapeutic Hypothermia in a Rat Model of Cardiac Arrest with Extracorporeal Life Support
BACKGROUND: To compare the hemodynamic, cardioprotective and metabolic effects of cannabinoid receptor agonist WIN55,212-2 with mild therapeutic hypothermia and normothermic control on post-resuscitation myocardial function in a rat model of extracorporeal life support (ECLS).
METHODS AND RESULTS: Ventricular fibrillation (VF) was induced in male Wistar rats. After 10 min of untreated VF, venoarterial ECLS was instituted for 60 min. At the beginning of ECLS animals were randomized to three groups of ten: normothermia, hypothermia (32°C) and WIN55,212 intravenous infusion (1 mg/kg/h). Cooling to 32°C or normothermia or drug infusion lasted for the entire ECLS. Plasma samples and myocardial biopsies were obtained and left-ventricular (LV) function was assessed by a conductance catheter at baseline and after weaning from ECLS. WIN55,212-2 administration produced pharmacologic hypothermia (32-34°C) and led to a significantly better recovery of the slope of the LV end-systolic pressure volume relationship (Ees) and Preload recruitable stroke work (PRSW) than hypothermia and normothermia: as percent of baseline 87+12 vs 54+9 vs 39+11 and 88+11 vs 59+10 vs 33+8 respectively (p<.01). LV stiffness expressed by end-diastolic pressure volume relationship (EDPVR) was significantly lower after WIN55,212-2 administration (p<.05). LV relaxation described by Tau was preserved after WIN55,212-2 treatment but not after hypothermia or normothermia (p<.01). WIN55,212-2 and not hypothermia significantly increased phosphorylation of the kinase ERK1 and 2 (2.8+0.4 and 2.5+0.3 vs 0.5+0.2 and 0.4+0.1 -fold of baseline levels) (p<.01). Both WIN55,212-2 and hypothermia but not normothermia increased phosphorylation of Akt. This resulted in a reduced cardiomyocyte apoptotic index (TUNEL, p<.01). WIN55,212-2 but not hypothermia nor normothermia preserved high energy phosphates content and energy charge and reduced lactate plasma concentration.
CONCLUSIONS: Pharmacologically induced hypothermia with WIN55,212-2 was more effective than mild therapeutic hypothermia in recovering myocardial function after ECLS and in improving myocardial protection through activation of the pro-survival kinases Akt and ERK1/2.
- © 2012 by American Heart Association, Inc.