title: Improved cardiac and neurologic outcomes with postresuscitation infusion of cannabinoid receptor agonist WIN55, 212-2 depend on hypothermia in a rat model of cardiac arrest.
abstract: OBJECTIVE
  To investigate the mechanisms of improved myocardial and neurological function and survival following i.v. administration of cannabinoid receptor agonist, WIN55, 212-2 in a rat model of cardiac arrest.
  
  
  METHODS
  Prospective randomized controlled experimental study.
  
  
  METHODS
  University-affiliated research institute.
  
  
  METHODS
  Thirty male Sprague-Dawley rats.
  
  
  METHODS
  Ventricular fibrillation was electrically induced in 30 male Sprague-Dawley rats weighing between 450 and 550 g. Cardiopulmonary resuscitation was initiated after 6 minutes of untreated ventricular fibrillation. The precordial compression was performed with a pneumatically driven mechanical chest compressor. No pharmacological agent was used during cardiopulmonary resuscitation. After 8 minutes of cardiopulmonary resuscitation, up to three 2-J defibrillations were attempted. The animals were then randomized into three groups: 1) WIN55, 212-2 hypothermia, 2) WIN55, 212-2 with normal body temperature, and 3) placebo control. Either WIN55, 212-2 (1.0 mg/kg/hr) or saline placebo was continuously infused for 2 hours. Except for the WIN55, 212-2 hypothermia group, the body temperature in the other two groups was maintained at 37.0 ± 0.2°C using an external heating lamp. Postresuscitation myocardial function was measured by echocardiogram. Neurological deficit scores and survival time were observed for up to 72 hours.
  
  
  RESULTS
  Blood temperatures decreased from 37°C to 33°C in 4 hours in animals in WIN55, 212-2 hypothermia group. Myocardial function, as measured by cardiac output, ejection fraction, and myocardial performance index, was significantly impaired in all animals after successful resuscitation when compared with the baseline values. There was a significant improvement in myocardial function in the animals treated with WIN55, 212-2 hypothermia beginning at 1 hour after start of infusion. However, no improvement was observed in the groups of WIN55, 212-2 with normal body temperature and placebo control. WIN55, 212-2 hypothermia group was associated with significantly improved neurologic deficit scores and survival time when compared with placebo control group and WIN55, 212-2 with normal body temperature group.
  
  
  CONCLUSIONS
  In a rat model of cardiac arrest, better postresuscitation myocardial function, neurological deficit scores, and longer duration of survival were observed by the pharmacologically induced hypothermia with WIN55, 212-2. The improved outcomes of cardiopulmonary resuscitation following administration of WIN55, 212-2 appeared to be the results from its temperature reduction effects.
authors.affiliation: 1Weil Institute of Critical Care Medicine, Rancho Mirage, CA. 2The Keck School of Medicine of the University of Southern California, Los Angeles, CA.
authors.forename: Linhao
authors.initials: L
authors.lastname: Ma
authors.forename: Xiaoye
authors.initials: X
authors.lastname: Lu
authors.forename: Jiefeng
authors.initials: J
authors.lastname: Xu
authors.forename: Shijie
authors.initials: S
authors.lastname: Sun
authors.forename: Wanchun
authors.initials: W
authors.lastname: Tang
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D063386:Cannabinoid Receptor Agonists / Q000627:therapeutic use*; D016887:Cardiopulmonary Resuscitation / Q000379:methods*; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006323:Heart Arrest / Q000188:drug therapy* / Q000503:physiopathology / Q000628:therapy; D007036:Hypothermia, Induced / Q000379:methods*; D008297:Male; D009025:Morpholines / Q000627:therapeutic use*; D009281:Naphthalenes / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D009025:Morpholines; D009281:Naphthalenes; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone