Cannabinoid 1 (CB1) receptor mediates WIN55, 212-2 induced hypothermia and improved survival in a rat post-cardiac arrest model.

OBJECTIVE

The nonselective Cannabinoid (CB) receptor agonist, WIN55, 212-2, was demonstrated to induce hypothermia and improve post-resuscitation outcomes in a rat post-cardiac arrest model. The present study was to explore the potential mechanisms of WIN55, 212-2 on thermoregulation following resuscitation and to investigate which class of CB receptors was involved in WIN55, 212-2-induced hypothermia.

METHODS

Ventricular fibrillation (VF) was induced and untreated for 6 min in 20 male Sprague-Dawley rats. Defibrillation was attempted after 8min of Cardiopulmonary resuscitation (CPR). Five min post-resuscitation, resuscitated animals were randomized to receive an intramuscular injection of selective CB1 receptors antagonist, SR141716A (5 mg kg(-1)); selective CB2 receptors antagonist SR144528 (5 mg kg(-1)); or placebo. Thirty min after injection, animals received continuous intravenous infusion of WIN55, 212-2 (1.0 mgkg(-1) h(-1)) for 4h while control animals received placebo. The identical temperature environment was maintained in all animals.

RESULTS

In animals treated with WIN55, 212-2, blood temperatures decreased progressively from 37 °C to 34 °C within 4h. This hypothermic effect was completely blocked by CB1 but not CB2 antagonist. Accordingly, significantly better cardiac output, ejection fraction and myocardial performance index, reduced neurological deficit scores, improved microcirculation and longer duration of survival were observed in WIN55, 212-2-treated animals, which were also completely abolished by pretreatment with CB1 antagonist.

CONCLUSIONS

Pharmacologically induced hypothermia with WIN55, 212-2 improved post-resuscitation myocardial and cerebral function, associated with a significantly increased duration of survival in a rat post-cardiac arrest model. The hypothermic and resulted beneficial effects of WIN55, 212-2 were mediated through CB1 receptors.