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

  • Yinlun Weng
    Affiliations
    Weil Institute of Critical Care Medicine, Rancho Mirage, CA, United States

    The Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China
    Search for articles by this author
  • Shijie Sun
    Affiliations
    Weil Institute of Critical Care Medicine, Rancho Mirage, CA, United States

    Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States
    Search for articles by this author
  • Jeonghyun Park
    Affiliations
    Weil Institute of Critical Care Medicine, Rancho Mirage, CA, United States
    Search for articles by this author
  • Sen Ye
    Affiliations
    Weil Institute of Critical Care Medicine, Rancho Mirage, CA, United States
    Search for articles by this author
  • Max Harry Weil
    Affiliations
    Weil Institute of Critical Care Medicine, Rancho Mirage, CA, United States

    Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States
    Search for articles by this author
  • Wanchun Tang
    Correspondence
    Corresponding author at: Weil Institute of Critical Care Medicine, 35100 Bob Hope Drive, Rancho Mirage, CA 92270, United States. Tel.: +1 760 778 4911; fax: +1 760 778 3468.
    Affiliations
    Weil Institute of Critical Care Medicine, Rancho Mirage, CA, United States

    Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States

    The Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China
    Search for articles by this author

      Abstract

      Aim

      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 8 min 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 mg kg−1 h−1) for 4 h 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 4 h. 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.

      Keywords

      To read this article in full you will need to make a payment
      Subscribe to Resuscitation
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Oddo M.
        • Ribordy V.
        • Feihl F.
        • et al.
        Early predictors of outcome in comatose survivors of ventricular fibrillation and non-ventricular fibrillation cardiac arrest treated with hypothermia: a prospective study.
        Crit Care Med. 2008; 36: 2296-2301
        • Aufderheide T.P.
        • Nichol G.
        • Rea T.D.
        • et al.
        A trial of an impedance threshold device in out-of-hospital cardiac arrest.
        N Engl J Med. 2011; 365: 798-806
      1. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest.
        N Engl J Med. 2002; 346: 549-556
        • Tsai M.S.
        • Barbut D.
        • Tang W.
        • et al.
        Rapid head cooling initiated coincident with cardiopulmonary resuscitation improves success of defibrillation and post-resuscitation myocardial function in a porcine model of prolonged cardiac arrest.
        J Am Coll Cardiol. 2008; 51: 1988-1990
        • Bernard S.A.
        • Gray T.W.
        • Buist M.D.
        • et al.
        Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia.
        N Engl J Med. 2002; 346: 557-563
        • Boddicker K.A.
        • Zhang Y.
        • Zimmerman M.B.
        • Davies L.R.
        • Kerber R.E.
        Hypothermia improves defibrillation success and resuscitation outcomes from ventricular fibrillation.
        Circulation. 2005; 111: 3195-3201
        • Lampe J.W.
        • Becker L.B.
        Rapid cooling for saving lives: a bioengineering opportunity.
        Expert Rev Med Devices. 2007; 4: 441-446
        • Rawls S.M.
        • Cabassa J.
        • Geller E.B.
        • Adler M.W.
        Cb1 receptors in the preoptic anterior hypothalamus regulate win 55, 212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6h-pyrrolo[3,2,1ij]quinolin-6-one]-induced hypothermia.
        J Pharmacol Exp Ther. 2002; 301: 963-968
        • Valiveti S.
        • Hammell D.C.
        • Earles D.C.
        • Stinchcomb A.L.
        Transdermal delivery of the synthetic cannabinoid win 55, 212-2: in vitro/in vivo correlation.
        Pharm Res. 2004; 21: 1137-1145
        • Sun S.
        • Tang W.
        • Song F.
        • et al.
        Pharmacologically induced hypothermia with cannabinoid receptor agonist win55, 212-2 after cardiopulmonary resuscitation.
        Crit Care Med. 2010; 38: 2282-2286
        • Institute of Laboratory Animal Resources (U.S.), ebrary Inc.
        Guide for the care and use of laboratory animals.
        1996
        • Stark R.A.
        • Nahrwold M.L.
        • Cohen P.J.
        Blind oral tracheal intubation of rats.
        J Appl Physiol. 1981; 51: 1355-1356
        • Sun S.
        • Weil M.H.
        • Tang W.
        • Kamohara T.
        • Klouche K.
        Delta-opioid receptor agonist reduces severity of postresuscitation myocardial dysfunction.
        Am J Physiol Heart Circ Physiol. 2004; 287: H969-H974
        • Weng Y.
        • Sun S.
        • Song F.
        • et al.
        Cholecystokinin octapeptide induces hypothermia and improves outcomes in a rat model of cardiopulmonary resuscitation.
        Crit Care Med. 2011; 39: 2407-2412
        • Tei C.
        New non-invasive index for combined systolic and diastolic ventricular function.
        J Cardiol. 1995; 26: 135-136
        • Spronk P.E.
        • Ince C.
        • Gardien M.J.
        • et al.
        Nitroglycerin in septic shock after intravascular volume resuscitation.
        Lancet. 2002; 360: 1395-1396
        • Rosenbluth M.J.
        • Lam W.A.
        • Fletcher D.A.
        Analyzing cell mechanics in hematologic diseases with microfluidic biophysical flow cytometry.
        Lab Chip. 2008; 8: 1062-1070
        • Hendrickx H.H.
        • Rao G.R.
        • Safar P.
        • Gisvold S.E.
        Asphyxia, cardiac arrest and resuscitation in rats. I: short term recovery.
        Resuscitation. 1984; 12: 97-116
        • Doyle K.P.
        • Suchland K.L.
        • Ciesielski T.M.
        • et al.
        Novel thyroxine derivatives, thyronamine and 3-iodothyronamine, induce transient hypothermia and marked neuroprotection against stroke injury.
        Stroke. 2007; 38: 2569-2576
        • Katz L.M.
        • Young A.
        • Frank J.E.
        • Wang Y.
        • Park K.
        Neurotensin-induced hypothermia improves neurologic outcome after hypoxic-ischemia.
        Crit Care Med. 2004; 32: 806-810
        • Knapp J.
        • Heinzmann A.
        • Schneider A.
        • et al.
        Hypothermia and neuroprotection by sulfide after cardiac arrest and cardiopulmonary resuscitation.
        Resuscitation. 2011; 82: 1076-1080
        • Nava F.
        • Carta G.
        • Gessa G.L.
        Permissive role of dopamine d(2) receptors in the hypothermia induced by delta(9)-tetrahydrocannabinol in rats.
        Pharmacol Biochem Behav. 2000; 66: 183-187
        • Rinaldi-Carmona M.
        • Barth F.
        • Millan J.
        • et al.
        Sr 144528, the first potent and selective antagonist of the cb2 cannabinoid receptor.
        J Pharmacol Exp Ther. 1998; 284: 644-650
        • Rinaldi-Carmona M.
        • Barth F.
        • Heaulme M.
        • et al.
        Sr 141716a, a potent and selective antagonist of the brain cannabinoid receptor.
        FEBS Lett. 1994; 350: 240-244
        • Rinaldi-Carmona M.
        • Barth F.
        • Heaulme M.
        • et al.
        Biochemical and pharmacological characterisation of sr 141716a, the first potent and selective brain cannabinoid receptor antagonist.
        Life Sci. 1995; 56: 1941-1947
        • Compton D.R.
        • Aceto M.D.
        • Lowe J.
        • Martin B.R.
        In vivo characterization of a specific cannabinoid receptor antagonist (sr 141716a): inhibition of delta 9-tetrahydrocannabinol-induced responses and apparent agonist activity.
        J Pharmacol Exp Ther. 1996; 277: 586-594
        • Dietrich W.D.
        • Busto R.
        • Alonso O.
        • Globus M.Y.
        • Ginsberg M.D.
        Intraischemic but not postischemic brain hypothermia protects chronically following global forebrain ischemia in rats.
        J Cereb Blood Flow Metab. 1993; 13: 541-549
        • Colbourne F.
        • Corbett D.
        Delayed postischemic hypothermia: a six month survival study using behavioral and histological assessments of neuroprotection.
        J Neurosci. 1995; 15: 7250-7260
        • Colbourne F.
        • Corbett D.
        Delayed and prolonged post-ischemic hypothermia is neuroprotective in the gerbil.
        Brain Res. 1994; 654: 265-272
        • Hickey R.W.
        • Ferimer H.
        • Alexander H.L.
        • et al.
        Delayed, spontaneous hypothermia reduces neuronal damage after asphyxial cardiac arrest in rats.
        Crit Care Med. 2000; 28: 3511-3516
        • Pacher P.
        • Hasko G.
        Endocannabinoids and cannabinoid receptors in ischaemia-reperfusion injury and preconditioning.
        Br J Pharmacol. 2008; 153: 252-262
        • Chen Y.
        • Chen S.Y.
        • Wang Q.
        • et al.
        Neuroprotective effect of preconditioning with cannabinoid receptor agonist win 55, 212-2 on focal cerebral ischemia: experiment with rats.
        Zhonghua Yi Xue Za Zhi. 2008; 88: 2219-2222
        • Fernandez-Lopez D.
        • Martinez-Orgado J.
        • Nunez E.
        • et al.
        Characterization of the neuroprotective effect of the cannabinoid agonist win-55212 in an in vitro model of hypoxic-ischemic brain damage in newborn rats.
        Pediatr Res. 2006; 60: 169-173
        • Niederhoffer N.
        • Hansen H.H.
        • Fernandez-Ruiz J.J.
        • Szabo B.
        Effects of cannabinoids on adrenaline release from adrenal medullary cells.
        Br J Pharmacol. 2001; 134: 1319-1327
        • Nishimura Y.
        • Naito Y.
        • Nishioka T.
        • Okamura Y.
        The effects of cardiac cooling under surface-induced hypothermia on the cardiac function in the in situ heart.
        Interact Cardiovasc Thorac Surg. 2005; 4: 101-105
        • Gardiner S.M.
        • March J.E.
        • Kemp P.A.
        • Bennett T.
        Regional haemodynamic responses to the cannabinoid agonist, win 55, 212-2, in conscious, normotensive rats, and in hypertensive, transgenic rats.
        Br J Pharmacol. 2001; 133: 445-453
        • Fries M.
        • Weil M.H.
        • Chang Y.T.
        • Castillo C.
        • Tang W.
        Microcirculation during cardiac arrest and resuscitation.
        Crit Care Med. 2006; 34: S454-S457