title: Feasibility of targeting ischaemia-related ventricular arrhythmias by mimicry of endogenous protection by endocannabinoids.
abstract: OBJECTIVE
  The hypothesis that endocannabinoids protect hearts against ventricular fibrillation (VF) induced by myocardial ischaemia and reperfusion was examined, and the concept that cannabinoids may represent a new class of anti-VF drug was tested.
  
  
  METHODS
  In rat isolated hearts (Langendorff perfusion), VF evoked by reperfusion after 60 min regional ischaemia is known to be exacerbated by inhibitors of endogenous protectants such as nitric oxide. This preparation was used to assay the effects of cannabinoid agonists and antagonists, and the protocols were varied to examine mechanisms.
  
  
  RESULTS
  Reperfusion-induced VF was not facilitated by relatively selective CB1 (1 μM AM251) or CB2 (1 μM AM630) antagonists. VF evoked during early (30 min) acute ischaemia was also unaffected. However, AM251 significantly increased the incidence of VF and the duration of VF episodes occurring during the later stage of acute ischaemia (30-60 min). AM630 had no such effects. In a separate study, cannabinoid perfusion (anandamide or 2-arachidonoylglycerol, both 0.01-1 μM) failed to reduce VF incidence concentration-dependently during 30 min ischaemia. In all these studies, changes in ancillary variables (QT, PR, heart rate) were unrelated to changes in VF.
  
  
  CONCLUSIONS
  Endocannabinoids are not endogenous anti-VF mediators during reperfusion, but may have a weak protective effect during the late stages of ischaemia, mediated via CB1 agonism. This does not suggest endocannabinoids are important endogenous protectants in these settings, or that CB1 (or CB2) receptors are useful novel targets for developing drugs for VF.
authors.affiliation: Cardiovascular Division, King's College London, London, UK.
authors.forename: Ellen
authors.initials: E
authors.lastname: Andrag
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Curtis
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000378:metabolism / Q000494:pharmacology*; D063388:Endocannabinoids / Q000378:metabolism / Q000494:pharmacology*; D005240:Feasibility Studies; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014693:Ventricular Fibrillation / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; C078814:anandamide
keywords: 2-arachidonoylglycerol; acute myocardial infarction; anandamide; antiarrhythmic; arrhythmia; endocannabinoid; myocardial ischaemia; proarrhythmia; sudden cardiac death; ventricular fibrillation