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Feasibility of targeting ischaemia‐related ventricular arrhythmias by mimicry of endogenous protection by endocannabinoids
Author(s) -
Andrag Ellen,
Curtis Michael J
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12252
Subject(s) - am251 , cannabinoid receptor , ventricular fibrillation , endocannabinoid system , ischemia , cannabinoid , anandamide , proarrhythmia , medicine , endogeny , cardiology , anesthesia , pharmacology , receptor , qt interval , agonist
Background and Purpose 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. Experimental Approach In rat isolated hearts ( L angendorff 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. Key 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 and Implications 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 .