Feasibility of targeting ischaemia‐related ventricular arrhythmias by mimicry of endogenous protection by endocannabinoids

Abstract

BACKGROUND AND PURPOSEThe 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 APPROACHIn 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. KEY RESULTSReperfusion-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 IMPLICATIONSEndocannabinoids 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. Abbreviations2-AG, 2-arachidonoylglycerol; CF, coronary flow; HR, heart rate; IZ, involved zone; SCD, sudden cardiac death; VF, ventricular fibrillation BJP British Journal of Pharmacology

Incidence and Risk Factors of Ventricular Fibrillation Before Primary Angioplasty in Patients With First ST‐Elevation Myocardial Infarction: A Nationwide Study in Denmark

“…11–12 Results from these studies may not be generalizable to the majority of SCDs or VF arrests due to MI that occurs outside the hospital.…”

Pharmacological profiling of the hemodynamic effects of cannabinoid ligands: a combined in vitro and in vivo approach

“…AM251 on its own produced a small and transient, but significant, depressor response in both anesthetized rats and WT mice. This is the first report of a vasodepressor response to AM251 in vivo, but a recent report has shown AM251 to increase coronary flow in rat isolated hearts (Andrag and Curtis ). It is unlikely that this response to AM251 is due to CB 1 receptor blockade, since inhibition of any constitutive CB 1 activity in controlling vascular tone would be expected to increase, rather than decrease, BP and that the response would be prolonged.…”

Endocannabinoids and the Cardiovascular System in Health and Disease

“…AEA also reduces epinephrine-induced arrhythmias, although this was CB 1 and CB 2 independent . However, more recently, neither AEA nor 2-AG were found to affect ischaemia-induced ventricular fibrillation, although a CB 1 antagonist (but not CB 2 antagonist) alone did have some positive effects during the later stage of acute ischaemia (Andrag and Curtis 2013). In isolated sinoatrial node samples from rabbits, AEA shortens the action potential duration and amplitude via CB 1 (Zhang et al 2013).…”