Cannabidiol and the CB1 receptor antagonist AM251 act synergistically to reduce ventricular arrhythmias following acute myocardial ischaemia in anaesthetised rats.

Claire Hepburn1, Sarah Walsh2, Cherry Wainwright2. 1The Robert Gordon University, School of Pharmacy and Life Sciences, Aberdeen, UK, 2The Robert Gordon University, Institute for Health and Welfare Research, Aberdeen, UK.

Cannabidiol (CBD), an atypical non-psychoactive phytocannabinoid with a complex pharmacology, can act as both an inverse agonist of CB1, CB2 and non-CB1/CB2 receptors and conversely, as a CB1 and CB2 agonist at micromolar concentrations. We have previously shown CBD to exert both a profound anti-arrhythmic and tissue sparing effect in the early stages of myocardial reperfusion (Walsh et al., 2010) in an in vivo rat model of coronary artery occlusion. However, the exact pharmacological targets via which these cardioprotective effects are mediated have yet to be identified. To explore the potential role of an action at CB1 receptors in the anti-arrhythmic effect of CBD, the present study examined whether co-administration of CBD with a selective CB1 receptor antagonist (AM251), altered the previously observed anti-arrhythmic effect of CBD.

Male Sprague Dawley (250-400g) rats were anaesthetised with sodium pentobarbitone (60mg kg-1 i.p.) and cannulated for mean arterial blood pressure (MABP) measurement, i.v. drug administration and artificial respiration. Both heart rate (HR) and the incidence of ventricular arrhythmias were recorded via a Lead I ECG. Following a 30 minute stabilisation period, myocardial ischaemia was induced via ligation of the left anterior descending coronary artery for 30 minutes. Experimental groups included; (i) vehicle control, (ii) CBD (50µg kg-1) alone, (iii) AM251 (1mg kg-1) alone, (iv) CBD followed by AM251, and (v) AM251 followed by CBD (n = 4-9 for all groups). All drugs were administered as bolus doses 5-10 min prior to coronary occlusion.

When given alone, both CBD and AM251 reduced the incidence of ventricular tachycardia (VT; 715±205 and 390±159, respectively vs. 1274±303 (control); P<0.05 AM251 vs. control) and the total number of ventricular ectopic beats (VEB; 977±229 and 634±181, respectively vs. 1727±416 (control); P<0.05 AM251 vs. control) compared with the control group. For the co-administration studies, when AM251 was administered 5 min after CBD, the number of arrhythmias occurring as VT (390±161) and the total VEB counts (477±192) were similar to those seen with AM251 alone. However, in animals treated with AM251 followed by CBD the anti-arrhythmic effect was significantly more pronounced (37±16 (VT) and 133±31 (total VEB); P<0.01) when compared with all other treatment groups. Furthermore, all treatment groups showed a trend towards a reduction in the incidence of ventricular fibrillation (VF). CBD and AM251 administered independently affected different phases of arrhythmias, phase 1b and phase 1a, respectively. Administration of AM251 prior to CBD appeared to produce an additive effect, with reductions in the number of VEBs in both arrhythmia phases. However when CBD administered prior to AM251, this additive effect is lost.

The ability of AM251 to suppress arrhythmias suggests that endogenously released cannabinoids may exert pro-arrhythmic effects via the CB1 receptor. Furthermore, the observation that the anti-arrhythmic effects of both AM251 and CBD are preserved when they are co-administered implies that a simple agonist/antagonist relationship at the CB1 receptor may not be responsible for the anti-arrhythmic effects of either alone. Interestingly, when the CB1 receptor is blocked prior to CBD administration, a synergistic anti-arrhythmic effect is observed which may suggest some cross-talk between the CB1 and other CB receptors in the heart during ischaemia. Moreover, the failure of CB1 antagonist pretreatment to inhibit the anti-arrhythmic effect of CBD suggests that CBD is not acting via activation of CB1 receptors to produce an additive effect. Finally, the dependence of this additive anti-arrhythmic effect upon the order in which the agents are administered suggests some complex interactions at the level of the CB1 receptor.

Walsh SK, Hepburn CY, Kane KA, Wainwright CL, Br J Pharmacol. 2010; 160:1234-1242.

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