Background and purpose: Cannabidiol (CBD) is a phytocannabinoid, with anti‐apoptotic, anti‐inflammatory and antioxidant effects and has recently been shown to exert a tissue sparing effect during chronic myocardial ischaemia and reperfusion (I/R). However, it is not known whether CBD is cardioprotective in the acute phase of I/R injury and the present studies tested this hypothesis.

Experimental approach: Male Sprague‐Dawley rats received either vehicle or CBD (10 or 50 µg·kg⁻¹ i.v.) 10 min before 30 min coronary artery occlusion or CBD (50 µg·kg⁻¹i.v.) 10 min before reperfusion (2 h). The appearance of ventricular arrhythmias during the ischaemic and immediate post‐reperfusion periods were recorded and the hearts excised for infarct size determination and assessment of mast cell degranulation. Arterial blood was withdrawn at the end of the reperfusion period to assess platelet aggregation in response to collagen.

Key results: CBD reduced both the total number of ischaemia‐induced arrhythmias and infarct size when administered prior to ischaemia, an effect that was dose‐dependent. Infarct size was also reduced when CBD was given prior to reperfusion. CBD (50 µg·kg⁻¹i.v.) given prior to ischaemia, but not at reperfusion, attenuated collagen‐induced platelet aggregation compared with control, but had no effect on ischaemia‐induced mast cell degranulation.

Conclusions and implications: This study demonstrates that CBD is cardioprotective in the acute phase of I/R by both reducing ventricular arrhythmias and attenuating infarct size. The anti‐arrhythmic effect, but not the tissue sparing effect, may be mediated through an inhibitory effect on platelet activation.

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