Assessment of proarrhythmogenic risk for cannabidiol using dog and rabbit cardiac preparations: the electrophysiological effects on action potential and transmembrane potassium currents

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Economic Development and Innovation Operative Programme GINOP-2.3.2-15-2016-00012, the National Research Development and Innovation Office (NKFIH K 135464 and NKFIH K 128851), the Ministry of Human Capacities Hungary (20391-3/2018/FEKUSTRAT and EFOP-3.6.2-16-2017-00006), and from the Eötvös Loránd Research Network Background Cannabidiol (CBD), a major active phytogenic cannabinoid, is one of the main constituents of cannabis. Cannabis has been widely used as recreational drug over the decades and its use is constantly increasing as hallucinogenic and/or medicinal agent. However, significant cardiovascular side effects can accompany its use ranging from arrhythmia to sudden cardiac death. Purpose The aim of the present work was to investigate the possible cardiac adverse electrophysiological effects of cannabidiol (CBD) on action potentials and various transmembrane potassium currents, such as the rapid (IKr) and slow (IKs) delayed rectifier, the transient outward (Ito) and inward rectifier (IK1) potassium currents in rabbit and dog cardiac preparations to assess the cardiac safety profile and proarrhythmic risk. Methods In the current study, conventional microelectrode and voltage clamp techniques were used to record the action potential and transmembrane ionic currents in dog and rabbit ventricular tissue preparations and enzymatically isolated myocytes, respectively. Results The results show that CBD lengthens APD90 significantly at the concentration of 5 µM both in dog and rabbit ventricular tissues without changing other action potential parameters significantly. To further investigate the APD90 lengthening effect of CBD, transmembrane potassium currents (IKr, IKs, Ito and IK1) were investigated in dog and/or rabbit ventricular myocytes using voltage clamp technique. CBD significantly inhibited IKr and IKs currents in rabbit ventricular myocytes with an estimated EC50 values of 4.9 and 3.1 µM, respectively. The effect of CBD on rabbit’s Ito current was not significant while it was significant on dog’s Ito current with an estimated EC50 value of 5 µM. IK1 was not responsive to CBD even at high concentration. Conclusion In conclusion, looking at the inhibitory effects of CBD on repolarizing potassium currents, despite of the fact that these calculated EC50 values are higher than pharmacokinetics based Cmax values of CBD recorded after smoking and oral intake, it can be speculated that in the presence of certain cardio active drugs or co-morbidity where CBD metabolism or cardiac repolarization reserve is impaired CBD can have an additive and proarrhythmic effect.