Cannabidiol protects against high glucose-induced oxidative stress and cytotoxicity in cardiac voltage-gated sodium channels.

Abstract

Cardiovascular complications are the major cause of mortality in diabetic patients. However, the molecular mechanisms underlying diabetes-associated arrhythmias are unclear. We hypothesized that high glucose could adversely affect Nav 1.5, the major cardiac sodium channel isoform of the heart, at least partially via oxidative stress. We further hypothesized that cannabidiol (CBD), one of the main constituents of Cannabis sativa, through its effects on Nav 1.5, could protect against high glucose-elicited oxidative stress and cytotoxicity. To test these ideas, we used CHO cells transiently co-transfected with cDNA encoding human Nav 1.5 α-subunit under control and high glucose conditions (50 or 100 mM for 24 hr). Several experimental and computational techniques were used, including voltage clamp of heterologous expression systems, cell viability assays, fluorescence assays and action potential modelling. High glucose evoked cell death associated with elevation in reactive oxygen species (ROS) right shifted the voltage dependence of conductance and steady-state fast inactivation, and increased persistent current leading to computational prolongation of action potential (hyperexcitability) which could result in long QT3 arrhythmia. CBD mitigated all the deleterious effects provoked by high glucose. Perfusion with lidocaine (a well-known sodium channel inhibitor with antioxidant effects) or co-incubation of Tempol (a well-known antioxidant) elicited protection, comparable to CBD, against the deleterious effects of high glucose. These findings suggest that, through its favourable antioxidant and sodium channel inhibitory effects, CBD may protect against high glucose-induced arrhythmia and cytotoxicity.