Protective Effect of Cannabidiol Against Oxidative Stress and Cytotoxicity Evoked by High Glucose 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 Nav1.5, the major cardiac sodium channel isoform, at least partially via oxidative stress. We further hypothesized that cannabidiol (CBD), one of the main constituents of Cannabis sativa, could guard against diabetes induced cardiomyopathy. We postulated that CBD, through its effects on Nav1.5, could protect against high glucose elicited oxidative stress and cytotoxicity. To test these ideas, we used Chinese hamster ovarian (CHO) cells transiently transfected with cDNA encoding Nav1.5 α-subunit and incubated the cells in control (10 mM) and high glucose (50 or 100 mM) conditions for 24 hours. 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 prolongation of action potential (hyperexcitability) which could result in long QT-3 arrhythmia. CBD mitigated the deleterious effects provoked by high glucose. Perfusion with lidocaine (a sodium channels inhibitor with anti-oxidant effects), or co-incubation of Tempol (an anti-oxidant) elicited protection, comparable to CBD, against the deleterious effects of high glucose. These findings suggest that, through its favorable anti-oxidant and sodium channel inhibitory effects, CBD may protect against high-glucose induced arrhythmia and cytotoxicity.