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

Abstract

Background and Purpose: Cardiovascular complications are the major cause of mortality in diabetic patients. However, the molecular mechanisms underlying diabetesassociated arrhythmias are unclear. We hypothesized that high glucose could adversely affect Na v 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 Na v 1.5, could protect against high glucose-elicited oxidative stress and cytotoxicity.Experimental Approach: To test these ideas, we used CHO cells transiently cotransfected with cDNA encoding human Na v 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.Key Results: 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.Conclusion and Implications: These findings suggest that, through its favourable antioxidant and sodium channel inhibitory effects, CBD may protect against high glucose-induced arrhythmia and cytotoxicity.

Mechanism and effects of the skeletal muscle Nav1.4 inhibition by cannabidiol

“…Although CBD holds therapeutic promise(Devinsky et al, 2017; Ghovanloo et al, 2018c; Kaplan et al, 2017; Patel et al, 2016; Ross et al, 2008; Pumroy et al, 2019; Fouda et al, 2020) and has been approved for two seizure disorders, its mechanisms of action remain largely unknown. We previously described the effects of CBD on Nav, which are among its proposed targets(Ghovanloo et al, 2018c).…”

Protein kinases mediate anti-inflammatory effects of cannabidiol and estradiol against high glucose in cardiac sodium channels

“…These deleterious cardiovascular complications are mainly attributed to hyperglycemia/high glucose (Pistrosch, Natali & Hanefeld, 2011). There is also a positive correlation between diabetes/high glucose and long QT (LQT) syndrome (Fouda, Ghovanloo & Ruben, 2020; Grisanti, 2018). LQT syndrome is a cardiac arrhythmogenic disorder, identified by a prolongation of the Q-T interval.…”

“…Voltage-gated sodium channels (Nav) underlie phase 0 of the cardiac action potential (Balser, 1999; Ruan, Liu & Priori, 2009). Changes in the biophysical properties of the primary cardiac sodium channel, Nav1.5, are linked to diabetes induced cardiovascular abnormalities (Fouda, Ghovanloo & Ruben, 2020; Yu et al, 2018). However, the mechanisms underlying hyperglycemia-induced inflammation, and how inflammation provokes cardiac dysfunction, are not well understood.…”

“…CBD lacks adverse cardiac toxicity and ameliorates diabetes/high glucose induced deletrious cardiomyopathy (Cunha et al, 1980; Izzo, Borrelli, Capasso, Di Marzo & Mechoulam, 2009; Rajesh et al, 2010). Recently, we showed that CBD rescues the biophysical substrate for LQT3 via direct inhibitory effects on cardiac sodium ion channels and indirect anti-oxidant effects (Fouda, Ghovanloo & Ruben, 2020). In addition, CBD inhibits the production of pro-inflammatory cytokines in vitro and in vivo (Nichols & Kaplan, 2020).…”

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“…Ventricular action potentials were simulated using a modified version of the O'Hara-Rudy model programmed in Matlab (O'Hara et al, 2011;Fouda et al, 2020). The code that was used to produce the model is available online from Washington University in St. Louis 1 .…”