Background and purposeCardiovascular anomalies are predisposing factors for diabetes-induced morbidity and mortality. Recently, we showed that high glucose induces changes in the biophysical properties of Nav1.5 that could be strongly correlated to diabetes-induced arrhythmia. However, the mechanisms underlying hyperglycemia-induced inflammation, and how inflammation provokes cardiac arrhythmia, are not well understood. We hypothesized that inflammation could mediate the high glucose-induced biophyscial changes on Nav1.5 through protein phosphorylation by protein kinases A and C. We also hypothesized that this signaling pathway is, at least partly, involved in the cardiprotective effects of CBD and E2.Experimental approachTo test these ideas, we used Chinese hamster ovarian (CHO) cells transiently co-transfected with cDNA encoding human Nav1.5 α-subunit under control, a cocktail of inflammatory mediators or 100 mM glucose conditions (for 24 hours). We used electrophysiological experiments and action potential modelling.Key ResultsInflammatory mediators, similar to 100 mM glucose, 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. In addition, activators of PK-A or PK-C replicated the inflammation-induced gating changes of Nav1.5. Inhibitors of PK-A or PK-C, CBD or E2 mitigated all the potentially deleterious effects provoked by high glucose/inflammation.Conclusions and implicationsThese findings suggest that PK-A and PK-C may mediate the anti-inflammatory effects of CBD and E2 against high glucose-induced arrhythmia. CBD, via Nav1.5, may be a cardioprotective therapeutic approach in diabetic postmenopausal population.Bullet pointsWhat is already known:Arrhythmias are among the common cardiac causes of morbidity and mortality in diabetes-related hyperglycemia.One of the diabetes-induced arrhythmias is long-QT syndrome, caused by gating defects in the cardiac voltage-gated sodium channel (Nav1.5).What this study adds:Inflammation and subsequent activation of PK-A and PK-C mediate the high glucose-induced electrophysiological changes of Nav1.5 in a manner consistent with the gating defects that underlie long-QT arrhythmia.Cannabidiol and estradiol rescue the high glucose induced Nav1.5 gating defects through, at least partly, this signaling pathway.Clinical significance:Inflammation/PK-A and PK-C signaling pathway could be a potential therapeutic target to prevent arrhythmias associated with diabetes.Cannabidiol may be a therapeutic approach to prevent cardiac complications in diabetes, especially in postmenopausal populations due to the decreased levels of the cardioprotective estrogen.