Increase in CO levels by upregulating late sodium current is proarrhythmic in the heart.

Background: Increased CO levels in the general circulation and/or in the myocardium are common under pathologic conditions.

Objective: The purpose of this study was to test the hypothesis that an increase in CO levels, and not just the subsequent extra- or intracellular acidosis, would augment late sodium current (I) and contribute to arrhythmogenesis in hearts with reduced repolarization reserve.

Methods: Monophasic action potential durations at 90% completion of repolarization (MAPD) from isolated rabbit hearts, I, and extra- (pH) and intracellular pH (pH) values from cardiomyocytes using the whole-cell patch-clamp techniques and 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester (BCECF-AM), respectively, were measured.

Results: Increasing CO levels from 5% to 10% and 20% and administration of 1 nM sea anemone toxin (ATX)-II increased I and prolonged both epicardial and endocardial MAPD (n = 7 and 10, respectively) without causing arrhythmic activities. Compared to 5% CO, 10% and 20% CO decreased pH and pH in hearts treated with 1 nM ATX-II, caused greater prolongation of MAPD, and elicited ventricular tachycardias. Increasing CO levels from 5% to 10% and 20% with pH maintained at 7.4 produced smaller changes in pH (P <.05) but similar increases in I, prolongation of MAPD, and incidence of ventricular tachycardias (n = 8). Inhibition of I reversed the increase in I, suppressed MAPD prolongations, and ventricular tachycardias induced by 20% CO. Increased phospho-calmodulin-dependent protein kinase II-δ (CaMKIIδ) and phospho-Na1.5 protein levels in hearts treated with 20% CO was attenuated by eleclazine.

Conclusion: Increased CO levels enhance I and are proarrhythmic factors in hearts with reduced repolarization reserve, possibly via mechanisms related to phosphorylation of CaMKIIδ and Na1.5.