An increase in CO 2 levels by upregulating late sodium current is proarrhythmic in the heart.

BACKGROUND: Increased CO2 levels in general circulation and/or in the myocardium are common under pathological conditions.

OBJECTIVE: To test the hypothesis that an increase in CO2 levels, but not just the subsequent extra- or intra-cellular acidosis, would augment late sodium current (INa,L ), and contribute to arrhythmogenesis in hearts with reduced repolarization reserve.

METHODS: Monophasic action potential durations at 90% completion of repolarization (MAPD90 ) from isolated rabbit hearts, INa,L and extra- (pHo ) and intra-cellular pH (pHi ) values from cardiomyocytes using the whole-cell patch-clamp techniques and BCECF-AM, respectively, were measured.

RESULTS: Increasing CO2 level from 5% to 10% and 20%, and administration of 1 nM sea anemone toxin (ATX)-II increased INaL and prolonged both epi- and endo-MAPD90 (n=7 and 10) without causing arrhythmic activities. Compared to 5% CO2 , 10% and 20% CO2 decreased pHo and pHi , in hearts treated with 1 nM ATX-II caused a greater prolongation of MAPD90 and elicited ventricular tachycardias. Increasing CO2 levels from 5% to 10% and 20% with pHo remained at 7.4 produced smaller changes in pHi (P < 0.05) but similar increase in INa,L , prolongation in MAPD90 and incidence of ventricular tachycardias (n=8). Inhibition of INa,L reversed the increase in INa,L , suppressed MAPD90 prolongations and ventricular tachycardias induced by 20% CO2 . Increased phospho-CaMKIIδ and phospho-NaV 1.5 protein levels in hearts treated with 20% CO2 was attenuated by eleclazine.

CONCLUSIONS: Increased CO2 levels enhance INa,L and are proarrhythmic factors in the heart with reduced repolarization reserve, possibly through mechanisms related to the phosphorylations of CaMKIIδ and NaV 1.5.