An increase of late sodium current induces delayed afterdepolarizations and sustained triggered activity in atrial myocytes

Abstract

This study determined the role of a slowly inactivating component of sodium current (I(Na)), late I(Na), to induce delayed afterdepolarizations (DADs) and triggered activity. We hypothesized that an increase of late I(Na) may induce not only early afterdepolarizations (EADs), but also intracellular calcium overload and DADs. Guinea pig atrial myocytes were studied using the whole cell patch-clamp technique. Anemone toxin II (ATX-II) (5-10 nmol/l) was used to enhance late I(Na). Ranolazine (10 micromol/l) and TTX (2 micromol/l) were applied to block ATX-II-induced late I(Na). ATX-II prolonged action potential duration and induced EADs. In the continuous presence of ATX-II, following the appearance of EADs, both DADs and sustained triggered activity occurred. Triggered activity was abolished and DADs were reduced by either ranolazine or TTX. Consistent with induction of DADs, ATX-II induced the transient inward current (I(TI)). The amplitude of I(TI) was significantly reduced by ranolazine. ATX-II induced only EADs, but no DADs, in the presence of the sodium-calcium exchange inhibitor KB-R7943 or the sarcoplasmic reticulum calcium release channel inhibitor ryanodine, or when the calcium chelator EGTA or BAPTA was included in the pipette solution. In conclusion, an increase of late I(Na), in addition to inducing EADs, can cause cellular calcium overload and induce DADs and sustained triggered activity in atrial myocytes. The data reveal that an increase of late I(Na) is a novel mechanism for initiation of atrial arrhythmic activity.

Heart failure modulates electropharmacological characteristics of sinoatrial nodes

“…Enhanced I Na-Late leads to intracellular Na + loading, which elevates intracellular Ca 2+ through the Na + /Ca 2+ exchanger, inducing a Ca 2+ -dependent transient inward current and triggering activity (16,20,27). However, to the best of our knowledge, the impact of the I Na-Late on SANs has not yet been studied.…”

Ranolazine Attenuates the Enhanced Reverse Na+-Ca2+ Exchange Current via Inhibiting Hypoxia-Increased Late Sodium Current in Ventricular Myocytes

“…Therefore inhibition of I Na.L is considered to be a new potential therapeutic target for treat patients afflicted with heart failure or ischemic heart disease (18,20,21). Approved by the US Food and Drug Administration (FDA) as an antianginal drug in 2006 (11,22), ranolazine (RAN) was first applied as an inhibitor of I Na.L in clinical treatment (12,23). Experimentally, RAN can relieve intracellular Na + and Ca 2+ overload caused by myocardial ischemia via blocking I Na.L (21, 24 -27).…”

The Significance of the Late Na+ Current for Arrhythmia Induction and the Therapeutic Antiarrhythmic Potential of Ranolazine

“…[50][51][52] If a DAD reaches threshold for an AP to occur, triggered activity and extrasystolic activity follow. 51,53 Pharmacological enhancement of I Na,late has been shown to induce DADs and triggered activity. 48,53 Furthermore, inhibition of I Na,late by ranolazine reduces the incidence of DADs and prevents triggered activity.…”

“…51,53 Pharmacological enhancement of I Na,late has been shown to induce DADs and triggered activity. 48,53 Furthermore, inhibition of I Na,late by ranolazine reduces the incidence of DADs and prevents triggered activity. 16,48,[53][54][55] Delayed afterdepolarizations have been observed in several types of cardiac tissue, including both atrial and ventricular myocytes, where they can lead to triggered activity and tachyarrhythmias.…”

“…48,53 Furthermore, inhibition of I Na,late by ranolazine reduces the incidence of DADs and prevents triggered activity. 16,48,[53][54][55] Delayed afterdepolarizations have been observed in several types of cardiac tissue, including both atrial and ventricular myocytes, where they can lead to triggered activity and tachyarrhythmias. 56 The second mechanism of arrhythmia in the heart is abnormal conduction and includes conduction block and reentry.…”