Eleutheroside B, a selective late sodium current inhibitor, suppresses atrial fibrillation induced by sea anemone toxin II in rabbit hearts

Eleutheroside B (EB) is the main active constituent derived from the Chinese herb Acanthopanax senticosus (AS) that has been reported to possess cardioprotective effects. In this study we investigated the effects of EB on cardiac electrophysiology and its suppression on atrial fibrillation (AF). Whole-cell recording was conducted in isolated rabbit atrial myocytes. The intracellular calcium ([Ca²⁺]_i) concentration was measured using calcium indicator Fura-2/AM fluorescence. Monophasic action potential (MAP) and electrocardiogram (ECG) synchronous recordings were conducted in Langendorff-perfused rabbit hearts using ECG signal sampling and analysis system. We showed that EB dose-dependently inhibited late sodium current (I_NaL), transient sodium current (I_NaT), and sea anemone toxin II (ATX II)-increased I_NaL with IC₅₀ values of 167, 1582, and 181 μM, respectively. On the other hand, EB (800 μM) did not affect L-type calcium current (I_CaL), inward rectifier potassium channel current (I_K), and action potential duration (APD). Furthermore, EB (300 μM) markedly decreased ATX II-prolonged the APD at 90% repolarization (APD₉₀) and eliminated ATX II-induced early afterdepolarizations (EADs), delayed afterdepolarizations (DADs), and triggered activities (TAs). Moreover, EB (200 μM) significantly suppressed ATX II-induced Na⁺-dependent [Ca²⁺]_i overload in atrial myocytes. In the Langendorff-perfused rabbit hearts, application of EB (200 μM) or TTX (2 μM) substantially decreased ATX II-induced incidences of atrial fibrillation (AF), ventricular fibrillation (VF), and heart death. These results suggest that augmented I_NaL alone is sufficient to induce AF, and EB exerts anti-AF actions mainly via blocking I_NaL, which put forward the basis of pharmacology for new clinical application of EB.

Keywords: atrial fibrillation; delayed afterdepolarization; early afterdepolarization; eleutheroside B; late sodium current; patch-clamp techniques.