Tohoku J. Exp. Med., 2011, 225(1)

A Sodium Channel Blocker, Pilsicainide, Produces Atrial Post-Repolarization Refractoriness through the Reduction of Sodium Channel Availability

KOJI FUKUDA,¹ JUN WATANABE,¹ TAKUYA YAGI,¹ YUJI WAKAYAMA,¹ MAKOTO NAKANO,¹ MASATERU KONDO,¹ KOJI KUMAGAI,¹ MASAHITO MIURA,¹ KUNIO SHIRATO¹ and HIROAKI SHIMOKAWA¹

¹Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan

Atrial fibrillation (AF) is the most common tachyarrhythmia. Shortening of atrial action potential duration (APD) and effective refractory period (ERP) is one of the crucial factors in the occurrence and maintenance of AF. ERP is usually shorter than APD, but ERP can be prolonged beyond action potential repolarization in some situations. It is termed as post-repolarization refractoriness (PRR) that is thought to be one of main anti-arrhythmic mechanisms of class I sodium channel blockers (SCBs). Most of anti-arrhythmic agents, including SCBs, have multi-channel blocking effects. It is unknown whether atrial PRR with SCBs is associated with the reduction of sodium channel availability. We therefore explored the relationship between the reduction of sodium channel availability with a pure SCB (pilsicainide or tetrodotoxin) and atrial PRR using the left atrial appendage from male guinea pigs (each group, n = 3~10). Employing a standard microelectrode technique, we evaluated APD measured at 90% repolarization (APD₉₀) and the sodium channel availability, judged from the maximal rate of rise of action potential (Vmax). At a 500-msec basic cycle length (BCL), pilsicainide prolonged atrial ERP assessed by a single extra-stimulus in response to the decrement of the Vmax in a dose-dependent manner without affecting APD₉₀. Furthermore, pilsicainide increased the ERP and decreased the Vmax in a rate-dependent manner without APD₉₀ prolongation at a shorter BCL (200 msec). Importantly, tetrodotoxin reproduced the effects of pilsicainide on atrial ERP, APD₉₀, and Vmax. These results indicate that SCBs produce atrial PRR through the reduction of sodium channel availability.

keywords —— action potential duration; anti-arrhythmic agents; atrial fibrillation; effective refractory period; sodium channels

© 2011 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2011, 225, 35-42

Correspondence: Koji Fukuda, M.D., Ph.D., Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.

e-mail: fukuda@cardio.med.tohoku.ac.jp