Alcohol-induced atrial tachyarrhythmias in rat hearts: molecular basis and effects of Na⁺ channel blockade

Takeshi Yamashita
Authors: Long-Tai Fu; Hiroyuki Iinuma; Yuji Iwasaki; Kouichi Sagara; Akiko Sekiguchi; Takeshi Yamashita

Background:Alcohol intake is well known as one of the predisposing factors for atrial fibrillation (AF), although the mechanisms remain unclear. As the arrhythmia occurs frequently with delay after drinking, short-term biochemical reconstruction of ion channels could play a role. To test this hypothesis, we have constructed a new model of this alcohol-induced AF. The purpose of the study was to examine (1) the underlying mechanisms and (2) the effects of Na⁺ channel blockade to prevent this arrhythmia.

Methods: Ethanol (0-4.4 g/kg) in combination with cyanamide (0-200 mg/kg) was injected intraperitoneally in SD rats. Gene expression of cardiac ion channels including 15 K⁺ and 2 HCN channels was assayed by RNase protection assay and Western blot analysis, and was correlated with electrophysiologic study in isolated-perfused hearts. Pilsicainide, a pure Na⁺ channel blocker clinically available in Japan, was used to assess the effects of Na⁺ channel blockade.

Results: Ethanol injection immediately but transiently upregulated Kv1.5 and HCN4 mRNA with a peak at 1 hour after the injection, and cyanamide significantly augmented these effects. Western blot also revealed a transient increase in Kv1.5 and HCN4 proteins peaking at 4 hours. According to the time-course of the upregulation of these genes, the number of repetitive atrial responses (RAR) by single extrastimulus significantly increased (from 4.8 to 23.2) with shortening of atrial refractory period (from 32 to 23 ms) and sinus cycle length (from 259 to 207 ms) between 2 and 4 hours after the injection, and thereafter these variables returned to the baseline value. Pilsicainide prolonged the refractoriness and depressed intraatrial conduction velocity in a dose-dependent manner. Irrespective of no apparent alterations in their multiplying parameter, wavelength, the drug effectively decreased the number of RAR induced by extrastimulus.

Conclusions: Alcohol caused short-term ion channel remodeling, leading to arrhythmogenic substrates with several-hour delay. Na⁺ channel blockade was effective also for this type of alcohol-induced AF, where ion channel remodeling of Kv1.5 and HCN4 occurred.