Published Online
on July 5, 2005

A more recent version of this article appeared on July 12, 2005

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Submitted on June 21, 2004
Revised on March 25, 2005
Accepted on March 30, 2005

Efferent Vagal Nerve Stimulation Protects Heart Against Ischemia-Induced Arrhythmias by Preserving Connexin43 Protein

Motonori Ando PhD, Rajesh G. Katare MD, Yoshihiko Kakinuma MD, Dongmei Zhang MD, Fumiyasu Yamasaki MD, Kazuyo Muramoto PhD, and Takayuki Sato MD^*

From the Department of Cardiovascular Control (M.A., R.G.K., Y.K., D.Z., T.S.), Kochi Medical School, Nankoku, Japan; Department of Clinical Laboratory (F.Y.), Kochi Medical School, Nankoku, Japan; and Department of Integrative Physiology (K.M.), Kochi Medical School, Nankoku, Japan.

^* To whom correspondence should be addressed. E-mail: tacsato-kochimed{at}umin.ac.jp.

Background--Myocardial ischemia (MI) leads to derangements in cellular electrical stability and the generation of lethal arrhythmias. Vagal nerve stimulation has been postulated to contribute to the antifibrillatory effect. Here, we suggest a novel mechanism for the antiarrhythmogenic properties of vagal stimulation during acute MI.

Methods and Results--Under anesthesia, Wistar rats underwent 30 minutes of left coronary artery (LCA) ligation with vagal stimulation (MI-VS group, n=11) and with sham stimulation (MI-SS group, n=12). Eight of the 12 rats in the MI-SS group had ventricular tachyarrhythmia (VT) during 30-minute LCA ligation; on the other hand, VT occurred in only 1 of the 11 rats in the MI-VS group (67% versus 9%, respectively). Atropine administration abolished the antiarrhythmogenic effect of vagal stimulation. Immunoblotting revealed that the MI-SS group showed a marked reduction in the amount of phosphorylated connexin43 (Cx43), whereas the MI-VS group showed only a slight reduction compared with the sham operation and sham stimulation group (37±20% versus 79±18%). Immunohistochemistry confirmed that the MI-induced loss of Cx43 from intercellular junctions was prevented by vagal stimulation. In addition, studies with rat primary-cultured cardiomyocytes demonstrated that acetylcholine effectively prevented the hypoxia-induced loss of phosphorylated Cx43 and ameliorated the loss of cell-to-cell communication as determined by Lucifer Yellow dye transfer assay, which supports the in vivo results.

Conclusions--Vagal nerve stimulation exerts antiarrhythmogenic effects accompanied by prevention of the loss of phosphorylated Cx43 during acute MI and thus plays a critical role in improving ischemia-induced electrical instability.

Key words: arrhythmia • connexins • electrical stimulation • gap junctions • vagus nerve

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