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

Kochi Medical School, Kôti, Kōchi, Japan
Circulation (Impact Factor: 14.43). 08/2005; 112(2):164-70. DOI: 10.1161/CIRCULATIONAHA.104.525493
Source: PubMed


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.
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.
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.

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Available from: Rajesh Katare, Feb 04, 2014
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    • "However, vagus nerve stimulation (VNS) has been demonstrated to exert protective anti-arrhythmic effects against ventricular tachycardia. The antiarrhythmic effects of VNS may accompany by preventing the loss of ventricular connexins [9]. In our present study, we observed that LL-TS could suppress AF via shortening AF duration and prolonging AF cycle length. "

    International Journal of Cardiology 10/2014; 179C:144-145. DOI:10.1016/j.ijcard.2014.10.114 · 4.04 Impact Factor
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    • "So far, in terms of the pleiotropic action of ACh, we determined that ACh plays a crucial role in suppressing cardiac remodeling by preventing myocardium loss,2,6,9,17 attenuating electric remodeling,5,18 and facilitating angiogenesis in an ischemic hind limb model.16 Initially these effects were supposed to be exerted by ACh released from vagal nerve endings; however, lines of evidence have suggested that this might not be the case because of the poor innervation of the vagal nerve in the cardiac ventricles in contrast to rich adrenergic nerve endings,19–21 and ACh from the vagal nerve ends degraded rapidly by acetylcholinesterase, meaning that ACh could not be distributed over all the ventricles. "
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    ABSTRACT: Murine and human ventricular cardiomyocytes rich in acetylcholine (Ach) receptors are poorly innervated by the vagus, compared with whole ventricular innervation by the adrenergic nerve. However, vagal nerve stimulation produces a favorable outcome even in the murine heart, despite relatively low ventricular cholinergic nerve density. Such a mismatch and missing link suggest the existence of a nonneuronal cholinergic system in ventricular myocardium. To examine the role of the nonneuronal cardiac cholinergic system, we generated choline acetyltransferase (ChAT)-expressing cells and heart-specific ChAT transgenic (ChAT-tg) mice. Compared with cardiomyocytes of wild-type (WT) mice, those of the ChAT-tg mice had high levels of ACh and hypoxia-inducible factor (HIF)-1α protein and augmented glucose uptake. These phenotypes were also reproduced by ChAT-overexpressing cells, which utilized oxygen less. Before myocardial infarction (MI), the WT and ChAT-tg mice showed similar hemodynamics; after MI, however, the ChAT-tg mice had better survival than did the WT mice. In the ChAT-tg hearts, accelerated angiogenesis at the ischemic area, and accentuated glucose utilization prevented post-MI remodeling. The ChAT-tg heart was more resistant to ischemia-reperfusion injury than was the WT heart. These results suggest that the activated cardiac ACh-HIF-1α cascade improves survival after MI. We conclude that de novo synthesis of ACh in cardiomyocytes is a pivotal mechanism for self-defense against ischemia.
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    • "The assessment of GJ function particularly under in vivo conditions is rather difficult.Most of the currently used methods provide only indirect evidence on the coupling status of GJs. Measurement of GJ permeability using small molecular weight dyes (Ruiz-Meana et al., 2001) or the determination of connexin phosphorylation (Ando et al., 2005) allows evaluation of coupling only at a certain time point. Although measuring conduction velocity by activation mapping techniques (Rohr et al., 1998; Henriquez et al., 2001), or tissue impedance (resistivity and phase angle) changes by the use of a four-pin electrode method (Kléber et al., 1987; Cinca et al., 1997; Padilla et al., 2003) make possible continuous recording, these methods represent also only indirect assessment of GJ function. "
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    ABSTRACT: Myocardial ischemia resulting from sudden occlusion of a coronary artery is one of the major causes in the appearance of severe, often life-threatening ventricular arrhythmias. Although the underlying mechanisms of these acute arrhythmias are many and varied, there is no doubt that uncoupling of gap junctions (GJs) play an important role especially in arrhythmias that are generated during phase Ib, and often terminate in sudden cardiac death. In the past decades considerable efforts have been made to explore mechanisms which regulate the function of GJs, and to find new approaches for protection against arrhythmias through the modulation of GJs. These investigations led to the development of GJ openers and inhibitors. The pharmacological modulation of GJs, however, resulted in conflicting results. It is still not clear whether opening or closing of GJs would be advantageous for the ischemic myocardium. Both maneuvers can result in protection, depending on the models, endpoints and the time of opening and closing of GJs. Furthermore, although there is substantial evidence that preconditioning decreases or delays the uncoupling of GJs, the precise mechanisms by which this attains have not yet been elucidated. In our own studies in anesthetized dogs preconditioning suppressed the ischemia and reperfusion-induced ventricular arrhythmias, and this protection was associated with the preservation of GJ function, manifested in less marked changes in electrical impedance, as well as in the maintenance of GJ permeability and phosphorylation of connexin43. Since we have substantial previous evidence that nitric oxide (NO) is an important trigger and mediator of the preconditioning-induced antiarrhythmic protection, we hypothesized that NO, among its several effects, may lead to this protection by influencing cardiac GJs. The hypotheses and theories relating to the pharmacological modulation of GJs will be discussed with particular attention to the role of NO.
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