Abstract
Diminished parasympathetic influence is central to the pathogenesis of cardiovascular diseases, including heart failure and hypertension. Stimulation of the vagus nerve has shown promise in treating cardiovascular disease, prompting renewed interest in understanding the signaling pathway(s) that mediate the vagal influence on cardiac physiology. Here, we evaluated the contribution of G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels to the effect of vagus nerve stimulation (VNS) on heart rate (HR), HR variability (HRV), and arrhythmogenesis in anesthetized mice. As parasympathetic fibers innervate both atria and ventricle, and GIRK channels contribute to the cholinergic impact on atrial and ventricular myocytes, we collected in vivo electrocardiogram recordings from mice lacking either atrial or ventricular GIRK channels, during VNS. VNS decreased HR and increased HRV in control mice, in a muscarinic receptor-dependent manner. This effect was preserved in mice lacking ventricular GIRK channels, but was nearly completely absent in mice lacking GIRK channels in the atria. In addition, atrial-specific ablation of GIRK channels conferred resistance to arrhythmic episodes induced by VNS. These data indicate that atrial GIRK channels are the primary mediators of the impact of VNS on HR, HRV, and arrhythmogenesis in the anesthetized mouse.
Highlights
The parasympathetic and sympathetic branches of the autonomic nervous system work antagonistically to maintain cardiovascular homeostasis (Gordan et al, 2015)
Our findings suggest that the impact of direct vagus nerve stimulation (VNS) on cardiac physiology in anesthetized mice is attributable primarily to activation of atrial GIRK channels
To test whether atrial GIRK channel activity was lost in SLNCre(+):Girk1fl/fl mice, we measured whole-cell currents evoked by CCh in sinoatrial nodal (SAN) cells from adult Cre(+)
Summary
The parasympathetic and sympathetic branches of the autonomic nervous system work antagonistically to maintain cardiovascular homeostasis (Gordan et al, 2015). Autonomic dysregulation, characterized by excessive sympathetic activation and diminished parasympathetic influence, is central to the pathogenesis of cardiovascular diseases including heart failure and hypertension (Bibevski and Dunlap, 2011; Schwartz and De Ferrari, 2011; Mancia and Grassi, 2014). Efferent fibers of the vagus nerve provide the parasympathetic innervation to the heart, and vagus nerve stimulation (VNS) has shown promise in the treatment of cardiovascular diseases, including heart failure and hypertension (Xie et al, 2014; Beaumont et al, 2015; Petkovich et al, 2015; Premchand et al, 2016; Smith et al, 2016). Parasympathetic regulation of heart rate (HR) is mediated via release of acetylcholine (ACh), which activates cardiac muscarinic M2 receptors (M2R) on sinoatrial and atrioventricular nodal cells, and atrial myocytes (Dhein et al, 2001). Ventricular myocytes express a GIRK1/GIRK4 channel, albeit at lower levels than in atrial myocytes, and this channel mediates the impact of cholinergic agonists on action potential duration and the excitability of ventricular myocytes (Koumi et al, 1997; Dobrzynski et al, 2001, 2002; Posokhova et al, 2010; Liang et al, 2014; Anderson et al, 2018)
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