Novel strategies and underlying protective mechanisms of modulation of vagal activity in cardiovascular diseases

Abstract

Cardiovascular disease remains a major cause of disability and death worldwide. Autonomic imbalance, characterized by suppressed vagal (parasympathetic) activity and increased sympathetic activity, correlates with various pathological conditions, including heart failure, arrhythmia, ischaemia/reperfusion injury and hypertension. Conventionally, pharmacological interventions, such as β-blocker treatment, have primarily targeted suppressing sympathetic over-activation, while vagal modulation has always been neglected. Emerging evidence has documented the improvement of cardiac and vascular function mediated by the vagal nerve. Many investigators have tried to explore the effective ways to enhance vagal tone and normalize the autonomic nervous system. In this review, we attempt to give an overview of these therapeutic strategies, including direct vagal activation (electrical vagal stimulation, ACh administration and ACh receptor activation), pharmacological modulation (adenosine, cholinesterase inhibitors, statins) and exercise training. This overview provides valuable information for combination therapy, contributing to establishment of a comprehensive system on vagal modulation from the aspects of clinical application and lifestyle improvement. In addition, the mechanisms contributing to the benefits of enhancing vagal tone are diverse and have not yet been fully defined. We endeavour to outline the recent findings that advance our knowledge regarding the many favourable effects exerted by vagal activation: anti-inflammatory pathways, modulation of NOS and NO signalling, regulation of redox state, improvement of mitochondrial biogenesis and function, and potential calcium regulation. This review may help to develop novel therapeutic strategies targeting enhancing vagal activity for the treatment of cardiovascular diseases.

© 2014 The British Pharmacological Society.

Figures

Figure 1

Schematic representation of signalling pathways and mechanisms regulated by vagal activation. The mechanisms contributing to the beneficial effect of improved vagal activity are multifactorial, including (1) its anti‐inflammatory effects by activating JAK2/STAT pathway and inhibiting NF‐κB activation which is dependent upon α7nACh receptor; (2) mitochondrial improvement (increasing mitochondrial biogenesis and function, mitochondrial KATP activation and inhibiting mitochondrial permeability transition pore (mPTP) opening); (3) redox state regulation (suppressing ROS generation and promoting ROS elimination); (4) increase in NO through PI3K/Akt/eNOS pathway; (5) down‐regulation of calcium overload. SOD2, Mn superoxide dismutase.

Figure 2

Beneficial effects on cardiac and vascular function are provided by the modulation of vagal activity, including direct vagal activation (vagal stimulation, ACh administration and ACh receptor activation), pharmacological modulation (adenosine, cholinesterase inhibitors, statins) and exercise training.