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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 \u03b2\u2010blocker treatment, have primarily targeted suppressing sympathetic over\u2010activation, 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, <jats:styled-content style=\"fixed-case\">ACh<\/jats:styled-content> administration and <jats:styled-content style=\"fixed-case\">ACh<\/jats:styled-content> 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\u2010inflammatory pathways, modulation of <jats:styled-content style=\"fixed-case\">NOS<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content> 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Linked Articles<\/jats:title><jats:p>This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/dx.doi.org\/10.1111\/bph.2015.172.issue-23\">http:\/\/dx.doi.org\/10.1111\/bph.2015.172.issue-23<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13010","type":"journal-article","created":{"date-parts":[[2014,11,7]],"date-time":"2014-11-07T09:35:58Z","timestamp":1415352958000},"page":"5489-5500","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Novel strategies and underlying protective mechanisms of modulation of vagal activity in cardiovascular diseases"],"prefix":"10.1111","volume":"172","author":[{"given":"Xi","family":"He","sequence":"first","affiliation":[{"name":"Department of Pharmacology Xi'an Jiaotong University Health Science Center  Xi'an 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