Abstract
The renin–angiotensin–aldosterone system (RAAS) impacts cardiovascular homeostasis via direct actions on peripheral blood vessels and via modulation of the autonomic nervous system. To date, research has primarily focused on the actions of the RAAS on the sympathetic nervous system. Here, we review the critical role of the RAAS on parasympathetic nerve function during normal physiology and its role in cardiovascular disease, focusing on hypertension. Angiotensin (Ang) II receptors are present throughout the parasympathetic nerves and can modulate vagal activity via actions at the level of the nerve endings as well as via the circumventricular organs and as a neuromodulator acting within brain regions. There is tonic inhibition of cardiac vagal tone by endogenous Ang II. We review the actions of Ang II via peripheral nerve endings as well as via central actions on brain regions. We review the evidence that Ang II modulates arterial baroreflex function and examine the pathways via which Ang II can modulate baroreflex control of cardiac vagal drive. Although there is evidence that Ang II can modulate parasympathetic activity and has the potential to contribute to impaired baseline levels and impaired baroreflex control during hypertension, the exact central regions where Ang II acts need further investigation. The beneficial actions of angiotensin receptor blockers in hypertension may be mediated in part via actions on the parasympathetic nervous system. We highlight important unknown questions about the interaction between the RAAS and the parasympathetic nervous system and conclude that this remains an important area where future research is needed.
Highlights
The renin–angiotensin–aldosterone system (RAAS) is a complex, multifaceted system
The effects of the RAAS are predominantly mediated by angiotensin (Ang) II binding to cell-surface AT1 Gq protein-coupled receptors
The actions of Ang II lead to vasopressin release, oxidative stress, inflammation, and activation of central brain regions leading to sympathetic activation [6,8]
Summary
The renin–angiotensin–aldosterone system (RAAS) is a complex, multifaceted system. Since the discovery of RAAS over a century ago, our understanding of it has expanded from one circulating hormone to multiple complementary and opposing enzymatic pathways that signal via autocrine and paracrine mechanisms [1,2]. Increasing research into the parasympathetic nervous system is advancing our understanding of the nuances of how it works in both health and disease. We review the role of the RAAS on parasympathetic nerve function during normal physiology and potential dysregulation in cardiovascular disease, focusing on hypertension. Increased sympathetic nervous system activity and reduced vagal tone are established characteristics of hypertension [19,20,21,22]. This dysregulation of the autonomic nervous system is correlated with progression of disease [23], is observed in those classed as borderline hypertensive [20], and has a genetic predisposition to developing hypertension [24]. The global and personal burden hypertension presents for cardiovascular mortality shows the need for new therapeutic treatments
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