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.

BACKGROUND: The phrase complete vagal withdrawal is often used when discussing autonomic control of the heart during exercise. However, more recent studies have challenged this assumption. We hypothesized that cardiac vagal activity increases during exercise and maintains cardiac function via transmitters other than acetylcholine. METHODS: Chronic direct recordings of cardiac vagal nerve activity, cardiac output, coronary artery blood flow, and heart rate were recorded in conscious adult sheep during whole-body treadmill exercise. Cardiac innervation of the left cardiac vagal branch was confirmed with lipophilic tracer dyes (DiO). Sheep were exercised with pharmacological blockers of acetylcholine (atropine, 250 mg), VIP (vasoactive intestinal peptide; [4Cl-D-Phe6,Leu17]VIP 25 µg), or saline control, randomized on different days. In a subset of sheep, the left cardiac vagal branch was denervated. RESULTS: Neural innervation from the cardiac vagal branch is seen at major cardiac ganglionic plexi, and within the fat pads associated with the coronary arteries. Directly recorded cardiac vagal nerve activity increased during exercise. Left cardiac vagal branch denervation attenuated the maximum changes in coronary artery blood flow (maximum exercise, control: 63.5±5.9 mL/min, n=8; cardiac vagal denervated: 32.7±5.6 mL/min, n=6, P= 2.5×10 ⁻⁷ ), cardiac output, and heart rate during exercise. Atropine did not affect any cardiac parameters during exercise, but VIP antagonism significantly reduced coronary artery blood flow during exercise to a similar level to vagal denervation. CONCLUSIONS: Our study demonstrates that cardiac vagal nerve activity actually increases and is crucial for maintaining cardiac function during exercise. Furthermore, our findings show the dynamic modulation of coronary artery blood flow during exercise is mediated by VIP.

The sensory innervation of the lung is well known to be innervated by nerve fibers of both vagal and sympathetic origin. Although the vagal afferent innervation of the lung has been well characterized, less is known about physiological effects mediated by spinal sympathetic afferent fibers. We hypothesized that activation of sympathetic spinal afferent nerve fibers of the lung would result in an excitatory pressor reflex, similar to that previously characterized in the heart. In this study, we evaluated changes in renal sympathetic nerve activity (RSNA) and hemodynamics in response to activation of TRPV1‐sensitive pulmonary spinal sensory fibers by agonist application to the visceral pleura of the lung and by administration into the primary bronchus in anesthetized, bilaterally vagotomized, adult Sprague‐Dawley rats. Application of bradykinin (BK) to the visceral pleura of the lung produced an increase in mean arterial pressure (MAP), heart rate (HR), and RSNA. This response was significantly greater when BK was applied to the ventral surface of the left lung compared to the dorsal surface. Conversely, topical application of capsaicin (Cap) onto the visceral pleura of the lung, produced a biphasic reflex change in MAP, coupled with increases in HR and RSNA which was very similar to the hemodynamic response to epicardial application of Cap. This reflex was also evoked in animals with intact pulmonary vagal innervation and when BK was applied to the distal airways of the lung via the left primary bronchus. In order to further confirm the origin of this reflex, epidural application of a selective afferent neurotoxin (resiniferatoxin, RTX) was used to chronically ablate thoracic TRPV1‐expressing afferent soma at the level of T1–T4 dorsal root ganglia pleura. This treatment abolished all sympatho‐excitatory responses to both cardiac and pulmonary application of BK and Cap in vagotomized rats 9–10 weeks post‐RTX. These data suggest the presence of an excitatory pulmonary chemosensitive sympathetic afferent reflex. This finding may have important clinical implications in pulmonary conditions inducing sensory nerve activation such as pulmonary inflammation and inhalation of chemical stimuli.

Blood flow through the coronary vasculature is essential to maintain myocardial function. As the metabolic demand of the heart increases, so does blood flow through the coronary arteries in a dynamic and adaptive manner. Several mechanisms, including local metabolic factors, mechanical forces and autonomic neural control, regulate coronary artery blood flow. To date, neural control has predominantly focused on the classical neurotransmitters of noradrenaline and acetylcholine. However, autonomic nerves, sympathetic, parasympathetic and sensory, release a variety of neurotransmitters that can directly affect the coronary vasculature. Reduced or altered coronary blood flow and autonomic imbalance are hallmarks of most cardiovascular diseases. Understanding the role of autonomic non‐adrenergic, non‐cholinergic cotransmitters in coronary blood flow regulation is fundamental to furthering our understanding of this vital system and developing novel targeted therapies.

A new paradigm is emerging in which cardiac vagal nerve activity is maintained and increases during exercise. This paradigm challenges decades of studies that have quoted a withdrawal of cardiac vagal activity during exercise. Here, we outline the existing evidence for increased cardiac vagal activity. We also explain why previous indirect methods used to measure vagal activity might have indirectly led to incorrect conclusions about the role of the cardiac vagus during exercise. We will review evidence that vagal control of the sinoatrial node and the ventricles differs and how vagal neurotransmitters other than acetylcholine may regulate cardiac function during exercise. We will also suggest future directions for research to uncover how the cardiac vagus influences cardiac function and the mechanisms behind the increase in cardiac vagal nerve activity during exercise.

We show that older, female sheep with chronic 2-kidney, 1-clip hypertension have similar cardiac and noncardiac exercise hemodynamic abnormalities as patients with HFpEF. This clinically relevant, translatable, and novel large animal model of HFpEF may be useful for elucidating mechanisms and developing treatments for this increasingly common syndrome with few clinically impactful therapies.