One day, as a neuroscience undergraduate, I took my seat in a lecture hall, pulled out my laptop and prepared for another day of learning about the fascinating organ that is the brain. Without any prior warning, the lecturer plugged in his computer system and Dion DiMucci’s “The Wanderer” began to play.

As the lyrics “Oh well, I’m the type of guy who will never settle down” echoed through the lecture hall of students, our heads turned to each other for reassurance that our confusion was shared. “Today,” the lecturer started, “we’re covering the vagus nerve.”

Fifty minutes later, the confusion had lifted. We learned how “vagus” means “wandering” in Latin, an apt name for a nerve that takes an extensive, winding path through the body.

The vagus nerve plays an important function in the branch of the human nervous system called the parasympathetic nervous system (PNS), often nicknamed the “rest and digest” system.

The human nervous system

The human nervous system has two main divisions: the central nervous system – or CNS – and the PNS. The CNS includes the brain and the spinal cord, whereas the PNS is made up of nerves that branch from the spinal cord and extend throughout the body, helping to regulate involuntary functions such as heart rate, digestion and breathing. 

The vagus nerve’s role in the regulation of processes such as heart rate, respiration, immune responses and the digestive system has been extensively studied. Now, Physiology Associate Professor Rohit Ramchandra and colleagues at the University of Auckland recently discovered a novel function for the “wanderer”, in exercise. Their study is published in Circulation Research.

The “wanderer” – inactive during exercise?

Vagal nerve activity in exercise is “understudied” and “controversial”, according to Ramchandra and colleagues.

For many years scientists, firmly believed that the sympathetic nervous system, often nicknamed “the fight or flight” system, is in overdrive during exercise. This helps the heart to beat faster, pumping much needed blood and oxygen around the body. In contrast, PNS activity was assumed to dial down or become completely absent during exercise. “Historically, no role for the PNS during exercise has been concluded due to the assumption that cardiac vagal nerve fibers only innervate the sinoatrial node (SAN) and the absence of changes in cardiac function with cholinergic blockers,” the researchers write.

Ramchandra and colleagues tested the hypothesis that cardiac vagal activity is actually elevated during exercise, and that denervation of the cardiac vagal branch would reduce heart function. They attached electrical recording devices to monitor cardiac vagal nerve activity (CVNA) in sheep during exercise. Sheep have similar cardiac anatomy and physiology to humans, and they are often utilized in laboratory experiments exploring heart disease.

Cardiac vagal nerve activity increased during exercise

“Our group has used ‘tour de force’ electrical recording techniques to directly monitor vagal nerve activity in exercising sheep and has found the activity in these vagal nerves going to the heart increases during exercise,” says Ramchandra.

An increase in CVNA occurred during the initiation of exercise, which then plateaued as the intensity increased.

“Our study finds the activity in these ‘rest and digest’ vagal nerves actually increases during exercise,” Ramchandra says.

When the researchers denervated the left cardiac vagal branch, cardiac function was impaired while the sheep exercised. This helped the team to prove a hypothesis regarding the role of acetylcholine in exercise. “The cardiac vagus nerve releases multiple mediators, and previous research has focused on a neurotransmitter, acetylcholine, which has no impact on our ability to exercise,” says Ramchandra.

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The researchers blocked acetylcholine receptors pharmacologically while the sheep exercised, and found it had no impact on cardiac function. “Taken together with the vagal denervation data, this finding suggests a separate mechanism for the effects of CVNA during exercise beyond acetylcholine-mediated signaling,” they explain.

Ramchandra and colleagues turned their attention to a different meditator – vasoactive intestinal peptide (VIP). They found that VIP was released by the vagus nerve during exercise. This “helps the coronary vessels dilate, allowing more blood to pump through the heart,” says Ramchandra.

“For the heart to sustain a high level of pumping, it needs a greater blood flow during exercise to fuel the increased work it is doing: our data indicate that the increase in vagal activity does just this.”

Improving exercise tolerance in heart failure patients

A limitation of the study, acknowledged by the researchers, is that only female sheep were tested. “While we anticipate the observations made in this study will be applicable to males, this will need to be tested in future studies,” Ramchandra and colleagues say.

The researchers’ follow-up study will explore whether this function of cardiac vagal nerves can be utilized to help heart failure patients improve their exercise tolerance. “This inability to carry out simple tasks involving exertion means that quality of life is severely compromised in these patients,” explains Ramchandra. “One potential reason why exercise tolerance is reduced is that the diseased heart simply does not receive enough blood.”

Reference: Shanks J, Pachen M, Chang JWH, George B, Ramchandra R. Cardiac vagal nerve activity increases during exercise to enhance coronary blood flow. Circ. Res. 2023;133(7):559-571. doi: 10.1161/CIRCRESAHA.123.323017

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