Group III/IV muscle afferents play an independent role in arterial baroreflex resetting during exercise in humans: is it the end of the road?

The cardiovascular response to exercise is governed by both central and peripheral mechanisms that promote alterations in parasympathetic and sympathetic neural activities to the heart and blood vessels to meet the metabolic demands of working skeletal muscle in an intensity-dependent manner. There are at least three distinct neural mechanisms participating in this cardiovascular regulation: (1) central command, (2) the exercise pressor reflex, and (3) the arterial baroreflex. Central command is a feedforward mechanism that, through signals originating in higher brain centres, activates cardiovascular and somatomotor systems in parallel. The exercise pressor reflex is a feedback mechanism originating in skeletal muscle comprising group III and IV skeletal muscle afferents that respond to both mechanical and metabolic stimuli. The arterial baroreflex represents a closed-loop, negative feedback control system involved in regulating arterial blood pressure. Mechanically sensitive receptors located in the carotid body and aortic arch relay information to the brainstem regarding beat-to-beat changes in blood pressure. The resultant neural feedback provides critical information to modulate heart rate (cardiac baroreflex) or peripheral vasoconstrictor outflow (sympathetic baroreflex) in order to maintain pressure homeostasis at rest and in response to perturbations such as standing (Fisher et al. 2015). Historically, the arterial baroreflex was believed to be ‘switched off’ or ‘overridden’ during exercise due to the linear relationship between heart rate and blood pressure that occurs during physical effort. However, in the 1980s, Donald's group from the Mayo Medical School found in animals that the open-loop stimulus–response relationship was shifted to operate around the prevailing arterial blood pressure of the exercise, without an alteration in the maximal gain or sensitivity of the reflex (Melcher & Donald, 1981). These results were confirmed later in humans by Raven's group from the University of North Texas (Potts et al. 1993). Therefore, it is now well accepted that the arterial baroreflex remains functional during exercise by resetting to operate around the prevailing pressure elicited by exercise workload indicating that the arterial baroreflex plays a pivotal role in the neural control of cardiovascular responses during exercise. Despite extensive knowledge of the arterial baroreflex resetting during exercise, the primarily mediator of this response remains controversial, since central command and/or exercise pressor reflex appears to play both independent and interactive roles (McIlveen et al. 2001). To address this issue, Hureau and colleagues recently published in The Journal of Physiology an elegant comprehensive and integrative experiment to investigate the possible independent role of group III and IV muscle afferents in the carotid baroreflex control of cardiovascular responses during exercise (Hureau et al. 2018). In their investigation, healthy young men performed electrically evoked (absence of central command) and voluntary (requiring central command) isometric one-legged knee extension at 15% maximum voluntary contraction (50 s contraction and 10 s relaxation for 10 min) under control conditions and following lumbar intrathecal injection of a μ-opioid receptor agonist, fentanyl, which attenuated the central projection of group III/IV muscle afferents at the level of the dorsal horn in the spinal cord without affecting force production (i.e. there was no effect on central command). Spontaneous carotid baroreflex control of arterial blood pressure and heart rate were assessed by rapid application of neck pressure (+40 mmHg) and neck suction (−60 mmHg) to simulate a hypotensive and hypertensive stimulus to the carotid baroreceptors, respectively. The findings showed that spontaneous carotid baroreflex sensitivity was similar at rest and during both electrically evoked and voluntary exercise independent of attenuation of group III/IV muscle afferents with fentanyl. As expected, under control conditions both electrically evoked and voluntary exercise resulted in a significant upward and rightward shift of the carotid baroreflex blood pressure and heart rate operating points. On the other hand, fentanyl injection attenuated the exercise-induced resetting of the operating point for arterial blood pressure and heart rate during both electrically evoked and voluntary exercise, indicating a reduced shift of the arterial baroreflex operating points with fentanyl and that these responses are independent of central command. The study by Hureau and colleagues represents a challenging in vivo human integrative physiology study which used pharmacological and physiological approaches to test the hypothesis that group III/IV muscle afferent feedback has, independent of central command, a critical role in the resetting of the carotid baroreflex blood pressure and heart rate operating points during exercise. Although the findings strongly support the author's initial hypothesis, certain aspects should be taken into consideration in interpreting the study's findings. Firstly, the volunteers were young healthy and recreationally active men, limiting extrapolation of the results to other populations. For example, it is well known that the mechanisms regulating arterial blood pressure differ between men and women, and, as mentioned by the authors in the discussion, the conclusions may not be generalizable to women. In addition, diseased individuals such as hypertensive patients present an impairment in arterial baroreflex control of blood pressure and overactivity of the exercise pressor reflex leading to an exaggerated cardiovascular responses to exercise (Barbosa et al. 2016a) which may directly affect the resetting of the arterial baroreflex. Thus, the precise mechanisms responsible for the arterial baroreflex resetting during exercise in these population should be specifically assessed by further studies. Secondly, Hureau and colleagues have used isometric one-legged knee extension exercise at very low intensity (15% maximum voluntary contraction), and whether the results can be replicated during higher intensities of exercise, different muscle sizes and other exercise modalities (i.e. dynamic vs. isometric) remains unknown. Indeed, a recent study found that carotid baroreflex-mediated reflex bradycardia during low-intensity cycling was similar to that observed at rest, but was smaller during moderate-intensity cycling (Barbosa et al. 2016b). These findings demonstrate that carotid baroreflex function during exercise is altered during moderate-intensity but not during low-intensity cycling (Barbosa et al. 2016b) indicating that exercise intensity is important for the arterial baroreflex function during dynamic exercise. In addition, it is important to consider that there is a progressive upward and rightward resetting of the carotid-cardiac baroreflex stimulus–response relationship. With this in mind, further studies are necessary in other populations such as women, older, sedentary and/or diseased individuals, and with different exercise modalities and intensities to definitively determine the critical role of group III and IV muscle afferents for the resetting of the arterial baroreflex during exercise, independently of central command. In conclusion, the heroic experiment of Hureau et al. (2018) advances the body of knowledge and allows us to better understand the neural control of the circulation during exercise in humans. Additionally, they have opened an avenue for research seeking to further clarify the interaction between central command and exercise pressor reflex on arterial baroreflex control during exercise. None declared. All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. The authors received scholarships from the Coordination for the Improvement of Higher Education Personnel (CAPES). Due to reference limits, we apologize for not citing all relevant articles. We thank Dr Lauro C. Vianna for his mentorship and critical feedback on this manuscript.