Welcome the carotid chemoreflex to the ‘neural control of the circulation during exercise’ club (2012)

Physical exercise requires rapid and precise responses of the cardiovascular and respiratory systems for a close matching of blood perfusion to the metabolic demand of exercising muscles. The mechanisms that mediate these responses began to be elucidated at the end of the 19th century and since then, a large body of evidence has consistently shown that cardiorespiratory responses during exercise are governed by the complex interaction of two main activating mechanisms: (1) the parallel influence of descending motor impulses originating from higher brain centres directed to skeletal muscles, with activation of autonomic neurons in the brainstem (central command mechanism – feedforward system) (Williamson, 2010); (2) afferent impulses generated from free nerve endings in skeletal muscles, conducted through thinly myelinated type III fibres (mainly mechanically sensitive) and unmyelinated type IV fibres (mainly metabolic sensitive), provide information to autonomic neurons in the brainstem about the mechanical and metabolic state of limb and respiratory skeletal muscles (peripheral mechanism – feedback system) (Rowell, 2004). These central and peripheral neural mechanisms reset the arterial baroreflex operating point, and lead to a decrease in parasympathetic activity and increase in sympathetic activity (Rowell, 2004; Williamson, 2010). Consequently, several cardiorespiratory responses take place, such as an increase in cardiac output, blood pressure and ventilation, as well as redistribution of blood flow predominantly to skeletal muscles and other highly metabolic tissues during exercise (e.g. myocardial and some brain regions) (Rowell, 2004; Williamson, 2010). Chemoreceptors in the brain (central chemoreceptors) and in the carotid sinus (peripheral chemoreceptors) are known to exert powerful influence over autonomic control during exposure to hypercapnia and hypoxia, respectively. However, the contribution of chemoreceptors to the autonomic response to exercise, and thus its influence on the cardiovascular response to exercise, has not received much attention. Stickland et al. (2007) showed for the first time that the inhibition of carotid chemoreceptors by closed-carotid infusion of dopamine or hyperoxic Ringer solution at rest did not change blood flow and conductance in the hindlimb of healthy dogs, but caused an immediate vasodilatory response in the hindlimb of dogs with heart failure. During mild exercise, inhibition of carotid chemoreceptors caused vasodilatation in the hindlimb of both healthy dogs and dogs with heart failure. In addition, it was shown that this response was entirely attributed to a decrease in the sympathetic restraint of skeletal muscle blood flow during exercise, since the vasodilatory response was abolished after infusion of an alpha adrenergic blocker (phentolamine) both in healthy dogs and in dogs with heart failure. Thereafter, Stickland et al. (2008) elegantly translated these findings to exercising healthy humans. They showed that the transient inhibition of the carotid chemoreceptors by inhalation of hyperoxic gas during dynamic handgrip exercise reduced muscle sympathetic nerve activity (MSNA) by approximately 35%, while the transient stimulation of the carotid chemoreceptors by inhalation of hypoxic gas increased MSNA with a similar time delay to that obtained with carotid chemoreceptors inhibition via hyperoxia. Hence, these results highlighted the important role of the carotid chemoreflex in regulating the sympathoexcitation during exercise in healthy humans. Nonetheless, at this point, it was not known if the carotid chemoreceptors indeed influence skeletal muscle blood flow and vascular conductance during exercise in humans. In a recent issue of The Journal of Physiology, Stickland et al. (2011) further advanced our overall understanding of the contribution of the carotid chemoreceptors to the cardiovascular responses to exercise in healthy humans. In this study, healthy subjects were evaluated at rest and during constant-work double leg extension exercise (i.e. leg kicking). The carotid chemoreflex was inhibited by inhalation of hyperoxic gas and/or by intravenous infusion of dopamine, whereas inhalation of hypoxic gas was used to activate the carotid chemoreflex. Femoral arterial blood velocity and diameter were measured with pulsed Doppler ultrasound, and then femoral blood flow and vascular conductance were calculated. Hyperoxia did not change resting blood flow and conductance, but increased blood flow and conductance during exercise in the first 45 s of administration. After that, blood flow and conductance decreased toward the values observed during normoxic exercise. Likewise, dopamine had no effect on steady-state blood flow and conductance at rest, but increased femoral blood flow and conductance during exercise. When hyperoxia was administered during dopamine infusion, the hyperoxia impact on blood flow and conductance was abolished. Inhalation of hypoxic gas increased blood flow and conductance at rest and during exercise, and administration of hypoxia during dopamine infusion did not affect blood flow or conductance. In summary, these results indicate that the carotid chemoreceptors contribute to the regulation of skeletal muscle blood flow and conductance during normoxic exercise in healthy humans, whereas under hypoxia reflex sympathoexcitation induced by carotid chemoreceptor stimulation seems to be overridden by local vasodilatory factors. The study by Stickland et al. (2011) represents an intricate in vivo human integrative physiology study, which used pharmacological and physiological approaches to test the hypothesis that the carotid chemoreflex regulates skeletal muscle blood flow during exercise. However, intriguingly, carotid chemoreflex-induced changes in the vasculature of exercising muscle were not accompanied by changes in systemic arterial pressure. This finding perhaps requires further investigation given the important role of sympathetically mediated vasoconstrictor tone within the exercising muscle to the pressor response during exercise. Furthermore, certain methodological issues should be taken into consideration to interpret the study's findings. Stickland et al. (2011) showed that the carotid chemoreceptor inhibition via hyperoxia led to a transient increase in blood flow and conductance that lasted approximately 45 s. After that, it is presumed that compensatory mechanisms could have blurred the interpretation of the role of carotid chemoreceptors. In addition to that, the intravenous dopamine infusion used by Stickland et al. could have caused systemic effects that jeopardize the interpretation about carotid chemoreceptor regulation of blood flow and conductance. Previously, Stickland et al. (2008) used short (i.e. hyperoxia administration for 1 min in the middle of 3 min of exercise) and repeated (two to five repetitions) bouts of hyperoxia to characterize the role of carotid chemoreceptors on MSNA regulation, carefully controlling respiratory rate, tidal volume and end-tidal carbon dioxide in order to avoid a possible confounding influence of these variables on the MSNA response. Using this protocol, a reduction in MSNA starting after 15 s of hyperoxia administration was observed, followed by recovery of MSNA in less than 15 s after return to normoxia. Thus, considering the transient response of the carotid chemoreceptors to variations in blood oxygen and the systemic effects of dopamine, a protocol consisting of short and repeated bouts of hyperoxia and hypoxia with control over respiratory variables, followed by calculation of each subject's mean response, could have strengthened the study design and data interpretation. Another methodological aspect is related to the subjects that were studied. The sample encompassed highly fit subjects (i.e. higher maximal oxygen consumption than normal). However, the impact of physical conditioning on the chemoreflex sensitivity is controversial; therefore, it is not known whether subjects with a normal level of physical fitness respond similarly. Moreover, the sample included men and women, and the investigators did not take into consideration in which phase of the menstrual cycle the experiment had taken place. The authors mentioned that no apparent differences were observed with chemoreceptor inhibition between men and women. However, care should be taken about the impact of sex on the carotid chemoreflex responses, since recent evidence has shown that women have lower sympathetic vasoconstrictor tone and an attenuated sympathetic vascular transduction. Thus, the influence of sex on carotid chemoreflex regulation of blood flow should be specifically assessed by further studies. Despite the considerations mentioned above, altogether the series of studies conducted by Stickland et al. (2008, 2011) have consistently shown that the transient inhibition of the carotid chemoreceptors leads to sympathoinhibition and vasodilatation in healthy humans and healthy dogs only during exercise. This suggests that the carotid chemoreflex is sensitized during exercise, which could be mediated by either a direct influence on the carotid receptors by some known excitatory mediators such as noradrenaline and angiotensin II, or indirectly by an interaction among inputs from the carotid chemoreceptors, central command and skeletal muscles at the brainstem. Moreover, Stickland et al. (2007) have shown that the transient inhibition of the carotid chemoreceptors leads to sympathoinhibition and vasodilatation at rest and during exercise in dogs with heart failure. Heart failure and other diseases, such as hypertension and sleep apnoea, have been characterized by enhanced chemosensitivity, high sympathetic activity at rest and during exercise, as well as exaggerated sympathetic restraint of blood flow to skeletal muscles due to impaired functional sympatholysis. Taking this into consideration, it is possible that the chemoreflex might have a large contribution to exercise intolerance in patients with these diseases. Consequently, the studies by Stickland et al. (2007, 2008, 2011) added another member to the ‘neural control of the circulation during exercise’ club, and opened a new avenue for research seeking to further clarify mechanisms associated with the cardiorespiratory responses to exercise, with potential implications for the pathophysiology of exercise intolerance. The authors apologize for not citing all relevant articles due to reference limitations. The authors are grateful to Dr Jerome A. Dempsey and Dr Antonio C. Nóbrega for their critical evaluation and helpful suggestions in preparing this manuscript, and also to Seth T. Fairfax for language review.