Central command: Feedforward control of the sympathoadrenal system during exercise

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1 J Phys Fitness Sports Med, 1(4): (2012) JPFSM: Review Article Central command: Feedforward control of the sympathoadrenal system during exercise Kanji Matsukawa *, Nan Liang and Kei Ishii Department of Integrative Physiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi, Minami-ku, Hiroshima , Japan Received: August 27, 2012 / Accepted: October 29, 2012 Abstract Feedforward control by higher brain centers (central command) plays a role in autonomic regulation of the cardiovascular system during exercise. To reveal central control of cardiac autonomic outflows, a series of experiments have been conducted in our laboratory using conscious or decerebrate animals. Contrary to the traditional concept of vagal withdrawal, central command does not decrease cardiac vagal outflow but allows cardiac sympathetic nerve activity (CSNA) to augment for cardiac acceleration at the onset of exercise. Presumably, central command may also cause an increase in preganglionic adrenal sympathetic nerve activity (AdSNA) at the same time, which in turn releases adrenaline into systemic circulation and contributes to an additional increase in heart rate (HR). Keywords : central command, feedforward control, sympathetic and parasympathetic nerve activity, adrenaline, adrenal medulla, exercise Introduction It has been hypothesized over a century that a central mechanism originating from higher brain centers plays an important role in controlling the cardiovascular system during exercise 1-5). Mitchell and colleagues 1,2,4) conducted an elegant study demonstrating that descending motor commands from higher brain centers have an effect on the cardiovascular response to exercise, and they termed the central mechanism as central command. Gandevia et al. 6) revealed, using totally conscious but paralyzed human subjects, that motor efforts are able to produce a similar cardiovascular response as actual motor performance. However, detailed information on the central circuits and descending pathways of central command remains obscure, and the fundamental characteristics of the centrally-induced responses in the sympathoadrenal system are little understood, because it is technically difficult to record sympathetic and parasympathetic outflows to various organs and tissues during volitional exercise in conscious animals and humans. Nonetheless, an attempt to directly identify the response in sympathetic nerve activity during exercise has been conducted. Ninomiya and colleagues 7,8) recorded for the first time cardiac and renal sympathetic nerve activity (CSNA and RSNA) during voluntary body movement in freely moving conscious cats and found abrupt increases in the sympathetic outflows prior to the onset of body movement, termed Mikomi response. Thereafter the response in sympathetic outflow to a static and dynamic exercise model in animals has been assessed. Matsukawa et al. 9,10) found a centrally-induced increase in RSNA at the onset of static exercise in conscious cats and at the onset of spontaneous overground locomotion in decerebrate cats. Tsuchimochi et al. 11) observed an exercise intensity dependent increase in CSNA at the onset of treadmill exercise in conscious cats. On the other hand, sympathetic outflow to non-contracting skeletal muscle and skin have been assessed during exercise in humans. Although skin sympathetic nerve activity increases at the onset of static exercise 12,13), similar to cardiac and renal sympathetic outflows, muscle sympathetic nerve activity does not change or slightly decreases at the initial period of static or dynamic exercise, and thereafter increases, probably due to exercise pressor reflex 14,15). Taken together, central command does not have uniform influence on the sympathoadrenal system at the onset of exercise, but selectively augments sympathetic outflow to a specific organ such as the heart, kidneys, and skin. Furthermore, if central command also augments preganglionic adrenal sympathetic nerve activity (AdSNA) to the adrenal medulla at the onset of exercise, released adrenaline may have an additional influence on the heart and blood vessels in circulatory transit time. Based on recent evidence obtained in our laboratory, using humans and conscious or decerebrate unanesthetized animals, this review provides novel information on central control of CSNA, cardiac vagal nerve activity (CVNA), and AdSNA during exercise. *Correspondence: matsuk@hiroshima-u.ac.jp

2 574 JPFSM : Matsukawa K, et al. Responses in cardiac sympathetic and parasympathetic outflow during exercise It has been thought that the change in HR during exercise is predominantly controlled by cardiac vagal withdrawal at the early phase of exercise or throughout a low to moderate intensity of exercise, and then by additional recruitment of stimulation of cardiac sympathetic outflow as exercise intensity is raised 16,17). As mentioned before, this view has been challenged by a recent finding that CSNA rapidly increases at the beginning of treadmill exercise in conscious cats, irrespective of exercise intensity 11). Furthermore, if the view, that cardiac vagal withdrawal plays a dominant role in the initial exercise tachycardia, is correct, the same size tachycardia would be expected in subjects with tetraplegia, who have the intact vagal nervous system, but lose supraspinal control of the whole sympathetic nervous system. As a matter of fact, the initial tachycardia at the onset of static arm exercise is blunted in the subjects with tetraplegia, as compared to normal subjects 18). In addition, the highfrequency component of the power spectrum of HR variability, as an indirect estimate of cardiac vagal efferent nerve activity (CVNA), decreases gradually throughout static exercise in the same manner in both normal and spinal cord-injured subjects 19). As opposed to the traditional view, central stimulation of CSNA, rather than cardiac vagal withdrawal, is expected to play an important role in cardiac acceleration at the onset of exercise. This hypothesis has been tested by directly recording CSNA and CVNA from nerve branches close to the right atrium in cats decerebrated at the precollicular-premammillary body level, which are able to induce spontaneous motor discharge under paralysis 20). The cardiac autonomic responses must be caused by central command alone, and not by exercise pressor reflex in the experimental condition. CSNA abruptly increased immediately before spontaneous motor activity, whereas CVNA did not decrease at that time, but slightly increased throughout the motor activity (Fig. 1). Since clear cardiac vagal withdrawal was Fig. 1 The average responses in cardiac sympathetic nerve activity (CSNA), cardiac vagal nerve activity (CVNA), heart rate (HR), and mean arterial blood pressure (MAP) during spontaneous fictive motor activity in over 55 trials in 4 decerebrate cats. * Significant (P<0.05) changes from the baseline levels. Horizontal dotted lines show the baseline levels of individual variables. Adapted from Kadowaki et al. 20).

3 JPFSM: Central command and cardiovascular adaptation during exercise 575 never found, HR was predominantly controlled by the increase in cardiac sympathetic outflow during spontaneous motor activity in decerebrate animals. Unlike the traditional concept of cardiac vagal withdrawal, central command allows cardiac sympathetic outflow to increase at the onset of exercise, but it may not produce cardiac vagal withdrawal. These responses in CSNA and CVNA were shown to be in agreement with the effects of autonomic blockades on the exercise tachycardia, when the effects of autonomic blockades on HR were reexamined. The exercise tachycardia, during treadmill exercise in conscious rats and during voluntary static handgrip exercise in humans, was more blunted by β-adrenergic receptor blockade with atenolol than by muscarinic blockade with atropine methyl nitrate 21,22). Central control of preganglionic adrenal sympathetic outflow and adrenaline secretion from the adrenal medulla Using electrical stimulation of the hypothalamic locomotor region, it was examined whether or not feedforward control by central command activates preganglionic AdSNA and releases catecholamines from the adrenal medulla. Hypothalamic stimulation caused rapid activation of preganglionic AdSNA (Fig. 2), which was followed by an immediate increase in adrenaline output 23). As soon as the hypothalamic stimulation was terminated, preganglionic AdSNA returned to the baseline level within a few seconds, and the elevated adrenaline output de- cayed within s 23). Thus, it is likely that feedforward control, by central command, of catecholamine secretion from the adrenal medulla plays a role in conducting rapid hormonal control of the cardiovascular system at the beginning of exercise. This hypothesis has been further tested using adrenalectomy (ADX) to examine to what extent and when plasma adrenaline contributed to tachycardia during treadmill exercise in conscious rats 22). The baseline heart rate (HR) was not influenced by ADX. A comparison of exercise tachycardia response, between intact and ADX rats (Fig. 3), showed that ADX did not affect the immediate increase in HR at 0-12 s from exercise onset, but reduced the subsequent increase in HR at s 22). Thus it is likely that the tachycardia, at the beginning of dynamic exercise, is predominantly determined by cardiac autonomic nerve activity, especially by a prompt increase in CSNA; and that the hormonal mechanism due to adrenal adrenaline contributes to a further increase in HR. To do this, central command must produce an abrupt increase in preganglionic AdSNA at the onset of exercise, which remains to be identified. Conclusion A new hypothesis about the role of central command in feedforward control of the sympathoadrenal system during exercise is illustrated in Fig. 4. Central command allows cardiac sympathetic outflow to be augmented prior Fig. 2 Typical changes of pre- and postganglionic adrenal sympathetic nerve activity (AdSNA) in response to central stimulation of the hypothalamic defense area. Preganglionic AdSNA did not change after IV administration of a ganglionic blocker (trimethaphan), although mean arterial blood pressure (MAP) largely decreased. Hypothalamic stimulation at 100 μa was able to increase preganglionic AdSNA under sympathetic ganglionic blockade. In contrast, postganglionic AdSNA was markedly inhibited by trimethaphan and could not be augmented by the hypothalamic stimulation. Adapted from Tsuchimochi et al. 23).

4 576 JPFSM : Matsukawa K, et al. Higher brain centers Central command Parasympathetic nervous system sympathoadrenal system Heart Adrenaline Adrenal medulla Kidney Vein Fig. 3 The changes in heart rate (HR), at the early period of dynamic treadmill exercise, are compared among the autonomic blockades in the intact (A) and adrenalectomized (ADX, B) conditions in 5 identical rats. The differences in HR response at the onset of exercise between the intact and ADX conditions are shown in C. The initial increase in HR at the onset of exercise was more strongly blunted by atenolol than by atropine, and was almost abolished by a combined injection of atropine and atenolol in both intact and ADX conditions. ADX did not affect the immediate increase in HR at 0-12 s from exercise onset, but reduced the subsequent increase in HR at s. Significant changes (P<0.05) from the control without any drugs. * Significant differences (P<0.05) in the HR response between intact and ADX conditions. Adapted from Wakasugi et al. 22). Fig. 4 A new hypothesis about the role of central command in feedforward control of the sympathoadrenal system during exercise. Central command allows cardiac sympathetic outflow to be augmented prior to the onset of exercise, which contributes to a rapid acceleration of cardiac rhythm. On the other hand, cardiac vagal withdrawal, induced by central command, may not play an important role in exercise tachycardia at the onset of exercise. Presumably, central command may cause an increase in preganglionic AdSNA at the same time, which in turn releases adrenaline into systemic circulation and contributes to an additional increase in HR. Acknowledgements We thank Ishida Tomoko for her excellent technical assistance. This review and the original studies were supported by Grant-in- Aids for Scientific Research (B) and for Exploratory Research from the Japan Society for the Promotion of Science. to the onset of exercise, which contributes to a rapid acceleration in cardiac rhythm. On the other hand, cardiac vagal withdrawal, induced by central command, may not play an important role in the exercise tachycardia at the onset of exercise. Presumably, at the same time, central command may cause an increase in preganglionic Ad- SNA, which in turn releases adrenaline into systemic circulation and contributes to an additional increase in HR. References 1) Goodwin GM, McCloskey DI, Mitchell JH Cardiovascular and respiratory responses to changes in central command during isometric exercise at constant muscle tension. J Physiol 226: ) Mitchell JH Neural control of the circulation during exercise. Med Sci Sports Exerc 22: ) Sadamoto T, Matsukawa K Cardiovascular responses during spontaneous overground locomotion in freely moving

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