The differential modulation of the baroreflex control mechanism in fight, flight or freeze behaviour

The baroreflex mechanism plays a key role in modulating and coordinating the cardiovascular response to physiological stressors during day-to-day activities. The concept of having uniform baroreflex control of different organs has become obsolete, because many studies have revealed regional differences in the baroreflex control of sympathetic outflow, such as renal (RSNA), lumbar (LSNA) and cardiac (CSNA) sympathetic nerve activity (SNA) in physiological conditions and in disease. Studies by Miki & Yoshimoto (2018) and Yoshimoto et al. (2011) brought the focus on differential baroreflex control in response to daily activities, such as sleep, exercise and the natural freezing defense behaviour of rats (Kondo et al., 2021). Given that the kidney is innervated mainly by sympathetic nerves and receives ∼20% of cardiac output, this raises the question of whether sympathetic control over the kidney plays a greater role in regulating blood pressure compared with other sympathetic beds during acute physiological changes. In the October issue of Experimental Physiology, Kondo et al. (2021) assessed acute changes in the baroreflex control of RSNA, LSNA and heart rate simultaneously in conscious rats in response to loud white noise. The noise stimulus caused a freezing response to prepare the cardiovascular system for the next phase of fight or flight. Few studies have examined differential baroreflex control of the SNA for more than two organs in the same animal in a conscious state. The authors of this study should be commended for their technically challenging experiments, which allowed an accurate comparison of the baroreflex control for three different organs together in freely moving rats. The major finding of the study was that the baroreflex control of RSNA was primarily modulated during freezing, with no changes in the LSNA baroreflex in the same animal. Meanwhile, the heart rate baroreflex was altered minimally, except for a leftward shift by ∼11 mmHg. A previous study from the same group showed a transient increase in the LSNA within the first 20 s of noise exposure before the rat freezes (Yoshimoto et al., 2010). However, LSNA was not altered afterwards during freezing, and the baroreflex control of LSNA remained unchanged at a time when RSNA and the RSNA baroreflex showed consistent sympatho-excitation. Likewise, psychological stress in humans caused a marked renal vasoconstriction with variable changes in muscle sympathetic activity, ranging from an increase to a decrease to no change (Dampney, 2015). The study by Kondo et al. (2021) is one of few to have shown remarkable adaptation of RSNA to enhanced sympatho-excitation, compared with other sympathetic beds during acute physiological changes. Therefore, blunting the maximum response of the RSNA can be suggested as a therapeutic target in conditions with excessive sympatho-excitation. The RSNA baroreflex findings during exercise and sleep in rats from the same group revealed increased maximum and minimum plateaus of the RSNA baroreflex curve, in addition to increased maximum gain and a rightward shift during exercise (Miki & Yoshimoto, 2018). The RSNA baroreflex curve after exercise was suppressed downward compared with the pre-exercise level. Meanwhile, heart rate and heart rate baroreflex parameters were not different from pre-exercise values. Thus, the increase in arterial blood pressure that was observed during exercise, followed by hypotension after exercise, resembles baroreflex changes that are seen in the RSNA. This indicates that the RSNA modulatory effect on the baroreflex plays a major role in blood pressure adaptations during physiological activities. The remaining question is, what are the mechanisms involved in initiating early RSNA baroreflex changes compared with other organs? We will summarize possible mechanisms and highlight the ones that require further investigation. Starting from the peripheral arc of the baroreflex, baroreceptors are innervated by C- and A-fibres. In the paraventricular nucleus, c-fos expression was markedly increased in response to psychological stress in humans. Moreover, retrograde labelling has shown that the sympathetic neurons to the kidneys are mostly from the rostral ventromedial medulla, where c-fos expression is greatly enhanced in response to stress (Dampney, 2015). Therefore, the sympathetic outflow to the kidney might be regulated by baroreceptor inputs being transmitted through sensory A-fibres, causing rapid adjustments in the RSNA baroreflex. The authors also suggested that the tonic activity of presympathetic vasomotor neurons in the nucleus tractus solitarii, rostral ventrolateral medulla and caudal ventrolateral medulla is enhanced by central fear command, causing differential modulation of the baroreflex. In other words, the brainstem is ‘listening’ more carefully to the small afferent signals coming from baroreceptors, causing RSNA sympatho-excitation at the maximum plateau of the baroreflex curve. Furthermore, alerting stimuli can activate cortical and hypothalamic regions where sensory visual, olfactory and auditory signals activate neurons in the dorsal medial hypothalamus, perifornical area and dorsolateral periaqueductal grey region (Dampney, 2015). These output neurons send signals to the rostral ventrolateral medulla, raphe nuclei and rostral ventromedial medulla that result in increased sympathetic outflow. It appears that each physiological stimulus and different stressors activate discrete brain regions, altering the baroreflex loop separately for each organ, but this warrants further exploration. In addition, studies focusing on heart rate baroreflex greatly outnumber those investigating the CSNA or the vagal component of the baroreflex. Therefore, it is important to study the parasympathetic control of the baroreflex pathway separately from the heart rate. Altogether, the peripheral and/or the central arm of the baroreflex has many components, theoretically capable of causing differential RSNA baroreflex adaptations, and the precise role of each mechanism is not yet established. In addition to the pattern of changes in RSNA and LSNA baroreflexes in acute conditions, further knowledge is required about the interaction of sympathetic nerves with end-organs. Indeed, the differential baroreflex modulation of blood pressure is related to end-organ responses, which can be studied during physiological changes. Moreover, single components of the baroreflex pathway can be removed one at a time to study how each component adapts to daily physiological activities. This can include, but is not limited to, sinoaortic denervation, vagotomy, renal denervation and ganglion blockade. In summary, the study by Kondo et al. (2021) provides more evidence of early adaptations in the baroreflex control of RSNA during physiological conditions compared with other sympathetic beds, such as the heart and the skeletal muscles. The sympathetic control mechanism for the kidneys merits primary attention when studying the cardiovascular response during acute physiological stressors, and future research in this area is needed to unravel the precise role of central components in the modulation of this mechanism. None declared.