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The nature of sympathetic rhythmicity

The adequate supply of nutrients and oxygen to all cells in our body and the removal of the metabolism products is a sine qua non for life. This condition results from an integrated work of multiple physiological systems. The sympathetic nervous system regulates the blood flow to all tissues through the continuous control of the heart activity and vascular resistance. At the blood vessel level, the sympathetic nerves determine the vasoconstrictor tone through the release of noradrenaline (and other co-transmitters) and the activation of adrenoreceptors expressed on vascular smooth muscle cells. Although persistent, the activity of the sympathetic discharge to blood vessels fluctuates in response to internal and external disturbances causing reflex modifications in the blood vessel diameter to adjust blood flow according to the metabolic demand (Guyenet, 2006). The control of cardiovascular function by the brain is the topic of investigation of several studies exploring its physiological relevance and involvement in the development of life-threatening cardiovascular dysfunctions. Since the original observations of the circulatory system in the 17th century, our understanding of how the sympathetic nervous system controls blood pressure in health and disease states has advanced significantly. In almost 145 years, the Journal of Physiology has published fundamental studies about the organization and functioning of the sympathetic nervous system, which laid the foundation for subsequent investigations. To celebrate the 600th volume of the journal, I would like to draw attention to an impactful study published 90 years ago by Adrian, Bronk and Phillips, describing, for the first time, the pattern of sympathetic discharge in mammals (Adrian et al., 1932). Edgar Douglas Adrian was awarded the 1932 Nobel Prize in Physiology and Medicine, jointly with Sir Charles Sherrington, for his discoveries on the basic principles of neuron function. His studies published in the Journal of Physiology in the 1920s and 1930s covered fundamental aspects in neurophysiology as the nature of the electrical signal transmission in nerves and their reception in the brain. In 1932, Adrian and colleagues employed a new technical arrangement to record from cervical and abdominal sympathetic nerves in rabbits and cats, reporting that their activity occurs in bursts as a ‘background of waxing and waning excitation’ larger than in the sensory and motor nerves. The authors also performed manipulations like asphyxia or vasoactive drug injections to demonstrate an association between fluctuations in the sympathetic activity amplitude and changes in blood pressure levels. It was then proposed that the sympathetic vasoconstrictor activity would be persistent but never show a regular discharge pattern compared with other nerves during a steady state. The pioneering descriptions about the mammalian sympathetic discharge by Adrian et al. (1932) fostered cardiovascular and neurophysiology researchers to investigate the mechanisms underlying the regulation of blood pressure levels by the sympathetic nervous system under different conditions. Currently, evidence indicates that a group of spinally projecting neurons located in the rostral ventrolateral surface of the medulla oblongata (a.k.a. RVLM) mainly defines the baseline vasoconstrictor activity (Guertzenstein & Silver, 1974; Ross et al., 1984). The activity of the RVLM pre-sympathetic neurons is determined by a balance of excitatory and inhibitory synaptic drives (Lipski et al., 1996; Moraes et al., 2013), although some RVLM neurons may also be capable of intrinsic firing based on pacemaker properties (Sun et al., 1988). The RVLM is interconnected with several brain regions, and its activity is also modulated by peripheral afferent information (such as from baroand chemoreceptors), indicating that this region also acts as an integrative site. The RVLM houses two groups of sympatho-excitatory neurons: (i) the C1 group, composed of glutamatergic cells (containing the vesicular glutamate transporter-2, VGLUT2) that also express the phenyl-ethanolamine N-methyl transferase (PNMT), hence synthesize adrenaline; and (ii) the non-C1 group, consisting of glutamatergic cells (VGLUT2-positive) that do not contain PNMT (Guyenet et al., 2013). These neurons may form subgroups in the RVLM and promote a regional control of sympathetic activity to different territories (Guyenet, 2006). The activation of these RVLM populations increases the sympathetic discharge and blood pressure levels, and plasticity in the RVLM (and other regions that communicate with the RVLM) is associated with the development of baseline sympathetic overactivity (Guyenet, 2006). In addition to the role of sympathetic nerves, the study by Adrian et al. (1932) also provided information about the pattern of sympathetic discharge. The authors observed that the voltage waves in the sympathetic nerves, although irregular, were in synchrony with respiration and heartbeats. The authors also identified that the respiratory rhythmicity in the sympathetic activity resulted from direct actions of the respiratory centre on the vasomotor centre (as it persisted after procedures that isolated the brainstem from sensory feedback) while the cardiac modulation disappeared after sectioning the aortic depressor nerve. With the development of newer amplifiers and computer-assisted analyses, studies confirmed that respiratory and cardiac-related oscillations are hallmarks of mammalian sympathetic discharge. Other rhythms were also identified at frequencies lower than respiration and higher than the heart rate (≥10 Hz), whose amplitude might vary depending on the animal species and experimental conditions (Barman & Gebber, 2000). Therefore, rhythmicity is an innate feature of the sympathetic nervous system, which was firstly described by Adrian et al. (1932). However, the physiological relevance of the sympathetic rhythms received less attention than the mechanisms regulating the absolute levels. But why would it be relevant to study the rhythmicity of sympathetic discharge?