Every breath you take: why sympathetic nerve activity comes in bursts.

Abstract

In this issue of The Journal of PhysiologyMandel & Schreihofer (2009) investigate the source of the hypoxia-related effects on sympathetic nerve activity. Hypoxia causes a profound change in the pattern of sympathetic nerve activity. Normally in an anaesthetized and paralysed preparation, sympathetic nerve activity is characterized by bursts of activity that tend to be grouped in phase with the pulse (baroreceptor modulated) and with respiration (generally an inspiratory and a post-inspiratory burst). These patterns occur on a background of activity that is generally referred to as ‘tone’. The source of sympathetic tone is still a matter for discussion, but is not the topic of the findings of Mandel & Schreihofer (2009) who have focused on the change in sympathetic activity in hypoxia. It is well known that supra-threshold activation of baroreceptor afferent neurons will cause sympathetic nerve activity to stop completely. This finding implies that the ongoing activity in sympathetic nerves is due to vasoconstrictor-type fibres and that others are silent. Here we find strong circumstantial evidence that the silent period between bursts of activity is mediated by activation of the same caudal ventrolateral medulla (CVLM) neurons that are GABAergic inhibitory interneurons and project to the rostral ventrolateral medulla (RVLM). This finding is novel and important. It suggests that while the neurons in the RVLM play a role in integrating inputs to provide a final excitatory output to sympathetic preganglionic neurons, the neurons in the CVLM play the opposite but equally important integrating role to inhibit sympathetic discharge. This excitation/inhibition phenomenon as a consequence of RVLM/CVLM interaction is well established in baroreceptor function (potent baroreceptor excitation will silence RVLM neurons) but is less well established in other situations where sympathetic bursting occurs. What are the implications for the normal physiological function of this interaction? As shown by Mandel & Schreihofer (2009) the change to a prolonged burst pattern is associated with marked fluctuations in arterial blood pressure. It remains to be seen if the same mechanism can explain similar phenomena such as the pressor and sympathoexcitatory responses seen after swallowing (Matsukawa & Ninomiya, 1987). In the paralysed anaesthetized ventilated cat, the inspiration-synchronous component of sympathetic discharge was estimated at about 25%; in situations such as that described here it is presumably considerably greater. Clinically, the respiratory modulation of sympathetic nerve activity is also likely to be of importance. Clonidine has a well-known potent sympatholytic effect that is responsible for its efficacy as a hypotensive agent. This effect of clonidine is achieved by a selective action to reduce tone, and the post-inspiratory peak in activity without affecting the inspiratory peak in activity (Koshiya & Guyenet, 1995); interestingly, the effect of clonidine parallels that of Ni2+ which also reduces tone but does not block respiratory activity (or other reflexes) (Miyawaki et al. 2003). Brainstem cardiovascular neurons are close to (Pilowsky et al. 1990) and probably influenced directly by (Sun et al. 1997) respiratory neurons. Such inputs are the most likely explanation for the respiratory modulation of sympathetic nerves (Pilowsky et al. 1994), presympathetic nerves (Haselton & Guyenet, 1989; Miyawaki et al. 1995) and GABAergic CVLM interneurons of the type studied in the current paper (Mandel & Schreihofer, 2006). The precise functional and structural relationship of respiratory and cardiovascular neurons remains an important area of investigation.