Effect of baroreceptor stimulation on the respiratory pattern: insights into respiratory-sympathetic interactions

Abstract

Sympathetic nerve activity (SNA) is modulated by respiratory activity which indicates the existence of direct interactions between the respiratory and sympathetic networks within the brainstem. Our experimental studies reveal that T(E) prolongation evoked by baroreceptor stimulation varies with respiratory phase and depends on the pons. We speculate that the sympathetic baroreceptor reflex, providing negative feedback from baroreceptors to the rostral ventrolateral medulla and SNA, has two pathways: one direct and independent of the respiratory-sympathetic interactions and the other operating via the respiratory pattern generator and is hence dependent on the respiratory modulation of SNA. Our experimental studies in the perfused in situ rat preparation and complementary computational modelling studies support the hypothesis that baroreceptor activation during expiration prolongs the T(E) via transient activation of post-inspiratory and inhibition of augmenting expiratory neurones of the Bötzinger Complex (BötC). We propose that these BötC neurones are also involved in the respiratory modulation of SNA, and contribute to the respiratory modulation of the sympathetic baroreceptor reflex.

Fig. 1

Response of the sympathetic (SNA, top pair of traces) and phrenic (PNA, middle pair of traces) nerve activities to transient increases in perfusion pressure (PP, bottom trace). (A1–A3) Stimulation was applied to the intact preparation during inspiration (A1), post-inspiration (A2) and late expiration (A3). Note that the stimulus applied during inspiration did not affect the respiratory pattern (A1), whereas the stimuli delivered during the expiratory phase prolonged expiration (A2, A3). This T_E prolongation was stronger when stimulus was applied later in expiration. (B) The effect of baroreceptor stimulation after pontine transection. The applied stimulus did not prolong expiration, but shortened the apneustic inspiratory PNA bursts. Traces from top to bottom: integrated and raw SNA, integrated and raw PNA, and perfusion pressure are shown on each panel.

Fig. 2

Conceptual model of interaction among respiratory-related activity of the ventral respiratory column (VRC), pontine circuits (PONS), sensory network in the nucleus tractus solitarii (NTS) and rostral and caudal ventrolateral medulla (RVLM/CVLM). The sympathetic baroreceptor reflex operates via two pathways (thick line, large arrows): one direct pathway includes baroreceptors, NTS baro-sensitive cells and CVLM, which inhibits RVLM and SNA; the other indirect pathway goes from baroreceptors through NTS and VRC, whose post-inspiratory neurones inhibit RVLM and SNA. Grey arrows represent the effects of VRC and PONS on RVLM providing respiratory modulation of SNA. Another grey arrow indicates the effects of VRC on PONS providing respiratory modulation of pontine neurones. Finally, two dashed arrows indicate central suppression of the baroreflex gain during inspiration which potentially can be provided by VRC or pontine neurones see details in the text).

Fig. 3

The schematic of the extended computational model showing interactions between different populations of respiratory neurones within major brainstem compartments involved in the control of breathing and sympathetic motor activity pons, RTN, BötC, pre-BötC, rVRG, VLM, Raphé, and NTS). A ‘sphere’ represents each population, which consists of 20–50 single-compartment neurones described in the Hodgkin–Huxley style. In comparison with the previous model (Smith et al., 2007), this model additionally incorporates RVLM and CVLM populations in the VLM, an IE phase-spanning population in the pons, and two populations of barosensitive cells in the NTS. The model includes three sources of tonic excitatory drive located in the pons, RTN and raphé shown as green triangles. These drives, especially those from the pontine and RTN sources project to multiple neural populations in the model (green arrows). However,to simplify the schematic, only the most important connections are shown connected to particular populations. The full structure of connections from each drive source (pons/RTN/raphé) to target neural populations of the model and the corresponding synaptic weights are in Table 1 in the Appendix.

Fig. 4

Simulations of the effect of phase-dependent barostimulation on the phrenic (PN) and sympathetic (SN) nerve outputs. Stimulus was applied during inspiration (A1), post-inspiration (A2) and late expiration (A3). In A1, the stimulus applied during inspiration had no effect on respiratory phase durations; SN activity during stimulation is attenuated due to baroreflex. In (A2, A3), the stimuli during expiration prolonged expiration, slightly when applied in post-inspiration or substantially, in late expiration. (B) After removal of the pontine compartment in the model, the applied stimulation does not prolong the expiratory period, but shorten the “apneustic” PN bursts if applied during inspiration. SN activity respiratory modulation is abolished. Traces are as Fig. 1. The phases of barostimulation are chosen approximately the same as in experimental examples in Fig. 1.

Fig. 5

Response to transient baroreceptor stimulation in the model and in situ. (A) Simulation results. The top pair of traces: membrane potential of a randomly chosen neurone from the post-I population of BötC and integrated spike histogram of the entire post-I population. Second pair of traces: membrane potential of a randomly chosen neurone from the aug-E population of BötC and spike histogram of the entire aug-E population. The applied stimulation (lowest trace) excited post-I neurones and inhibited aug-E neurones. After the stimulus ended, the aug-E neuroneactivated again. The transient changes in post-I and aug-E activities prolonged expiration. (B) Experimental results in situ preparation: the applied baro-stimulus activated post-I and suppressed aug-E activities. These changes in neurone activity were associated with decreased SNA output and prolongation of expiration. Traces in (B): top two traces show an extracellular recording from a post-I neurone in BötC and the histogram of its activity; the next pair of traces show a simultaneous extracellular recording from an aug-E neurone of BötC and the corresponding histogram; the remaining traces show the integrated phrenic nerve activity (PNA), integrated thoracic sympathetic nerve activity (tSNA), and perfusion pressure (PP). The response to the applied barostimulation in the in situ preparation is associated with increases in post-I and decreases in aug-E activity and prolongation of the expiratory phase. These neuronal activity patterns of the recorded post-I and aug-E neurones are consistent with the proposed connectivity between these two types of neurones located in the BötC.