Sympathoexcitation during chemoreflex active expiration is mediated byl-glutamate in the RVLM/Bötzinger complex of rats

Abstract

Moraes DJ, Zoccal DB, Machado BH. Sympathoexcitation during chemoreflex active expiration is mediated by L-glutamate in the RVLM/Bötzinger complex of rats. J Neurophysiol 108: 610 -623, 2012. First published April 25, 2012 doi:10.1152/jn.00057.2012The involvement of glutamatergic neurotransmission in the rostral ventrolateral medulla/Bötzinger/pre-Bötzinger complexes (RVLM/ BötC/pre-BötC) on the respiratory modulation of sympathoexcitatory response to peripheral chemoreflex activation (chemoreflex) was evaluated in the working heart-brain stem preparation of juvenile rats. We identified different types of baro-and chemosensitive presympathetic and respiratory neurons intermingled within the RVLM/BötC/preBötC. Bilateral microinjections of kynurenic acid (KYN) into the rostral aspect of RVLM (RVLM/BötC) produced an additional increase in frequency of the phrenic nerve (PN: 0.38 Ϯ 0.02 vs. 1 Ϯ 0.08 Hz; P Ͻ 0.05; n ϭ 18) and hypoglossal (HN) inspiratory response (41 Ϯ 2 vs. 82 Ϯ 2%; P Ͻ 0.05; n ϭ 8), but decreased postinspiratory (35 Ϯ 3 vs. 12 Ϯ 2%; P Ͻ 0.05) and late-expiratory (24 Ϯ 4 vs. 2 Ϯ1%; P Ͻ 0.05; n ϭ 5) abdominal (AbN) responses to chemoreflex. Likewise, expiratory vagal (cVN; 67 Ϯ 6 vs. 40 Ϯ 2%; P Ͻ 0.05; n ϭ 5) and expiratory component of sympathoexcitatory (77 Ϯ 8 vs. 26 Ϯ 5%; P Ͻ 0.05; n ϭ 18) responses to chemoreflex were reduced after KYN microinjections into RVLM/BötC. KYN microinjected into the caudal aspect of the RVLM (RVLM/pre-BötC; n ϭ 16) abolished inspiratory responses [PN (n ϭ 16) and HN (n ϭ 6)], and no changes in magnitude of sympathoexcitatory (n ϭ 16) and expiratory (AbN and cVN; n ϭ 10) responses to chemoreflex, producing similar and phase-locked vagal, abdominal, and sympathetic responses. We conclude that in relation to chemoreflex activation 1) ionotropic glutamate receptors in RVLM/BötC and RVLM/preBötC are pivotal to expiratory and inspiratory responses, respectively; and 2) activation of ionotropic glutamate receptors in RVLM/BötC is essential to the coupling of active expiration and sympathoexcitatory response.

Specific Respiratory Neuron Types Have Increased Excitability That Drive Presympathetic Neurones in Neurogenic Hypertension

“…At 5% CO 2 , the inspiratory firing patterns of phrenic (PN), hypoglossal nerve (HN), and superior laryngeal nerve (SLN) were similar between rat strains and to those described previously 26,37,38 ( Figure S1A and Table S1 in the online-only Data Supplement). There was no rat strain difference in PN frequency or duration ( Figure S1A; Table S1).…”

“…13,26,27,29 As with the thoracic sympathetic nerve, 13 we observed that all 3 sympathetic nerves recorded (ie, external and internal cervical sympathetic nerves [eCSN, iCSN], respectively, lumbar sympathetic) had augmented respiratory-modulation in SH rats (Figure S3A and S3B; Table S2). Specifically, SH rats exhibit increased inspiratory (iCSN, P<0.05 and eCSN, P<0.01; Figure S3B) and post-I-related sympathetic bursts (P<0.001; Figure S3B) and also an additional pre-I peak in the iCSN only ( Figure S3B) relative to that seen in Wistar rats (P<0.01; Figure S3A).…”

“…In both cell types, distinct intrinsic ionic channels seem responsible for generating enhanced neuronal excitability. This raises the intriguing idea that excessive sympathetic activity in SH (and other models) [26][27][28][29] results, in part, from alterations in ionic conductances in distinct respiratory neuron types.Previous electrophysiological studies have documented that a persistent sodium current (I NaP ) and a potassium-dominated leak current are coexpressed in pre-BötC preinspiratory neurons, and that their relative ratio of expression provides a mechanism for intrinsic burst generation. 39,[50][51][52][53][54][55] Our finding that pre-I neurons in the SH rat have reduced leak, and enhanced I NaP currents provide an explanation for their enhanced excitability.…”

“…Likely mechanisms contributing include elevated reflex afferent drive from both peripheral chemoreceptors 14,15 and kidney, 16,17 saltangiotensin II, [18][19][20][21] inflammation, [22][23][24] and respiration. 13,[25][26][27][28][29] Respiratory modulation of sympathetic activity or respiratory-sympathetic coupling has been observed in many sympathetic postganglionic outflows. 13,21,[28][29][30][31][32][33] Clinical studies have purported that by controlling breathing depth and rate (using RespeRate) blood pressure can be lowered 34 in patients with hypertension.…”

Time delay of baroreflex control and oscillatory pattern of sympathetic activity in patients with metabolic syndrome and obstructive sleep apnea

“…Since there are direct connections between ventrolateral respiratory neurons and presympathetic neurons in the rostral ventral lateral medulla (26), an increased respiratory drive may cause a leak to these presympathetic neurons, not only increasing the sympathetic outflow (26) but also changing their oscillatory profile. Effects of stimulation of chemoreceptors on sympathetic nerve activity reinforce our hypothesis (27). We cannot discard a possible influence of peripheral stretching pulmonary mechanoreceptors, which via vagal afferent neurons can affect the presympathetic neurons in the medulla (18).…”