Sympatho-excitation during chemoreflex active expiration is mediated by L-glutamate in the RVLM/Bötzinger complex of rats

The 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/pre-BötC. 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 ± 0.02 vs. 1 ± 0.08 Hz; P < 0.05; n = 18) and hypoglossal (HN) inspiratory response (41 ± 2 vs. 82 ± 2%; P < 0.05; n = 8), but decreased postinspiratory (35 ± 3 vs. 12 ± 2%; P < 0.05) and late-expiratory (24 ± 4 vs. 2 ±1%; P < 0.05; n = 5) abdominal (AbN) responses to chemoreflex. Likewise, expiratory vagal (cVN; 67 ± 6 vs. 40 ± 2%; P < 0.05; n = 5) and expiratory component of sympathoexcitatory (77 ± 8 vs. 26 ± 5%; P < 0.05; n = 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 = 16) abolished inspiratory responses [PN (n = 16) and HN (n = 6)], and no changes in magnitude of sympathoexcitatory (n = 16) and expiratory (AbN and cVN; n = 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/pre-BötC 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.

Control of breathing and blood pressure by parafacial neurons in conscious rats

New Findings: • What is the central question of this study? The main purpose of the present manuscript was to investigate the cardiorespiratory responses to hypoxia or hypercapnia in conscious rats submitted to neuronal blockade of the parafacial region. We clearly showed that the integrity of parafacial region is important for the respiratory responses elicited by peripheral and central chemoreflex activation in freely behavior rats. • What is the main finding and its importance? Since the parafacial region is part of the respiratory rhythm generator, they are essential for postnatal survival, which is probably due to their contribution to chemoreception in conscious rats. The retrotrapezoid nucleus (RTN), located in the parafacial region, contains glutamatergic neurons that express the transcriptor factor Phox2b and that are suggested to be central respiratory chemoreceptors. Studies in anaesthetized animals or in vitro have suggested that RTN neurons are important in the control of breathing by influencing respiratory rate, inspiratory amplitude and active expiration. However, the contribution of these neurons to cardiorespiratory control in conscious rats is not clear. Male Holtzman rats (280-300 g, n= 6-8) with bilateral stainless-steel cannulae implanted into the RTN were used. In conscious rats, the microinjection of the ionotropic glutamatergic agonist NMDA (5 pmol in 50 nl) into the RTN increased respiratory frequency (by 42%), tidal volume (by 21%), ventilation (by 68%), peak expiratory flow (by 24%) and mean arterial pressure (MAP, increased by 16 ± 4, versus saline, 3 ± 2 mmHg). Bilateral inhibition of the RTN neurons with the GABAA agonist muscimol (100 pmol in 50 nl) reduced resting ventilation (52 ± 34, versus saline, 250 ± 56 ml min-1 kg-1 with absolute values) and attenuated the respiratory response to hypercapnia and hypoxia. Muscimol injected into the RTN slightly reduced resting MAP (decreased by 13 ± 7, versus saline, increased by 3 ± 2 mmHg), without changing the effects of hypercapnia or hypoxia on MAP and heart rate. The results suggest that RTN neurons activate facilitatory mechanisms important to the control of ventilation in resting, hypoxic or hypercapnic conditions in conscious rats. © 2012 The Authors. Experimental Physiology © 2012 The Physiological Society.

Vagal afferent control of abdominal expiratory activity in response to hypoxia and hypercapnia in rats

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Short-term sustained hypoxia induces changes in the coupling of sympathetic and respiratory activities in rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Peripheral chemoreceptors and cardiorespiratory coupling: a link to sympatho-excitation

Chronic intermittent hypoxia (CIH) has been identified as a relevant risk factor for the development of enhanced sympathetic outflow and arterial hypertension. Several studies have highlighted the importance of peripheral chemoreceptors for the cardiovascular changes elicited by CIH. However, the effects of CIH on the central mechanisms regulating sympathetic outflow are not fully elucidated. Our research group has explored the hypothesis that the enhanced sympathetic drive following CIH exposure is, at least in part, dependent on alterations in the respiratory network and its interaction with the sympathetic nervous system. In this report, I discuss the changes in the discharge profile of baseline sympathetic activity in rats exposed to CIH, their association with the generation of active expiration and the interactions between expiratory and sympathetic neurones after CIH conditioning. Together, these findings are consistent with the theory that mechanisms of central respiratory–sympathetic coupling are a novel factor in the development of neurogenic hypertension.