Modulation of respiratory responses to chemoreflex activation by l-glutamate and ATP in the rostral ventrolateral medulla of awake rats

Abstract

Presympathetic neurons in the different anteroposterior aspects of rostral ventrolateral medulla (RVLM) are colocalized with expiratory [Bötzinger complex (BötC)] and inspiratory [pre-Bötzinger complex (pre-BötC)] neurons of ventral respiratory column (VRC), suggesting that this region integrates the cardiovascular and respiratory chemoreflex responses. In the present study, we evaluated in different anteroposterior aspects of RVLM of awake rats the role of ionotropic glutamate and purinergic receptors on cardiorespiratory responses to chemoreflex activation. The bilateral ionotropic glutamate receptors antagonism with kynurenic acid (KYN) (8 nmol/50 nl) in the rostral aspect of RVLM (RVLM/BötC) enhanced the tachypneic (120 ± 9 vs. 180 ± 9 cpm; P < 0.01) and attenuated the pressor response (55 ± 2 vs. 15 ± 1 mmHg; P < 0.001) to chemoreflex activation (n = 7). On the other hand, bilateral microinjection of KYN into the caudal aspect of RVLM (RVLM/pre-BötC) caused a respiratory arrest in four awake rats used in the present study. Bilateral P2X receptors antagonism with PPADS (0.25 nmol/50 nl) in the RVLM/BötC reduced chemoreflex tachypneic response (127 ± 6 vs. 70 ± 5 cpm; P < 0.001; n = 6), but did not change the chemoreflex pressor response. In addition, PPADS into the RVLM/BötC attenuated the enhancement of the tachypneic response to chemoreflex activation elicited by previous microinjections of KYN into the same subregion (188 ± 2 vs. 157 ± 3 cpm; P < 0.05; n = 5). Our findings indicate that: 1) L-glutamate, but not ATP, in the RVLM/BötC is required for pressor response to peripheral chemoreflex and 2) both transmitters in the RVLM/BötC are required for the processing of the ventilatory response to peripheral chemoreflex activation in awake rats.

Mecanismos purinérgicos no bulbo ventrolateral rostral modulam respostas cardiovasculares e respiratórias promovidas pela ativação dos quimiorreceptores centrais e periféricos.

“…Furthermore, inhibition of P2X receptors within the more caudal RVLM (at the level of the Bötzinger complex) blunted the ventila tory, but not pressure response elicited by peripheral che moreceptor activation in conscious rats. 23 In light of our evidence that P2Y1 receptors expressed on C1 cell mediate the peripheral chemoreceptor pressure response, we propose that differential expression of P2 receptors throughout the ventrolateral medulla could allow for parallel processing of respiratory and cardiovascular components of the peripheral chemoreflex.It is also possible that P2Y1 receptors regulate other excit atory reflexes at the level of the RVLM. For example, we show that pharmacological blockade of P2Y1 receptors in the RVLM caused a modest reduction in the somatosympa thetic reflex by reducing the SNA peak elicited by electric stimulation of the sciatic nerve in anesthetized rats.…”

“…preBözinger complex blunted the respiratory response evoked by peripheral chemoreceptor activation in awake rats. 23 These results suggest that purinergic signaling contributes to the peripheral chemoreflex mechanism. However, the identity of P2 receptors regulating the peripheral chemoreflex at this level of the brain stem is unknown.…”

“…Esse processo constitui o quimirreflexo periférico, o qual consiste num dos principais elementos na manuntenção da homeostase cardiorrespiratória (MACHADO, 2001; PRABHAKAR, 2013). Os ajustes promovidos pela ativação desse reflexo se caracterizam por aumento da pressão arterial, decorrente de um incremento na atividade simpática vascular e o aumento da ventilação (BARROS et al, 2002; ZOCCAL et al, 2008) KOSHIYA, 1995; GUYENET, 1996a;MORAES et al, 2011). …”

“…Níveis elevados de ATP nesta região também foram detectados em resposta a hipóxia (redução na PO2), mesmo em animais com os quimiorreceptores periféricos desnervados (GOURINE et al, 2005b (quimiosenssíveis) com a técnica da optogenética promove aumento da pressão arterial e da respiração (ABBOTT et al, 2009a(ABBOTT et al, , 2009b BURKE et al, 2015). MORAES et al, 2011). …”

“…Neste sentido, já está bem estabelecido que a sinalização purinérgica pode atuar ao longo de toda a cadeia neural da via do quimioreflexo periférico (ALVARES et al, 2014;MACHADO, 2006;FUNK, 2013;MORAES et al, 2011; MOREIRA et al, 2015;PATON et al, 2001; A sinalização purinérgica pode atuar na região do bulbo ventrolateral rostral como moduladora de respostas quimiorreceptoras centrais e periféricas (GOURINE et al, 2005a …”