Ventrolateral medulla mechanisms involved in cardiorespiratory responses to central chemoreceptor activation in rats

Abstract

A rise in arterial Pco(2) stimulates breathing and sympathetic activity to the heart and blood vessels. In the present study, we investigated the involvement of the retrotrapezoid nucleus (RTN) and glutamatergic mechanisms in the Bötzinger/C1 region (Bötz/C1) in these responses. Splanchnic sympathetic nerve discharge (sSND) and phrenic nerve discharge (PND) were recorded in urethane-anesthetized, sino-aortic-denervated, vagotomized, and artificially ventilated rats subjected to hypercapnia (end-expiratory CO(2) from 5% to 10%). Phrenic activity was absent at end-expiratory CO(2) of 4%, and strongly increased when end-expiratory CO(2) reached 10%. Hypercapnia also increased sSND by 103 ± 7%. Bilateral injections of the GABA-A agonist muscimol (2 mM) into the RTN eliminated the PND and blunted the sSND activation (Δ = +56 ± 8%) elicited by hypercapnia. Injections of NMDA receptor antagonist AP-5 (100 mM), non-NMDA receptor antagonist 6,7-dinitro-quinoxaline-2,3-dione (DNQX; 100 mM) or metabotropic glutamate receptor antagonist (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG; 100 mM) bilaterally into the Bötz/C1 reduced PND (Δ = +43 ± 7%, +52 ± 6% or +56 ± 11%, respectively). MCPG also reduced sSND (Δ = +41 ± 7%), whereas AP-5 and DNQX had no effect. In conclusion, the increase in sSND caused by hypercapnia depends on increased activity of the RTN and on metabotropic receptors in the Bötz/C1, whereas PND depends on increased RTN activity and both ionotropic and metabotropic receptors in the Bötz/C1.

Central chemoreceptors and neural mechanisms of cardiorespiratory control

“…The results suggest that central chemoreceptor-induced phrenic nerve activity (PNA) is dependent on RTN, as previously demonstrated (22,24,27), whereas sympathoexcitation and pressor responses are only partially mediated by RTN (24). The reduced sympathoexcitation produced by hypercapnia after injection of the NMDA glutamate antagonist (AP-5) into the RTN, might also be the result of the decrease in the excitability of RVLM presympathetic neurons after removing baseline facilitatory glutamatergic signals from the RTN (Figure 2).…”

“…Recently, we have shown that inhibition of the chemosensitive neurons located in the RTN eliminated resting breathing and reduced the sympathoexcitatory responses produced by central chemoreceptor activation (24). The results suggest that central chemoreceptor-induced phrenic nerve activity (PNA) is dependent on RTN, as previously demonstrated (22,24,27), whereas sympathoexcitation and pressor responses are only partially mediated by RTN (24).…”

“…An essential step for motor neuron hypercapnia-induced phrenic nerve activity is activation of RTN neurons by CO 2 /H + , which in turn send excitatory signals to activate the CPG, either directly or through activation of metabotropic and ionotropic glutamate receptors in the RVLM. Signals from the RTN that activate metabotropic receptors in the RVLM may also increase sympathetic activity to the cardiovascular system (24). CPG = central pattern generator; commNTS = commissural nucleus tractus solitarii; IgluR = glutamatergic ionotropic receptors; MgluR = glutamatergic metabotropic receptors; RTN = retrotrapezoid nucleus; RVLM = rostral ventrolateral medulla; SPGn = sympathetic preganglionic neurons.…”

“…Because the RVLM presympathetic neurons do not seem to be intrinsically pH-sensitive (23), their response to CO 2 must rely on synaptic inputs, especially from RTN neurons that are a plausible source of CO 2 -dependent excitation (24).…”

Neurônios catecolaminérgicos do tronco encefálico participam dos ajustes respiratórios induzidos por hipóxia e hipercapnia.

“…Está bem estabelecido na literatura a contribuição do grupamento C1 durante a ativação dos quimiorreceptores periféricos e centrais, no que diz respeito ao controle autônomo, mais especificamente na modulação da atividade simpática Koshiya, Guyenet, 1996;Moreira et al, 2006;Takakura et al, 2011;Moraes et al, 2013). No entanto, a participação dos neurônios C1 no controle respiratório só foi descoberta recentemente Burke et al, 2014).…”