Control of sympathetic vasomotor tone by catecholaminergic C1 neurones of the rostral ventrolateral medulla oblongata

Abstract

AimsIncreased sympathetic tone in obstructive sleep apnoea results from recurrent episodes of systemic hypoxia and hypercapnia and might be an important contributor to the development of cardiovascular disease. In this study, we re-evaluated the role of a specific population of sympathoexcitatory catecholaminergic C1 neurones of the rostral ventrolateral medulla oblongata in the control of sympathetic vasomotor tone, arterial blood pressure, and hypercapnia-evoked sympathetic and cardiovascular responses.Methods and resultsIn anaesthetized rats in vivo and perfused rat working heart brainstem preparations in situ, C1 neurones were acutely silenced by application of the insect peptide allatostatin following cell-specific targeting with a lentiviral vector to express the inhibitory Drosophila allatostatin receptor. In anaesthetized rats with denervated peripheral chemoreceptors, acute inhibition of 50% of the C1 neuronal population resulted in ∼50% reduction in renal sympathetic nerve activity and a profound fall in arterial blood pressure (by ∼25 mmHg). However, under these conditions systemic hypercapnia still evoked vigorous sympathetic activation and the slopes of the CO2-evoked sympathoexcitatory and cardiovascular responses were not affected by inhibition of C1 neurones. Inhibition of C1 neurones in situ resulted in a reversible fall in perfusion pressure and the amplitude of respiratory-related bursts of thoracic sympathetic nerve activity.ConclusionThese data confirm a fundamental physiological role of medullary catecholaminergic C1 neurones in maintaining resting sympathetic vasomotor tone and arterial blood pressure. However, C1 neurones do not appear to mediate sympathoexcitation evoked by central actions of CO2.

Mechanisms involved in regulation of Systemic Blood Pressure

“…Vasomotor tone is the sum of the muscular forces intrinsic to the blood vessel opposing an increase in vessel diameter [6]. This is mediated by vascular smooth muscle cells (VSMCs) in the media layer of vessel walls.…”

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

“…Furthermore, selective acti vation of C1 cells by channelrhodopsin2 has been shown to increase breathing, sympathetic activity, and blood pres sure, [44][45][46] whereas inhibition of C1 cells by activation of the allostatin receptor did the opposite. 47 However, despite the critical role of C1 cells in regulation of cardiorespiratory function, the identity of neurotransmitters and downstream effectors responsible for peripheral chemoreflex control of autonomic function at the level of the ventrolateral medulla remains incomplete.…”

“…Furthermore, selective acti vation of C1 cells by channelrhodopsin2 has been shown to increase breathing, sympathetic activity, and blood pres sure, [44][45][46] whereas inhibition of C1 cells by activation of the allostatin receptor did the opposite. 47 However, despite the critical role of C1 cells in regulation of cardiorespiratory function, the identity of neurotransmitters and downstream effectors responsible for peripheral chemoreflex control of autonomic function at the level of the ventrolateral medulla remains incomplete.Our results indicate that peripheral chemoreflex control of breathing, sympathetic activity, and blood pressure depends on both glutamate and purinergic signaling at the level of the RVLM. Specifically, we show in anesthetized rats that bilat eral injections of kynurenic acid significantly decreased the ventilatory, sympathetic, and pressor responses to peripheral chemoreceptor activation.…”

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

“…quanto da estimulação aguda dos catecolaminérgicos do grupamento C1 (Abbott et al, 2010;Kanbar et al, 2010;Marina et al,2011;Abbott et al, 2012;Burke et al, 2014;Menuet et al, 2017;Wenker et al, 2017). Os primeiros estudos avaliaram os efeitos da ativação seletiva dos neurônios C1 (optogenética) sobre os parâmetros cardiovasculares e demonstraram que a ativação optogenética do grupamento C1 promove um aumento expressivo da pressão arterial e da atividade simpática, tanto em animais anestesiados (Abbott et al, 2010) quanto em animais não anestesiados (Kanbar et al, 2010), reproduzindo os efeitos observados com as técnicas convencionais de estimulação quimíca ou elétrica do RVLM (Abbott et al, 2010;Kanbar et al, 2010).…”

“…Os primeiros estudos avaliaram os efeitos da ativação seletiva dos neurônios C1 (optogenética) sobre os parâmetros cardiovasculares e demonstraram que a ativação optogenética do grupamento C1 promove um aumento expressivo da pressão arterial e da atividade simpática, tanto em animais anestesiados (Abbott et al, 2010) quanto em animais não anestesiados (Kanbar et al, 2010), reproduzindo os efeitos observados com as técnicas convencionais de estimulação quimíca ou elétrica do RVLM (Abbott et al, 2010;Kanbar et al, 2010). Já com os estudos nos quais a inibição seletiva dos neurônios C1 foram avaliadas em animais anestesiados (Marina et al, 2011; 2017) e não anestesiadas (Wenker et al, 2017), foi demonstrado que de fato os neurônios C1…”