Chronic intermittent hypoxia augments sympatho-excitatory response to ATP but not to l-glutamate in the RVLM of rats

Abstract

The development of sympathetic overactivity and hypertension in rats submitted to chronic intermittent hypoxia (CIH) involve alterations in the central mechanisms controlling respiratory and autonomic functions. Herein, we assessed whether CIH alters glutamatergic and/or purinergic signaling in the ventrolateral medulla (VLM), a region that encompasses the pre-sympathetic neurons and respiratory neurons of the ventral respiratory column. Groups of juvenile rats were exposed for 10 days to CIH (6% O(2) for 40s, every 9min, 8h/day) or normoxia (controls). Following treatment, in situ working heart-brainstem preparations were performed to record simultaneously respiratory and sympathetic motor outputs. In separate CIH and control groups, the VLM was dissected for western-blot analyses of ionotropic glutamatergic and P2 receptors. l-glutamate microinjections (1, 3 or 10mM) into VLM of control (n=6) and CIH groups (n=10) produced similar increases of sympathetic and abdominal activities associated with phrenic nerve inhibition; immunoreactive NMDAR1 and GluR2/3 densities at the VLM were also alike between groups (n=4). In contrast, VLM microinjections of ATP (1, 10 or 50mM) evoked larger sympatho-excitatory responses in CIH (n=8) than in control rats (n=7, P<0.05) whilst the abdominal increase and phrenic nerve inhibition were of comparable magnitudes. The immunoreactive densities of P2X3 and P2X4 receptors, but not P2X1 and P2Y2, were 20% higher in VLM of CIH (n=8; P<0.05) than controls (n=8). Altogether, our findings suggest that CIH augments purinergic signaling in the VLM, supporting the concept that nucleotides play a role in the dynamic central control of the sympathetic autonomic function.

Chronic intermittent hypoxia increases sympathetic control of blood pressure: role of neuronal activity in the hypothalamic paraventricular nucleus

“…Expression is also observed in downstream sympathetic regulatory cell groups, including neurons in the hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla (8,27). Importantly, full expression of hypertension in our 7-day CIH model critically depends on activator protein-1 transcriptional regulation of MnPO neurons by FosB/⌬FosB (8).These and other observations (7,9,40,41,46,70) indicate that exaggerated SNA and the neurogenic component of CIHinduced hypertension are complex and might not arise solely from the sensitization of arterial chemoreceptors. In the present study, we sought to determine the early contribution of forebrain/hypothalamic neural mechanisms in hypertension induced by 7 days of CIH.…”

“…These and other observations (7,9,40,41,46,70) indicate that exaggerated SNA and the neurogenic component of CIHinduced hypertension are complex and might not arise solely from the sensitization of arterial chemoreceptors. In the present study, we sought to determine the early contribution of forebrain/hypothalamic neural mechanisms in hypertension induced by 7 days of CIH.…”

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

“…In vitro, loose-patch recordings from RTN neurons show that P2 receptor blockers decreased responsiveness to both 10% and 15% CO 2 also by 30%. In the slice, the contribution of purinergic signalling to RTN chemoreception did not increase with temperature (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) • C) and was retained in low extracellular Ca 2+ medium. Conversely, the gap junction blockers carbenoxolone and cobalt decreased neuronal CO 2 /H + sensitivity by an amount similar to P2 receptor antagonists.…”

“…57 Previous evidence showed that C1 cells are key determinants of the sympa thoexcitatory response to peripheral chemoreceptor activa tion. 15 In addition, an animal model of OSA showed that chronic intermittent hypoxia increased sympathoexcitatory responsiveness to RVLM injections of ATP, 28 suggesting that purinergic signaling in this region contributes to OSA induced activation of sympathetic activity and hypertension. Here, we show that purinergic signaling contributes to the peripheral chemoreflex at the level of the RVLM by a P2Y1 receptor-dependent mechanism.…”

“…9,18 However, purinergic signaling has also been impli cated in the peripheral chemoreflex, [19][20][21][22] including at the level of the RVLM. 23 For example, chemosensitive RTN neurons 24,25 and presympathetic RVLM neurons 26 are activated by puriner gic agonists, application of purinergic agonists into the RVLM increased breathing 27,28 and blood pressure 29,30 in anesthetized rats, and inhibition of P2 receptors in the nearby Bötzinger and Abstract-Catecholaminergic C1 cells of the rostral ventrolateral medulla (RVLM) are key determinants of the sympathoexcitatory response to peripheral chemoreceptor activation. Overactivation of this reflex is thought to contribute to increased sympathetic activity and hypertension; however, molecular mechanisms linking peripheral chemoreceptor drive to hypertension remain poorly understood.…”