Key points• The retrotrapezoid nucleus (RTN) is an important site of chemoreception, i.e. the mechanism by which the brain regulates breathing in response to changes in tissue CO 2 /H + .• Mechanisms underlying RTN chemoreception appear to involve direct CO 2 /H + -mediated neuronal activation and indirect neuronal activation by CO 2 -evoked ATP release (i.e. purinergic signalling) from astrocytes.• Here, we show in vitro and in vivo that purinergic signalling in the RTN contributes to ∼30% of RTN chemoreception.• Purinergic drive in the RTN involves gap junction hemichannels but not P2Y1 receptors.• These results clearly indicate that purinergic signalling contributes to integrated output of the RTN during hypercapnia and thus is an important determinant of respiratory drive.Abstract Central chemoreception is the mechanism by which the brain regulates breathing in response to changes in tissue CO 2 /H + . A brainstem region called the retrotrapezoid nucleus (RTN) contains a population of CO 2 /H + -sensitive neurons that appears to function as an important chemoreceptor. Evidence also indicates that CO 2 -evoked ATP release from RTN astrocytes modulates activity of CO 2 /H + -sensitive neurons; however, the extent to which purinergic signalling contributes to chemoreception by RTN neurons is not clear and the mechanism(s) underlying CO 2 /H + -evoked ATP release is not fully elucidated. The goals of this study are to determine the extent to which ATP contributes to RTN chemoreception both in vivo and in vitro, and whether purinergic drive to chemoreceptors relies on extracellular Ca 2+ or gap junction hemichannels. We also examine the possible contribution of P2Y1 receptors expressed in the RTN to the purinergic drive to breathe. We show that purinergic signalling contributes, in part, to the CO 2 /H + sensitivity of RTN neurons. In vivo, phrenic nerve recordings of respiratory activity in adult rats show that bilateral injections of pyridoxal-phosphate-6-azophenyl-2 ,4 -disulfonate (PPADS, a P2 receptor blocker) decreased the ventilatory response to CO 2 by 30%. 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 (22-35• 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. Inhibition of the P2Y1 receptor in the RTN had no effect on CO 2 responsivness in vitro or in vivo; thus, the identity of P2 receptors underlying the purinergic component of RTN chemoreception remains unknown. These results support the possibility that CO 2 /H + -evoked ATP release is mediated by a mechanism involving gap junction hemichannels. Abbreviations etCO 2 , end-expiratory CO 2 ; MAP, mean arterial pressure; pFRG, parafacial respiratory group; NA, phrenic nerve activity; RTN, retr...
Several brain regions are thought to function as important sites of chemoreception including the nucleus of the solitary tract (NTS), medullary raphe and retrotrapezoid nucleus (RTN). In the RTN, mechanisms of chemoreception involve direct H(+)-mediated activation of chemosensitive neurons and indirect modulation of chemosensitive neurons by purinergic signalling. Evidence suggests that RTN astrocytes are the source of CO2-evoked ATP release. However, it is not clear whether purinergic signalling also influences CO2/H(+) responsiveness of other putative chemoreceptors. The goals of this study are to determine if CO2/H(+)-sensitive neurons in the NTS and medullary raphe respond to ATP, and whether purinergic signalling in these regions influences CO2 responsiveness in vitro and in vivo. In brain slices, cell-attached recordings of membrane potential show that CO2/H(+)-sensitive NTS neurons are activated by focal ATP application; however, purinergic P2-receptor blockade did not affect their CO2/H(+) responsiveness. CO2/H(+)-sensitive raphe neurons were unaffected by ATP or P2-receptor blockade. In vivo, ATP injection into the NTS increased cardiorespiratory activity; however, injection of a P2-receptor blocker into this region had no effect on baseline breathing or CO2/H(+) responsiveness. Injections of ATP or a P2-receptor blocker into the medullary raphe had no effect on cardiorespiratory activity or the chemoreflex. As a positive control we confirmed that ATP injection into the RTN increased breathing and blood pressure by a P2-receptor-dependent mechanism. These results suggest that purinergic signalling is a unique feature of RTN chemoreception.
Catecholaminergic C1 cells of the rostral ventrolateral medulla (RVLM) are key determinants of the sympathoexcitatory response to peripheral chemoreceptor activation. Over-activation 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. We have recently determined that activation of P2Y1-receptors in the RVLM mimicked effects of peripheral chemoreceptor activation. Therefore, we hypothesize that P2Y1-receptors regulate peripheral chemoreceptor drive in this region. Here we determine if P2Y1-receptors are expressed by C1 neurons in the RVLM and contribute to peripheral chemoreceptor control of breathing, sympathetic activity and blood pressure. We found that injection of a specific P2Y1-receptor agonist (MRS2365) into the RVLM of anesthetized adult rats increased phrenic nerve activity (PNA) (~55%), sympathetic nerve activity (SNA) (38 ± 6%), and blood pressure (23 ± 1 mmHg), whereas application of a specific P2Y1-receptor antagonist (MRS2179) decreased peripheral chemoreceptor-mediated activation of PNA, SNA and blood pressure. To establish that P2Y1 receptors are expressed by C1 cells, we determine in the brain slice preparation using cell-attached recording techniques that cells responsive to MRS2365 are immunoreactive for tyrosine hydroxylase (TH, a marker of C1 cells), and we determine in vivo that C1 lesion animals do not respond to RVLM injection of MRS2365. These data identify P2Y1-receptors as key determinants of peripheral chemoreceptor regulation of breathing, SNA and blood pressure.
The arterial partial pressure (P CO 2 ) of carbon dioxide is virtually constant because of the close match between the metabolic production of this gas and its excretion via breathing. Blood gas homeostasis does not rely solely on changes in lung ventilation, but also to a considerable extent on circulatory adjustments that regulate the transport of CO 2 from its sites of production to the lungs. The neural mechanisms that coordinate circulatory and ventilatory changes to achieve blood gas homeostasis are the subject of this review. Emphasis will be placed on the control of sympathetic outflow by central chemoreceptors. High levels of CO 2 exert an excitatory effect on sympathetic outflow that is mediated by specialized chemoreceptors such as the neurons located in the retrotrapezoid region. In addition, high CO 2 causes an aversive awareness in conscious animals, activating wakepromoting pathways such as the noradrenergic neurons. These neuronal groups, which may also be directly activated by brain acidification, have projections that contribute to the CO 2 -induced rise in breathing and sympathetic outflow. However, since the level of activity of the retrotrapezoid nucleus is regulated by converging inputs from wake-promoting systems, behavior-specific inputs from higher centers and by chemical drive, the main focus of the present manuscript is to review the contribution of central chemoreceptors to the control of autonomic and respiratory mechanisms.
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