Central Chemosensitive Neurons Research Articles

Lethal avian influenza A (H5N1) virus replicates in pontomedullary chemosensitive neurons and depresses hypercapnic ventilatory response in mice.

The highly pathogenic H5N1 (HK483) viral infection causes a depressed hypercapnic ventilatory response (dHCVR, 20%↓) at 2 days postinfection (dpi) and death at 7 dpi in mice, but the relevant mechanisms are not fully understood. Glomus cells in the carotid body and catecholaminergic neurons in locus coeruleus (LC), neurokinin 1 receptor (NK1R)-expressing neurons in the retrotrapezoid nucleus (RTN), and serotonergic neurons in the raphe are chemosensitive and responsible for HCVR. We asked whether the dHCVR became worse over the infection period with viral replication in these cells/neurons. Mice intranasally inoculated with saline or the HK483 virus were exposed to hypercapnia for 5 min at 0, 2, 4, or 6 dpi, followed by immunohistochemistry to determine the expression of nucleoprotein of H5N1 influenza A (NP) alone and coupled with 1) tyrosine hydroxylase (TH) in the carotid body and LC, 2) NK1R in the RTN, and 3) tryptophan hydroxylase (TPH) in the raphe. HK483 viral infection blunted HCVR by ∼20, 50, and 65% at 2, 4, and 6 dpi. The NP was observed in the pontomedullary respiratory-related nuclei (but not in the carotid body) at 4 and 6 dpi, especially in 20% of RTN NK1R, 35% of LC TH, and ∼10% raphe TPH neurons. The infection significantly reduced the local NK1R or TPH immunoreactivity and population of neurons expressing NK1R or TPH. We conclude that the HK483 virus infects the pontomedullary respiratory nuclei, particularly chemosensitive neurons in the RTN, LC, and raphe, contributing to the severe depression of HCVR and respiratory failure at 6 dpi. NEW & NOTEWORTHY The H5N1 virus infection is lethal due to respiratory failure, but the relevant mechanisms remain unclear. In this study, we demonstrated a gradual diminution of hypercapnic ventilatory response to a degree, leading to respiratory failure over a 6-day infection. Death was associated with viral replication in the pontomedullary respiratory-related nuclei, especially the central chemosensitive neurons. These results not only provide insight into the mechanisms of the lethality of H5N1 viral infection but also offer clues in the development of corresponding treatments to minimize and prevent respiratory failure.

A Preliminary Ionic Current Model for Central Chemosensitive Neurons

Although the magnitude of the firing rate response of chemosensitive neurons to increased CO2/H+ has been associated primarily with accelerating pathways, recent studies have suggested that an additional braking pathway related with multiple factors can also limit the effect of neuronal responses to CO2. Such a braking pathway is thought to be driven by a hyperpolarizing effect that limits the sensitivity of the cell. In a previous study we have investigated the role of both pathways in the magnitude of the firing rate response in individual neurons using a computational model of single respiratory neurons based on the Hodgkin-Huxley formulation. That model resulted in a larger hypercapnic-induced firing rate response after inhibition of the braking pathway but its behavior did not completely agree with the rhythm and pattern that characterizes chemosensitive respiratory neurons. In this study we developed a more physiologically realistic model that includes a set of pH- and Ca2+-sensitive K+currents and reproduces the behavior of respiratory neurons. Our simulations show that both the inhibition of acid-sensitive depolarizing currents, as well as the release from inhibition of a hyperpolarizing current, play a significant role on the increased firing rate response of the neuron to increased acidotic conditions. We consider that this model is a potentially useful adjunct for on-going research into the braking pathways involved in the chemosensitive response of neurons from different nuclei in the brainstem.

TASK-2: a K2P K+ channel with complex regulation and diverse physiological functions

TASK-2 (K2P5.1) is a two-pore domain K+ channel belonging to the TALK subgroup of the K2P family of proteins. TASK-2 has been shown to be activated by extra- and intracellular alkalinization. Extra- and intracellular pH-sensors reside at arginine 224 and lysine 245 and might affect separate selectivity filter and inner gates respectively. TASK-2 is modulated by changes in cell volume and a regulation by direct G-protein interaction has also been proposed. Activation by extracellular alkalinization has been associated with a role of TASK-2 in kidney proximal tubule bicarbonate reabsorption, whilst intracellular pH-sensitivity might be the mechanism for its participation in central chemosensitive neurons. In addition to these functions TASK-2 has been proposed to play a part in apoptotic volume decrease in kidney cells and in volume regulation of glial cells and T-lymphocytes. TASK-2 is present in chondrocytes of hyaline cartilage, where it is proposed to play a central role in stabilizing the membrane potential. Additional sites of expression are dorsal root ganglion neurons, endocrine and exocrine pancreas and intestinal smooth muscle cells. TASK-2 has been associated with the regulation of proliferation of breast cancer cells and could become target for breast cancer therapeutics. Further work in native tissues and cells together with genetic modification will no doubt reveal the details of TASK-2 functions that we are only starting to suspect.

Contributions of CO2, pHi, and pHo to the signaling pathway of chemosensitive neurons in the locus coeruleus

Central chemosensitive neurons increase their firing rate (FR) upon exposure to hypercapnic acidosis (HA: 15% CO2, pHo 7.0). Multiple signaling pathways have been proposed to account for this increase including changes in Ca2+, CO2, pHi, and pHo. To determine the relative contributions of ΔpHi, ΔpHo, and CO2 to an increased FR, we used the rapid diffusion of a weak acid technique to clamp pHi. A change in pHi is believed to be the major signal in the chemosensitive (CS) response due to strong correlations between the degree of intracellular acidification and the increase of FR in HA (P<0.05). In fact, an intracellular acidification (0.24 ± 0.04 U) with no change in pHo or CO2 elicits an increase in FR of 1.4 ± 0.5 Hz. However, this FR response can still be elicited without any change in pHi (1.4 ± 0.1 Hz). Only when both pHi and pHo are clamped, does hypercapnia not result in an increase in FR (0.4 ± 0.3 Hz in 5% CO2 to 0.16 ± 0.1 Hz in 15% CO2). Thus, the increase in FR seen upon HA with pHi clamped is likely due to the change in pHo (0.45 U) during the HA exposure. Our data suggest that ΔpHi and ΔpHo can both lead to an increase in FR in response to HA, while CO2 alone does not appear to have a significant contribution. It appears that ΔpHi or ΔpHo saturates the FR response because ΔFR with HA is not different than ΔFR with ΔpHi only or ΔpHo only. These data strongly support the multiple factors model of chemosensitivity. [NIH grants RO1 HL56683 and F32 HL80877].

Effect of intracellular pH clamping on the response to hypercapnia of locus coeruleus (LC) neurons

Central chemosensitive neurons increase their firing rate (FR) upon exposure to hypercapnia. Currently, pHi is believed to be the major signal in the chemosensitive (CS) response; however, a new model has been proposed suggesting that multiple factors (such as Ca++, CO2, pHi, and pHo) contribute to the CS response. While there is evidence for a significant role of pHi in the CS response, we hypothesize that hypercapnic acidosis (HA) can still increase FR even with no change in pHi. To test this hypothesis, we developed a method to clamp pHi using rapid diffusion of the weak acid, acetic acid, through the cell membrane according to the relationship: pHi = pHo + log ([C2H3O2] i/[C2H3O2] o). Pontine brainstem slices (300 μm) were cut from neonatal rat pups (P4-P16). FR of LC neurons was measured with whole cell patch pipettes, pHi was measured by fluorescence imaging using the dye pyranine, and neurons were loaded from the patch pipette with 50 mM acetate. Extracellular acetate was varied to set pHi at desired values using the weak acid diffusion technique. We eliminated pHi decreases (0.07 ± 0.06 pH unit, p>0.05, n=8) of LC neurons upon exposure to HA (15% CO2, pHo 7.0) compared to the normal response (0.25 ± 0.03 pH unit, p<0.05, n=20). Despite pHi clamping, HA induced an increase in FR (CS index = 144 ± 14%, n=7) similar to controls (140 ± 5%, n=17). While a decrease in pHi is sufficient to elicit the chemosensitive response, these data indicate that intracellular acidification is not required. A chemosensitive response to hypercapnia without a change in pHi strongly supports the multiple factors model of chemosensitivity. [NIH grants RO1 HL56683 and F32 HL80877].

Somatic vs. dendritic responses to hypercapnia in chemosensitive locus coeruleus neurons from neonatal rats.

Cardiorespiratory control is mediated in part by central chemosensitive neurons that respond to increased CO(2) (hypercapnia). Activation of these neurons is thought to involve hypercapnia-induced decreases in intracellular pH (pH(i)). All previous measurements of hypercapnia-induced pH(i) changes in chemosensitive neurons have been obtained from the soma, but chemosensitive signaling could be initiated in the dendrites of these neurons. In this study, membrane potential (V(m)) and pH(i) were measured simultaneously in chemosensitive locus coeruleus (LC) neurons from neonatal rat brain stem slices using whole cell pipettes and the pH-sensitive fluorescent dye pyranine. We measured pH(i) from the soma as well as from primary dendrites to a distance 160 mum from the edge of the soma. Hypercapnia [15% CO(2), external pH (pH(o)) 7.00; control, 5% CO(2), pH(o) 7.45] resulted in an acidification of similar magnitude in dendrites and soma ( approximately 0.26 pH unit), but acidification was faster in the more distal regions of the dendrites. Neither the dendrites nor the soma exhibited pH(i) recovery during hypercapnia-induced acidification; but both regions contained pH-regulating transporters, because they exhibited pH(i) recovery from an NH(4)Cl prepulse-induced acidification (at constant pH(o) 7.45). Exposure of a portion of the dendrites to hypercapnic solution did not increase the firing rate, but exposing the soma to hypercapnic solution resulted in a near-maximal increase in firing rate. These data show that while the pH(i) response to hypercapnia is similar in the dendrites and soma, somatic exposure to hypercapnia plays a major role in the activation of chemosensitive LC neurons from neonatal rats.

Current Progress in Molecular Responses to Acidosis in the Central Nervous System

The ventral medullary surface of the medulla oblongata is known as the site of the central chemosensitive neurons in humans. These neurons sense decrease in pH of the cerebrospinal fluid followed by hypercapnia (increased arterial CO2) and induce hyperventilation. Recently, several advances have been made in understanding central chemosensitivity at the molecular and cellular levels. Recent studies have identified several transcription factors such as c-Jun, c-Fos, FosB and small Maf proteins that may play critical roles in the brain adaptation to hypercapnia. Hypercapnic stimulation also activates c-Jun NH2-terminal kinase (JNK) cascade via influx of extracellular Ca2+ through voltage-gated Ca2+ channels. In addition, several transmembrane proteins including Rhombex-29 (rhombencephalic expression protein-29 kDa) and Past-A (proton-associated sugar transporter-A) have been implicated in regulation of H+ sensitivity and brain acidosismediated energy metabolism, respectively. These novel discoveries may provide new insights into the design for new drugs and understanding of neurological disorders. This review focuses on the properties of genes stimulated by acidosis in response to hypercapnia and discusses current knowledge on the molecular basis of neuronal regulation during acidosis. Keywords: extracellular acidosis, ventral medullary surface of the medulla oblongata, acidosis-induced genes, nuclear transcription factors, terminal kinase, voltage-gated ca channels, glucose homeostasis

Cellular mechanisms involved in CO2 and acid signaling in chemosensitive neurons

An increase in CO(2)/H(+) is a major stimulus for increased ventilation and is sensed by specialized brain stem neurons called central chemosensitive neurons. These neurons appear to be spread among numerous brain stem regions, and neurons from different regions have different levels of chemosensitivity. Early studies implicated changes of pH as playing a role in chemosensitive signaling, most likely by inhibiting a K(+) channel, depolarizing chemosensitive neurons, and thereby increasing their firing rate. Considerable progress has been made over the past decade in understanding the cellular mechanisms of chemosensitive signaling using reduced preparations. Recent evidence has pointed to an important role of changes of intracellular pH in the response of central chemosensitive neurons to increased CO(2)/H(+) levels. The signaling mechanisms for chemosensitivity may also involve changes of extracellular pH, intracellular Ca(2+), gap junctions, oxidative stress, glial cells, bicarbonate, CO(2), and neurotransmitters. The normal target for these signals is generally believed to be a K(+) channel, although it is likely that many K(+) channels as well as Ca(2+) channels are involved as targets of chemosensitive signals. The results of studies of cellular signaling in central chemosensitive neurons are compared with results in other CO(2)- and/or H(+)-sensitive cells, including peripheral chemoreceptors (carotid body glomus cells), invertebrate central chemoreceptors, avian intrapulmonary chemoreceptors, acid-sensitive taste receptor cells on the tongue, and pain-sensitive nociceptors. A multiple factors model is proposed for central chemosensitive neurons in which multiple signals that affect multiple ion channel targets result in the final neuronal response to changes in CO(2)/H(+).

Past-A, a Novel Proton-Associated Sugar Transporter, Regulates Glucose Homeostasis in the Brain

The ventral medullary surface (VMS) of the medulla oblongata is known to be the site of the central chemosensitive neurons in mammals. These neurons sense excess H+/CO2 dissolved in the CSF and induce hyperventilation. To elucidate the mechanism of neuronal cell adaptation to changes of H+/CO2, we screened for hypercapnia-induced genes in the VMS. Here, we report cloning and characterization of a novel gene called proton-associated sugar transporter-A (Past-A), which is induced in the brain after hypercapnia and mediates glucose uptake along the pH gradient. Past-A comprises 751 amino acid residues containing 12 membrane-spanning helices, several conserved sugar transport motifs, three proline-rich regions, and leucine repeats. Past-A transcript was expressed predominantly in the brain. Moreover, the Past-A-immunoreactive neural cells were found in the VMS of the medulla oblongata, and the number of immunoreactive cells was increased by hypercapnic stimulation. Transient transfection of Past-A in COS-7 cells leads to the expression of a membrane-associated 82 kDa protein that possesses a glucose transport activity. The acidification of extracellular medium facilitated glucose uptake, whereas the addition of carbonyl cyanide m-chlorophenylhydrazone, a protonophore, inhibited glucose import. Together, our results indicate that Past-A is a brain-specific glucose transporter that may represent an adaptation mechanism regulating sugar homeostasis in neuronal cells after hypercapnia.

Intracellular pH regulation of neurons in chemosensitive and nonchemosensitive areas of brain slices

The role of changes of intracellular pH (pH i) as the proximal signal in central chemosensitive neurons has been studied. pH i recovery from acidification is mediated by Na +/H + exchange in all medullary neurons and pH i recovery from alkalinization is mediated by Cl −/HCO 3 − exchange in most medullary neurons. These exchangers are more sensitive to inhibition by changes in extracellular pH (pH o) in neurons from chemosensitive regions compared to those from nonchemosensitive regions. Thus, neurons from chemosensitive regions exhibit a maintained intracellular acidification in response to hypercapnic acidosis but they show pH i recovery in response to isohydric hypercapnia. A similar pattern of pH i response is seen in other CO 2/H +-responsive cells, including glomus cells, sour taste receptor cells, and chemosensitive neurons from snails, suggesting that a maintained fall of pH i is a common feature of the proximal signal in all CO 2/H +-sensitive cells. To further evaluate the potential role of pH i changes as proximal signals for chemosensitive neurons, studies must be done to: determine why a lack of pH i recovery from hypercapnic acidosis is seen in some nonchemosensitive neurons; establish a correlation between hypercapnia-induced changes of pH i and membrane potential (V m); compare the hypercapnia-induced pH i changes seen in neuronal cell bodies with those in dendritic processes; understand why the V m response to hypercapnia of many chemosensitive neurons is washed out when using whole cell patch pipettes; and employ knock out mice to investigate the role of certain proteins in the CO 2/H + response of chemosensitive neurons.

Ventrolateral neurons of medullary organotypic cultures: intracellular pH regulation and bioelectric activity

The hypothesized role of the intracellular pH (pH i) as a proximate stimulus for central chemosensitive neurons is reviewed on the basis of data obtained from organotypic cultures of the medulla oblongata (obex level) of new born rats (OMC). Within OMC a subset of neurons responds to hypercapnia as do neurons in the same (or similar) brain areas in vivo. Maneuvers altering intra- and/or extracellular pH (pH o) such as hypercapnia, bicarbonate-withdrawal, or ammonium pre-pulses, evoked well defined changes of the neuronal pH i. During hypercapnia (pH o 7.0) or bicarbonate-withdrawal (pH o 7.4) most ventrolateral neurons adopted a pH i which was ≤0.2 pH units below the steady state pH i, while signs of pH i-regulation occurred only in a small fraction of neurons. During all treatments leading to intracellular acidosis, bioelectric activity of chemosensitive neurons increased and was often indistinguishable from the response to hypercapnia, regardless of whether pH o was unchanged, decreased or increased during the treatment. These data strongly suggest that the pH i acts as proximate stimulus. The mode of acid extrusion of chemosensitive neurons is, therefore, of major importance for the control of central chemosensitivity. Immunocytochemical data, pH i measurements and neuropharmacological studies with novel drugs pointed to the Na +/H + exchanger subtype 3 (NHE3) as a main acid extruder in ventrolateral chemosensitive neurons. Possible functions and neuropharmacological strategies arising from this very local NHE3 expression are discussed.

Developmental changes of the response of in vivo ventilation to acute and chronic hypercapnia in rats

As part of our studies of the role of changes of intracellular pH (pHi) in central chemosensitive neurons, we began studying the in vivo ventilatory response to increased inspired CO2. Our hope was to identify distinct sub-populations of rats with widely different CO2 sensitivity of in vivo ventilation so that we could study the cellular responses to hypercapnia (pHi changes and increased chemosensitive neuron firing rate) and look for a correlation with the in vivo ventilatory patterns. Ventilation in neonatal Sprague-Dawley rats (P1-P21) was studied using a dual chamber Respiromax Plethysmograph. Weight specific minute ventilation (VE) was measured as a function of inspired CO2 over the range of 0-5%. VE increased linearly with increasing CO2 due entirely to increased tidal volume (no change in respiratory frequency) [1]. The VE response to increased CO2 varied among individuals and from day to day in a given individual. The CO2 sensitivity of ventilation (determined as the slope of the VE vs.inspired % CO2 curve) showed a biphasic relationship with age. CO2 sensitivity was high in newborn rats (P1) and decreased to a minimum value at P7-P8. It increased again to reach a level at P14 that was very similar to the CO2 sensitivity in adults [1]. The basis for this developmental pattern is unknown but it is not due to changes in the CO2 responsiveness of chemosensitive neurons from the locus coeruleus, since these neurons show a constant increased firing rate of about 44% in response to hypercapnia (10% CO2). In an attempt to vary CO2 sensitivity, we reared neonatal rats in a chronic hypercapnic (CH) environment [2] and studied the effect of this treatment on VE and on CO2 sensitivity of VE. We reared time pregnant mothers in an environment of constant CH (7% CO2) for 1week prior to the birth of the pups and maintained the mother and pups in the CH environment until the neonates were tested (at least 6additional days). These neonates exhibited retarded growth (smaller by 1-2g) for the first 2weeks of life but attained the same weight as control rats (reared in room air) by P16. These CH rats exhibited higher CO2 sensitivity than control rats at days P6-P9 and then showed lower values that were indistinguishable from control rats from P10->P19. Other litters were exposed to severe CH (10%) using the same protocol as for the 7% CH rats. Litters were culled in these severe CH rats (1/3 of the litter sacrificed at birth), but even so these rats showed marked growth retardation that got worse with increasing age. These rats exhibited an even higher CO2 sensitivity than control or 7% CH rats at P6-P9 and then showed values that were similar to control rats at P10->P19. VE increased with increasing exposure to CH from (mean ± SE; n = 14) 892 ± 100 (control) to 960 ± 109 (7% CH) to 1127 ± 108 (10% CH)ml-min-1-kg-1. We suggest that CH results in a slowing of development so that CO2 sensitivity of VE remains elevated longer after birth. The biphasic developmental pattern suggests that after birth rats display a neonatal pattern of chemosensitivity that decreases during the first week of life and is replaced after the second week by a more adult form of chemosensitivity. A critical period of low in seen between these two periods. The CO2 sensitivity of VE mechanistic basis for this biphasic pattern is unknown as is the effect of CH on the properties of central chemosensitive neurons and both of these questions should be fruitful areas of future work.

Rhombex-29, a novel gene of the PLP/DM20-M6 family cloned from rat medulla oblongata by differential display.

The ventral medullary surface (VMS) is known as the site of the central chemosensitive neurons. These neurons sense excess CO(2)/H(+) dissolved in the cerebrospinal fluid that superfuses the VMS and induce hyperventilation. We hypothesized that genes specific for hyperventilation are expressed much more highly in VMS neurons than in extra-VMS neurons in other parts of the central nervous system (CNS). Applying the differential display technique to the brain of adult rats, we differentiated the mRNAs of the VMS neurons from those of cerebral cortex neurons. Seventeen candidate clones were selected, and their sequences were analyzed. Among these 17 clones, one encodes a novel four-transmembrane protein, which we named rat Rhombex-29. Structural analysis and the phylogenic tree showed that rat Rhombex-29 is homologous to the major CNS myelin protein PLP/DM20-M6 family and belongs to the intermediate type between mouse M6b and shark DMgamma. As the embryos grew into adult rats, constant expression of rat Rhombex-29 mRNA was found in the brain. Hypercapnic stimulation increased expression of rat Rhombex-29 mRNA in the VMS neurons but not in the cerebral cortex neurons. These results indicate that the VMS neurons are endowed with a novel gene, rat Rhombex-29, that is sensitive to H(+).

Respiratory sensitivity of rat brain-stem surface to chemical stimuli.

ArticleRespiratory sensitivity of rat brain-stem surface to chemical stimuli.T Hori, G I Roth, and W S YamamotoT Hori, G I Roth, and W S YamamotoPublished Online:01 Jun 1970https://doi.org/10.1152/jappl.1970.28.6.721MoreSectionsPDF (1 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Back to Top Next Download PDF FiguresReferencesRelatedInformationCited ByCellular Localization of Acid-Sensing Ion Channel 1 in Rat Nucleus Tractus Solitarii20 August 2017 | Cellular and Molecular Neurobiology, Vol. 38, No. 1Regulation of Breathing and Autonomic Outflows by Chemoreceptors30 September 2014The caudal solitary complex is a site of central CO2 chemoreception and integration of multiple systems that regulate expired CO2Respiratory Physiology & Neurobiology, Vol. 173, No. 3Molecular responses to acidosis of central chemosensitive neurons in brainCellular Signalling, Vol. 17, No. 7Glutamatergic neuronal projections from the marginal layer of the rostral ventral medulla to the respiratory centers in rats1 January 2004 | The Journal of Comparative Neurology, Vol. 473, No. 1In vitro study of H+-sensitive neurons in the ventral medullary surface of neonate ratsBrain Research, Vol. 777, No. 1-2PHYSIOLOGICAL ROLE OF BRAIN ENDOTHELIN IN THE CENTRAL AUTONOMIC CONTROL: FROM NEURON TO KNOCKOUT MOUSEProgress in Neurobiology, Vol. 51, No. 5Changes in medullary extracellular pH, sympathetic and phrenic nerve activity during brainstem perfusion with CO2 enriched solutionsJournal of the Autonomic Nervous System, Vol. 51, No. 1Retrotrapezoid nucleus lesions decrease phrenic activity and CO2 sensitivity in ratsRespiration Physiology, Vol. 97, No. 1Endothelin-sensitive areas in the ventral surface of the rat medullaJournal of the Autonomic Nervous System, Vol. 36, No. 2Acetylcholine and central chemosensitivity: in vitro study in the newborn ratRespiration Physiology, Vol. 81, No. 2Kainic acid on the rat ventral medullary surface depresses hypoxic and hypercapnic ventilatory responsesRespiration Physiology, Vol. 80, No. 1Respiratory and vasomotor responses to focal cooling of the ventral medullary surface (VMS) of the ratRespiration Physiology, Vol. 74, No. 1Hypoventilation and apnoea induced by the substance P antagonist [D-Pro 2 ,D-Trp 7,9 ]-SP in the ventrolateral rat medullaActa Physiologica Scandinavica, Vol. 134, No. 1The distribution of substance P-, enkephalin-and dynorphin-immunoreactive neurons in the medulla of the rat and their contribution to bulbospinal pathwaysNeuroscience, Vol. 23, No. 12-Deoxyglucose uptake in the central nervous system during systemic hypercapnia in the peripherally chemodenervated ratExperimental Neurology, Vol. 88, No. 3Central chemosensitivity to H+ and CO2 in the rat respiratory center in vitroBrain Research, Vol. 333, No. 2Pressor effect of CO2 in the rat: different thresholds of the central cardiovascular and respiratory responses to CO2Journal of the Autonomic Nervous System, Vol. 10, No. 1The physiology and pharmacology of emesisMolecular Aspects of Medicine, Vol. 7, No. 5ReferencesCentral ChemoreceptorsEFFECTS OF URETHANE-CHLORALOSE ANAESTHESIA ON RESPIRATION IN THE RATClinical and Experimental Pharmacology and Physiology, Vol. 9, No. 2Central chemosensitivity: A respiratory drive21 June 2005H+-Sensitivity and pattern of discharge of neurons in the chemosensitive areas of the ventral medulla oblongata of rats in vitroPfl�gers Archiv European Journal of Physiology, Vol. 388, No. 1Chemical Alterations of Cerebrospinal Fluid Acting on Respiratory and Circulatory Control SystemsEffect of H+ on the membrane potential of silent cells in the ventral and dorsal surface layers of the rat medulla in vitroPfl�gers Archiv European Journal of Physiology, Vol. 376, No. 3Effect of H+ on spontaneous neuronal activity in the surface layer of the rat medulla oblongata in vitroPfl�gers Archiv European Journal of Physiology, Vol. 371, No. 1-2Carbon dioxide sensitivity of the central chemosensitive mechanismsPfl�gers Archiv European Journal of Physiology, Vol. 367, No. 3pH sensitivity of cells located at the ventrolateral surface of the cat medulla oblongata in vitroPfl�gers Archiv European Journal of Physiology, Vol. 364, No. 3pH-sensitive cells at ventro–lateral surface of rat medulla oblongataNature, Vol. 256, No. 5515Separation of central effects of CO2 and nicotine on ventilation and blood pressureRespiration Physiology, Vol. 15, No. 3Die Antwort der Atmung auf isolierte �nderung des Liquor-pH: Untersuchungen an anaesthesierten und dezerebrierten Katzen vor und w�hrend VagusblockadePfl�gers Archiv European Journal of Physiology, Vol. 325, No. 4 More from this issue > Volume 28Issue 6June 1970Pages 721-4 https://doi.org/10.1152/jappl.1970.28.6.721PubMed5427278History Published online 1 June 1970 Published in print 1 June 1970 Metrics