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Tino Krell - One of the best experts on this subject based on the ideXlab platform.

  • Chemoreceptors with C-terminal pentapeptides for CheR and CheB binding are abundant in bacteria that maintain host interactions
    Computational and structural biotechnology journal, 2020
    Co-Authors: Alvaro Ortega, Tino Krell
    Abstract:

    Abstract Chemosensory pathways represent a major prokaryotic signal transduction mechanism that is based on signal sensing by Chemoreceptors. An essential feature of chemosensory pathways is the CheR and CheB mediated control of Chemoreceptor methylation causing pathway adaptation. At their C-terminal extension the Tar and Tsr model Chemoreceptors contain a pentapeptide that acts as an additional CheR and CheB binding site. The relevance of this pentapeptide is poorly understood since pentapeptide removal from Tar/Tsr causes receptor inactivation, whereas many other Chemoreceptors do not require this pentapeptide for correct function. We report here a bioinformatic analysis of pentapeptide containing Chemoreceptors. These receptors were detected in 11 bacterial phyla and represent approximately 10 % of all Chemoreceptors. Pentapeptide containing Chemoreceptors are mainly found in Gram-negative bacteria, are of low abundance in Gram-positive species and almost absent from archaea. Almost 50 % of TarH ( Tar h omologue) ligand binding domain containing Chemoreceptors possess pentapeptides, whereas Chemoreceptor families with other ligand binding domains are devoid of pentapeptides. The abundance of Chemoreceptors with C-terminal pentapeptides correlated negatively with the number of Chemoreceptor genes per genome. The consensus sequence reveals a negative net charge for many pentapeptides. Pentapeptide containing Chemoreceptors are very abundant in the order Enterobacterales, particularly in the families Pectobacterium and Dickeya, where they represent about 50 % of the total number. In contrast, bacteria with primarily free living lifestyles have a reduced number of pentapeptides such as approximately 1 % for Pseudomonadales. It is proposed that pentapeptide function is related to mechanisms that permit host interaction.

  • structural basis for polyamine binding at the dcache domain of the mcpu Chemoreceptor from pseudomonas putida
    Journal of Molecular Biology, 2018
    Co-Authors: Jose A Gavira, Alvaro Ortega, Miguel A. Matilla, David Martinmora, Bertrand Morel, Maria Teresa Conejeromuriel, Andres Corrallugo, Tino Krell
    Abstract:

    Abstract Many bacteria can move chemotactically to a variety of compounds and the recognition of chemoeffectors by the Chemoreceptor ligand binding domain (LBD) defines the specificity of response. Many Chemoreceptors were found to recognize different amino and organic acids, but the McpU Chemoreceptor from Pseudomonas putida was identified as the first Chemoreceptor that bound specifically polyamines. We report here the three-dimensional structure of McpU-LBD in complex with putrescine at a resolution of 2.4 A, which fitted well a solution structure generated by small-angle X-ray scattering. Putrescine bound to a negatively charged pocket in the membrane distal module of McpU-LBD. Similarities exist in the binding of putrescine to McpU-LBD and taurine to the LBD of the Mlp37 Chemoreceptor of Vibrio cholerae. In both structures, the primary amino group of the respective ligand is recognized by hydrogen bonds established by two aspartate and a tyrosine side chain. This feature may be used to predict the ligands of Chemoreceptors with unknown function. Analytical ultracentrifugation revealed that McpU-LBD is monomeric in solution and that ligand binding does not alter this oligomeric state. This sensing mode thus differs from that of the well-characterised four-helix bundle domains where ligands bind to two sites at the LBD dimer interface. Although there appear to be different sensing modes, results are discussed in the context of data, indicating that Chemoreceptors employ the same mechanism of transmembrane signaling. This work enhances our understanding of CACHE domains, which are the most abundant sensor domains in bacterial Chemoreceptors and sensor kinases.

  • High-Throughput Screening to Identify Chemoreceptor Ligands
    Methods of Molecular Biology, 2018
    Co-Authors: Matilde Fernández, Alvaro Ortega, Miriam Rico-jiménez, David Martín-mora, Abdelali Daddaoua, Miguel A. Matilla, Tino Krell
    Abstract:

    : The majority of bacterial Chemoreceptors remain functionally un-annotated. The knowledge of Chemoreceptor function, however, is indispensable to understanding the evolution of the chemotaxis system in bacteria with different lifestyles. Significant progress in the annotation of Chemoreceptor function has been made using experimental strategies that are based on the individual, genetically engineered ligand binding domain (LBD) of Chemoreceptors. There is now evidence that all major classes of LBDs can be produced as individual domains that retain their ligand binding activity. Here, we provide a protocol for the combined use of high-throughput ligand screening using Differential Scanning Fluorimetry followed by Isothermal Titration Calorimetry to identify and characterize ligands that bind to recombinant Chemoreceptor LBDs. This approach has been shown to be very efficient for determining the function of novel Chemoreceptors.

  • Assigning Chemoreceptors to chemosensory pathways in Pseudomonas aeruginosa.
    Proceedings of the National Academy of Sciences of the United States of America, 2017
    Co-Authors: Davi R. Ortega, Tino Krell, Aaron D. Fleetwood, Caroline S. Harwood, Grant J. Jensen, Igor B. Zhulin
    Abstract:

    In contrast to Escherichia coli, a model organism for chemotaxis that has 5 Chemoreceptors and a single chemosensory pathway, Pseudomonas aeruginosa PAO1 has a much more complex chemosensory network, which consists of 26 Chemoreceptors feeding into four chemosensory pathways. While several Chemoreceptors were rigorously linked to specific pathways in a series of experimental studies, for most of them this information is not available. Thus, we addressed the problem computationally. Protein–protein interaction network prediction, coexpression data mining, and phylogenetic profiling all produced incomplete and uncertain assignments of Chemoreceptors to pathways. However, comparative sequence analysis specifically targeting Chemoreceptor regions involved in pathway interactions revealed conserved sequence patterns that enabled us to unambiguously link all 26 Chemoreceptors to four pathways. Placing computational evidence in the context of experimental data allowed us to conclude that three chemosensory pathways in P. aeruginosa utilize one Chemoreceptor per pathway, whereas the fourth pathway, which is the main system controlling chemotaxis, utilizes the other 23 Chemoreceptors. Our results show that while only a very few amino acid positions in receptors, kinases, and adaptors determine their pathway specificity, assigning receptors to pathways computationally is possible. This requires substantial knowledge about interacting partners on a molecular level and focusing comparative sequence analysis on the pathway-specific regions. This general principle should be applicable to resolving many other receptor–pathway interactions.

  • Sensory Repertoire of Bacterial Chemoreceptors.
    Microbiology and Molecular Biology Reviews, 2017
    Co-Authors: Alvaro Ortega, Igor B. Zhulin, Tino Krell
    Abstract:

    SUMMARY Chemoreceptors in bacteria detect a variety of signals and feed this information into chemosensory pathways that represent a major mode of signal transduction. The five Chemoreceptors from Escherichia coli have served as traditional models in the study of this protein family. Genome analyses revealed that many bacteria contain much larger numbers of Chemoreceptors with broader sensory capabilities. Chemoreceptors differ in topology, sensing mode, cellular location, and, above all, the type of ligand binding domain (LBD). Here, we highlight LBD diversity using well-established and emerging model organisms as well as genomic surveys. Nearly a hundred different types of protein domains that are found in Chemoreceptor sequences are known or predicted LBDs, but only a few of them are ubiquitous. LBDs of the same class recognize different ligands, and conversely, the same ligand can be recognized by structurally different LBDs; however, recent studies began to reveal common characteristics in signal-LBD relationships. Although signals can stimulate Chemoreceptors in a variety of different ways, diverse LBDs appear to employ a universal transmembrane signaling mechanism. Current and future studies aim to establish relationships between LBD types, the nature of signals that they recognize, and the mechanisms of signal recognition and transduction.

Richard J A Wilson - One of the best experts on this subject based on the ideXlab platform.

  • the essential role of peripheral respiratory Chemoreceptor inputs in maintaining breathing revealed when co2 stimulation of central Chemoreceptors is diminished
    The Journal of Physiology, 2013
    Co-Authors: Edward T Oconnor, Ines Zuna, Marie-noëlle Fiamma, Richard J A Wilson
    Abstract:

    Key points • Central sleep apnoea is a condition characterized by oscillations between apnoea and hyperpnoea during sleep, which can have many serous health implications. • Each ventilatory overshoot following an apnoea attenuates peripheral Chemoreceptor input which, in turn, has the potential to cause a further apnoea. • In a decerebrate, vagotomized, in situ rat preparation, we show that central apnoeas can be overcome both physiologically (with high peripheral CO2) and pharmacologically (with peripheral pituitary adenylate cyclase-activating peptide). • We also show that the central apnoeic threshold, i.e. the CO2 level at which the animal stops breathing, can be lowered by increasing peripheral Chemoreceptor stimulation. • These data suggest that stimulation of peripheral Chemoreceptors may prevent central apnoeas, re-affirming the peripheral Chemoreceptors as possible therapeutic targets for some sleep apnea phenotypes. Abstract  Central sleep apnoea is a condition characterized by oscillations between apnoea and hyperpnoea during sleep. Studies in sleeping dogs suggest that withdrawal of peripheral Chemoreceptor (carotid body) activation following transient ventilatory overshoots plays an essential role in causing apnoea, raising the possibility that sustaining carotid body activity during ventilatory overshoots may prevent apnoea. To test whether sustained peripheral Chemoreceptor activation is sufficient to drive breathing, even in the absence of central Chemoreceptor stimulation and vagal feedback, we used a vagotomized, decerebrate dual-perfused in situ rat preparation in which the central and peripheral Chemoreceptors are independently and artificially perfused with gas-equilibrated medium. At varying levels of carotid body stimulation (CB PO2/PCO2: 40/60, 100/40, 200/15, 500/15 Torr), we decreased the brainstem perfusate PCO2 in 5 Torr steps while recording phrenic nerve activity to determine the central apnoeic thresholds. The central apnoeic thresholds decreased with increased carotid body stimulation. When the carotid bodies were strongly stimulated (CB 40/60), the apnoeic threshold was 3.6 ± 1.4 Torr PCO2 (mean ± SEM, n = 7). Stimulating carotid body afferent activity with either hypercapnia (60 Torr PCO2) or the neuropeptide pituitary adenylate cyclase-activating peptide restored phrenic activity during central apnoea. We conclude that peripheral stimulation shifts the central apnoeic threshold to very hypocapnic levels that would likely increase the CO2 reserve and have a protective effect on breathing. These data demonstrate that peripheral respiratory Chemoreceptors are sufficient to stave off central apnoeas when the brainstem is perfused with low to no CO2.

  • a negative interaction between central and peripheral respiratory Chemoreceptors may underlie sleep induced respiratory instability a novel hypothesis
    Advances in Experimental Medicine and Biology, 2008
    Co-Authors: Richard J A Wilson
    Abstract:

    Central (brainstem) and peripheral (carotid body) respiratory chemoreflexes act in concert to modulate breathing during sleep, maintaining blood gases (PCO 2 and PO 2 ) within narrow limits. Increases in both central and peripheral chemoreflex gain have been reported in clinical populations that experience central sleep apnoea and likely underlie the pathophysiology of this disorder. However, how central-peripheral Chemoreceptor interaction affects the apparent gain of each chemoreflex is controversial. Data from our laboratory demonstrate that there is a negative interaction between central and peripheral Chemoreceptors in the rat, such that brainstem hypocapnia augments peripheral chemoreflex gain in response to both carotid body PCO 2 and PO 2 . We note that a negative interaction may also occur in humans, especially relevant in those experiencing chronic hypocapnia. Interestingly, chronic hypocapnia occurs in populations prone to central sleep apnea, such as congestive heart failure (CHF) patients and individuals sleeping at high altitude. These observations lead us to propose the novel hypothesis that a negative interaction between Chemoreceptors results in an augmented peripheral Chemoreceptor gain when the central Chemoreceptors are hypocapnic, thereby contributing directly to breathing instability during sleep.

Paul M Pilowsky - One of the best experts on this subject based on the ideXlab platform.

  • ampa kainate receptors mediate sympathetic Chemoreceptor reflex in the rostral ventrolateral medulla
    Brain Research, 1996
    Co-Authors: Takashi Miyawaki, Jane B Minson, Leonard F Arnolda, Ida J Llewellynsmith, John Chalmers, Paul M Pilowsky
    Abstract:

    Abstract Previous studies have reported that information from carotid Chemoreceptors activates sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM) exclusively viaN-methyl- d -aspartic acid (NMDA) receptors. In this study, we examined the possible involvement of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors in the RVLM on sympathetic Chemoreceptor reflex in pentobarbitone anaesthetised, vagotomised and artificially ventilated rats. Carotid Chemoreceptor stimulation with brief N2 inhalation increased splanchnic sympathetic nerve activity and arterial pressure in animals that had received an intravenous injection of the non-competitive NMDA receptor blocker, MK-801 (2 mg/kg). RVLM sympathetic premotor neurons could also be activated by brief hypoxia in the presence of MK-801. However, microinjection of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, a selective AMPA/kainate receptor antagonist, 2 mM, 100 nl) into the RVLM after intravenous MK-801 abolished the hypoxia evoked sympathoexcitatory response. These results demonstrate that AMPA/kainate receptors in the RVLM are involved in the Chemoreceptor reflex pathway.

  • AMPA/kainate receptors mediate sympathetic Chemoreceptor reflex in the rostral ventrolateral medulla
    Brain Research, 1996
    Co-Authors: Takashi Miyawaki, Jane B Minson, Leonard F Arnolda, Ida J Llewellyn-smith, John Chalmers, Paul M Pilowsky
    Abstract:

    Abstract Previous studies have reported that information from carotid Chemoreceptors activates sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM) exclusively viaN-methyl- d -aspartic acid (NMDA) receptors. In this study, we examined the possible involvement of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors in the RVLM on sympathetic Chemoreceptor reflex in pentobarbitone anaesthetised, vagotomised and artificially ventilated rats. Carotid Chemoreceptor stimulation with brief N2 inhalation increased splanchnic sympathetic nerve activity and arterial pressure in animals that had received an intravenous injection of the non-competitive NMDA receptor blocker, MK-801 (2 mg/kg). RVLM sympathetic premotor neurons could also be activated by brief hypoxia in the presence of MK-801. However, microinjection of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, a selective AMPA/kainate receptor antagonist, 2 mM, 100 nl) into the RVLM after intravenous MK-801 abolished the hypoxia evoked sympathoexcitatory response. These results demonstrate that AMPA/kainate receptors in the RVLM are involved in the Chemoreceptor reflex pathway.

Marie-noëlle Fiamma - One of the best experts on this subject based on the ideXlab platform.

  • the essential role of peripheral respiratory Chemoreceptor inputs in maintaining breathing revealed when co2 stimulation of central Chemoreceptors is diminished
    The Journal of Physiology, 2013
    Co-Authors: Edward T Oconnor, Ines Zuna, Marie-noëlle Fiamma, Richard J A Wilson
    Abstract:

    Key points • Central sleep apnoea is a condition characterized by oscillations between apnoea and hyperpnoea during sleep, which can have many serous health implications. • Each ventilatory overshoot following an apnoea attenuates peripheral Chemoreceptor input which, in turn, has the potential to cause a further apnoea. • In a decerebrate, vagotomized, in situ rat preparation, we show that central apnoeas can be overcome both physiologically (with high peripheral CO2) and pharmacologically (with peripheral pituitary adenylate cyclase-activating peptide). • We also show that the central apnoeic threshold, i.e. the CO2 level at which the animal stops breathing, can be lowered by increasing peripheral Chemoreceptor stimulation. • These data suggest that stimulation of peripheral Chemoreceptors may prevent central apnoeas, re-affirming the peripheral Chemoreceptors as possible therapeutic targets for some sleep apnea phenotypes. Abstract  Central sleep apnoea is a condition characterized by oscillations between apnoea and hyperpnoea during sleep. Studies in sleeping dogs suggest that withdrawal of peripheral Chemoreceptor (carotid body) activation following transient ventilatory overshoots plays an essential role in causing apnoea, raising the possibility that sustaining carotid body activity during ventilatory overshoots may prevent apnoea. To test whether sustained peripheral Chemoreceptor activation is sufficient to drive breathing, even in the absence of central Chemoreceptor stimulation and vagal feedback, we used a vagotomized, decerebrate dual-perfused in situ rat preparation in which the central and peripheral Chemoreceptors are independently and artificially perfused with gas-equilibrated medium. At varying levels of carotid body stimulation (CB PO2/PCO2: 40/60, 100/40, 200/15, 500/15 Torr), we decreased the brainstem perfusate PCO2 in 5 Torr steps while recording phrenic nerve activity to determine the central apnoeic thresholds. The central apnoeic thresholds decreased with increased carotid body stimulation. When the carotid bodies were strongly stimulated (CB 40/60), the apnoeic threshold was 3.6 ± 1.4 Torr PCO2 (mean ± SEM, n = 7). Stimulating carotid body afferent activity with either hypercapnia (60 Torr PCO2) or the neuropeptide pituitary adenylate cyclase-activating peptide restored phrenic activity during central apnoea. We conclude that peripheral stimulation shifts the central apnoeic threshold to very hypocapnic levels that would likely increase the CO2 reserve and have a protective effect on breathing. These data demonstrate that peripheral respiratory Chemoreceptors are sufficient to stave off central apnoeas when the brainstem is perfused with low to no CO2.

Jerome A Dempsey - One of the best experts on this subject based on the ideXlab platform.

  • peripheral Chemoreceptors determine the respiratory sensitivity of central Chemoreceptors to co2 role of carotid body co2
    The Journal of Physiology, 2015
    Co-Authors: Curtis A Smith, Gregory M Blain, K S Henderson, Jerome A Dempsey
    Abstract:

    We asked if the type of carotid body (CB) Chemoreceptor stimulus influenced the ventilatory gain of the central Chemoreceptors to CO2. The effect of CB normoxic hypocapnia, normocapnia and hypercapnia (carotid body  ≈ 22, 41 and 68 mmHg, respectively) on the ventilatory CO2 sensitivity of central Chemoreceptors was studied in seven awake dogs with vascularly-isolated and extracorporeally-perfused CBs. Chemosensitivity with one CB was similar to that in intact dogs. In four CB-denervated dogs, absence of hyper-/hypoventilatory responses to CB perfusion with of 19–75 mmHg confirmed separation of the perfused CB circulation from the brain. The group mean central CO2 response slopes were increased 303% for minute ventilation ()(P ≤ 0.01) and 251% for mean inspiratory flow rate (VT/TI) (P ≤ 0.05) when the CB was hypercapnic vs. hypocapnic; central CO2 response slopes for tidal volume (VT), breathing frequency (fb) and rate of rise of the diaphragm EMG increased in 6 of 7 animals but the group mean changes did not reach statistical significance. Group mean central CO2 response slopes were also increased 237% for (P ≤ 0.01) and 249% for VT/TI(P ≤ 0.05) when the CB was normocapnic vs. hypocapnic, but no significant differences in any of the central ventilatory response indices were found between CB normocapnia and hypercapnia. These hyperadditive effects of CB hyper-/hypocapnia agree with previous findings using CB hyper-/hypoxia.We propose that hyperaddition is the dominant form of Chemoreceptor interaction in quiet wakefulness when the chemosensory control system is intact, response gains physiological, and carotid body Chemoreceptors are driven by a wide range of O2 and/or CO2. Key points The influence of specific carotid body (CB) normoxic hypocapnia, hypercapnia and normocapnia on the ventilatory sensitivity of central Chemoreceptors to systemic hypercapnia was assessed in seven awake dogs with extracorporeal perfusion of the vascularly isolated CB. Chemosensitivity in this preparation was similar to that in the intact animal. Separation of CB circulation from that of the brain was confirmed. When the isolated CB was hypercapnic vs. hypocapnic and when the isolated CB was normocapnic vs. hypocapnic, the group mean central CO2 response slopes of minute ventilation () (P ≤ 0.01) and mean inspiratory flow rate (VT/TI) (P ≤ 0.05) increased significantly. Tidal volume (VT), breathing frequency (fb)and rate of rise of diaphragm EMG were increased in 6 of 7 dogs but did not achieve statistical significance. We propose that hyperaddition is the dominant form of Chemoreceptor interaction under conditions of quiet wakefulness in intact animals and over a wide range of CB and . Introduction Peripheral–central Chemoreceptor interactive effects on control of breathing have been observed using animal models with isolated perfusion of the carotid body and/or central Chemoreceptors in such varied conditions as eupnoea, apnoea, hypercapnia, and hypoxia (Day & Wilson, 2007,2009; Smith et al. 2007,2010; Blain et al. 2009,2010; Dempsey et al. 2012; Fiamma et al. 2013). However, the exact nature of these Chemoreceptor interactions are controversial with studies in a wide variety of experimental preparations and theoretical models claiming additive, hyperadditive, or hypoadditive effects on the control of breathing (Duffin, 1990; Duffin & Mateika, 2013; Teppema & Smith, 2013; Wilson & Day, 2013). Based on these divergent findings some investigators (Wilson & Day, 2013; Guyenet, 2014) have suggested a ‘hybrid’ model as a basis for peripheral–central interaction, whereby variations in both the experimental models and in the prevailing physiological conditions and/or Chemoreceptor stimuli may markedly alter the nature of the Chemoreceptor interactions (also see Discussion). Accordingly, in the present study we have tested the nature of the peripheral–central interaction under novel experimental conditions consisting of hypercapnic stimulation and hypocapnic inhibition at the level of the isolated CB Chemoreceptor. This represents an important advance in addressing the interaction problem for several reasons. First, comparing normoxic hypercapnia/hypocapnia to results from our prior use of hypoxia/hyperoxia at the carotid body (Blain et al. 2010) provides a test of the equivalence of the observed hyperadditive interactive effect in the presence of both major peripheral Chemoreceptor stimuli, i.e. CO2 and O2. Second, perturbations in per se have widespread physiological significance in the control of breathing and breathing stability during wakefulness and sleep, which appear to depend critically upon peripheral–central Chemoreceptor interactions (Smith et al. 2007; Dempsey et al. 2012; Fiamma et al. 2013). Third, we tested these interactive effects in a unique awake canine preparation which incorporates two essential characteristics for quantifying the nature of these interactions, namely (a) that the preparation’s chemoresponsiveness is within the physiological range and close to that in the intact animal, and (b) that central and peripheral Chemoreceptors are truly separated both anatomically and functionally. Fourth, although there is no direct evidence we are aware of that the carotid sinus nerve discharge pattern can encode information concerning the nature of the carotid body stimulus, there are some lines of evidence showing that carotid body hypercapnia might have quite different cardiorespiratory influences from carotid body hypoxaemia. For example, in the awake goat, carotid body hypoxia, even for very short periods beyond the acute phase, progressively increased the ventilatory response whereas specific carotid body hypercapnia did not (Bisgard et al. 1986). In anesthetized goats short periods of hypoxia sensitized output of the carotid body Chemoreceptor (Nielsen et al. 1988), whereas hypercapnia did not (Engwall et al. 1988). In anaesthetized rats, carotid body denervation prevented the response of CO2 sensitive neurons in the retrotrapezoid nucleus to very brief exposures of reduced , but had no effect on their response to inhaled CO2(Mulkey et al. 2004). In anaesthetized rats conditioned by exposure to chronic intermittent hypoxia for 10 days, acute intermittent hypoxia elicited long-term facilitation of carotid sinus nerve output whereas acute intermittent hyperoxic hypercapnia did not (Peng et al. 2003). Further, in awake humans, acute periods of arterial isocapnic hypoxaemia or asphyxia elicited marked lingering after-effects on muscle sympathetic nerve activity once the stimulus was removed whereas similar periods of arterial normoxic hypercapnia did not (Morgan et al. 1995; Xie et al. 2000,2001). We found that, in the awake dog, specific carotid body stimulation/inhibition by means of hyper- or hypocapnia resulted in hyperadditive interaction when the central Chemoreceptors were stimulated by means of increased . The similarity of these hyperadditive interactions to those caused primarily by means of changes in carotid body suggest that short-term changes in and at the carotid body have equivalent effects on peripheral–central interaction for a given change in baseline ventilation.

  • Role of central/peripheral Chemoreceptors and their interdependence in the pathophysiology of sleep apnea.
    Advances in Experimental Medicine and Biology, 2012
    Co-Authors: Jerome A Dempsey, Curtis A Smith, Gregory M Blain, Yuansheng Gong, Mihaela Teodorescu
    Abstract:

    Unstable periodic breathing with intermittent ventilatory overshoots and undershoots commonly occurs in chronic heart failure, in hypoxia, with chronic opioid use and in certain types of obstructive sleep apnea. Sleep promotes breathing instability because it unmasks a highly sensitive dependence of the respiratory control system on Chemoreceptor input, because transient cortical arousals promote ventilatory overshoots and also because upper airway dilator muscle tonicity is reduced and airway collapsibility enhanced. We will present data in support of the premise that carotid Chemoreceptors are essential in the pathogenesis of apnea and periodicity; however it is the hyperadditive influence of peripheral Chemoreceptor sensory input on central chemosensitivity that accounts for apnea and periodic breathing. This Chemoreceptor interdependence also provides a significant portion of the normal drive to breathe in normoxia (i.e. eupnea) and in acute hypoxia. Finally, we discuss the effects of preventing transient hypocapnia (via selective increases in FICO2) on centrally mediated types of periodic breathing and even some varieties of cyclical obstructive sleep apnea.

  • role of central peripheral Chemoreceptors and their interdependence in the pathophysiology of sleep apnea
    Advances in Experimental Medicine and Biology, 2012
    Co-Authors: Jerome A Dempsey, Curtis A Smith, Gregory M Blain, Yuansheng Gong, Mihaela Teodorescu
    Abstract:

    Unstable periodic breathing with intermittent ventilatory overshoots and undershoots commonly occurs in chronic heart failure, in hypoxia, with chronic opioid use and in certain types of obstructive sleep apnea. Sleep promotes breathing instability because it unmasks a highly sensitive dependence of the respiratory control system on Chemoreceptor input, because transient cortical arousals promote ventilatory overshoots and also because upper airway dilator muscle tonicity is reduced and airway collapsibility enhanced. We will present data in support of the premise that carotid Chemoreceptors are essential in the pathogenesis of apnea and periodicity; however it is the hyperadditive influence of peripheral Chemoreceptor sensory input on central chemosensitivity that accounts for apnea and periodic breathing. This Chemoreceptor interdependence also provides a significant portion of the normal drive to breathe in normoxia (i.e. eupnea) and in acute hypoxia. Finally, we discuss the effects of preventing transient hypocapnia (via selective increases in FICO2) on centrally mediated types of periodic breathing and even some varieties of cyclical obstructive sleep apnea.