Central Chemosensitivity Research Articles

Association between ventilatory response to hypercapnia and obstructive sleep apnea–hypopnea index in asymptomatic subjects

The majority of awake ventilatory control studies have shown normal or decreased ventilatory response to hypercapnia (HCVR) in obstructive sleep apnea-hypopnea syndrome (OSAHS) patients. These findings are contrary to experimental studies suggesting increased loop gain and greater breathing instability in OSAHS patients. We have investigated the relationship between central chemoreflex sensitivity tested by HCVR and obstructive sleep apnea/hypopnea index (OSAHI) in asymptomatic subjects. Twenty normal volunteers (10 men and 10 women) from the general population without physical complaints including sleep-related symptoms were included. The subjects were studied for awake ventilatory responses to hypoxia (HVR) and hypercapnia. Overnight polysomnography (PSG) was performed in two consecutive nights with the first night used as acclimatization. The subjects have an average body mass index (BMI) of 27 +/- 5 SD kg/m(2), ages of 35 +/- 9 SD years and Epworth sleepiness scale of 2.1 +/- 1.8 SD. A positive linear relationship was found between HCVR and logarithmically transformed OSAHI (r = 0.67, p = 0.001). BMI and age were not significantly correlated to HCVR or Log OSAHI. No relationship was found between HVR and Log OSAHI (r = 0.25, p = 0.29). Percentage oxygen saturation nadir during sleep was found to significantly correlate to both daytime HCVR (r = -0.60, p = 0.005) and Log OSAHI (r = -0.65, p = 0.002) and tended to correlate to HVR (r = -0.41, p = 0.07). Arousal index during sleep was not associated with either HCVR (p = 0.93) or HVR (p = 0.26). In conclusion, heightened central chemosensitivity was positively related to OSAHI in asymptomatic volunteers. We believe these findings are in keeping with the evolving theory of loop gain being a significant factor for respiratory control instability and obstructive apnea genesis. The mechanism can be applied to asymptomatic subjects with even minimal sleep-disordered breathing.

Brainstem respiratory control: Substrates of respiratory failure of multiple system atrophy

Multiple system atrophy may manifest with severe respiratory disorders, including sleep apnea and laryngeal stridor, which reflect a failure of automatic control of respiration. This function depends on a pontomedullary network of interconnected neurons located in the parabrachial/Kölliker Fuse nucleus in the pons, nucleus of the solitary tract, and ventrolateral medulla. Neurons in the preBötzinger complex expressing neurokinin-1 receptors are critically involved in respiratory rhythmogenesis, whereas serotonergic neurons in the medullary raphe and glutamatergic neurons located close to the ventral medullary surface are involved in central chemosensitivity to hypercapnia, hypoxia, or both. Pathological studies using selective neurochemical markers indicate that these neuronal groups are affected in multiple system atrophy. This finding may provide potential anatomical substrates for the respiratory manifestations of the disease.

Exercise Test Response Characteristics are Altered in Obstructive Sleep Apnea Patients

Obstructive Sleep Apnea (OSA) patients frequently report symptoms of physical fatigue and lack of energy, and this disorder induces cardiovascular autonomic imbalance and predisposes them to hypertension. Yet, little is known about the cardiovascular response to exercise in OSA and, perhaps, the extent that such features may be useful clinically in triaging at risk individuals for medical decisions, e.g. diagnostic assessment for OSA. PURPOSE: To assess whether exercise testing, by virtue of related alterations in cardiopulmonary regulation, might aid in discriminating between individuals with and without OSA. METHODS: Twenty-three normotensive adults with diagnosed OSA [BMI = 33.1 ± 5.5 kg/m2; age = 45.6 ± 10.7yr; Apnea Hypopnea Index (AHI) = 24.7 ± 13.5 events/ hr;] and 9 apparently healthy controls (BMI = 29.5 ± 5.5 kg/m2; age = 40.2 ± 8.1 yr; AHI = 4.9 ± 0.1) completed a maximal cardiopulmonary exercise tolerance test on a cycle ergometer, including measures of oxygen consumption (VO2pk), ventilation, (VE), heart rate (HR), and blood pressure (BP). RESULTS: Age, BMI, resting HR and BP were not different between overweight subjects with OSA vs. without OSA (P > 0.05). Peak systolic and diastolic BP were significantly higher in the OSA group (P = 0.04) and remained higher (P < 0.05) up to 3-min post-exercise (low load recovery). Exercise HR for the OSA group was lower during both submaximal (P = 0.03) and peak exercise (P = 0.03), compared to the overweight controls. Despite no differences in VO2pk (P > 0.05), peak VE was significantly higher for the OSA group (P = 0.04). This hyperventilatory response may result from augmented peripheral and central chemosensitivity to CO2 resulting from repeated episodes of intermittent hypoxia during sleep. CONCLUSION: Blunted HR and altered ventilatory response characteristics in standardized exercise tests and/or protracted BP recovery following exercise testing should be investigated further as potential markers to better identify patients who might benefit from diagnostic overnight polysomnography testing. Supported by a grant from Res Med Sleep Disordered Breathing Foundation, Poway, CA.

Locus coeruleus is a central chemoreceptive site in toads

The locus coeruleus (LC) has been suggested as a CO2 chemoreceptor site in mammals. This nucleus is a mesencephalic structure of the amphibian brain and is probably homologous to the LC in mammals. There are no data available for the role of LC in the central chemoreception of amphibians. Thus the present study was designed to investigate whether LC of toads (Bufo schneideri) is a CO2/H+ chemoreceptor site. Fos immunoreactivity was used to verify whether the nucleus is activated by hypercarbia (5% CO2 in air). In addition, we assessed the role of noradrenergic LC neurons on respiratory and cardiovascular responses to hypercarbia by using 6-hydroxydopamine lesion. To further explore the role of LC in central chemosensitivity, we examined the effects of microinjection of solutions with different pH values (7.2, 7.4, 7.6, 7.8, and 8.0) into the nucleus. Our main findings were that 1) a marked increase in c-fos-positive cells in the LC was induced after 3 h of breathing a hypercarbic gas mixture; 2) chemical lesions in the LC attenuated the increase of the ventilatory response to hypercarbia but did not affect ventilation under resting conditions; and 3) microinjection with acid solutions (pH = 7.2, 7.4, and 7.6) into the LC elicited an increased ventilation, indicating that the LC of toads participates in the central chemoreception.

Serotonergic and glutamatergic neurons at the ventral medullary surface of the human infant: Observations relevant to central chemosensitivity in early human life

Central chemoreception is the mechanism by which the brain detects the level of carbon dioxide (CO 2) in the arterial blood and alters breathing accordingly in order to maintain it within physiological levels. The ventral surface of the medulla oblongata (VMS) of animals has long been recognized as a site of chemosensitivity, culminating in the recent identification of chemosensitive serotonergic (5-HT) and glutamatergic (Glut) neurons in this region. In this study, we analyzed the distribution of 5-HT and Glut neurons and their receptors in the arcuate nucleus (Arc) at the VMS of the human infant, using single-and double-label immunohistochemistry with specific antibodies. We also examined the expression of astrocytes, as experimental evidence suggests that astrocytes mediate, at least in part, central chemosensitivity via 5-HT and/or Glut receptors. We identified a small number of 5-HT neurons (approximately 5% of Arc neurons), distributed over the entire extent of the VMS, a large number of Glut neurons (approximately 95% of Arc neurons) that localized almost exclusively to the medial Arc, and a large number of astrocytes distributed across the entire extent of the VMS. The Arc also contained 5-HT 1A, kainate (GluR5), and 5-HT 2A receptors, which localized predominantly to 5-HT neurons, glutamate neurons and astrocytes, respectively. Astrocytes also expressed the vesicular glutamate transporter 2 and low levels of 5-HT 1A and kainate (GluR5) receptors, indicating that astrocytes may store and release glutamate, possibly in response to stimulation by 5-HT and/or Glut. These observations suggest that important functional interactions exist between 5-HT, glutamate, and astrocytes in the Arc. They also support the idea that the Arc is homologous to chemosensitive zones at the VMS in experimental animals. These data are important towards delineating the role of the human Arc in modulation of homeostasis, and its dysfunction in brainstem-associated pathologies such as the sudden infant death syndrome.

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

Sleep in Restrictive and Neuromuscular Respiratory Disorders

Thoracic restrictive disorders (i.e., chest wall deformities or neuromuscular diseases), may predispose to sleep-disordered breathing, poor sleep quality, and nocturnal hypoventilation. These disorders intensify the effects of reductions in both respiratory center output and central chemosensitivity and increases in upper airway resistance that occur with the onset of sleep. Normally, rapid eye movement (REM) sleep suppresses the activity of nondiaphragmatic breathing muscles, further reducing ventilation. Diaphragmatic or upper airway muscle weakness and reduced chest wall compliance in patients with thoracic restrictive disorders enhance the severity of sleep-disordered breathing during REM sleep, worsening gas exchange abnormalities and sleep fragmentation and impairing daytime functioning. Although daytime respiratory function and nocturnal oxygen saturation are not well correlated, some markers may be useful for identifying patients with thoracic restriction at risk for sleep-disordered breathing. Although some patients may respond to continuous positive airway pressure (CPAP) alone, noninvasive positive pressure ventilation (NPPV) is a more important part of disease management for patients with restrictive thoracic disorders. This technique improves nocturnal ventilation and sleep quality but may also contribute to sleep fragmentation in some patients. If the patient is an unsuitable candidate for or fails NPPV, tracheostomy mechanical ventilation should be considered.

Exercise Tolerance, Exercise Hyperpnea and Central Chemosensitivity to Carbon Dioxide in Sleep Apnea Syndrome in Heart Failure Patients

Sleep apnea syndrome (SAS) and exercise hyperpnea are common in patients with chronic heart failure (CHF), and although it is not known whether they are both regulated by the same mechanisms, the hypothesis of the present study was that they are related to augmented central chemosensitivity. The oxygen desaturation index (ODI) was evaluated in 29 patients and those with ODI > 5 times/h underwent polysomnography. Patients with an apnea-hypopnea index (AHI) > 15 /h without evidence of obstructive apnea were defined as central SAS (CSAS). Cardiopulmonary exercise testing was performed to determine peak oxygen uptake and the VE-VCO2 slope. A hypercapnic gas mixture (7% CO2/93% O2) was used to activate the central chemoreflex. Nine patients had central SAS (CHF-CSAS) and 20 did not have apnea (CHF-nonSAS). Patients with CHF-CSAS had a lower peak oxygen uptake than the CHF-nonSAS group (13.0+/-2.4 vs 16.9+/-4.3 ml x kg(-1) x min(-1), p < 0.05). There was a significant correlation between central chemosensitivity and the AHI (r = 0.63, p < 0.05), between central chemosensitivity and the VE - VCO2 slope (r = 0.50, p < 0.01), whereas the VE-VCO2 slope showed an insignificant tendency to correlate with AHI (r = 0.44, p = 0.07). Conclusion CHF-CSAS is associated with impaired exercise tolerance and elevated central chemosensitivity is the responsible mechanism for CSAS and exercise hyperpnea.

Improvement of Excessive Exercise Ventilation after Coronary Artery Bypass Graft Surgery: Relation with Cardiopulmonary Function and Central Chemosensitivity

Improvement of Excessive Exercise Ventilation after Coronary Artery Bypass Graft Surgery: Relation with Cardiopulmonary Function and Central Chemosensitivity

Significance of extracellular potassium in central respiratory control studied in the isolated brainstem–spinal cord preparation of the neonatal rat

The significance of extracellular potassium in central respiratory control was investigated using the isolated brainstem-spinal cord preparation of the neonatal rat. Depth profiles of extracellular potassium activity ([K+])ECF in the medulla were measured with ion-sensitive microelectrodes. Although [K+]ECF increased with depth in medullary tissue during control (4 mM) and low (1 mM) potassium concentration ([K+])CSF superfusion, this gradient disappeared with higher [K+]CSF. With low [K+]CSF (1 mM), respiratory CO2 responsiveness was abolished, and increased with high [K+]CSF (8 mM). Respiratory frequency (fR) was diminished at low [K+]CSF (1 mM), and increased with elevated [K+]CSF (8 and 16 mM); with yet higher [K+]CSF (32 mM) apnea occurred after a transient increase in fR. Perforated patch recording revealed that high [K+]ECF decreased membrane resistance, depolarized membrane potential, and increased firing frequency in most of the recorded medullary neurons. High [K+]ECF also increased excitatory and inhibitory post-synaptic potentials of medullary neurons and augmented the functional connectivity among neurons. It is concluded that [K+]ECF is of importance in the maintenance of respiratory rhythm and central chemosensitivity.

Role of central sympathoexcitation in enhanced hypercapnic chemosensitivity in patients with heart failure

Background Enhanced central hypercapnic chemosensitivity is known to mediate excessive exercise ventilation and to indicate a poor prognosis in patients with chronic heart failure. The present study was designed to elucidate the role of central sympathetic activity in the enhancement of hypercapnic chemosensitivity. Methods Central hypercapnic chemosensitivity and plasma norepinephrine were measured in 99 patients with chronic heart failure. In 40 patients, the α index was derived from simultaneous analysis of R-R interval and systolic blood pressure variability. The effects of a central sympatholytic agent, guanfacine (0.25 mg/day), on hypercapnic chemosensitivity and exercise ventilatory response were studied in 20 of these patients. Results Hypercapnic chemosensitivity was enhanced in 76% of the patients and correlated significantly with plasma norepinephrine levels ( r = 0.49, P < .01) at rest. There was a significant inverse relationship between central chemosensitivity and the α index ( r = −0.41, P < .01). Guanfacine significantly reduced plasma norepinephrine levels by 29% ( P < .01) and chemosensitivity by 31% ( P < .01). The beneficial effect of central sympathoinhibition with guanfacine was observed specifically in patients who had enhanced chemosensitivity prior to drug administration. Similarly, the patients with excessive exercise ventilation showed a greater reduction in exercise ventilation with this agent. Conclusions The present findings suggest that central sympathoexcitation could play an important role in the pathogenesis of enhanced hypercapnic chemosensitivity and a resultant increase in exercise ventilation in chronic heart failure.

Central histamine contributes to the inspiratory off-switch mechanism via H1 receptors in mice

Central histaminergic neurons are distributed in areas of the medulla and pons concerned with respiratory rhythm generation, but their effects on breathing pattern are unknown. We examined breathing pattern during hypercapnic responses in wild type (WT) and H1 receptor knockout (H1RKO) mice at 9-10 weeks of age before and after vagotomy. Minute ventilation increased with PaCO(2) increase equally in both genotypes; respiratory rate response was lower and tidal volume (V(T)) response higher in H1RKO mice than in WT mice. The V(T)-inspiratory time (T(I)) relation during hypercapnia was hyperbolic in both groups, with the curve in H1RKO mice shifted right-upward. After vagotomy, the V(T)-T(I) relation was a vertical line, which shifted right in H1RKO mice. We conclude that alterations of inspiratory off-switch and respiratory rhythm generation change breathing pattern without affecting central chemosensitivity in H1RKO. Histamine might affect breathing pattern centrally via H1 receptors.

CO2 central chemosensitivity: why are there so many sensing molecules?

CO2 central chemoreceptors (CCRs) play a critical role in respiratory and cardiovascular controls. Although the primary sensory cells and their neuronal networks remain elusive, recent studies have begun to shed insight into the molecular mechanisms of several pH sensitive proteins. These putative CO2/pH-sensing molecules are expressed in the brainstem, detect P(CO2) at physiological levels, and couple the P(CO2) to membrane excitability. Functional analysis suggests that multiple CO2/pH-sensing molecules are needed to achieve high sensitivity and broad bandwidth of the CCRs. In contrast to the diversity of pH sensitive molecules, molecular mechanisms for CO2 sensing are rather general. The sensing molecules detect pH changes rather than molecular CO2. One or a few titratable amino acid residues in these proteins are usually involved. Protonation of these residues may lead to a change in protein conformation that is coupled to a change in channel activity. Depending on the location of the protonation sites, a membrane protein can detect extra- and/or intracellular pH.

New concepts in abnormalities of respiratory control in children.

Respiratory control disorders such as apnea of prematurity, apparent life-threatening events, sudden infant death syndrome, and central hypoventilation are relatively frequent conditions in the pediatric age range and are associated with substantial morbidity and mortality. The explosion of technological breakthroughs in biology and medicine has facilitated our understanding of the fundamental mechanisms that govern the development of brain regions underlying respiratory control functions. Recent critically important discoveries encompass the identification of neurons that constitute the central respiratory rhythm generator in the brainstem, the conceptual framework allowing for many neurons located in multiple strategic regions within the brain to coordinate central chemosensitivity, the discovery of long-term and short-term plasticity in hypoxic ventilatory regulation, and the recent uncovering of specific gene mutations in children affected with congenital central hypoventilation syndrome. While the developmental aspects of control breathing are only now being actively explored in the context of our current understanding, it is likely that such efforts will yield important novel approaches to the clinical and pharmacologic management of these disorders in the near future.

The Effect of Upper Airway Structural Changes on Central Chemosensitivity in Obstructive Sleep Apnea-Hypopnea

The Effect of Upper Airway Structural Changes on Central Chemosensitivity in Obstructive Sleep Apnea-Hypopnea

Regulation of External Respiration and Gas Exchange during a 20-Day Exposure to Sessions of Intermittent Normobaric Hypoxia

A study was made of the effects of a 20-day course of intermittent normobaric hypoxia (INH) on the parameters of gas exchange and the regulation of respiration in healthy volunteers. A phasic change in oxygen consumption at rest was observed: it decreased on the 10th day of the INH course and increased on the 20th day, with a parallel increase in the efficiency of pulmonary ventilation. According to the hypercapnic test, the ventilatory response threshold decreased, whereas ventilatory sensitivity increased; these effects were most pronounced during the first ten days of INH training and still detectable in recovery. It was assumed that the first phase of training (up to the tenth day) is associated with compensatory activation of pulmonary ventilation owing to an increase in peripheral and central chemosensitivity to the CO2 stimulus. In the second phase, which was associated with further slight changes in the parameters of external respiration, the gas exchange level is restored owing to an adaptive increase in efficiency of oxygen utilization in cells and tissues.

The effect of upper airway structural changes on central chemosensitivity in obstructive sleep apnea-hypopnea.

We examined the efficiency of upper airway structural changes in uvulopalatopharyngoplasty and/or tonsillectomy on central chemosensitivity, and whether the outcome of such surgeries can be predicted by the central chemosensitivity in obstructive sleep apnea-hypopnea syndrome (OSAHS) patients. In 11 patients with OSAHS group, the average of the hypercapnic ventilatory response (HCVR) slope was 1.93 +/- 0.20 L/min/mm Hg preoperatively and 1.78 +/- 0.22 L/min/mm Hg postoperatively. The average of the mouth occlusion pressure at 0.1 second after the onset of inspiration (P (0.1)) slope was 0.47 +/- 0.06 cm H (2)O/mm Hg and 0.44 +/- 0.08 cm H (2)O/mm Hg, before and after surgery, respectively. There were no significant differences before and after treatment, although OSAHS was improved by these surgeries. In control group with 5 patients, the HCVR slope and P (0.1) slope also showed no significant difference before and after the procedure. When we divided the 11 OSAHS patients into 7 responders (apnea-hypopnea index < 20 events/h and > 50% reduction) and 4 poor responders, there was a significant difference between the average HCVR slope of responders (1.59 +/- 0.21 L/min/mm Hg) and that of poor responders (2.52 +/- 0.20 L/min/mm Hg). We saw no significant difference in physiologic (age, body mass index, one-piece tonsil weight), blood gas values, cephalometric, spirometric, or sleep parameters.

Tentative role of the Na+/H+ exchanger type 3 in central chemosensitivity of respiration.

In vitro studies by Wiemann et al. (1999, 2001) have shown cultured CO2/H+ sensitive neurons from the ventrolateral medulla oblongata of newborn rats to enhance their bioelectric activity upon intracellular acidification induced by selective inhibition of the Na+/H+ exchanger type 3 (NHE-3). Recently, Kiwull- Schône et al. (2001) demonstrated the presence of NHE-3 mRNA in the adult rabbit brainstem, and likewise found NHE-3 immunoreactive neurons in brain-stem areas, which have prevalence for central chemosensitivity. The same study revealed that NHE-3 inhibition by the brain-permeant substance S8218 (Aventis Pharma) also significantly modified the central respiratory CO2-response of brain-stem in vivo. KeywordsObstructive Sleep ApneaPhrenic NerveIntracellular AcidificationBioelectric ActivityThreshold PaC0These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Central sympathetic chemosensitivity and Kir1 potassium channels in the cat

The possible involvement of potassium channels in central chemosensitivity, with special reference to the Kir1.1 potassium channel, was investigated by studying the CO 2 response of presympathetic neurons in the rostroventrolateral medulla (RVLM) in the absence or presence of various K + channel inhibitors. Synaptic input to RVLM neurons was blocked by local injection of ω-agatoxin and ω-conotoxin. Activity of RVLM neurons was measured by recording the electrical activity in preganglionic (WR-T 3) or postganglionic (renal) sympathetic nerves after perfusion of the lower brainstem via the left vertebral artery with CO 2-enriched saline solution. Unspecific K + channel blockade by BaCl 2 reduced the excitatory response of sympathetic activity after CO 2-perfusion to 56% of control. A quantitatively similar inhibition of the central CO 2 response was obtained after administration of 9-fluorenylmethylchloroformate (FMOC-Cl) which eliminates pH sensitivity of Kir1 and Kir4.1. Furthermore, two structurally different Kir1 inhibiting toxins, tertiapin and Lq2, also reduced the central CO 2 response to ∼50% of control. In contrast, charybdotoxin (CTX) had no effect on the CO 2 response. Using RT-PCR the expression of mRNA homologous to rat Kir1 mRNA was identified in the cat medulla oblongata. These data suggest that a modulation of potassium channel activity possibly via Kir1 may contribute to central chemosensitivity.

Hypercapnic and hypoxic ventilatory responses in long-term streptozotocin-diabetic rats during conscious and pentobarbital-induced anesthetic states

To clarify the diabetes mellitus (DM)-associated changes in the respiratory neuronal control system, acute ventilatory responses to progressively increasing hypercapnia (6%) and hypoxia (10%) were compared between normal (N) and streptozotocin (60 mg/kg, i.v.) -DM rats for a long period up to 28 weeks. The same comparison was conducted during the anesthetic state induced with pentobarbital (35 mg/kg, i.p.). During the conscious state, basic ventilatory parameters, such as respiratory rate, tidal volume and minute ventilation, were not impaired in DM rats, but ventilatory responses to hypercapnia and hypoxia were reduced significantly at 16 weeks and later after streptozotocin injection. The reduced responses in DM rats were not recovered by insulin treatment (5–6 U/body, s.c., daily). During the anesthetic state, both hypoxic and hypercapnic responses were depressed more intensely in N rats than in DM rats, resulting in an equivalent level of the response in the two groups. The present study demonstrated that ventilatory responses to hypercapnia and hypoxia were reduced in a long-term DM condition. This may be derived from the impairment of the peripheral and central chemosensitivity. The reduction in ventilatory responses was exaggerated during the anesthetic state.