Hypercapnic Ventilatory Response Research Articles

Effect of Facemask in Congenital Central Hypoventilation Syndrome

Introduction: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder with a mutation in the PHOX2B gene. Patients need ventilatory support by noninvasive ventilation or tracheostomy to treat alveolar hypoventilation. Patients with CCHS have a defect in chemosensitivity signal integration. Recently, due to the COVID-19 pandemic, the entire world has had to get used to wearing medical masks (MM). Objectives: The aim of the study was to evaluate the effect of an MM on gas exchange and to determine the role of central and peripheral chemoresponsiveness on the partial pressure of transcutaneous carbon dioxide (PtcCO₂) in patients with CCHS wearing an MM. Methods: This study was based on the analysis of recordings obtained without and with an MM during hospitalization and was conducted to assess the impact of MM on PtcCO₂ and SpO₂ recordings with the SenTec Digital Monitor and their relationships with peripheral CO₂ chemosensitivity obtained during tidal breathing measurement and with the hypercapnic hyperoxic ventilatory response. Results: Sixteen patients were included (13 boys) and were 10.2 (7.5; 18.5) years old. The use of an MM had a negative impact on gas exchange in patients with CCHS. The median PtcCO₂ increased significantly. Peripheral chemosensitivity correlated with MM-induced PtcCO₂ changes (R = −0.72, p = 0.005), but central chemosensitivity (the hypercapnic ventilator response slope) did not (R = −0.22, p = 0.510). Conclusion: The use of an MM had a negative impact on gas exchange in patients with CCHS.

Peripheral hypercapnic chemosensitivity in trained and untrained females and males during exercise.

Hypercapnic chemosensitivity is the response to the increased partial pressure of carbon dioxide and results from central and peripheral chemosensor stimulation. The hypercapnic chemosensitivity of the peripheral chemoreceptors is potentially impacted by acute exercise, aerobic fitness, and sex. We sought to determine the peripheral chemoresponse to transient hypercapnia at rest and during exercise in males and females of various fitness. We hypothesized that 1) higher fitness participants would have lower hypercapnic chemosensitivity compared with those with lower fitness and 2) males would have a higher chemoresponse than females. Forty healthy participants (20 females) participated in one test day involving transient hypercapnic chemosensitivity testing and a maximal exercise test. Chemosensitivity testing involved two breaths of 10% CO2 repeated five times (45 s to 1 min between repeats) at rest and the first two stages of a maximal exercise test. There was no significant difference between higher and lower aerobic fitness groups, (mean difference 0.23 ± 0.22 rest; -0.07 ± 0.04 stage 1; 0.11 ± 0.17 stage 2 L/mmHg·min) during each stage (P = 0.472). However, we saw a significant increase in the hypercapnic response during stage 1 (0.98 ± 0.4 L/mmHg·min) compared with rest (0.79 ± 0.5 L/mmHg·min; P = 0.01). Finally, at 80 W, males had a higher chemoresponse compared with females, which persisted following body surface area correction (0.56 ± 0.2 vs. 0.42 ± 0.2 L/mmHg·min·m2, for females and males respectively (P = 0.038). Our findings suggest that sex, unlike aerobic fitness, influences peripheral hypercapnic chemosensitivity and that context (i.e., rest vs. exercise) is an important consideration.NEW & NOTEWORTHY The hypercapnic chemoresponse to transient CO2 showed an increase during acute physical activity; however, this response did not persist with further increases in intensity and was not different between participants of different aerobic fitness. Males and females show a differing response to CO2 during exercise when compared with an iso-V̇co2. Our results suggest that adaptations that lead to increased aerobic fitness do not impact the hypercapnic ventilatory response but there is an effect of sex.

Intravenous iron therapy improves the hypercapnic ventilatory response and sleep disordered breathing in chronic heart failure

Intravenous iron therapy improves the hypercapnic ventilatory response and sleep disordered breathing in chronic heart failure

CO2 exposure enhances Fos expression in hypothalamic neurons in rats during the light and dark phases of the diurnal cycle.

Orexinergic (OX) neurons in the lateral hypothalamus (LH), perifornical area (PFA) and dorsomedial hypothalamus (DMH) play a role in the hypercapnic ventilatory response, presumably through direct inputs to central pattern generator sites and/or through interactions with other chemosensitive regions. OX neurons can produce and release orexins, excitatory neuropeptides involved in many functions, including physiological responses to changes in CO2/pH. Thus, in the present study, we tested the hypothesis that different nuclei (LH, PFA and DMH) where the orexinergic neurons are located, show distinct activation by CO2 during the light-dark cycle phases. For this purpose, we evaluated the Fos and OXA expression by immunohistochemistry to identify neurons that co-localize Fos + OXA in the LH, LPeF, MPeF and DMH in the light-inactive and dark-active phase in Wistar rats subjected to 3h of normocapnia or hypercapnia (7% CO2). Quantitative analyses of immunoreactive neurons show that hypercapnia caused an increase in the number of neurons expressing Fos in the LH, LPeF, MPeF and DMH in the light and dark phases. In addition, the number of Fos + OXA neurons increased in the LPeF and DMH independently of the phases of the diurnal cycle; whereas in the MPeF, this increase was observed exclusively in the light phase. Thus, we suggest that OX neurons are selectively activated by hypercapnia throughout the diurnal cycle, reinforcing the differential role of nuclei in the hypothalamus during central chemosensitivity.

A new neuromodulatory mechanism in the lateral hypothalamus regulating the hypercapnic ventilatory response in conscious rats.

Experimental PhysiologyVolume 107, Issue 11 p. 1212-1213 VIEWPOINT A new neuromodulatory mechanism in the lateral hypothalamus regulating the hypercapnic ventilatory response in conscious rats Ana C. Takakura, Corresponding Author Ana C. Takakura [email protected] orcid.org/0000-0001-6273-0760 Department of Pharmacology, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, São Paulo, Brazil Correspondence Ana C. Takakura, Department of Pharmacology, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Avenida Prof. Lineu Prestes, 1524, 05508-000, São Paulo, SP, Brazil. Email: [email protected]Search for more papers by this author Ana C. Takakura, Corresponding Author Ana C. Takakura [email protected] orcid.org/0000-0001-6273-0760 Department of Pharmacology, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, São Paulo, Brazil Correspondence Ana C. Takakura, Department of Pharmacology, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Avenida Prof. Lineu Prestes, 1524, 05508-000, São Paulo, SP, Brazil. Email: [email protected]Search for more papers by this author First published: 15 August 2022 https://doi.org/10.1113/EP090733 Handling Editor: Ken O'Halloran Linked articles: This Viewpoint highlights an article by Rodrigues et al. To read this paper, visit https://doi.org/10.1113/EP090318. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume107, Issue111 November 2022Pages 1212-1213 RelatedInformation

Melanin-concentrating hormone regulates the hypercapnic chemoreflex by acting in the lateral hypothalamic area.

What is the central question of this study? Melanin-concentrating hormone (MCH) suppresses the hypercapnic chemoreflex: what is the mechanism by which this effect is produced? What is the main finding and its importance? MCH acting in the lateral hypothalamic area but not in the locus coeruleus in rats, in the light period, attenuates the hypercapnic chemoreflex. The data provide new insight into the role of MCH in the modulation of the hypercapnic ventilatory response. Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide involved in a broad range of homeostatic functions including regulation of the hypercapnic chemoreflex. We evaluated whether MCH modulates the hypercapnic ventilatory response by acting in the lateral hypothalamic area (LHA) and/or in the locus coeruleus (LC). Here, we measured pulmonary ventilation ( ), body temperature, electroencephalogram (EEG) and electromyogram (EMG) of unanaesthetized adult male Wistar rats before and after microinjection of MCH (0.4mM) or MCH receptor 1 (MCH1-R) antagonist (SNAP-94847; 63mM) into the LHA and LC, in room air and 7% CO2 conditions during wakefulness and sleep in the dark and light periods. MCH intra-LHA caused a decreased CO2 ventilatory response during wakefulness and sleep in the light period, while SNAP-94847 intra-LHA increased this response, during wakefulness in the light period. In the LC, MCH or the MCH1-R antagonist caused no change in the hypercapnic ventilatory response. Our results suggest that MCH, in the LHA, exerts an inhibitory modulation of the hypercapnic ventilatory response during the light-inactive period in rats.

Sexually dimorphic effects of prenatal diazepam exposure on respiratory control and the monoaminergic system of neonate and young rats.

Pregnancy is highly affected by anxiety disorders, which may be treated with benzodiazepines, especially diazepam (DZP), that can cross the placental barrier and interact with the fetalGABAergic system. We tested whether prenatal exposure to DZP promotes sex-specific postnatal changes in the respiratory control of rats. We evaluated ventilation ([Formula: see text]) and oxygen consumption ([Formula: see text] O2) in resting conditions and under hypercapnia (7% CO2) and hypoxia (10% O2) in newborn [postnatal day (P) 0-1 and P12-13)] and young (P21-22) rats from mothers treated with DZP during pregnancy. We also analyzed brainstem monoamines at the same ages. DZP exposure had minimal effects on room air-breathing variables in females, but caused hypoventilation (drop in [Formula: see text]/[Formula: see text] O2) in P12-13 males, lasting until P21-22. The hypercapnic ventilatory response was attenuated in P0-1 and P12-13 DZP-treated females mainly by a decrease in tidal volume (VT), whereas males had a reduction in respiratory frequency (fR) at P12-13. Minor changes were observed in hypoxia, but an attenuation in [Formula: see text] was seen in P12-13 males. In the female brainstem, DZP increased dopamine concentration and decreased 5-hydroxyindole-3-acetic acid (5-HIAA) and the 3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine ratio at P0-1, and reduced DOPAC concentration at P12-13. In males, DZP decreased brainstem noradrenaline at P0-1. Our results demonstrate that prenatal DZP exposure reduces CO2 chemoreflex only in postnatal females and does not affect hypoxia-induced hyperventilation in both sexes. In addition, prenatal DZP alters brainstem monoamine concentrations throughout development differently in male and female rats.

Leptin-mediated neural targets in obesity hypoventilation syndrome.

Obesity hypoventilation syndrome (OHS) is defined as daytime hypercapnia in obese individuals in the absence of other underlying causes. In the United States, OHS is present in 10%-20% of obese patients with obstructive sleep apnea and is linked to hypoventilation during sleep. OHS leads to high cardiorespiratory morbidity and mortality, and there is no effective pharmacotherapy. The depressed hypercapnic ventilatory response plays a key role in OHS. The pathogenesis of OHS has been linked to resistance to an adipocyte-produced hormone, leptin, a major regulator of metabolism and control of breathing. Mechanisms by which leptin modulates the control of breathing are potential targets for novel therapeutic strategies in OHS. Recent advances shed light on the molecular pathways related to the central chemoreceptor function in health and disease. Leptin signaling in the nucleus of the solitary tract, retrotrapezoid nucleus, hypoglossal nucleus, and dorsomedial hypothalamus, and anatomical projections from these nuclei to the respiratory control centers, may contribute to OHS. In this review, we describe current views on leptin-mediated mechanisms that regulate breathing and CO2 homeostasis with a focus on potential therapeutics for the treatment of OHS.

Awake Hypercapnic Ventilatory Response in Obstructive Sleep Apnea Syndrome

Background and Objective Decreased ventilatory response to carbon dioxide or hypercapnic ventilatory response (HCVR) is a feature of pediatric obstructive sleep apnea (OSA) and is also known to diminish during sleep in obese adolescents (age, 12–16 years) with OSA. It reduces minute ventilation, air flow, and tidal volume during inspiration, as well as upper airway obstruction. The purpose of this study was to investigate awake HCVR in adult patients with OSA and to elucidate its association with sleep apnea.Methods HCVR was measured before performing polysomnography (PSG). PSG is performed as the evaluation method during sleep, and the severity of apnea is evaluated by apnea hypopnea index. Patient background, PSG data and HCVR were examined.Results Awake HCVR was greater in patients with severe OSA than in patients with mild and moderate OSA, and in severe OSA patients, the HCVR during awaking was higher in patients with larger changes in saturation of percutaneous oxygen during sleep. Awake HCVR did not differ by age, but it was greater in morbidly obese patients with OSA than in thin patients with OSA. The most frequent apnea pattern of OSA was obstructive, regardless of severity; although with an increasing severity of OSA, the central pattern decreased and the mixed pattern increased in frequency. The appearance of the mixed pattern increased in the augmented HCVR group.Conclusions This study suggested that awake HCVR could be used as an index of progression and a factor to determine the effects of treatment in patients with OSA.

The effect of central growth hormone action on hypoxia ventilatory response in conscious mice

Growth hormone (GH)-responsive neurons regulate several homeostatic behaviors including metabolism, energy balance, arousal, and stress response. Therefore, it is possible that GH-responsive neurons play a role in other responses such as CO2/H+-dependent breathing behaviors. Here, we investigated whether central GH receptor (GHR) modulates respiratory activity in conscious unrestrained mice. First, we detected clusters of GH-responsive neurons in the tyrosine hydroxylase-expressing cells in the rostroventrolateral medulla (C1 region) and within the locus coeruleus (LC). No significant expression was detected in phox2b-expressing cells in the retrotrapezoid nucleus. Whole body plethysmography revealed a reduction in the tachypneic response to hypoxia (FiO2 = 0.08) without changing baseline breathing and the hypercapnic ventilatory response. Contrary to the physiological findings, we did not find significant differences in the number of fos-activated cells in the nucleus of the solitary tract (NTS), C1, LC and paraventricular nucleus of the hypothalamus (PVH). Our finding suggests a possible secondary role of central GH action in the tachypneic response to hypoxia in conscious mice.

Carotid body responses to O2 and CO2 in hypoxia-tolerant naked mole rats.

Naked mole rats (NMRs) exhibit blunted hypoxic (HVR) and hypercapnic ventilatory responses (HCVR). The mechanism(s) underlying these responses are largely unknown. We hypothesized that attenuated carotid body (CB) sensitivity to hypoxia and hypercapnia contributes to the near absence of ventilatory responses to hypoxia and CO2 in NMRs. We measured ex vivo CB sensory nerve activity, phrenic nerve activity (an estimation of ventilation), and blood gases in urethane-anesthetized NMRs and C57BL/6 mice breathing normoxic, hypoxic, or hypercapnic gases. CB morphology, carbon monoxide, and H2 S levels were also determined. Relative to mice, NMRs had blunted CB and HVR. Morphologically, NMRs have larger CBs, which contained more glomus cells than in mice. Furthermore, NMR glomus cells form a dispersed pattern compared to a clustered pattern in mice. Hemeoxygenase (HO)-1 mRNA was elevated in NMR CBs, and an HO inhibitor increased CB sensitivity to hypoxia in NMRs. This increase was blocked by an H2 S synthesis inhibitor, suggesting that interrupted gas messenger signaling contributes to the blunted CB responses and HVR in NMRs. Regarding hypercapnia, CB and ventilatory responses to CO2 in NMRs were larger than in mice. Carbonic anhydrase (CA)-2 mRNA is elevated in NMR CBs, and a CA inhibitor blocked the augmented CB response to CO2 in NMRs, indicating CA activity regulates augmented CB response to CO2 . Consistent with our hypothesis, impaired CB responses to hypoxia contribute in part to the blunted HVR in NMRs. Conversely, the HCVR and CB are more sensitive to CO2 in NMRs.

Histamine/H1 receptor signaling in the parafacial region increases activity of chemosensitive neurons and respiratory activity in rats.

Histaminergic neurons of the tuberomammillary nucleus (TMN) are pH sensitive and contribute to CO2/H+-dependent behaviors including arousal and respiratory activity. TMN neurons project to several respiratory centers including the ventral parafacial region (pF), where the chemosensitive retrotrapezoid (RTN) neurons are located, and since RTN neurons are an important source of CO2/H+-dependent respiratory drive, we wondered whether histamine contributes to RTN chemoreception. To test this, we characterized effects of histamine on mean arterial pressure (MAP) and diaphragm muscle activity (DIAEMG) in urethane-anesthetized, vagotomized, and artificially ventilated male Wistar rats. Unilateral injection of histamine in the pF (25 mM) increased DIAEMG amplitude without changing DIAEMG frequency and MAP. Bilateral injections of the H1 receptor antagonist diphenhydramine hydrochloride (DPH; 0.5 mM) into the pF decreased baseline DIAEMG amplitude and frequency and MAP. Despite the strong inhibitory effect of DPH on baseline breathing, the hypercapnic ventilatory response was preserved under these experimental conditions. At the cellular level, chemosensitive RTN neurons showed a dose-dependent excitatory response to histamine that was blunted by DPH and mimicked by H1 receptor agonist 2-pyridylethylamine dihydrochloride (2PYEA) both under control conditions and when fast neurotransmitter receptors were blocked. We also tested effects of 2PYEA in the presence of serotonin, another wake-on neurotransmitter that activates RTN chemoreceptors partly by activation of Gq-coupled receptors. We found that the response to 2PYEA was diminished in serotonin, suggesting that RTN neurons have a limited capacity to respond to multiple Gq-coupled modulators. These results suggest that histamine can modulate breathing at the pF level by a mechanism involving H1 receptors.NEW & NOTEWORTHY Histamine/H1 receptor signaling activates retrotrapezoid (RTN) neurons under control conditions and to a lesser extent in the presence of serotonin. These results suggest that RTN neurons have a limited capacity to respond to simultaneous activation of multiple Gq-coupled receptors.

Induction of Day-Time Periodic Breathing is Associated With Augmented Reflex Response From Peripheral Chemoreceptors in Male Patients With Systolic Heart Failure.

Spontaneous day-time periodic breathing (sPB) constitutes a common phenomenon in systolic heart failure (HF). However, it is unclear whether PB during wakefulness could be easily induced and what are the physiological and clinical correlates of patients with HF in whom PB induction is possible. Fifty male HF patients (age 60.8 ± 9.8 years, left ventricle ejection fraction 28.0 ± 7.4%) were prospectively screened and 46 enrolled. After exclusion of patients with sPB the remaining underwent trial of PB induction using mild hypoxia (stepwise addition of nitrogen gas to breathing mixture) which resulted in identification of inducible (iPB) in 51%. All patients underwent assessment of hypoxic ventilatory response (HVR) using transient hypoxia and of hypercapnic ventilatory response (HCVR) employing Read’s rebreathing method. The induction trial did not result in any adverse events and minimal SpO2 during nitrogen administration was ∼85%. The iPB group (vs. non-inducible PB group, nPB) was characterized by greater HVR (0.90 ± 0.47 vs. 0.50 ± 0.26 L/min/%; p <0.05) but comparable HCVR (0.88 ± 0.54 vs. 0.67 ± 0.68 L/min/mmHg; p = NS) and by worse clinical and neurohormonal profile. Mean SpO2 which induced first cycle of PB was 88.9 ± 3.7%, while in sPB mean SpO2 preceding first spontaneous cycle of PB was 96.0 ± 2.5%. There was a reverse relationship between HVR and the relative variation of SpO2 during induced PB (r = −0.49, p = 0.04). In summary, PB induction is feasible and safe in HF population using simple and standardized protocol employing incremental, mild hypoxia. Pathophysiology of iPB differs from sPB, as it relies mostly on overactive peripheral chemoreceptors. At the same time enhanced HVR might play a protective role against profound hypoxia during iPB.

Past questions, present results, future perspectives: Interacting chemosensitive areas and the hypercapnic ventilatory response.

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Long-Term Hypercaloric Diet Consumption Exacerbates Age-Induced Dysmetabolism and Carotid Body Dysfunction: Beneficial Effects of CSN Denervation.

Carotid bodies (CBs) are metabolic sensors whose dysfunction is involved in the genesis of dysmetabolic states. Ageing induces significant alterations in CB function also prompting to metabolic deregulation. On the other hand, metabolic disease can accelerate ageing processes. Taking these into account, we evaluated the effect of long-term hypercaloric diet intake and CSN resection on age-induced dysmetabolism and CB function. Experiments were performed in male Wistar rats subjected to 14 or 44 weeks of high-fat high-sucrose (HFHSu) or normal chow (NC) diet and subjected to either carotid sinus nerve (CSN) resection or a sham procedure. After surgery, the animals were kept on a diet for more than 9 weeks. Metabolic parameters, basal ventilation, and hypoxic and hypercapnic ventilatory responses were evaluated. CB type I and type II cells, HIF-1α and insulin receptor (IR), and GLP-1 receptor (GLP1-R)-positive staining were analyzed by immunofluorescence. Ageing decreased by 61% insulin sensitivity in NC animals, without altering glucose tolerance. Short-term and long-term HFHSu intake decreased insulin sensitivity by 55 and 62% and glucose tolerance by 8 and 29%, respectively. CSN resection restored insulin sensitivity and glucose tolerance. Ageing decreased spontaneous ventilation, but short-term or long-term intake of HFHSu diet and CSN resection did not modify basal ventilatory parameters. HFHSu diet increased hypoxic ventilatory responses in young and adult animals, effects attenuated by CSN resection. Ageing, hypercaloric diet, and CSN resection did not change hypercapnic ventilatory responses. Adult animals showed decreased type I cells and IR and GLP-1R staining without altering the number of type II cells and HIF-1α. HFHSu diet increased the number of type I and II cells and IR in young animals without significantly changing these values in adult animals. CSN resection restored the number of type I cells in HFHSu animals and decreased IR-positive staining in all the groups of animals, without altering type II cells, HIF-1α, or GLP-1R staining. In conclusion, long-term hypercaloric diet consumption exacerbates age-induced dysmetabolism, and both short- and long-term hypercaloric diet intakes promote significant alterations in CB function. CSN resection ameliorates these effects. We suggest that modulation of CB activity is beneficial in exacerbated stages of dysmetabolism.

Abnormal hypoxic and hypercapnic ventilatory responses in 5XFAD Alzheimer’s disease mice

Alzheimer’s disease (AD) is a neurodegenerative disease commonly associated with aging. Along with regression in cognition and memory, AD patients often have respiratory disturbances such as sleep apnea, insufficient ventilation during sleep, and shortness of breath. Further, at least one chemosensitive region located in the pons, the locus coeruleus, undergoes dramatic degeneration during AD progression. These observations suggest chemoreception may be altered during the progression of AD. To begin testing this hypothesis, we examined the hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses on 5XFAD mice (&gt;6months) using whole body plethysmography. Preliminary data showed a reduced capacity to lower metabolic rate and body temperature during hypoxia (5.5% inspired O2) in 5XFAD mice, such that average oxygen consumption was reduced by 34.8 ± 2.8% (S.E.M) and body temperature fell to 33.5 ± 0.4°C. In wild type (WT) mice oxygen consumption was reduced by 53% and body temperature fell to 32.8°C. Further, 5XFAD mice sustained a slight ventilatory increase (1.3 ± 3.6% increase from baseline) during hypoxia while WT mice reduced ventilation by 5%. 5XFAD mice also displayed a reduced hypercapnic ventilatory response, showing little increase in tidal volume in response to hypercapnia; but they appeared to augment this with a greater increase in breathing frequency compared to WT mice. The net result, however, was an increase in ventilation by 122 ± 22% from baseline in response to 5% CO2 while WT mice had a 181 ± 26% increase from baseline to the same challenge. Our data suggest that ventilatory chemoresponses are altered by disease progression in the 5XFAD mouse model. These alterations may contribute to the respiratory disturbances observed in AD patients.

The Elevated Central Chemosensitivity in Obstructive Sleep Apnea Patients with Hypertension.

PurposeHypertension is a common comorbidity in obstructive sleep apnea (OSA), in which dysfunction of the autonomic nervous system plays an integral part. Chemoreflex is essential for ventilatory control and cardiovascular activity. This study aimed to determine whether central chemosensitivity was increased in OSA patients with hypertension and the potential role of the autonomic nerve activity in this relationship.Patients and MethodsA total of 77 men with OSA were included in this cross-sectional study. We measured hypercapnic ventilatory response (HCVR) by the rebreathing method under isoxic hyperoxia to test the central ventilatory chemosensitivity since hyperoxia silences the peripheral chemoreceptors’ response to CO2. To elevate the autonomic nerve activity, time-domain, frequency-domain, and non-linear variables of heart rate variability were calculated over 5-min records. Univariate and multivariate linear regression analyses were used to find the determinants of HCVR.ResultsThe median HCVR was 2.3 (1.8, 3.3), 2.1 (1.6, 3.0), and 3 (2.2, 3.7) L/min/mmHg in all participants, OSA patients, and OSA patients with hypertension, respectively. Hypertension was significantly associated with elevated HCVR after adjusting for age, central obesity, OSA severity, daytime sleepiness, and diabetes mellitus. Compared with OSA patients, OSA patients with hypertension had higher body mass index, worse nocturnal hypoxia, and lower time-domain variables and frequency-domain variables. After adjusting for age, apnea-hypopnea index, central obesity, and beta-blocker usage, approximate entropy was independently negatively associated with HCVR in OSA patients with hypertension.ConclusionThis study demonstrated elevated central chemosensitivity in OSA patients with hypertension. Compared with OSA patients, OSA patients with hypertension had attenuated parasympathetic nerve activity. This study preliminarily illustrated that elevated central chemosensitivity might be associated with weak adaptability of the cardiac autonomic nervous system in OSA patients with hypertension.

Melanin‐Concentrating Hormone (MCH) Decreases the Hypercapnic Ventilatory Response by Acting in the Lateral Hypothalamic Area (LHA)

MCH plays an inhibitory role in the central hypercapnic chemoreflex, but the mechanisms were unclear so far. In this study, we tested the hypothesis that MCH1‐R receptors activation in LHA and/or Locus coeruleus (LC) is involved in the modulation of hypercapnic ventilatory response during the sleep/wake cycle. To do this, we measured pulmonary ventilation (VE), body temperature, EEG and EMG of unanesthetized male Wistar rats before and after microinjection of the MCH agonist (MCH, 0.4 mM) into the LHA and LC, or the MCH1‐R antagonist (SNAP‐94847; 63 mM), into the LHA, in room air and in 7% CO2 during wakefulness and sleep, in the dark and light periods. MCH intra‐LHA decreased the CO2 ventilatory response by 27% during wakefulness (VE = 1923 ± 384; n = 7 versus 2645 ± 293 mL kg‐1 min‐1; n = 6; P &lt; 0.0001) and 16% during sleep (VE = 1914 ± 228; n = 6 versus2273 ± 243 mL kg‐1 min‐1; n = 4; P &lt; 0.005) in the light, but not in the dark period while SNAP‐94847 intra‐LHA caused an increased CO2 ventilatory response during wakefulness in the light period, compared with the control group (VE = 2547 ± 277; n = 6 versus 2106 ± 329 mL kg‐1 min‐1; n = 6; P &lt; 0.05). In the LC, MCH caused no change in the hypercapnic ventilatory response of rats. Our results suggest that MCH via MCH1‐R in the LHA, but not in the LC, exerts an inhibitory modulation of the hypercapnic ventilatory response during the light‐inactive period in rats.

The effect of brain serotonin deficiency on breathing during sleep is magnified by age

Serotonin is an important mediator modulating behavior, metabolism, sleep, control of breathing, and upper airway function but the role of aging in serotonin‐mediated effects has not been previously defined. Our study aimed to examine the effect of brain serotonin deficiency on breathing during sleep and metabolism in younger and older mice.We measured breathing during sleep, hypercapnic ventilatory response (HCVR), CO2 production (VCO2), and O2 consumption (VO2) in 16‐18 week old and 40‐44 week old mice with genetic deficiency of tryptophan hydroxylase 2 (Tph2), which regulates serotonin synthesis specifically in neurons, and Tph2+/+ controls.In younger mice, Tph2knockout resulted in an increase in VCO2 and VO2 as a result of an increase in motor activity without any effect on HCVR and breathing during sleep. In contrast, in older mice, Tph2knockout caused not only increases in metabolic rate and motor activity but also weight loss, suppression of the HCVR, a decrease in maximal inspiratory flow during non‐rapid eye movement (NREM) sleep, and oxyhemoglobin desaturation during rapid eye movement (REM) sleep. Neither serotonin deficiency nor aging affected the frequency of flow limited breaths (a marker of upper airway closure) or apneas. Serotonin deficiency increased the amount and efficiency of sleep only in older animals.In older mice, brain serotonin deficiency decreases hypercapnic sensitivity leading to hypoventilation and hypoxemia during REM sleep, which were absent at younger age. The serotonin pathway may play a role in the prevention of sleep‐disordered breathing in older individuals.

Neonatal and adult heterotypic inflammation sex‐dependently prime adult microglia in respiratory control regions without impairing adult breathing

Adults often encounter diverse inflammatory stimuli, yet only some adults are prone to breathing deficits after adult inflammation. The determinants of adult susceptibility to breathing deficits during inflammation is understudied and likely involves microglia, the resident immune cells of the central nervous system. In non‐respiratory control regions, neonatal inflammation primes adult microglia for exaggerated inflammatory responses to otherwise harmless inflammatory stimuli, such as adult subthreshold heterotypic inflammation (differing neonatal and adult inflammatory stimuli). Since male and female microglia have sexually dimorphic developmental trajectories, we hypothesized that neonatal inflammation would sex‐dependently prime adult microglia in respiratory control regions to subthreshold heterotypic inflammation, contributing to impaired adult breathing. Using flow cytometry to assess microglia number (%CD11bhighCD45low / homogenates) and priming, adult male medullary microglia after neonatal inflammation (LPS 1mg/kg, i.p.) and adult subthreshold heterotypic inflammation (polyIC 478ug/kg, i.p.) were primed (neonatal LPS + adult polyIC: 25±7% microglia n=9; neonatal LPS + adult saline: 18±2% microglia, n=9; neonatal saline + adult saline: 10±2% microglia, n=9, p&lt;0.05; neonatal saline + adult polyIC: 11±2% microglia, n=8, p&lt;0.0001). In females, neonatal inflammation increased, but did not prime, medullary microglia to adult heterotypic inflammation (neonatal LPS + adult polyIC: 17±3% microglia, n=6; neonatal saline + adult saline: 11±1% microglia, n=6; neonatal saline + adult polyIC: 11±2% microglia, n=6, p&lt;0.005; neonatal LPS + saline: 14±2% microglia, n=8, p&gt;0.9). To test whether these primed microglia in respiratory control regions contribute to adult breathing deficits, breathing was assessed using plethysmography in adults after neonatal and adult heterotypic inflammation. Contrary to our hypothesis, neonatal and adult heterotypic inflammation did not impair adult eupneic breathing, the hypercapnic ventilatory response, or the hypoxic ventilatory response in adult males (p&gt;0.9) or females (p&gt;0.9). Therefore, adults after neonatal and adult heterotypic inflammation are able maintain breathing in response to low levels of inflammation despite primed medullary microglia. Primed microglia, however, are prone to augmented inflammatory responses and may induce significant deficits to breathing when faced with more severe inflammatory challenges.