Regulation of breathing pattern by IL-10

Proinflammatory cytokines like interleukin-1β (IL-1β) affect the control of breathing. Our aim is to determine the effect of the anti-inflammatory cytokine IL-10 οn the control of breathing. IL-10 knockout mice (IL-10−/−, n = 10) and wild-type mice (IL-10+/+, n = 10) were exposed to the following test gases: hyperoxic hypercapnia 7% CO2-93% O2, normoxic hypercapnia 7% CO2-21% O2, hypoxic hypercapnia 7% CO2-10% O2, and hypoxic normocapnia 3% CO2-10% O2. The ventilatory function was assessed using whole body plethysmography. Recombinant mouse IL-10 (rIL-10; 10 μg/kg) was administered intraperitoneally to wild-type mice ( n = 10) 30 min before the onset of gas challenge. IL-10 was administered in neonatal medullary slices (10–30 ng/ml, n = 8). We found that IL-10−/−mice exhibited consistently increased frequency and reduced tidal volume compared with IL-10+/+mice during room air breathing and in all test gases (by 23.62 to 33.2%, P < 0.05 and −36.23 to −41.69%, P < 0.05, respectively). In all inspired gases, the minute ventilation of IL-10−/−mice was lower than IL-10+/+(by −15.67 to −22.74%, P < 0.05). The rapid shallow breathing index was higher in IL-10−/−mice compared with IL-10+/+mice in all inspired gases (by 50.25 to 57.5%, P < 0.05). The intraperitoneal injection of rIL-10 caused reduction of the respiratory rate and augmentation of the tidal volume in room air and also in all inspired gases (by −12.22 to −29.53 and 32.18 to 45.11%, P < 0.05, respectively). IL-10 administration in neonatal rat ( n = 8) in vitro rhythmically active medullary slice preparations did not affect either rhythmicity or peak amplitude of hypoglossal nerve discharge. In conclusion, IL-10 may induce a slower and deeper pattern of breathing.

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Role of components of the phagocytic NADPH oxidase in oxygen sensing

Journal of Applied Physiology ◽

10.1152/japplphysiol.00564.2001 ◽

2002 ◽

Vol 93 (4) ◽

pp. 1357-1364 ◽

Cited By ~ 32

Author(s):

K. A. Sanders ◽

K. M. Sundar ◽

L. He ◽

B. Dinger ◽

S. Fidone ◽

...

Keyword(s):

Nadph Oxidase ◽

Carotid Body ◽

Minute Ventilation ◽

Mutant Mice ◽

Whole Body ◽

Type I ◽

Null Mutant ◽

Wild Type ◽

Null Mutant Mice

It has been hypothesized that O2sensing in type I cells of the carotid body and erythropoietin (EPO)-producing cells of the kidney involves protein components identical to the NADPH oxidase system responsible for the respiratory burst of phagocytes. In the present study, we evaluated O2sensing in mice with null mutant genotypes for two components of the phagocytic oxidase. Whole body plethysmography was used to study unanesthetized, unrestrained mice. When exposed to an acute hypoxic stimulus, gp91phox-null mutant and wild-type mice increased their minute ventilation by similar amounts. In contrast, p47phox-null mutant mice demonstrated increases in minute ventilation in response to hypoxia that exceeded that of their wild-type counterparts: 98.0 ± 18.0 vs. 20.0 ± 13.0% ( n = 11, P = 0.003). In vitro recordings of carotid sinus nerve (CSN) activity demonstrated that resting (basal) neural activity was marginally elevated in p47phox-null mutant mice. With hypoxic challenge, mean CSN discharge was 1.5-fold greater in p47phox-null mutant than in wild-type mice: 109.61 ± 13.29 vs. 72.54 ± 7.65 impulses/s ( n = 8 and 7, respectively, P = 0.026). Consequently, the hypoxia-evoked CSN discharge (stimulus-basal) was ∼58% larger in p47phox-null mutant mice. Quantities of EPO mRNA in kidney were similar in gp91phox- and p47phox-null mutant mice and their respective wild-type controls exposed to hypobaric hypoxia for 72 h. These findings confirm the previous observation that absence of the gp91phoxcomponent of the phagocytic NADPH oxidase does not alter the O2-sensing mechanism of the carotid body. However, absence of the p47phoxcomponent significantly potentiates ventilatory and chemoreceptor responses to hypoxia. O2sensing in EPO-producing cells of the kidney appears to be independent of the gp91phoxand p47phoxcomponents of the phagocytic NADPH oxidase.

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Modified control of breathing in genetically obese (ob/ob) mice

Journal of Applied Physiology ◽

10.1152/jappl.1996.81.2.716 ◽

1996 ◽

Vol 81 (2) ◽

pp. 716-723 ◽

Cited By ~ 88

Author(s):

C. Tankersley ◽

S. Kleeberger ◽

B. Russ ◽

A. Schwartz ◽

P. Smith

Keyword(s):

Tidal Volume ◽

Minute Ventilation ◽

Whole Body ◽

Breathing Frequency ◽

Wild Type ◽

Genetic Determinants ◽

Human Obesity ◽

Ventilatory Control ◽

Age Dependent ◽

Whole Body Plethysmography

Attenuated hypercapnic chemosensitivity and hypoventilation are characteristics periodically associated with human obesity. We tested the hypothesis that ventilatory control is altered by genetic determinants and age-dependent factors that influence the obese phenotype. To this end, the magnitude and pattern of breathing were examined before and associated with the development of obesity in C57BL/6J mice homozygous and heterozygous at the ob gene locus. Breathing frequency and tidal volume were measured using whole body plethysmography, and minute ventilation was assessed during acute hypoxic and hypercapnic challenges with intermittent room air exposures. In age- and weight-matched mice before pronounced obesity, significant (P < 0.05) reductions in hypercapnic ventilatory sensitivity occurred in mutant (ob/ob) mice relative to wild-type (+/+) homozygotes primarily because of an attenuated tidal volume. Longitudinal studies indicated that mutant ob mice developed rapid baseline breathing relative to the wild type, accompanying a twofold greater increase in body mass. Early differences between homozygotes in hypercapnic ventilatory sensitivity were maintained through 230 days. These data demonstrate that genetic determinants at or closely linked to the ob locus influence hypercapnic ventilation before the emergence of pronounced obesity, whereas changes in baseline breathing appear due to age-dependent increases in body weight.

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Abstract 15445: The Sirtuin SIRT3 Blocks Doxorubicin-induced Cardiac Hypertrophic Response of Mice

Circulation ◽

10.1161/circ.130.suppl_2.15445 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Vinodkumar Pillai ◽

Sadhana Samant ◽

Nagalingam Sundaresan ◽

Gene Kim ◽

Mahesh P Gupta

Keyword(s):

Negative Regulator ◽

Neonatal Rat ◽

Whole Body ◽

Wild Type ◽

Electron Microscopic ◽

Specific Expression ◽

Rat Cardiomyocytes ◽

Fluorescent Intensity ◽

Hypertrophic Response

Background and objective: Doxorubicin is a chemotherapeutic drug widely used to treat variety of cancers. One of the serious side effects of doxorubicin is its toxicity to the heart. Previously, we have shown that overexpression of SIRT3 blocks the hypertrophic response of the heart to agonist treatments. This study was undertaken to investigate whether SIRT3 can also attenuate the doxorubicin-induced cardiac hypertrophic response in mice. Methods and results: Neonatal rat cardiomyocytes overexpressed with SIRT3 and treated with doxorubicin (10μM) showed 28% reduced mean fluorescent intensity for CM-H 2 DCFDA dye, compared to mock infected control cells treated with doxorubicin, thus suggesting that SIRT3 was capable of blocking doxorubicin-induced ROS synthesis in cardiomyocytes. To examine the cardioprotective effects of SIRT3 in doxorubicin-induced cardiotoxicity in vivo ; we used a cumulative dose of 15mg/kg of doxorubicin for two different time points. One group of mice was treated intraperitoneally with 5mg/kg doxorubicin or an equal volume of saline every two weeks for a total of three doses. Transgenic mice having cardiac specific expression of SIRT3 (SIRT3-Tg) showed 33% reduced HW/BW ratio compared to control mice. Echocardiographic evaluation of hearts showed significantly reduced fractional shortening in control mice, compared to SIRT3-Tg mice (24.6 vs 34.7 %, P<0.05). SIRT3-Tg mice also showed significantly reduced fetal gene expression for ANF, βMHC and collagen-1 as determined by RT-PCR. Masson’s trichrome staining showed significantly reduced fibrosis in doxorubicin treated SIRT3-Tg mice compared to its control. Furthermore, electron microscopic analysis showed preserved mitochondrial and sarcomeres structures in doxorubicin treated SIRT3-Tg hearts, whereas in wild-type hearts these structures were highly disorganized. Second group of mice that received 15mg/kg dose for two weeks also showed similar results. Contrary to this, whole body SIRT3 knockout mice showed exacerbated cardiac hypertrophic response compared to wild-type mice in response to doxorubicin treatment. Conclusion: These results demonstrated that SIRT3 is an endogenous negative regulator of doxorubicin-induced cardiac hypertrophic response.

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Connexin26 mediates CO2-dependent regulation of breathing via glial cells of the medulla oblongata

Communications Biology ◽

10.1038/s42003-020-01248-x ◽

2020 ◽

Vol 3 (1) ◽

Cited By ~ 3

Author(s):

Joseph van de Wiel ◽

Louise Meigh ◽

Amol Bhandare ◽

Jonathan Cook ◽

Sarbjit Nijjar ◽

...

Keyword(s):

Glial Cells ◽

Minute Ventilation ◽

Dominant Negative ◽

Structural Motif ◽

Wild Type ◽

Arterial Blood ◽

Highly Sensitive ◽

Fundamental Process ◽

Regulation Of Breathing ◽

Direct Sensing

AbstractBreathing is highly sensitive to the PCO2 of arterial blood. Although CO2 is detected via the proxy of pH, CO2 acting directly via Cx26 may also contribute to the regulation of breathing. Here we exploit our knowledge of the structural motif of CO2-binding to Cx26 to devise a dominant negative subunit (Cx26DN) that removes the CO2-sensitivity from endogenously expressed wild type Cx26. Expression of Cx26DN in glial cells of a circumscribed region of the mouse medulla - the caudal parapyramidal area – reduced the adaptive change in tidal volume and minute ventilation by approximately 30% at 6% inspired CO2. As central chemosensors mediate about 70% of the total response to hypercapnia, CO2-sensing via Cx26 in the caudal parapyramidal area contributed about 45% of the centrally-mediated ventilatory response to CO2. Our data unequivocally link the direct sensing of CO2 to the chemosensory control of breathing and demonstrates that CO2-binding to Cx26 is a key transduction step in this fundamental process.

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The affinity of hemoglobin for oxygen affects ventilatory responses in mutant mice with Presbyterian hemoglobinopathy

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00104.2003 ◽

2003 ◽

Vol 285 (4) ◽

pp. R747-R753 ◽

Cited By ~ 7

Author(s):

Masahiko Izumizaki ◽

Masakatsu Tamaki ◽

Yo-ichi Suzuki ◽

Michiko Iwase ◽

Takuji Shirasawa ◽

...

Keyword(s):

Minute Ventilation ◽

Globin Gene ◽

Open Circuit ◽

Mutant Mice ◽

Whole Body ◽

Wild Type ◽

Peripheral Tissues ◽

Ventilatory Responses ◽

Significant Difference ◽

In The Wild

The purpose of this study was to test whether chronically enhanced O2 delivery to tissues, without arterial hyperoxia, can change acute ventilatory responses to hypercapnia and hypoxia. The effects of decreased hemoglobin (Hb)-O2 affinity on ventilatory responses during hypercapnia (0, 5, 7, and 9% CO2 in O2) and hypoxia (10 and 15% O2 in N2) were assessed in mutant mice expressing Hb Presbyterian (mutation in the β-globin gene, β108 Asn → Lys). O2 consumption during normoxia, measured via open-circuit methods, was significantly higher in the mutant mice than in wild-type mice. Respiratory measurements were conducted with a whole body, unrestrained, single-chamber plethysmograph under conscious conditions. During hypercapnia, there was no difference between the slopes of the hypercapnic ventilatory responses, whereas minute ventilation at the same levels of arterial PCO2 was lower in the Presbyterian mice than in the wild-type mice. During both hypoxic exposures, ventilatory responses were blunted in the mutant mice compared with responses in the wild-type mice. The effects of brief hyperoxia exposure (100% O2) after 10% hypoxia on ventilation were examined in anesthetized, spontaneously breathing mice with a double-chamber plethysmograph. No significant difference was found in ventilatory responses to brief hypoxia between both groups of mice, indicating possible involvement of central mechanisms in blunted ventilatory responses to hypoxia in Presbyterian mice. We conclude that chronically enhanced O2 delivery to peripheral tissues can reduce ventilation during acute hypercapnic and hypoxic exposures.

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Ventilatory response to hyperoxia in newborn mice heterozygous for the transcription factor Phox2b

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00875.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. R1691-R1696 ◽

Cited By ~ 27

Author(s):

N. Ramanantsoa ◽

V. Vaubourg ◽

S. Dauger ◽

B. Matrot ◽

G. Vardon ◽

...

Keyword(s):

Transcription Factor ◽

Ventilatory Response ◽

Minute Ventilation ◽

Whole Body ◽

Wild Type ◽

Peripheral Chemoreceptor ◽

Newborn Mice ◽

Apnea Duration ◽

Autonomic Reflex ◽

Hypoventilation Syndrome

Heterozygous mutations of the transcription factor PHOX2B have been found in most patients with central congenital hypoventilation syndrome, a rare disease characterized by sleep-related hypoventilation and impaired chemosensitivity to sustained hypercapnia and sustained hypoxia. PHOX2B is a master regulator of autonomic reflex pathways, including peripheral chemosensitive pathways. In the present study, we used hyperoxic tests to assess the strength of the peripheral chemoreceptor tonic drive in Phox2b+/− newborn mice. We exposed 69 wild-type and 67 mutant mice to two hyperoxic tests (12-min air followed by 3-min 100% O2) 2 days after birth. Breathing variables were measured noninvasively using whole body flow plethysmography. The initial minute ventilation decrease was larger in mutant pups than in wild-type pups: −37% (SD 13) and −25% (SD 18), respectively, P < 0.0001. Furthermore, minute ventilation remained depressed throughout O2 exposure in mutants, possibly because of their previously reported impaired CO2 chemosensitivity, whereas it returned rapidly to the normoxic level in wild-type pups. Hyperoxia considerably increased total apnea duration in mutant compared with wild-type pups ( P = 0.0001). A complementary experiment established that body temperature was not influenced by hyperoxia in either genotype group and, therefore, did not account for genotype-related differences in the hyperoxic ventilatory response. Thus partial loss of Phox2b function by heterozygosity did not diminish the tonic drive from peripheral chemoreceptors.

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Ventilatory responses during and following hypercapnic gas challenge are impaired in male but not female endothelial NOS knock-out mice

Scientific Reports ◽

10.1038/s41598-021-99922-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Paulina M. Getsy ◽

Sripriya Sundararajan ◽

Walter J. May ◽

Graham C. von Schill ◽

Dylan K. McLaughlin ◽

...

Keyword(s):

Tidal Volume ◽

Minute Ventilation ◽

Whole Body ◽

Inspiratory Time ◽

Male And Female ◽

Knock Out ◽

Ventilatory Responses ◽

Knock Out Mice ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

AbstractThe roles of endothelial nitric oxide synthase (eNOS) in the ventilatory responses during and after a hypercapnic gas challenge (HCC, 5% CO2, 21% O2, 74% N2) were assessed in freely-moving female and male wild-type (WT) C57BL6 mice and eNOS knock-out (eNOS-/-) mice of C57BL6 background using whole body plethysmography. HCC elicited an array of ventilatory responses that were similar in male and female WT mice, such as increases in breathing frequency (with falls in inspiratory and expiratory times), and increases in tidal volume, minute ventilation, peak inspiratory and expiratory flows, and inspiratory and expiratory drives. eNOS-/- male mice had smaller increases in minute ventilation, peak inspiratory flow and inspiratory drive, and smaller decreases in inspiratory time than WT males. Ventilatory responses in female eNOS-/- mice were similar to those in female WT mice. The ventilatory excitatory phase upon return to room-air was similar in both male and female WT mice. However, the post-HCC increases in frequency of breathing (with decreases in inspiratory times), and increases in tidal volume, minute ventilation, inspiratory drive (i.e., tidal volume/inspiratory time) and expiratory drive (i.e., tidal volume/expiratory time), and peak inspiratory and expiratory flows in male eNOS-/- mice were smaller than in male WT mice. In contrast, the post-HCC responses in female eNOS-/- mice were equal to those of the female WT mice. These findings provide the first evidence that the loss of eNOS affects the ventilatory responses during and after HCC in male C57BL6 mice, whereas female C57BL6 mice can compensate for the loss of eNOS, at least in respect to triggering ventilatory responses to HCC.

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003 Treatment of Sleep Disordered Breathing with Leptin Loaded Exosomes

SLEEP ◽

10.1093/sleep/zsab072.002 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A1-A2

Author(s):

Carla Freire ◽

Huy Pho ◽

Jacob Ramsey ◽

Stone Streeter ◽

Ryo Kojima ◽

...

Keyword(s):

Sleep Apnea ◽

Sleep Disordered Breathing ◽

Imaging System ◽

Minute Ventilation ◽

Upper Airway ◽

Control Of Breathing ◽

Obstructive Sleep ◽

Hypoventilation Syndrome ◽

Disordered Breathing

Abstract Introduction Obstructive sleep apnea (OSA) is characterized by recurrent periods of upper airway obstruction. The prevalence of OSA exceeds 50% in obese individuals and in 10–20% of obese patients OSA coexists with obesity hypoventilation syndrome (OHS) defined as daytime hypercapnia and hypoventilation during sleep attributed to the depressed control of breathing. There is no effective pharmacotherapy for OSA and OHS. Leptin is a potent respiratory stimulant and a potential therapeutic candidate. However, diet-induced obesity (DIO) results in reduced permeability of the blood-brain barrier (BBB) for leptin. Previous studies have shown that the BBB can be penetrated by exosomes, natural nanoparticles that can be used as drug delivery vehicles. In this study, we aimed to determine if exosomes overcome the BBB and treat OSA and OHS in DIO mice. Methods o examine the ability of exosomes to cross the BBB, male, lean (n=5) and DIO (n=5) C57BL/6J mice were injected with fluorescent exosomes or saline into the lateral tail vein. After 4h fluorescent exosomes biodistribution was evaluated by an in vitro imaging system (IVIS). Saline injected mice images were used for background adjustment. A separate subgroup of male, DIO (n=10) and lean (n=10) mice were headmounted with EEG and nuchal EMG leads. Sleep studies were performed in a plethysmography chamber and mice received saline, empty exosomes, free leptin, or leptin-loaded exosomes in a crossover manner. Results Exosomes were successfully delivered to the brain and the transport across the BBB was more efficient in DIO mice with 2-times greater relative fluorescence units measured in DIO when compared to lean mice (p<0.005). In DIO mice, exosomal leptin induced dramatic 1.7-2.2-fold increases in minute ventilation and 1.5-2.0-fold increases in maximal inspiratory flow during both flow-limited (upper airway/sleep apnea) and non-flow limited breathing (control of breathing) (p<0.05). In contrast, free leptin had no effect. Lean mice did not present significant sleep disordered breathing and no differences were observed between groups. Conclusion We demonstrated that exosomes overcome the BBB and that leptin-loaded exosomes treat OSA and OHS in DIO mice. Support (if any) R01HL 128970, R01HL 138932, R61 HL156240, U18 DA052301, FAPESP 2018/08758-3

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Dynamic Changes in Respiratory Frequency/Tidal Volume May Predict Failures of Ventilatory Liberation in Patients on Prolonged Mechanical Ventilation and Normal Preliberation Respiratory Frequency/Tidal Volume Values

The American Surgeon ◽

10.1177/000313481207800138 ◽

2012 ◽

Vol 78 (1) ◽

pp. 69-73 ◽

Cited By ~ 1

Author(s):

Raeanna C. Adams ◽

Oliver L. Gunter ◽

Jonathan R. Wisler ◽

Melissa L. Whitmill ◽

James Cipolla ◽

...

Keyword(s):

Mechanical Ventilation ◽

Tidal Volume ◽

Prolonged Mechanical Ventilation ◽

Respiratory Frequency ◽

Dynamic Changes ◽

Mechanically Ventilated ◽

Rapid Shallow Breathing Index ◽

Shallow Breathing ◽

Mean Time ◽

Better Than

Rapid shallow breathing index (RSBI, respiratory frequency [f] divided by tidal volume [Vt]) has been used to prognosticate liberation from mechanical ventilation (LMV). We hypothesize that dynamic changes in RSBI predict failed LMV better than isolated RSBI measurements. We conducted a retrospective study of patients who were mechanically ventilated (MV) for longer than 72 hours. Failed LMV was defined as need for reinstitution of MV within 48 hours post-LMV. Ventilatory frequency (f) and Vt (liters) were serially recorded. The instantaneous RSBI (i-RSBI) was defined as f/Vt. Dynamic f/Vt ratio (d-RSBI) was defined as the ratio between two consecutive i-RSBI (f/Vt) measurements ([f2/Vt2]/[f1/Vt1]). RSBI Product (RSB-P) was defined as (i-RSBI 3 d-RSBI). Data from 32 patients were analyzed (Acute Physiology and Chronic Health Evaluation II 13.4, male 69%, mean age 57 years). Mean length of stay was 19.5 days (11.5 ventilator; 14.1 intensive care unit days). For LMV failures, mean time to reinstitution of invasive MV was 20.8 hours. All patients had pre-LMV i-RSBI less than 100. Failed LMVs had higher i-RSBI values (68.9, n = 18) than successful LMVs (44.2, n = 23, P < 0.01). Failures had higher d-RSBI (1.48) than successful LMVs (1.05, P < 0.04). The RSB-P was higher for failed LMVs (118) than for successful LMVs (48.8, P < 0.01) with failures having larger proportion of pre-LMV d-RSBI values greater than 1.5 (39.0 vs 10.7%, P < 0.03). Pre-LMV RSB-P may offer early prediction of failed LMV in patients on MV for longer than 72 hours despite normal pre-LMV i-RSBI. Divergence between RSB-P for successful and failed LMVs occurred earlier than i-RSBI divergence with a greater proportion of pre-LMV d-RSBI greater than 1.5 among failures.

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Role of the carotid bodies in chemosensory ventilatory responses in the anesthetized mouse

Journal of Applied Physiology ◽

10.1152/japplphysiol.00025.2004 ◽

2004 ◽

Vol 97 (4) ◽

pp. 1401-1407 ◽

Cited By ~ 26

Author(s):

Masahiko Izumizaki ◽

Mieczyslaw Pokorski ◽

Ikuo Homma

Keyword(s):

Tidal Volume ◽

Carotid Body ◽

Minute Ventilation ◽

Respiratory Frequency ◽

Whole Body ◽

Sudden Increase ◽

Ventilatory Responses ◽

Carotid Bodies ◽

Before And After ◽

Carotid Body Denervation

We examined the effects of carotid body denervation on ventilatory responses to normoxia (21% O2 in N2 for 240 s), hypoxic hypoxia (10 and 15% O2 in N2 for 90 and 120 s, respectively), and hyperoxic hypercapnia (5% CO2 in O2 for 240 s) in the spontaneously breathing urethane-anesthetized mouse. Respiratory measurements were made with a whole body, single-chamber plethysmograph before and after cutting both carotid sinus nerves. Baseline measurements in air showed that carotid body denervation was accompanied by lower minute ventilation with a reduction in respiratory frequency. On the basis of measurements with an open-circuit system, no significant differences in O2 consumption or CO2 production before and after chemodenervation were found. During both levels of hypoxia, animals with intact sinus nerves had increased respiratory frequency, tidal volume, and minute ventilation; however, after chemodenervation, animals experienced a drop in respiratory frequency and ventilatory depression. Tidal volume responses during 15% hypoxia were similar before and after carotid body denervation; during 10% hypoxia in chemodenervated animals, there was a sudden increase in tidal volume with an increase in the rate of inspiration, suggesting that gasping occurred. During hyperoxic hypercapnia, ventilatory responses were lower with a smaller tidal volume after chemodenervation than before. We conclude that the carotid bodies are essential for maintaining ventilation during eupnea, hypoxia, and hypercapnia in the anesthetized mouse.

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