Leptin receptor expression in the dorsomedial hypothalamus stimulates breathing during NREM sleep in db/db mice

Abstract Study Objectives Obesity leads to obstructive sleep apnea (OSA), which is recurrent upper airway obstruction during sleep, and obesity hypoventilation syndrome (OHS), hypoventilation during sleep resulting in daytime hypercapnia. Impaired leptin signaling in the brain was implicated in both conditions, but mechanisms are unknown. We have previously shown that leptin stimulates breathing and treats OSA and OHS in leptin- deficient ob/ob mice and leptin-resistant diet-induced obese mice and that leptin’s respiratory effects may occur in the dorsomedial hypothalamus (DMH). We hypothesized that leptin receptor LepR b–deficient db/db mice have obesity hypoventilation and that restoration of leptin signaling in the DMH will increase ventilation during sleep in these animals. Methods We measured arterial blood gas in unanesthetized awake db/db mice. We subsequently infected these animals with Ad-LepR b or control Ad-mCherry virus into the DMH and measured ventilation during sleep as well as CO2 production after intracerebroventricular (ICV) infusions of phosphate-buffered saline or leptin. Results Awake db/db mice had elevated CO2 levels in the arterial blood. Ad-LepR b infection resulted in LepR b expression in the DMH neurons in a similar fashion to wildtype mice. In LepR b-DMH db/db mice, ICV leptin shortened REM sleep and increased inspiratory flow, tidal volume and minute ventilation during NREM sleep without any effect on the quality of NREM sleep or CO2 production. Leptin had no effect on upper airway obstruction in these animals. Conclusion Leptin stimulates breathing and treats obesity hypoventilation acting on LepR b-positive neurons in the DMH.

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Leptin receptor expression in the dorsomedial hypothalamus stimulates breathing during NREM sleep in db/db mice

10.1101/2020.09.29.318758 ◽

2020 ◽

Author(s):

Huy Pho ◽

Slava Berger ◽

Carla Freire ◽

Lenise J Kim ◽

Mi-Kyung Shin ◽

...

Keyword(s):

Airway Obstruction ◽

Leptin Receptor ◽

Minute Ventilation ◽

Upper Airway ◽

Nrem Sleep ◽

Receptor Expression ◽

Upper Airway Obstruction ◽

Dorsomedial Hypothalamus ◽

Obstructive Sleep ◽

Alveolar Hypoventilation

ABSTRACTObesity can lead to recurrent upper airway obstruction (obstructive sleep apnea, OSA) during sleep as well as alveolar hypoventilation. We have previously shown that leptin stimulates breathing and treats OSA in leptin-deficient ob/ob mice and leptin-resistant diet-induced obese mice. Our previous data also suggest that leptin’s respiratory effects may occur in the dorsomedial hypothalamus (DMH). We selectively expressed leptin receptor LepRb in the DMH neurons of obese LepRb-deficient db/db mice (LepRb-DMH mice), which hypoventilate at baseline, and showed that intracerebroventricular injection of leptin in these animals increased inspiratory flow, tidal volume and minute ventilation during NREM sleep without any effect on the quality of NREM sleep or CO2 production. Leptin had no effect on upper airway obstruction in LepRb-DMH animals. We conclude that leptin stimulates breathing and treats obesity related hypoventilation acting on LepRb-positive neurons in the DMH.

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Compensatory responses to upper airway obstruction in obese apneic men and women

Journal of Applied Physiology ◽

10.1152/japplphysiol.00021.2011 ◽

2012 ◽

Vol 112 (3) ◽

pp. 403-410 ◽

Cited By ~ 24

Author(s):

Chien-Hung Chin ◽

Jason P. Kirkness ◽

Susheel P. Patil ◽

Brian M. McGinley ◽

Philip L. Smith ◽

...

Keyword(s):

Sleep Apnea ◽

Airway Obstruction ◽

Rem Sleep ◽

Minute Ventilation ◽

Upper Airway ◽

Nrem Sleep ◽

Upper Airway Obstruction ◽

Men And Women ◽

Compensatory Responses ◽

Obstructive Sleep

Defective structural and neural upper airway properties both play a pivotal role in the pathogenesis of obstructive sleep apnea. A more favorable structural upper airway property [pharyngeal critical pressure under hypotonic conditions (passive Pcrit)] has been documented for women. However, the role of sex-related modulation in compensatory responses to upper airway obstruction (UAO), independent of the passive Pcrit, remains unclear. Obese apneic men and women underwent a standard polysomnography and physiological sleep studies to determine sleep apnea severity, passive Pcrit, and compensatory airflow and respiratory timing responses to prolonged periods of UAO. Sixty-two apneic men and women, pairwise matched by passive Pcrit, exhibited similar sleep apnea disease severity during rapid eye movement (REM) sleep, but women had markedly less severe disease during non-REM (NREM) sleep. By further matching men and women by body mass index and age ( n = 24), we found that the lower NREM disease susceptibility in women was associated with an approximately twofold increase in peak inspiratory airflow ( P = 0.003) and inspiratory duty cycle ( P = 0.017) in response to prolonged periods of UAO and an ∼20% lower minute ventilation during baseline unobstructed breathing (ventilatory demand) ( P = 0.027). Thus, during UAO, women compared with men had greater upper airway and respiratory timing responses and a lower ventilatory demand that may account for sex differences in sleep-disordered breathing severity during NREM sleep, independent of upper airway structural properties and sleep apnea severity during REM sleep.

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Tracheostomy and respiratory dead space in emphysema

Journal of Applied Physiology ◽

10.1152/jappl.1964.19.1.92 ◽

1964 ◽

Vol 19 (1) ◽

pp. 92-96 ◽

Cited By ~ 8

Author(s):

Herman F. Froeb ◽

Byong M. Kim

Keyword(s):

Airway Obstruction ◽

Dead Space ◽

Arterial Oxygen Saturation ◽

Upper Airway ◽

Alveolar Ventilation ◽

Upper Airway Obstruction ◽

Arterial Oxygen ◽

Lower Airway ◽

Arterial Blood ◽

Lower Airway Obstruction

Acute experimentation to judge the effects of reduction of dead space with tracheostomy breathing was performed on four subjects with lower airway obstruction (bronchitis and emphysema) and on two subjects with upper airway obstruction (carcinoma of the larynx and tracheal stenosis). With tracheostomy breathing, the reduction in dead space led to a decrease in minute ventilation except in the two patients with upper airway obstruction. Alveolar ventilation decreased except when alveolar hypoventilation was present to start with. There was no change or an increase in Pacoco2 and H+ in the subjects with lower airway obstruction and small increases in arterial oxygen saturation and Paoo2 occurred. A decrease in Pacoco2 and H+ occurred in one of two patients with upper airway obstruction. Reduction of dead space per se with tracheostomy breathing brings about small changes in alveolar ventilation and gas exchange in the lungs of patients with chronic bronchitis and emphysema. Note:(With the Technical Assistance of Roy Engstrom, Mabel Pearson, and Tom Purcell) physiological dead space and tracheostomy; arterial blood gases with tracheostomy breathing; tracheostomy versus mouth breathing; emphysema and tracheostomy breathing Submitted on February 11, 1963

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Cardiorespiratory evaluation of brachycephalic syndrome in dogs

Pesquisa Veterinária Brasileira ◽

10.1590/1678-5150-pvb-5376 ◽

2018 ◽

Vol 38 (6) ◽

pp. 1130-1136 ◽

Cited By ~ 1

Author(s):

Raphaela A.M. Canola ◽

Marlos G. Sousa ◽

Jaislane B. Braz ◽

Wilmer Alejandro Z. Restan ◽

Diego I. Yamada ◽

...

Keyword(s):

Airway Obstruction ◽

Clinical Manifestations ◽

Upper Airway ◽

Cor Pulmonale ◽

Indirect Measurement ◽

Upper Airway Obstruction ◽

Control Group ◽

Upper Respiratory Tract ◽

Arterial Blood ◽

A Prospective Study

ABSTRACT: Brachycephalic syndrome (BS) in dogs is characterized by the combination of primary and secondary upper respiratory tract abnormalities and may result in significant upper airway obstruction. It can trigger inspiratory dyspnea, culminating in secondary respiratory distress, soft tissue edema, upper airway obstruction, turbulent airflow, inspiratory noise, and even death. These changes lead to increased resistance of the air passages, which can cause elevation of pulmonary pressure and clinical manifestations attributable to pulmonary hypertension. The consequence is right-sided cardiac remodeling (Cor pulmonale) with possible progression to right congestive heart failure. To investigate the effects of BS on the cardiovascular system, 28 animals were recruited for a prospective study and assigned to either the Brachycephalic Group (BG), composed of 22 French bulldogs with BS or the Control Group (CG), which was composed of 6 healthy Beagle dogs. All animals underwent a detailed physical examination, as well as laboratory analyses, electrocardiography, echocardiography, chest radiography and indirect measurement of systemic arterial blood pressure. The most relevant finding was a lower PaO2 (90.6±12.9mmHg) in BG as compared to CG (104.9±5.2), (p≤0.05), possibly attributable to hypoventilation due to anatomical alterations.

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High flow versus conventional nasal cannula for oxygenation and ventilation maintenance during surgery with intravenous deep sedation by propofol: a randomized controlled study

BMC Anesthesiology ◽

10.1186/s12871-021-01432-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Amorn Vijitpavan ◽

Yanin Kooncharoensuk

Keyword(s):

Airway Obstruction ◽

Deep Sedation ◽

Upper Airway ◽

High Flow ◽

Upper Airway Obstruction ◽

Blood Gas ◽

Physical Status ◽

Arterial Blood Gas ◽

Mouth Dryness ◽

Arterial Blood

Abstract Background The dead space washout and provision of some level of positive airway pressure by nasal high-flow (NHF) cannula could improve the efficiency of ventilation, oxygenation and maintenance of the upper airway in patients undergoing deep sedation. This study aimed to compare the incidences of events represented oxygenation and ventilation, i.e. desaturation and upper airway obstruction, and arterial blood gas (ABG) levels between using NHF cannula and conventional nasal cannula (NC2) during deep sedation of adult surgical patients. Methods In this prospective randomized single-blinded study, the patients who were 20–80 years old, ASA physical status of 1 to 3, scheduled for surgery under intravenous sedation (IVS) were included. The patients were randomly divided into two groups, i.e., NC2 or NHF groups. Propofol infusion was given to maintain deep sedation. The desaturation (SpO2 < 92%) and upper airway obstruction events (presence of snoring with paradoxical breathing) after application of NC2 or NHF were observed and collected. Other outcomes included interventions during IVS, such as jaw lifting or airway instrument insertion, mouth dryness, and post- ABG analyses were also collected and compared. Results Thirty-six patients undergoing endovascular surgery were randomized into NC2 or NHF groups (18 in each group). No patients dropped out of the study. There were no significant differences in age, sex, ASA physical status, pre-sedation and pre-application of NC2 and NHF ABG analyses (PaO2, SaO2, pH, PaCO2, and PaO2/FiO2). NHF group had significantly lower in the incidence of desaturation [5 (27.78%) vs 13 (72.22%), p = 0.008], upper airway obstruction [4 (22.22%) vs 13 (72.22%), p = 0.003], and airway maneuver [6 (33.33%) vs 13 (72.22%), p = 0.019] than NC2 group. There were no differences in the ABG analyses after oxygen supplementation and no significant differences in mouth dryness between groups. Conclusion The use of NHF cannula in patients undergoing endovascular surgery under deep sedation reduced desaturation events and required fewer airway interventions than NC2 with no difference in arterial blood gas analyses and mouth dryness.

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Using the pathophysiology of obstructive sleep apnea to teach cardiopulmonary integration

AJP Advances in Physiology Education ◽

10.1152/advan.90137.2008 ◽

2008 ◽

Vol 32 (3) ◽

pp. 196-202 ◽

Cited By ~ 10

Author(s):

Michael G. Levitzky

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Airway Obstruction ◽

Upper Airway ◽

Blood Gases ◽

Upper Airway Obstruction ◽

Systemic Hypertension ◽

Arterial Blood Gases ◽

Arterial Blood ◽

Obstructive Sleep

Obstructive sleep apnea (OSA) is a common disorder of upper airway obstruction during sleep. The effects of intermittent upper airway obstruction include alveolar hypoventilation, altered arterial blood gases and acid-base status, and stimulation of the arterial chemoreceptors, which leads to frequent arousals. These arousals disturb sleep architecture and cause hypersomnolence. Chronic intermittent alveolar and systemic arterial hypoxia-hypercapnia can cause pulmonary and systemic hypertension, with effects on the right and left ventricles, and even the renal system. The pathophysiology of OSA can therefore be used to review and integrate many topics in pulmonary and cardiovascular physiology in the context of problem-based learning, a guided discussion, or a formal lecture. The discussion begins with a case scenario, followed by a definition of the disorder, the common symptoms and signs of OSA, and a description of an apneic event. These are related to the physiology of the upper airway in OSA, normal alterations in the respiratory system during sleep, the effects of apnea on gas exchange and arterial blood gases, and the cardiovascular consequences of alterations in alveolar and systemic arterial Po2 and Pco2. The treatment of OSA, particularly how the use of continuous positive airway pressure relates to the pathophysiology of the disorder, is discussed briefly.

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Induction of periodic breathing during sleep causes upper airway obstruction in humans

Journal of Applied Physiology ◽

10.1152/jappl.1986.61.4.1438 ◽

1986 ◽

Vol 61 (4) ◽

pp. 1438-1443 ◽

Cited By ~ 102

Author(s):

E. Onal ◽

D. L. Burrows ◽

R. H. Hart ◽

M. Lopata

Keyword(s):

Airway Obstruction ◽

Upper Airway ◽

Periodic Breathing ◽

Nrem Sleep ◽

Upper Airway Obstruction ◽

Respiratory Pattern ◽

Normal Male ◽

Added Resistance ◽

Upper Airways ◽

Resistive Loading

To test the hypothesis that occlusive apneas result from sleep-induced periodic breathing in association with some degree of upper airway compromise, periodic breathing was induced during non-rapid-eye-movement (NREM) sleep by administering hypoxic gas mixtures with and without applied external inspiratory resistance (9 cmH2O X l-1 X s) in five normal male volunteers. In addition to standard polysomnography for sleep staging and respiratory pattern monitoring, esophageal pressure, tidal volume (VT), and airflow were measured via an esophageal catheter and pneumotachograph, respectively, with the latter attached to a tight-fitting face mask, allowing calculation of total pulmonary system resistance (Rp). During stage I/II NREM sleep minimal period breathing was evident in two of the subjects; however, in four subjects during hypoxia and/or relief from hypoxia, with and without added resistance, pronounced periodic breathing developed with waxing and waning of VT, sometimes with apneic phases. Resistive loading without hypoxia did not cause periodicity. At the nadir of periodic changes in VT, Rp was usually at its highest and there was a significant linear relationship between Rp and 1/VT, indicating the development of obstructive hypopneas. In one subject without added resistance and in the same subject and in another during resistive loading, upper airway obstruction at the nadir of the periodic fluctuations in VT was observed. We conclude that periodic breathing resulting in periodic diminution of upper airway muscle activity is associated with increased upper airway resistance that predisposes upper airways to collapse.

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