Systemic Administration of Serotonin 2A/2C Agonist Improves Upper Airway Stability in Zucker Rats

Ogasa, Toshiyuki; Ray, Andrew D.; Michlin, Charles; Farkas, Gaspar A.; Grant, Brydon J. B.; Magalang, Ulysses J.

doi:10.1164/rccm.200312-1674oc

Cited by 32 publications

(35 citation statements)

References 40 publications

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“…Third, we recognize that dynamic responses during anesthesia cannot be extrapolated to sleep. Nonetheless, the isolated murine upper airway exhibited pressure-flow dynamics, a passive Pcrit, and dynamic neuromuscular responses that were remarkably similar to those previously demonstrated across species (27,30,43,49,51) and in sleeping subjects (36). Despite differences in upper airway anatomy and size, it is nonetheless remarkable that inspiratory airflow limitation and critical closure occur at similar levels of pharyngeal critical pressure in normal sleeping humans and in anesthetized dogs, rabbits, cats, rats, and mice (10,27,42,49,51,54).…”

Section: Discussionsupporting

confidence: 74%

“…In contrast to previous methods for assessing these parameters in larger animals (1, 8 -10, 27, 30, 40), the present approach obviated the need for an intraluminal pressure-monitoring cannula in the pharynx, which might have produced artifactual changes in our measurements of upper airway properties in the mouse. Despite this methodological difference, pressure-flow dynamics in the isolated murine upper airway resembled those previously demonstrated in the larger anesthetized animals and sleeping humans and yielded comparable levels of passive Pcrit (27,30,46,47,49,51,53), suggesting similarities in the mechanical determinants of pharyngeal patency across species.…”

Section: Discussionsupporting

confidence: 52%

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Neuromechanical control of the isolated upper airway of mice

Liu¹,

Pichard

Schneider³

et al. 2008

Journal of Applied Physiology

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Liu A, Pichard L, Schneider H, Patil SP, Smith PL, Polotsky V, Schwartz AR. Neuromechanical control of the isolated upper airway of mice. J Appl Physiol 105: 1237-1245, 2008. First published July 24, 2008 doi:10.1152/japplphysiol.90461.2008.-We characterized the passive structural and active neuromuscular control of pharyngeal collapsibility in mice and hypothesized that pharyngeal collapsibility, which is elevated by anatomic loads, is reduced by active neuromuscular responses to airflow obstruction. To address this hypothesis, we examined the dynamic control of upper airway function in the isolated upper airway of anesthetized C57BL/6J mice. Pressures were lowered downstream and upstream to the upper airway to induce inspiratory airflow limitation and critical closure of the upper airway, respectively. After hyperventilating the mice to central apnea, we demonstrated a critical closing pressure (Pcrit) of Ϫ6.2 Ϯ 1.1 cmH2O under passive conditions that was unaltered by the state of lung inflation. After a period of central apnea, lower airway occlusion led to progressive increases in phasic genioglossal electromyographic activity (EMGGG), and in maximal inspiratory airflow (V Imax) through the isolated upper airway, particularly as the nasal pressure was lowered toward the passive Pcrit level. Moreover, the active Pcrit fell during inspiration by 8.2 Ϯ 1.4 cmH2O relative to the passive condition (P Ͻ 0.0005). We conclude that upper airway collapsibility (passive Pcrit) in the C57BL/6J mouse is similar to that in the anesthetized canine, feline, and sleeping human upper airway, and that collapsibility falls markedly under active conditions. Active EMGGG and V Imax responses dissociated at higher upstream pressure levels, suggesting a decrease in the mechanical efficiency of upper airway dilators. Our findings in mice imply that anatomic and neuromuscular factors interact dynamically to modulate upper airway function, and provide a novel approach to modeling the impact of genetic and environmental factors in inbred murine strains. obstructive sleep apnea; upper airway collapsibility; critical closing pressure OBSTRUCTIVE SLEEP APNEA is a common disorder with a wide spectrum of neurocognitive, metabolic, and cardiovascular consequences (28,37,39,52,61). Its clinical sequelae stem from frequent nocturnal arousals and/or oxyhemoglobin desaturations, which result from recurrent episodes of upper airway obstruction during sleep (41). Obstruction has been related to elevations in pharyngeal collapsibility during sleep (12,36,47,53), although the mechanism for these elevations is not well understood.Structural alterations and disturbances in neuromuscular control account for elevations in upper airway collapsibility in sleep apnea patients compared with normal controls (36). Boney and soft tissue defects can increase pharyngeal collapsibility by elevating the pressure in tissues around the pharynx (15-19, 59). The impact of structural alterations on upper airway collapsibility may be mitigated by increases in lung volu...

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Section: Discussionsupporting

confidence: 74%

Section: Discussionsupporting

confidence: 52%

Neuromechanical control of the isolated upper airway of mice

Liu¹,

Pichard

Schneider³

et al. 2008

Journal of Applied Physiology

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“…It was suggested that in isofl urane-anesthetized, lean and obese Zucker rats, systemic administration of 5-HT 2A and 2C receptor agonist [2,5-dimethoxy-4-iodoaminophentamine] improved upper airway collapsibility [16] . In similar trials, treatment responses may differ between both genders because of the genetic differences between male and female OSAS patients.…”

Section: Discussionmentioning

confidence: 99%

Association of the –1438G/A Polymorphism of the 5-HT<sub>2A </sub>Receptor Gene with Obstructive Sleep Apnea Syndrome

Bayazıt

Yılmaz

Çiftçi

et al. 2006

ORL

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Objective: Serotonergic neurons innervating motoneurons increase their firing rates in response to respiratory challenges, and long-term facilitation of respiratory activity in response to hypoxia is serotonin (5-HT) dependent. Polymorphism of the genes which code for 5-HT receptors may affect functions of the serotonergic system, and may be associated with obstructive sleep apnea syndrome (OSAS). The objective in this study was to assess the significance of T102C and –1438G/A polymorphisms of the 5-HT_2A receptor gene in OSAS. Methods: Fifty-five patients with OSAS and 102 healthy volun teers were included for genetic analyses of T102C and –1438G/A polymorphisms of the 5-HT_2A receptor gene. Results: For the T102C polymorphism, there was no significant difference between the patients and controls and both genders (p > 0.05). For the –1438G/A polymorphism, the A/A and G/A genotypes were overrepresented in the patients and controls, respectively (p = 0.045). In the control group, the genotypes of both genders were not significantly different (p > 0.05). In the patients, the A/A and G/A genotypes were overrepresented in males and females, respectively (p = 0.035). Concerning males, the A/A genotype was overrepresented in patients (p = 0.007). Conclusion: Serotonergic mechanisms appear to be related to OSAS. The T102C polymorphism of the 5-HT_2A receptor gene is not associated with OSAS. However, the –1438G/A polymorphism is associated with OSAS occurrence, especially in male patients. This polymorphism may also be associated with different OSAS incidences of both genders.

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“…In particular, the serotonin 2A receptor has been found to be the predominant excitatory serotonin receptor subtype at hypoglossal motor neurons (28), and administration of serotonin 2A receptor agonist improves upper airway stability in animal models (29). Although HTR2A may influence SDB through pleiotropic pathways (influencing both airway function and obesity), the association we observed was attenuated with BMI adjustment.…”

Section: Discussionmentioning

confidence: 60%

A Candidate Gene Study of Obstructive Sleep Apnea in European Americans and African Americans

Larkin¹,

Patel²,

Goodloe³

et al. 2010

Am J Respir Crit Care Med

104

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Rationale: Obstructive sleep apnea (OSA) is hypothesized to be influenced by genes within pathways involved with obesity, craniofacial development, inflammation, and ventilatory control. Objectives: We conducted the first candidate gene study of OSA using family data from European Americans and African Americans, selecting biologically plausible genes from within these pathways. Methods: A total of 1,080 single nucleotide polymorphisms (SNPs) were genotyped in 729 African Americans and 505 SNPs were genotyped in 694 European Americans. Coding for SNPs additively, association testing on the apnea-hypopnea index (AHI) as a continuous trait, and OSA as a dichotomous trait (AHI >15) was conducted using methods that account for familial correlations in models adjusted for age, age-squared, and sex, with and without body mass index. Measurements and Main Results: In European Americans, variants within C-reactive protein (CRP) and glial cell line-derived neurotrophic factor (GDNF) were associated with AHI (CRP: b 5 4.6; SE 5 1.1; P 5 0.0000402) (GDNF: b 5 4.3; SE 5 1; P 5 0.0000201) and with the dichotomous OSA trait (CRP: odds ratio 5 2.4; 95% confidence interval, 1.5-3.9; P 5 0.000170) (GDNF: odds ratio 5 2; 95% confidence interval, 1.4-2.89; P 5 0.0000433). In African Americans, rs9526240 within serotonin receptor 2a (HTR2A: odds ratio 5 2.1; 95% confidence interval, 1.5-2.9; P 5 0.00005233) was associated with OSA. Conclusions: This candidate gene analysis identified the potential role of genes operating through intermediate disease pathways to influence sleep apnea phenotypes, providing a framework for focusing future replication studies.Keywords: sleep apnea; body mass index; genetics; candidate gene study Sleep-disordered breathing (SDB) or its clinical counterpart, obstructive sleep apnea (OSA), is a common disorder characterized by intermittent collapse of the upper airway during sleep-disrupting breathing, and associated with significant morbidity including daytime sleepiness, hypertension, and elevated cardiovascular risk. It has been recognized for more than three decades that SDB aggregates within families, suggesting the presence of a genetic basis for this disease (1). Approximately 30-40% of the variance in the most common disease-defining metric for SDB, the apnea-hypopnea index (AHI), has been estimated to be explained by genetic factors (2). Having a first-degree relative with SDB increases one's risk of the disorder by more than 1.5-fold (2). Several genome-wide linkage and association studies have been conducted for SDB-related traits (3-5) (summarized in Riha [6]). The latter have been limited by considering only a handful of polymorphisms in one gene or by consideration of more than a few genes in each given population, and by limited statistical power. To date, no genetic variants have been shown to associate strongly with SDB.We postulated that identifying genetic variants for SDB would be facilitated by studying polymorphisms in genes in pathways intermediate to SDB and previously established ...

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Systemic Administration of Serotonin 2A/2C Agonist Improves Upper Airway Stability in Zucker Rats

Cited by 32 publications

References 40 publications

Neuromechanical control of the isolated upper airway of mice

Neuromechanical control of the isolated upper airway of mice

Association of the –1438G/A Polymorphism of the 5-HT<sub>2A </sub>Receptor Gene with Obstructive Sleep Apnea Syndrome

A Candidate Gene Study of Obstructive Sleep Apnea in European Americans and African Americans

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