Serotonergic Modulation of Ventilation and Upper Airway Stability in Obese Zucker Rats

Nakano, Hitoo; Magalang, Ulysses J.; Lee, Shin-Da; Krasney, J. A.; Farkas, Gaspar A.

doi:10.1164/ajrccm.163.5.2004230

Cited by 62 publications

(77 citation statements)

References 34 publications

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“…We hypothesized that the obese NZO mouse has upper airway narrowing, as described in other obese animal models (9,12,14,24). Support for this hypothesis comes from the unusual observation by staff at the Jackson Laboratory (Bar Harbor, Maine) that obese NZO mice occasionally sleep upright (see Figure E1 in the online supplement).…”

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confidence: 80%

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Altered Upper Airway and Soft Tissue Structures in the New Zealand Obese Mouse

Brennick¹,

Pack²,

Ko³

et al. 2009

Am J Respir Crit Care Med

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Rationale: The effect of obesity on upper airway soft tissue structure and size was examined in the New Zealand Obese (NZO) mouse and in a control lean mouse, the New Zealand White (NZW). Objectives: We hypothesized that the NZO mouse has increased volume of neck fat and upper airway soft tissues and decreased pharyngeal airway caliber. Methods: Pharyngeal airway size, volume of the upper airway soft tissue structures, and distribution of fat in the neck and body were measured using magnetic resonance imaging (MRI). Dynamic MRI was used to examine the differences in upper airway caliber between inspiration and expiration in NZO versus NZW mice. Measurements and Main Results:The data support the hypothesis that, in obese NZO versus lean NZW mice, airway caliber was significantly smaller (P , 0.03), with greater parapharyngeal fat pad volumes (P , 0.0001) and a greater volume of other upper airway soft tissue structures (tongue, P 5 0.003; lateral pharyngeal walls, P 5 0.01; soft palate, P 5 0.02). Dynamic MRI showed that the airway of the obese NZO mouse dilated during inspiration, whereas in the lean NZW mouse, the upper airway was reduced in size during inspiration. Conclusions: In addition to the increased volume of pharyngeal soft tissue structures, direct fat deposits within the tongue may contribute to airway compromise in obesity. Pharyngeal airway dilation during inspiration in NZO mice compared with narrowing in NZW mice suggests that airway compromise in obese mice may lead to muscle activation to defend upper airway patency during inspiration.

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confidence: 80%

“…This effect of obesity is found not only in humans but has also been observed in several animal models of obesity. Airway narrowing and increased collapsibility have been shown in the obese Zucker rats (9)(10)(11)(12), and increased upper airway resistance has been demonstrated in obese pigs (13,14).…”

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confidence: 99%

Altered Upper Airway and Soft Tissue Structures in the New Zealand Obese Mouse

Brennick¹,

Pack²,

Ko³

et al. 2009

Am J Respir Crit Care Med

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“…The obese Zucker rat, a genetic model of morbid obesity, presents many of the same metabolic and cardiopulmonary deficits as noted in obese humans, including increased risks of type 2 diabetes mellitus, 1 hypertension, 2 respiratory dysfunction, [3][4][5] upper airway narrowing 6 and poor exercise capacity. 7,8 Various factors, such as insulin resistance, nocturnal hypoxia, hypertension and poor exercise capacity, often observed in the obesity, may directly or indirectly contribute to the excessive rates of cardiovascular diseases and vascular dysfunctions.…”

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confidence: 99%

Altered insulin-mediated and insulin-like growth factor-1-mediated vasorelaxation in aortas of obese Zucker rats

2006

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Objective: Insulin and insulin-like growth factor-1 (IGF-1) have vasorelaxant effects in vivo, which is dependent on nitric oxide (NO) production. The aim of this study was to investigate the vasorelaxant responses mediated by insulin and/or IGF-1 in aortas of obese Zucker rats. Methods: The thoracic aortas of eight lean and eight obese Zucker rats (6 months old) were isolated for vasorelaxation analysis. Insulin-induced and IGF-1-induced vasorelaxant responses were evaluated by the isometric tension of aortic rings in the organ bathes. The roles of phosphatidylinositol 3-kinase (PI3K) and nitric oxide synthase (NOS) in vasorelaxant responses were examined by treating selective inhibitors, such as wortmannin (an inhibitor of PI3K) and N o -nitro-L-arginine methyl ester (L-NAME, a NOS inhibitor). In addition, the vascular responses to sodium nitroprusside (SNP), a direct vasodilator of vascular smooth muscle, were examined. Results: The insulin-induced vasorelaxation in aortas of obese rats was significantly decreased, whereas the IGF-1-induced vasorelaxation was significantly increased, compared with that in lean rats. After the pre-administration of wortmannin or L-NAME, the altered insulin-induced or IGF-1-induced vasorelaxation was abolished. There was no significant difference in the SNP-induced vasorelaxation between lean and obese rats. Conclusion: Our findings suggested that the decreased insulin-mediated vasorelaxation in obese rats appeared to be counteracted by the increased IGF-1-mediated vasorelaxation. Furthermore, the NO-dependent pathway was involved in the altered vasorelaxant responses. However, the SNP-induced vasorelaxation was not changed in obese rats.

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“…Studies in pigs and bulldogs highlight the impact of structural narrowing on upper airway patency, particularly when neuromuscular activity wanes during rapid eye movement (REM) sleep (14,24,58). Recently, investigators have demonstrated that obesity can also impose structural loads on the airway (5) that elevate pharyngeal collapsibility in the fa/fa rat and that serotonergic mechanisms can offset this mechanical effect (27). We have demonstrated that a similar defect in leptin signaling in obese ob/ob mice accounts for the development of the obesity-hypoventilation syndrome in a murine model (29,38), suggesting that mouse strains may ultimately serve to probe the genetic determinants of sleeprelated breathing disorders.…”

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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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Serotonergic Modulation of Ventilation and Upper Airway Stability in Obese Zucker Rats

Cited by 62 publications

References 34 publications

Altered Upper Airway and Soft Tissue Structures in the New Zealand Obese Mouse

Altered Upper Airway and Soft Tissue Structures in the New Zealand Obese Mouse

Altered insulin-mediated and insulin-like growth factor-1-mediated vasorelaxation in aortas of obese Zucker rats

Neuromechanical control of the isolated upper airway of mice

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