Pharmacotherapy of obstructive sleep apnea

Lin, Chia Mo; Huang, Yu; Guilleminault, Christian

doi:10.1517/14656566.2012.666525

Cited by 17 publications

(10 citation statements)

References 96 publications

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“…The discrepancy may be explained in part by the inverse dose-dependent effects of mirtazapine on GG activity, indicating possible within-drug interaction (60). Because serotonin therapy has been shown to be largely ineffective for patients with OSA and in animal models (8)(9)(10), any beneficial effects of lowdose mirtazapine (16,60) in retrospect are likely mediated by its antagonism of α 2 -adrenergic receptors. At higher doses, the resultant increase in serotonin release may actually suppress excitatory inputs to HMs via presynaptic inhibition (reviewed in ref.…”

Section: Discussionmentioning

confidence: 99%

“…Current standard treatment using continuous positive airway pressure (CPAP) to restore upper airway patency is effective but has a poor adherence rate (5), whereas alternative treatments such as oral-appliance therapy, weight loss, upper-airway surgery, and hypoglossal nerve stimulation are not always effective (6,7). Pharmacotherapy is currently an unmet need for the management of patients with OSA (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

“…However, related preclinical and clinical studies to date have been disappointing (8)(9)(10). Moreover, many candidate drugs have side effects such as drowsiness, weight gain, and suppression of REM sleep, which are counterproductive for OSA (14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

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α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea

Song¹,

Poon²

2017

JCI Insight

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea

Song¹,

Poon²

2017

JCI Insight

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“…In humans, attempts to treat sleep-disordered breathing by enhancing the central levels of 5-HT with reuptake blockers or L-tryptophan have yielded mixed results (307,561). However, data from rats point to a stronger excitatory effect of NE than 5-HT on upper airway motoneurons (142) as well as a reduced availability of the excitatory 5-HT receptors in XII motoneurons during the normal sleep period (574).…”

Section: Neural Control Of the Upper Airway In Sleep-disordered Breatmentioning

confidence: 99%

Neural Control of the Upper Airway: Respiratory and State‐Dependent Mechanisms

Kubin

2016

Comprehensive Physiology

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Upper airway muscles subserve many essential for survival orofacial behaviors, including their important role as accessory respiratory muscles. In the face of certain predisposition of craniofacial anatomy, both tonic and phasic inspiratory activation of upper airway muscles is necessary to protect the upper airway against collapse. This protective action is adequate during wakefulness, but fails during sleep which results in recurrent episodes of hypopneas and apneas, a condition known as the obstructive sleep apnea syndrome (OSA). Although OSA is almost exclusively a human disorder, animal models help unveil the basic principles governing the impact of sleep on breathing and upper airway muscle activity. This article discusses the neuroanatomy, neurochemistry, and neurophysiology of the different neuronal systems whose activity changes with sleep-wake states, such as the noradrenergic, serotonergic, cholinergic, orexinergic, histaminergic, GABAergic and glycinergic, and their impact on central respiratory neurons and upper airway motoneurons. Observations of the interactions between sleep-wake states and upper airway muscles in healthy humans and OSA patients are related to findings from animal models with normal upper airway, and various animal models of OSA, including the chronic-intermittent hypoxia model. Using a framework of upper airway motoneurons being under concurrent influence of central respiratory, reflex and state-dependent inputs, different neurotransmitters, and neuropeptides are considered as either causing a sleep-dependent withdrawal of excitation from motoneurons or mediating an active, sleep-related inhibition of motoneurons. Information about the neurochemistry of state-dependent control of upper airway muscles accumulated to date reveals fundamental principles and may help understand and treat OSA.

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“…However, the reduction in noradrenergic and serotonergic inputs cannot be the main cause of the inhibition of HMNs activity during sleep, because pharmacological strategies to applicate 5‐HT and NE reuptake inhibitors or their receptor specific agonists, have been unsuccessful (Lin et al . ). There may be some other neurotransmitters that also alter HMN excitability, and such changes become dramatic across the sleep‐wake state.…”

mentioning

confidence: 97%

Signaling mechanism underlying the histamine‐modulated action of hypoglossal motoneurons

Liu

Luo

et al. 2016

Journal of Neurochemistry

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Histamine, an important modulator of the arousal states of the central nervous system, has been reported to contribute an excitatory drive at the hypoglossal motor nucleus to the genioglossus (GG) muscle, which is involved in the pathogenesis of obstructive sleep apnea. However, the effect of histamine on hypoglossal motoneurons (HMNs) and the underlying signaling mechanisms have remained elusive. Here, whole-cell patch-clamp recordings were conducted using neonatal rat brain sections, which showed that histamine excited HMNs with an inward current under voltage-clamp and a depolarization membrane potential under current-clamp via histamine H 1 receptors (H 1 Rs). The phospholipase C inhibitor U-73122 blocked H 1 Rs-mediated excitatory effects, but protein kinase A inhibitor and protein kinase C inhibitor did not, indicating that the signal transduction cascades underlying the excitatory action of histamine on HMNs were H 1 R/G q/11 / phospholipase C/inositol-1,4,5-trisphosphate (IP 3 ). The effects of histamine were also dependent on extracellular Na + and intracellular Ca 2+ , which took place via activation of Na + -Ca 2+ exchangers. These results identify the signaling molecules associated with the regulatory effect of histamine on HMNs.The findings of this study may provide new insights into therapeutic approaches in obstructive sleep apnea.

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Pharmacotherapy of obstructive sleep apnea

Cited by 17 publications

References 96 publications

α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea

α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea

Neural Control of the Upper Airway: Respiratory and State‐Dependent Mechanisms

Signaling mechanism underlying the histamine‐modulated action of hypoglossal motoneurons

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