Is there a link between intermittent hypoxia-induced respiratory plasticity and obstructive sleep apnoea? Exp Physiol

Department of Comparative Biosciences, University of Wisconsin Madison, 2015 Linden Drive, Madison, WI 53706, USA.
Experimental Physiology (Impact Factor: 2.67). 02/2007; 92(1):27-37. DOI: 10.1113/expphysiol.2006.033720
Source: PubMed


Although neuroplasticity is an important property of the respiratory motor control system, its existence has been appreciated only in recent years and, as a result, its functional significance is not completely understood. The most frequently studied models of respiratory plasticity is respiratory long-term facilitation (LTF) following acute intermittent hypoxia and enhanced LTF following chronic intermittent hypoxia. Since intermittent hypoxia is a prominent feature of sleep-disordered breathing, LTF and/or enhanced LTF may compensate for factors that predispose to sleep-disordered breathing, particularly during obstructive sleep apnoea (OSA). Long-term facilitation has been studied most frequently in rats, and exhibits interesting properties consistent with a role in stabilizing breathing during sleep. Specifically, LTF: (1) is prominent in upper airway respiratory motor activity, suggesting that it stabilizes upper airways and maintains airway patency; (2) is most prominent during sleep in unanaesthetized rats; and (3) exhibits sexual dimorphism (greatest in young male and middle-aged female rats; smallest in middle-aged male and young female rats). Although these features are consistent with the hypothesis that upper airway LTF minimizes the prevalence of OSA in humans, there is little direct evidence for such an effect. Here we review advances in our understanding of LTF and its underlying mechanisms and present evidence concerning a potential role for LTF in maintaining upper airway patency, stabilizing breathing and preventing OSA in humans. Regardless of the relationship between LTF and OSA, a detailed understanding of cellular and synaptic mechanisms that underlie LTF may guide the development of new drugs to regulate upper airway tone, thereby offsetting the tendency for upper airway collapse characteristic of heavy snoring and OSA.

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Available from: Gordon Mitchell, Oct 13, 2014
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    • "On one hand, a high loop gain would be expected to increase robustly the output from the central pattern generator to the upper airway dilator muscles, which will in turn act to stiffen the airway, thereby preserving pharyngeal patency. Indeed, intermittent hypoxia can induce long-term facilitation, which may be one mechanism leading to increased upper airway motor tone in OSA patients during wakefulness (Mahamed & Mitchell, 2007; Mateika & Narwani, 2009). On the other hand, a high loop gain will also cause disproportionately large fluctuations in response to small disturbances in ventilation, which can contribute to upper airway compromise when output to these muscles is at its nadir. "
    The Journal of Physiology 07/2014; 592(14). DOI:10.1113/jphysiol.2014.271841 · 5.04 Impact Factor
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    • "However, little is known concerning the role of NO in hypoxia-induced respiratory plasticity. Thus, we tested the hypothesis that NO is necessary for phrenic longterm facilitation (pLTF), a form of serotonin (5-HT)- dependent respiratory motor plasticity induced by acute intermittent hypoxia (AIH) (Bach and Mitchell, 1996; Mitchell et al., 2001; Mahamed and Mitchell, 2007; MacFarlane et al., 2008). "
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    ABSTRACT: Acute intermittent hypoxia (AIH) induces phrenic long-term facilitation (pLTF) by a mechanism that requires spinal serotonin (5-HT) receptor activation and NADPH oxidase (NOX) activity. Here, we investigated whether: 1) spinal nitric oxide synthase (NOS) activity is necessary for AIH-induced pLTF; 2) episodic exogenous nitric oxide (NO) is sufficient to elicit phrenic motor facilitation (pMF) without AIH (i.e. pharmacologically); and 3) NO-induced pMF requires spinal 5-HT2B receptor and NOX activation. In anesthetised, mechanically ventilated adult male rats, AIH (3x5min episodes; 10% O2; 5min) elicited a progressive increase in the amplitude of integrated phrenic nerve bursts (i.e. pLTF), which lasted 60 min post-AIH (45.1 ± 8.6% baseline). Pre-treatment with intrathecal (i.t.) injections of a neuronal NOS inhibitor (nNOS-inhibitor-1) near the phrenic motor nucleus attenuated pLTF (14.7 ± 2.5%), whereas an inducible NOS (iNOS) inhibitor (1400W) had no effect (56.3 ± 8.0%). Episodic i.t. injections (3x5μl volume; 5mins) of a NO donor (sodium nitroprusside; SNP) elicited pMF similar in time-course and magnitude (40.4 ± 6.0%, 60 min post-injection) to AIH-induced pLTF. SNP-induced pMF was blocked by a 5-HT2B receptor antagonist (SB206553), a superoxide dismutase mimetic (MnTMPyP), and two NOX inhibitors (apocynin and DPI). Neither pLTF nor pMF were affected by pre-treatment with a PKG inhibitor (KT-5823). Thus, spinal nNOS activity is necessary for AIH-induced pLTF, and episodic spinal NO is sufficient to elicit pMF by a mechanism that requires 5-HT2B receptor activation and NOX-derived ROS formation, which indicates AIH (and NO) elicits spinal respiratory plasticity by a nitrergic-serotonergic mechanism.
    Neuroscience 03/2014; 269. DOI:10.1016/j.neuroscience.2014.03.014 · 3.36 Impact Factor
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    • "3.1. Sleep apnea and long-term facilitation of ventilation and upper airway muscle activity There is much interest in establishing the stimuli and/or conditions that promote mechanisms that stabilize breathing, while minimizing mechanisms that foster breathing instability (Mahamed and Mitchell, 2007; Mateika and Narwani, 2009; White, 2007). This attraction led to the hypothesis that respiratory plasticity may have a role in preventing cyclical events associated with sleep apnea. "
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    ABSTRACT: This review examines the role that respiratory plasticity has in the maintenance of breathing stability during sleep in individuals with sleep apnea. The initial portion of the review considers the manner in which repetitive breathing events may be initiated in individuals with sleep apnea. Thereafter, the role that two forms of respiratory plasticity, progressive augmentation of the hypoxic ventilatory response and long-term facilitation of upper airway and respiratory muscle activity, might have in modifying breathing events in humans is examined. In this context, present knowledge regarding the initiation of respiratory plasticity in humans during wakefulness and sleep is addressed. Also, published findings which reveal that exposure to intermittent hypoxia promotes breathing instability, at least in part, because of progressive augmentation of the hypoxic ventilatory response and the absence of long-term facilitation, are considered. Next, future directions are presented and are focused on the manner in which forms of plasticity that stabilize breathing might be promoted while diminishing destabilizing forms, concurrently. These future directions will consider the potential role of circadian rhythms in the promotion of respiratory plasticity and the role of respiratory plasticity in enhancing established treatments for sleep apnea.
    Respiratory Physiology & Neurobiology 04/2013; 188(3). DOI:10.1016/j.resp.2013.04.010 · 1.97 Impact Factor
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