Invited review: Intermittent hypoxia and respiratory plasticity

Department of Comparative Biosciences, University of Wisconsin, Madison, Wisconsin 53706, USA.
Journal of Applied Physiology (Impact Factor: 3.06). 07/2001; 90(6):2466-75.
Source: PubMed


Intermittent hypoxia elicits long-term facilitation (LTF), a persistent augmentation (hours) of respiratory motor output. Considerable recent progress has been made toward an understanding of the mechanisms and manifestations of this potentially important model of respiratory plasticity. LTF is elicited by intermittent but not sustained hypoxia, indicating profound pattern sensitivity in its underlying mechanism. During intermittent hypoxia, episodic spinal serotonin receptor activation initiates cell signaling events, increasing spinal protein synthesis. One associated protein is brain-derived neurotrophic factor, a neurotrophin implicated in several forms of synaptic plasticity. Our working hypothesis is that increased brain-derived neurotrophic factor enhances glutamatergic synaptic currents in phrenic motoneurons, increasing their responsiveness to bulbospinal inspiratory inputs. LTF is heterogeneous among respiratory outputs, differs among experimental preparations, and is influenced by age, gender, and genetics. Furthermore, LTF is enhanced following chronic intermittent hypoxia, indicating a degree of metaplasticity. Although the physiological relevance of LTF remains unclear, it may reflect a general mechanism whereby intermittent serotonin receptor activation elicits respiratory plasticity, adapting system performance to the ever-changing requirements of life.

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    • "Hypocapnic suppression of LTF has been demonstrated in both humans and rats [21] [119], and most likely reflects post synaptic changes underpinning LTF at the motor neuron level. Given motor neuron LTF is thought to be due to facilitation of post-synaptic excitatory neurotransmission [20], reduced excitatory stimuli during hypocapnia would render LTF incapable of amplifying motor neuron output. Nevertheless, although suppressed during hypocapnia, robust pLTF has been demonstrated once normocapnia or hypercapnia are re-instated [36]. "
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    ABSTRACT: Intermittent hypoxia and unstable breathing are key features of obstructive sleep apnoea (OSA), the most common pathological problem of breathing in sleep. Unstable ventilatory control is characterised by high loop gain (LG), and likely contributes to cyclical airway obstruction by promoting airway collapse during periods of low ventilatory drive. Potential new strategies to treat OSA include manipulations designed to lower LG. However, the contribution of inherent versus induced LG abnormalities in OSA remains unclear. Hence, a better understanding of the mechanisms causing high LG in OSA is needed to guide the design of LG based treatments. OSA patients exhibit abnormal chemoreflex control which contributes to increased LG. These abnormalities have been shown to normalise after continuous positive airway pressure treatment, suggesting induced rather than inherent trait abnormalities. Experimental intermittent hypoxia, mimicking OSA, increases hypoxic chemosensitivity and induces long term facilitation; a sustained increase in ventilatory neural output which outlasts the original stimulus. These neuroplastic changes induce the same abnormalities in chemoreflex control as seen in OSA patients. This review outlines the evidence to support that a key component of high LG in OSA is induced by intermittent hypoxia, and is reversed by simply preventing this inducing stimulus. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Sleep Medicine Reviews 10/2014; 22. DOI:10.1016/j.smrv.2014.10.003 · 8.51 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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    • "This form of respiratory plasticity was referred to as long-term facilitation (Fig. 1). Some of the neuromodulators responsible for initiating long-term facilitation, including serotonin (Fregosi and Mitchell, 1994; Mateika and Narwani, 2009; Millhorn et al., 1980b; Mitchell et al., 2001a,b), norepinephrine (Mody et al., 2011; Stettner et al., 2012) and adenosine (Golder et al., 2008; Hoffman et al., 2010; Hoffman and Mitchell, 2011; Hoffman et al., 2012; Nichols et al., 2012) have been identified. In addition, many components of the cellular pathways involved in the initiation of long-term facilitation have been determined (Dale- Nagle et al., 2010; Hoffman et al., 2012; Macfarlane et al., 2008; Macfarlane and Mitchell, 2009; Macfarlane et al., 2009; Satriotomo et al., 2012). "
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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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