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.
"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). "
[Show abstract][Hide abstract] 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.
"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). "
[Show abstract][Hide abstract] 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.
"Although the exact mechanisms are currently unclear, such data suggests that OSA may not only affect blood pressure acutely but may also alter regulatory mechanisms involved in the sympathetic nervous system to produce chronic effects on blood pressure and allow for the development of maladaptive states such as hypertension. Acute or chronic intermittent hypoxia models are most frequently used to experimentally emulate the neurocirculatory changes associated with OSA due to the fact that intermittent hypoxia is a prominent feature of OSA (i.e., patients with OSA experience brief and repeated episodes of hypoxia) and that acute intermittent hypoxia (AIH) is capable of inducing phrenic long-term facilitation (LTF) in which progressive and sustained increase in phrenic motor output develops independent of changes in chemo-afferent input (Mitchell et al., 2001). It is well known that respiration markedly modulates the sympathetic nervous system (Adrian et al., 1932) and it is possible that respiratory LTF may induce sympathetic LTF (Zoccal et al., 2008) and contribute to the development of hypertension. "
[Show abstract][Hide abstract] ABSTRACT: There is a large amount of evidence linking obstructive sleep apnea (OSA), and the associated intermittent hypoxia that accompanies it, with the development of hypertension. For example, cross-sectional studies demonstrate that the prevalence of hypertension increases with the severity of OSA (Bixler et al., 2000; Grote et al., 2001) and an initial determination of OSA is associated with a three-fold increase for future hypertension (Peppard et al., 2000). Interestingly, bouts of intermittent hypoxia have also been shown to affect sympathetic output associated with the baroreflex and chemoreflex, important mechanisms in the regulation of arterial blood pressure. As such, the possibility exists that changes in the baroreflex and chemoreflex may contribute to the development of chronic hypertension observed in OSA patients. The aim of the current article is to briefly review the response of the baroreflex and chemoreflex to intermittent hypoxic exposure and to evaluate evidence for the hypothesis that modification of these autonomic reflexes may, at least in part, support the comorbidity observed between chronic hypertension and OSA.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.