scholarly journals Formation and maintenance of ventilatory long-term facilitation require NMDA but not non-NMDA receptors in awake rats

2008 ◽  
Vol 105 (3) ◽  
pp. 942-950 ◽  
Author(s):  
Michelle McGuire ◽  
Chun Liu ◽  
Ying Cao ◽  
Liming Ling
Keyword(s):  
Nmda Receptors ◽  
Serotonin Receptor ◽  
Nmda Antagonist ◽  
Sprague Dawley ◽  
Receptor Antagonism ◽  
Sprague Dawley Rats ◽  
Episodic Hypoxia ◽  
Long Term Facilitation ◽  
Awake Rats

N-methyl-d-aspartate (NMDA) receptor antagonism in the phrenic motonucleus area eliminates phrenic long-term facilitation (pLTF; a persistent augmentation of phrenic nerve activity after episodic hypoxia) in anesthetized rats. However, whether NMDA antagonism can eliminate ventilatory LTF (vLTF) in awake rats is unclear. The role of non-NMDA receptors in LTF is also unknown. Serotonin receptor antagonism before, but not after, episodic hypoxia eliminates pLTF, suggesting that serotonin receptors are required for induction, but not maintenance, of pLTF. However, because NMDA and non-NMDA ionotropic glutamate receptors are directly involved in mediating the inspiratory drive to phrenic, hypoglossal, and intercostal motoneurons, we hypothesized that these receptors are required for both formation and maintenance of vLTF. vLTF, induced by five episodes of 5-min poikilocapnic hypoxia (10% O2) with 5-min normoxia intervals, was measured with plethysmography in conscious adult male Sprague-Dawley rats. Either (±)-2-amino-5-phosphonovaleric acid (APV; NMDA antagonist, 1.5 mg/kg) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; non-NMDA antagonist, 10 mg/kg) was systemically (ip) injected ∼30 min before hypoxia. APV was also injected immediately after or 20 min after episodic hypoxia in additional groups. As control, vehicle was similarly injected in each rat 1–2 days before. Regardless of being injected before or after episodic hypoxia, vehicle did not alter vLTF (∼23%), whereas APV eliminated vLTF while having little effect on baseline ventilation or hypoxic ventilatory response. In contrast, CNQX enhanced vLTF (∼34%) while decreasing baseline ventilation. Collectively, these results suggest that activation of NMDA but not non-NMDA receptors is necessary for formation and maintenance of vLTF in awake rats.

Effect of hypoxic episode number and severity on ventilatory long-term facilitation in awake rats

2002 ◽  
Vol 93 (6) ◽  
pp. 2155-2161 ◽  
Author(s):  
Michelle McGuire ◽  
Yi Zhang ◽  
David P. White ◽  
Liming Ling
Keyword(s):  
Respiratory Activity ◽  
Minute Ventilation ◽  
Severe Hypoxia ◽  
Sprague Dawley ◽  
Hypoxic Episode ◽  
Sprague Dawley Rats ◽  
Episodic Hypoxia ◽  
Long Term Facilitation ◽  
Awake Rats

Episodic hypoxia induces a persistent augmentation of respiratory activity, termed long-term facilitation (LTF). Phrenic LTF saturates in anesthetized animals such that additional episodes of stimulation cause no further increase in LTF magnitude. The present study tested the hypothesis that 1) ventilatory LTF also saturates in awake rats and 2) more severe hypoxia and hypoxic episodes increase the effectiveness of eliciting ventilatory LTF. Minute ventilation was measured in awake, male Sprague-Dawley rats by plethysmography. LTF was elicited by five episodes of 10% O2 poikilocapnic hypoxia (magnitude: 17.3 ± 2.8% above baseline, between 15 and 45 min posthypoxia, duration: 45 min) but not 12 or 8% O2. LTF was also elicited by 10, 20, and 72 episodes of 12% O2(19.1 ± 2.2, 18.9 ± 1.8, and 19.8 ± 1.6%; 45, 60, and 75 min, respectively) but not by three or five episodes. These results show that there is a certain range of hypoxia that induces ventilatory LTF and that additional hypoxic episodes may increase the duration but not the magnitude of this response.

scholarly journals Selected Contribution: Phrenic long-term facilitation requires 5-HT receptor activation during but not following episodic hypoxia

2001 ◽  
Vol 90 (5) ◽  
pp. 2001-2006 ◽  
Author(s):  
D. D. Fuller ◽  
A. G. Zabka ◽  
T. L. Baker ◽  
G. S. Mitchell
Keyword(s):  
Receptor Antagonist ◽  
Phrenic Nerve ◽  
Receptor Activation ◽  
Sprague Dawley ◽  
Nerve Activity ◽  
Sprague Dawley Rats ◽  
Episodic Hypoxia ◽  
Baseline Levels ◽  
Long Term Facilitation

Episodic hypoxia evokes a sustained augmentation of respiratory motor output known as long-term facilitation (LTF). Phrenic LTF is prevented by pretreatment with the 5-hydroxytryptamine (5-HT) receptor antagonist ketanserin. We tested the hypothesis that 5-HT receptor activation is necessary for the induction but not maintenance of phrenic LTF. Peak integrated phrenic nerve activity (∫Phr) was monitored for 1 h after three 5-min episodes of isocapnic hypoxia (arterial Po 2 = 40 ± 2 Torr; 5-min hyperoxic intervals) in four groups of anesthetized, vagotomized, paralyzed, and ventilated Sprague-Dawley rats [ 1) control ( n = 11), 2) ketanserin pretreatment (2 mg/kg iv; n = 7), and ketanserin treatment 0 and 45 min after episodic hypoxia ( n = 7 each)]. Ketanserin transiently decreased ∫Phr, but it returned to baseline levels within 10 min. One hour after episodic hypoxia, ∫Phr was significantly elevated from baseline in control and in the 0- and 45-min posthypoxia ketanserin groups. Conversely, ketanserin pretreatment abolished phrenic LTF. We conclude that 5-HT receptor activation is necessary to initiate (during hypoxia) but not maintain (following hypoxia) phrenic LTF.

Selected Contribution: Intermittent hypoxia induces phrenic long-term facilitation in carotid-denervated rats

2003 ◽  
Vol 94 (1) ◽  
pp. 399-409 ◽  
Author(s):  
Ryan W. Bavis ◽  
Gordon S. Mitchell
Keyword(s):  
Detectable Effect ◽  
Sprague Dawley ◽  
Neuron Activation ◽  
Sprague Dawley Rats ◽  
Burst Amplitude ◽  
Episodic Hypoxia ◽  
Before And After ◽  
Inspiratory Activity ◽  
Long Term Facilitation

Episodic hypoxia elicits a long-lasting augmentation of phrenic inspiratory activity known as long-term facilitation (LTF). We investigated the respective contributions of carotid chemoafferent neuron activation and hypoxia to the expression of LTF in urethane-anesthetized, vagotomized, paralyzed, and ventilated Sprague-Dawley rats. One hour after three 5-min isocapnic hypoxic episodes [arterial Po 2(PaO2 ) = 40 ± 5 Torr], integrated phrenic burst amplitude was greater than baseline in both carotid-denervated ( n = 8) and sham-operated ( n = 7) rats ( P < 0.05), indicating LTF. LTF was reduced in carotid-denervated rats relative to sham ( P < 0.05). In this and previous studies, rats were ventilated with hyperoxic gas mixtures (inspired oxygen fraction = 0.5) under baseline conditions. To determine whether episodic hyperoxia induces LTF, phrenic activity was recorded under normoxic (PaO2 = 90–100 Torr) conditions before and after three 5-min episodes of isocapnic hypoxia (PaO2 = 40 ± 5 Torr; n = 6) or hyperoxia (PaO2 > 470 Torr; n= 6). Phrenic burst amplitude was greater than baseline 1 h after episodic hypoxia ( P < 0.05), but episodic hyperoxia had no detectable effect. These data suggest that hypoxia per se initiates LTF independently from carotid chemoafferent neuron activation, perhaps through direct central nervous system effects.

Chronic intermittent hypoxia enhances ventilatory long-term facilitation in awake rats

2003 ◽  
Vol 95 (4) ◽  
pp. 1499-1508 ◽  
Author(s):  
Michelle McGuire ◽  
Yi Zhang ◽  
David P. White ◽  
Liming Ling
Keyword(s):  
Intermittent Hypoxia ◽  
Chronic Intermittent Hypoxia ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Freely Behaving ◽  
Long Term Facilitation ◽  
Awake Rats

This study examined the effect of chronic intermittent hypoxia (CIH: 5 min 11-12% O2/5 min air, 12 h/night, 7 nights) on ventilatory long-term facilitation (LTF) and determined the persistence period of this CIH effect in awake rats. LTF, elicited by 5 or 10 episodes of 5 min 12% O2, was measured four times in the same Sprague-Dawley rats by plethysmography, before and 8 h, 3 days, and 7 days after CIH treatment. Resting ventilation was unchanged after CIH. Five episodes of 12% O2 did not initially elicit LTF but elicited LTF (23.5 ± 1.4% above baseline) 8 h after CIH, which partially remained at 3 days (11.4 ± 2.2%, P < 0.05) and disappeared at 7 days. Ten episodes initially elicited LTF (17.7 ± 1.1%, 45-min duration) and elicited an enhanced LTF (29.1 ± 1.5%, 75 min) 8 h after CIH. These results demonstrated that CIH enhanced ventilatory LTF in conscious, freely behaving rats in two ways: 1) a previously ineffective protocol induced LTF; and 2) LTF magnitude was increased and LTF duration prolonged, and this CIH effect on LTF persisted for at least 3 days.

Expression of hypoglossal long-term facilitation differs between substrains of Sprague-Dawley rat

2001 ◽  
Vol 4 (3) ◽  
pp. 175-181 ◽  
Author(s):  
D. D. FULLER ◽  
T. L. BAKER ◽  
M. BEHAN ◽  
G. S. MITCHELL
Keyword(s):  
Neural Plasticity ◽  
Genetic Influences ◽  
Hypoglossal Nucleus ◽  
Sprague Dawley ◽  
Sd Rat ◽  
Sd Rats ◽  
Episodic Hypoxia ◽  
Serotonin Immunoreactivity ◽  
Long Term Facilitation

Long-term facilitation (LTF) is a prolonged, serotonin-dependent augmentation of respiratory motor output following episodic hypoxia. Previous observations lead us to hypothesize that LTF is subject to genetic influences and, as a result, differs between Sprague-Dawley (SD) rats from two vendors, Harlan (H) and Charles River Laboratories/Sasco (CRL/S). Using a blinded experimental design, we recorded integrated phrenic (∫Phr) and hypoglossal neurograms in anesthetized, vagotomized, paralyzed, and ventilated rats. At 60 min following three 5-min hypoxic episodes (PaO2 = 40 ± 1 Torr; 5-min hyperoxic intervals), ∫Phr was elevated from baseline in both SD substrains (i.e., LTF; P < 0.05). Conversely, hypoglossal LTF was present in CRL/S but not H rats ( P < 0.05 between substrains). Serotonin immunoreactivity within the hypoglossal nucleus was not different between H and CRL/S rats. We conclude that the expression of hypoglossal LTF differs between SD rat substrains, indicating a difference in their genetic predisposition to neural plasticity.

scholarly journals Periodicity During Hypercapnic and Hypoxic Stimulus Is Crucial in Distinct Aspects of Phrenic Nerve Plasticity

2016 ◽  
pp. 133-143 ◽  
Author(s):  
I. STIPICA ◽  
I. PAVLINAC DODIG ◽  
R. PECOTIC ◽  
Z. DOGAS ◽  
Z. VALIC ◽  
...  
Keyword(s):  
Phrenic Nerve ◽  
Sprague Dawley ◽  
Long Term Effects ◽  
Burst Frequency ◽  
Mechanically Ventilated ◽  
Sprague Dawley Rats ◽  
Pattern Sensitivity ◽  
Long Term Facilitation ◽  
Nerve Plasticity

This study was undertaken to determine pattern sensitivity of phrenic nerve plasticity in respect to different respiratory challenges. We compared long-term effects of intermittent and continuous hypercapnic and hypoxic stimuli, and combined intermittent hypercapnia and hypoxia on phrenic nerve plasticity. Adult, male, urethane-anesthetized, vagotomized, paralyzed, mechanically ventilated Sprague-Dawley rats were exposed to: acute intermittent hypercapnia (AIHc or AIHcO2), acute intermittent hypoxia (AIH), combined intermittent hypercapnia and hypoxia (AIHcH), continuous hypercapnia (CHc), or continuous hypoxia (CH). Peak phrenic nerve activity (pPNA) and burst frequency were analyzed during baseline (T0), hypercapnia or hypoxia exposures, at 15, 30, and 60 min (T60) after the end of the stimulus. Exposure to acute intermittent hypercapnia elicited decrease of phrenic nerve frequency from 44.25±4.06 at T0 to 35.29±5.21 at T60, (P=0.038, AIHc) and from 45.5±2.62 to 37.17±3.68 breaths/min (P=0.049, AIHcO2), i.e. frequency phrenic long term depression was induced. Exposure to AIH elicited increase of pPNA at T60 by 141.0±28.2 % compared to baseline (P=0.015), i.e. phrenic long-term facilitation was induced. Exposure to AIHcH, CHc, or CH protocols failed to induce long-term plasticity of the phrenic nerve. Thus, we conclude that intermittency of the hypercapnic or hypoxic stimuli is needed to evoke phrenic nerve plasticity.

Recurrent laryngeal nerve activity exhibits a 5-HT-mediated long-term facilitation and enhanced response to hypoxia following acute intermittent hypoxia in rat

2012 ◽  
Vol 112 (7) ◽  
pp. 1144-1156 ◽  
Author(s):  
Tara G. Bautista ◽  
Tao Xing ◽  
Angelina Y. Fong ◽  
Paul M. Pilowsky
Keyword(s):  
Recurrent Laryngeal Nerve ◽  
Neural Plasticity ◽  
Intermittent Hypoxia ◽  
Serotonin Receptor ◽  
Laryngeal Nerve ◽  
Sprague Dawley ◽  
Nerve Activity ◽  
Adductor Muscles ◽  
Long Term Facilitation

A progressive and sustained increase in inspiratory-related motor output (“long-term facilitation”) and an augmented ventilatory response to hypoxia occur following acute intermittent hypoxia (AIH). To date, acute plasticity in respiratory motor outputs active in the postinspiratory and expiratory phases has not been studied. The recurrent laryngeal nerve (RLN) innervates laryngeal abductor muscles that widen the glottic aperture during inspiration. Other efferent fibers in the RLN innervate adductor muscles that partially narrow the glottic aperture during postinspiration. The aim of this study was to investigate whether or not AIH elicits a serotonin-mediated long-term facilitation of laryngeal abductor muscles, and if recruitment of adductor muscle activity occurs following AIH. Urethane anesthetized, paralyzed, unilaterally vagotomized, and artificially ventilated adult male Sprague-Dawley rats were subjected to 10 exposures of hypoxia (10% O2 in N2, 45 s, separated by 5 min, n = 7). At 60 min post-AIH, phrenic nerve activity and inspiratory RLN activity were elevated (39 ± 11 and 23 ± 6% above baseline, respectively). These responses were abolished by pretreatment with the serotonin-receptor antagonist, methysergide ( n = 4). No increase occurred in time control animals ( n = 7). Animals that did not exhibit postinspiratory RLN activity at baseline did not show recruitment of this activity post-AIH ( n = 6). A repeat hypoxia 60 min after AIH produced a significantly greater peak response in both phrenic and RLN activity, accompanied by a prolonged recovery time that was also prevented by pretreatment with methysergide. We conclude that AIH induces neural plasticity in laryngeal motoneurons, via serotonin-mediated mechanisms similar to that observed in phrenic motoneurons: the so-called “Q-pathway”. We also provide evidence that the augmented responsiveness to repeat hypoxia following AIH also involves a serotonergic mechanism.

scholarly journals Ventilatory long-term facilitation in unanesthetized rats

2001 ◽  
Vol 91 (2) ◽  
pp. 709-716 ◽  
Author(s):  
E. B. Olson ◽  
C. J. Bohne ◽  
M. R. Dwinell ◽  
A. Podolsky ◽  
E. H. Vidruk ◽  
...  
Keyword(s):  
Intermittent Hypoxia ◽  
Time Course ◽  
Minute Ventilation ◽  
Carbon Dioxide Production ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Baseline Values ◽  
Long Term Facilitation ◽  
Feedback Time

We tested the hypothesis that unanesthetized rats exhibit ventilatory long-term facilitation (LTF) after intermittent, but not continuous, hypoxia. Minute ventilation (V˙e) and carbon dioxide production (V˙co 2) were measured in unanesthetized, unrestrained male Sprague-Dawley rats via barometric plethysmography before, during, and after exposure to continuous or intermittent hypoxia. Hypoxia was either isocapnic [inspired O2 fraction (Fi O2 ) = 0.08–0.09 and inspired CO2 fraction (Fi CO2 ) = 0.04] or poikilocapnic (Fi O2 = 0.11 and Fi CO2 = 0.00). Sixty minutes after intermittent hypoxia, V˙e orV˙e/V˙co 2 was significantly greater than baseline in both isocapnic and poikilocapnic conditions. In contrast, 60 min after continuous hypoxia,V˙e andV˙e/V˙co 2 were not significantly different from baseline values. These data demonstrate ventilatory LTF after intermittent hypoxia in unanesthetized rats. Ventilatory LTF appeared similar in its magnitude (after accounting for CO2 feedback), time course, and dependence on intermittent hypoxia to phrenic LTF previously observed in anesthetized, vagotomized, paralyzed rats.

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