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.

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.

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 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.

Time-dependent phrenic nerve responses to carotid afferent activation: intact vs. decerebellate rats

1993 ◽  
Vol 265 (4) ◽  
pp. R811-R819 ◽  
Author(s):  
F. Hayashi ◽  
S. K. Coles ◽  
K. B. Bach ◽  
G. S. Mitchell ◽  
D. R. McCrimmon
Keyword(s):  
Phrenic Nerve ◽  
Carotid Sinus ◽  
Carotid Sinus Nerve ◽  
Short Term ◽  
Nerve Activity ◽  
A Value ◽  
Afferent Activation ◽  
Term Potentiation ◽  
Long Term Facilitation

The objectives were to determine 1) respiratory responses to carotid chemoreceptor inputs in anesthetized rats and 2) whether the cerebellar vermis plays a role in these responses. A carotid sinus nerve was stimulated (20 Hz) with five 2-min trains, each separated by approximately 3 min. During stimulation, respiratory frequency (f), peak amplitude of integrated phrenic nerve activity (integral of Phr), and their product (f x integral of Phr) immediately increased. As stimulation continued, integral of Phr progressively increased to a plateau [short-term potentiation (STP)], but f and f x integral of Phr decreased [short-term depression (STD)] to a value still above control. Upon stimulus termination, integral of Phr progressively decreased but remained above control; f and f x integral of Phr transiently decreased below baseline. After the final stimulation, integral of Phr remained above control for at least 30 min [long-term facilitation (LTF)]. Repeated 5-min episodes of isocapnic hypoxia also elicited STP, STD, and LTF. Vermalectomy lowered the CO2-apneic threshold and eliminated LTF. In conclusion, carotid chemoreceptor activation in rats elicits STP and LTF similar to that in cats; the vermis may play a role in LTF. A new response, STD, was observed.

scholarly journals Cervical spinal 5-HT2A and 5-HT2B receptors are both necessary for moderate acute intermittent hypoxia-induced phrenic long-term facilitation

2019 ◽  
Vol 127 (2) ◽  
pp. 432-443 ◽  
Author(s):  
Arash Tadjalli ◽  
Gordon S. Mitchell
Keyword(s):  
Receptor Antagonist ◽  
Broad Spectrum ◽  
Intermittent Hypoxia ◽  
Receptor Activation ◽  
Mapk Signaling ◽  
Receptor Subtypes ◽  
Receptor Antagonists ◽  
Erk Mapk ◽  
Long Term Facilitation

Serotonin (5-HT) is a key regulator of spinal respiratory motor plasticity. For example, spinal 5-HT receptor activation is necessary for the induction of phrenic long-term facilitation (pLTF), a form of respiratory motor plasticity triggered by moderate acute intermittent hypoxia (mAIH). mAIH-induced pLTF is blocked by cervical spinal application of the broad-spectrum 5-HT-receptor antagonist, methysergide. However, methysergide does not allow distinctions between the relative contributions of different 5-HT receptor subtypes. Intravenous administration of the Gq protein-coupled 5-HT2A/2C receptor antagonist ketanserin blocks mAIH-induced pLTF when administered before, but not after, mAIH; thus, 5-HT2 receptor activation is necessary for the induction but not maintenance of mAIH-induced pLTF. However, systemic ketanserin administration does not identify the site of the relevant 5-HT2A/2C receptors. Furthermore, this approach does not differentiate between the roles of 5-HT2A versus 5-HT2C receptors, nor does it preclude involvement of other Gq protein-coupled metabotropic 5-HT receptors capable of eliciting long-lasting phrenic motor facilitation, such as 5-HT2B receptors. Here we tested the hypothesis that mAIH-induced pLTF requires cervical spinal 5-HT2 receptor activation and determined which 5-HT2 receptor subtypes are involved. Anesthetized, paralyzed, and ventilated adult male Sprague Dawley rats were pretreated intrathecally with cervical (~C3-C5) spinal injections of subtype selective 5-HT2A/2C, 5-HT2B, or 5-HT2C receptor antagonists before mAIH. Whereas cervical spinal 5-HT2C receptor inhibition had no impact on mAIH-induced pLTF, pLTF was no longer observed after pretreatment with either 5-HT2A/2C or 5-HT2B receptor antagonists. Furthermore, spinal pretreatment with an MEK/ERK MAPK inhibitor blocked phrenic motor facilitation elicited by intrathecal injections of 5-HT2A but not 5-HT2B receptor agonists. Thus, mAIH-induced pLTF requires concurrent cervical spinal activation of both 5-HT2A and 5-HT2B receptors. However, these distinct receptor subtypes contribute to phrenic motor facilitation via distinct downstream signaling cascades that differ in their requirement for ERK MAPK signaling. The demonstration that both 5-HT2A and 5-HT2B receptors make unique contributions to mAIH-induced pLTF advances our understanding of mechanisms that underlie 5-HT-induced phrenic motor plasticity. NEW & NOTEWORTHY Moderate acute intermittent hypoxia (mAIH) triggers a persistent enhancement in phrenic motor output, an effect termed phrenic long-term facilitation (pLTF). mAIH-induced pLTF is blocked by cervical spinal application of the broad-spectrum serotonin (5-HT) receptor antagonist methysergide, demonstrating the need for spinal 5-HT receptor activation. However, the exact type of 5-HT receptors required for initiation of pLTF remains unknown. To the best of our knowledge, the present study is the first to demonstrate that 1) spinal coactivation of two distinct Gq protein-coupled 5-HT2 receptor subtypes is necessary for mAIH-induced pLTF, and 2) these receptors contribute to pLTF via cascades that differ in their requirement for ERK MAPK signaling.

scholarly journals Adrenergic α1 receptor activation is sufficient, but not necessary for phrenic long-term facilitation

2014 ◽  
Vol 116 (11) ◽  
pp. 1345-1352 ◽  
Author(s):  
A. G. Huxtable ◽  
P. M. MacFarlane ◽  
S. Vinit ◽  
N. L. Nichols ◽  
E. A. Dale ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Receptor Antagonist ◽  
Adrenergic Receptors ◽  
Intermittent Hypoxia ◽  
Receptor Agonist ◽  
Receptor Activation ◽  
Motor Nucleus ◽  
Long Term Facilitation ◽  
Dose Dependent

Acute intermittent hypoxia (AIH; three 5-min hypoxic episodes) causes a form of phrenic motor facilitation (pMF) known as phrenic long-term facilitation (pLTF); pLTF is initiated by spinal activation of Gq protein-coupled 5-HT2 receptors. Because α1 adrenergic receptors are expressed in the phrenic motor nucleus and are also Gq protein-coupled, we hypothesized that α1 receptors are sufficient, but not necessary for AIH-induced pLTF. In anesthetized, paralyzed, and ventilated rats, episodic spinal application of the α1 receptor agonist phenylephrine (PE) elicited dose-dependent pMF (10 and 100 μM, P < 0.05; but not 1 μM). PE-induced pMF was blocked by the α1 receptor antagonist prazosin (1 mM; −20 ± 20% at 60 min, −5 ± 21% at 90 min; n = 6). Although α1 receptor activation is sufficient to induce pMF, it was not necessary for AIH-induced pLTF because intrathecal prazosin (1 mM) did not alter AIH-induced pLTF (56 ± 9% at 60 min, 78 ± 12% at 90 min; n = 9). Intravenous (iv) prazosin (150 μg/kg) appeared to reduce pLTF (21 ± 9% at 60 min, 26 ± 8% at 90 min), but this effect was not significant. Hypoglossal long-term facilitation was unaffected by intrathecal prazosin, but was blocked by iv prazosin (−4 ± 14% at 60 min, −13 ± 18% at 90 min), suggesting different LTF mechanisms in different motor neuron pools. In conclusion, Gq protein-coupled α1 adrenergic receptors evoke pMF, but they are not necessary for AIH-induced pLTF.

Ampakine pretreatment enables a single hypoxic episode to produce phrenic motor facilitation with no added benefit of additional episodes

2021 ◽  
Author(s):  
Prajwal Pradeep Thakre ◽  
Michael D. Sunshine ◽  
David D. Fuller
Keyword(s):  
Ampa Receptors ◽  
Phrenic Nerve ◽  
Statistical Significance ◽  
Sprague Dawley ◽  
Hypoxic Episode ◽  
Sprague Dawley Rats ◽  
Burst Amplitude ◽  
Acute Increase ◽  
Long Term Facilitation ◽  
Sustained Increase

Repeated short episodes of hypoxia produces a sustained increase in phrenic nerve output lasting well beyond AIH exposure (i.e., phrenic long term facilitation, pLTF). Pretreatment with ampakines, drugs which allosterically modulate AMPA receptors, enables a single brief episode of hypoxia to produce pLTF, lasting up to 90 min after hypoxia. Here we tested the hypothesis that ampakine pretreatment would enhance the magnitude of pLTF evoked by repeated bouts of hypoxia. Phrenic nerve output was recorded in urethane-anesthetized, mechanically ventilated and vagotomized adult male Sprague-Dawley rats. Initial experiments demonstrated that ampakine CX717 (15 mg/kg, intravenous) caused an acute increase in phrenic nerve inspiratory burst amplitude reaching 70±48% baseline (BL) after 2 min (P=0.01. This increased bursting was not sustained (2±32%BL at 60 min, P=0.9). When CX717 was delivered 2 min prior to a single episode of isocapnic hypoxia (5-min, PaO2 = 44±9 mmHg) facilitation of phrenic nerve burst amplitude occurred (96±62%BL at 60 min, P<0.001). However, when CX717 was given 2 min prior to three, 5-min hypoxic episodes (PaO2 = 45±6 mmHg) pLTF was attenuated and did not reach statistical significance (24±29%BL, P=0.08). In the absence of CX717 pretreatment, pLTF was observed after three (74±33%BL at 60 min, P<0.001) but not one episode of hypoxia (1±8%BL at 60 min, P=0.9). We conclude that pLTF is not enhanced when ampakine pretreatment is followed by repeated bouts of hypoxia. Rather, the combination of ampakine and a single hypoxic episode appears to be ideal for producing sustained increase in phrenic motor output.

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.

Glucocorticoids reduce responses to AMPA receptor activation and blockade in nucleus tractus solitarius

2003 ◽  
Vol 284 (5) ◽  
pp. H1751-H1761 ◽  
Author(s):  
Sylvan S. Shank ◽  
Deborah A. Scheuer
Keyword(s):  
Arterial Pressure ◽  
Ampa Receptors ◽  
Sympathetic Nerve Activity ◽  
Nucleus Tractus Solitarius ◽  
Receptor Activation ◽  
Sprague Dawley ◽  
Nerve Activity ◽  
Renal Sympathetic Nerve Activity ◽  
Sprague Dawley Rats ◽  
Renal Sympathetic

We tested the hypothesis that glucocorticoids attenuate changes in arterial pressure and renal sympathetic nerve activity (RSNA) in response to activation and blockade of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors within the nucleus of the solitary tract (NTS). Experiments were performed in Inactin-anesthetized male Sprague-Dawley rats treated for 7 ± 1 days with a subcutaneous corticosterone (Cort) pellet or in control rats. Baseline mean arterial pressure (MAP) was significantly higher in Cort-treated rats (109 ± 2 mmHg, n = 39) than in control rats (101 ± 1 mmHg, n = 48, P < 0.05). In control rats, microinjection of AMPA (0.03, 0.1, and 0.3 pmol/100 nl) into the NTS significantly decreased MAP at all doses and decreased RSNA at 0.1 and 0.3 pmol/100 nl. Responses to AMPA in Cort-treated rats were attenuated at all doses of AMPA ( P < 0.05). Responses to the AMPA-kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) were also significantly reduced in Cort-treated rats relative to control rats. Blockade of glucocorticoid type II receptors with mifepristone significantly enhanced responses to CNQX in both control and Cort rats. We conclude that glucocorticoids attenuate MAP and RSNA responses to activation and blockade of AMPA receptors in the NTS.

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