scholarly journals Ventilatory long-term facilitation is evident after initial and repeated exposure to intermittent hypoxia in mice genetically depleted of brain serotonin

2014 ◽  
Vol 116 (3) ◽  
pp. 240-250 ◽  
Author(s):  
Stephen Hickner ◽  
Najaah Hussain ◽  
Mariana Angoa-Perez ◽  
Dina M. Francescutti ◽  
Donald M. Kuhn ◽  
...  
Keyword(s):  
Tidal Volume ◽  
Intermittent Hypoxia ◽  
Tryptophan Hydroxylase ◽  
Breathing Frequency ◽  
Wild Type ◽  
Tryptophan Hydroxylase 2 ◽  
Daily Exposure ◽  
Spontaneously Breathing ◽  
Long Term Facilitation

Our study was designed to determine if central nervous system (CNS) serotonin is required for the induction of ventilatory long-term facilitation (LTF) in intact, spontaneously breathing mice. Nineteen tryptophan hydroxylase 2-deficient (Tph2−/−) mice, devoid of serotonin in the CNS, and their wild-type counterparts (Tph2+/+) were exposed to intermittent hypoxia each day for 10 consecutive days. The ventilatory response to intermittent hypoxia was greater in the Tph2+/+ compared with the Tph2−/− mice (1.10 ± 0.10 vs. 0.77 ± 0.01 ml min−1·percent−1 oxygen; P ≤ 0.04). Ventilatory LTF, caused by increases in breathing frequency, was evident in Tph2+/+ and Tph2−/− mice following exposure to intermittent hypoxia each day; however, the magnitude of the response was greater in the Tph2+/+ compared with the Tph2−/− mice (1.11 ± 0.02 vs. 1.05 ± 0.01 normalized to baseline on each day; P ≤ 0.01). The magnitude of ventilatory LTF increased significantly from the initial to the finals days of the protocol in the Tph2−/− (1.06 ± 0.02 vs. 1.11 ± 0.03 normalized to baseline on the initial days; P ≤ 0.004) but not in the Tph2+/+ mice. This enhanced response was mediated by increases in tidal volume. Body temperature and metabolic rate did not account for differences in the magnitude of ventilatory LTF observed between groups after acute and repeated daily exposure to intermittent hypoxia. We conclude that ventilatory LTF, after acute exposure to intermittent hypoxia, is mediated by increases in breathing frequency and occurs in the absence of serotonin, although the magnitude of the response is diminished. This weakened response is enhanced following repeated daily exposure to intermittent hypoxia, via increases in tidal volume, to a similar magnitude evident in Tph2+/+ mice. Thus the magnitude of ventilatory LTF following repeated daily exposure to intermittent hypoxia is not dependent on the presence of CNS serotonin.

scholarly journals Impact of repeated daily exposure to intermittent hypoxia and mild sustained hypercapnia on apnea severity

2012 ◽  
Vol 112 (3) ◽  
pp. 367-377 ◽  
Author(s):  
Sanar S. Yokhana ◽  
David G. Gerst ◽  
Dorothy S. Lee ◽  
M. Safwan Badr ◽  
Tabarak Qureshi ◽  
...  
Keyword(s):  
Tidal Volume ◽  
Intermittent Hypoxia ◽  
Esophageal Pressure ◽  
Control Group ◽  
Apnea Hypopnea Index ◽  
Respiratory Drive ◽  
Sleep Study ◽  
Daily Exposure ◽  
Long Term Facilitation

We examined whether exposure to intermittent hypoxia (IH) during wakefulness impacted on the apnea/hypopnea index (AHI) during sleep in individuals with sleep apnea. Participants were exposed to twelve 4-min episodes of hypoxia in the presence of sustained mild hypercapnia each day for 10 days. A control group was exposed to sustained mild hypercapnia for a similar duration. The intermittent hypoxia protocol was completed in the evening on day 1 and 10 and was followed by a sleep study. During all sleep studies, the change in esophageal pressure (ΔPes) from the beginning to the end of an apnea and the tidal volume immediately following apneic events were used to measure respiratory drive. Following exposure to IH on day 1 and 10, the AHI increased above baseline measures ( day 1: 1.95 ± 0.42 fraction of baseline, P ≤ 0.01, vs. day 10: 1.53 ± 0.24 fraction of baseline, P < 0.06). The indexes were correlated to the hypoxic ventilatory response (HVR) measured during the IH protocol but were not correlated to the magnitude of ventilatory long-term facilitation (vLTF). Likewise, ΔPes and tidal volume measures were greater on day 1 and 10 compared with baseline (ΔPes: −8.37 ± 0.84 vs. −5.90 ± 1.30 cmH20, P ≤ 0.04; tidal volume: 1,193.36 ± 101.85 vs. 1,015.14 ± 119.83 ml, P ≤ 0.01). This was not the case in the control group. Interestingly, the AHI on day 10 (0.78 ± 0.13 fraction of baseline, P ≤ 0.01) was significantly less than measures obtained during baseline and day 1 in the mild hypercapnia control group. We conclude that enhancement of the HVR initiated by exposure to IH may lead to increases in the AHI during sleep and that initiation of vLTF did not appear to impact on breathing stability. Lastly, our results suggest that repeated daily exposure to mild sustained hypercapnia may lead to a decrease in breathing events.

scholarly journals Ventilatory long‐term facilitation is altered in tryptophan hydroxylase 2 knock out mice

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Stephen James Hickner ◽  
Mariana Angoa-Perez ◽  
Donald M Kuhn ◽  
Jason H Mateika
Keyword(s):  
Tryptophan Hydroxylase ◽  
Tryptophan Hydroxylase 2 ◽  
Knock Out ◽  
Knock Out Mice ◽  
Long Term Facilitation

scholarly journals Sleep state dependence of ventilatory long-term facilitation following acute intermittent hypoxia in Lewis rats

2010 ◽  
Vol 109 (2) ◽  
pp. 323-331 ◽  
Author(s):  
A. Nakamura ◽  
E. B. Olson ◽  
J. Terada ◽  
J. M. Wenninger ◽  
G. E. Bisgard ◽  
...  
Keyword(s):  
Tidal Volume ◽  
Eye Movement ◽  
Intermittent Hypoxia ◽  
Nrem Sleep ◽  
Rapid Eye Movement ◽  
Lewis Rats ◽  
Vigilance State ◽  
Long Term Facilitation ◽  
Sustained Hypoxia

Ventilatory long-term facilitation (vLTF) is a form of respiratory plasticity induced by acute intermittent hypoxia (AIH). Although vLTF has been reported in unanesthetized animals, little is known concerning the effects of vigilance state on vLTF expression. We hypothesized that AIH-induced vLTF is preferentially expressed in sleeping vs. awake male Lewis rats. Vigilance state was assessed in unanesthetized rats with chronically implanted EEG and nuchal EMG electrodes, while tidal volume, frequency, minute ventilation (V̇e), and CO2 production were measured via plethysmography, before, during, and after AIH (five 5-min episodes of 10.5% O2 separated by 5-min normoxic intervals), acute sustained hypoxia (25 min of 10.5% O2), or a sham protocol without hypoxia. Vigilance state was classified as quiet wakefulness (QW), light and deep non-rapid eye movement (NREM) sleep (l-NREM and d-NREM sleep, respectively), or rapid eye movement sleep. Ventilatory variables were normalized to pretreatment baseline values in the same vigilance state. During d-NREM sleep, vLTF was observed as a progressive increase in V̇e post-AIH (27 ± 5% average, 30–60 min post-AIH). In association, V̇e/V̇co2 (36 ± 2%), tidal volume (14 ± 2%), and frequency (7 ± 2%) were increased 30–60 min post-AIH during d-NREM sleep. vLTF was significant but less robust during l-NREM sleep, was minimal during QW, and was not observed following acute sustained hypoxia or sham protocols in any vigilance state. Thus, vLTF is state-dependent and pattern-sensitive in unanesthetized Lewis rats, with the greatest effects during d-NREM sleep. Although the physiological significance of vLTF is not clear, its greatest significance to ventilatory control is most likely during sleep.

scholarly journals Generation of active expiration by serotoninergic mechanisms of the ventral medulla of rats

2016 ◽  
Vol 121 (5) ◽  
pp. 1135-1144 ◽  
Author(s):  
Eduardo V. Lemes ◽  
Eduardo Colombari ◽  
Daniel B. Zoccal
Keyword(s):  
Adult Male ◽  
Intermittent Hypoxia ◽  
Abdominal Muscle ◽  
Receptor Antagonism ◽  
Retrotrapezoid Nucleus ◽  
Agonist And Antagonist ◽  
Parafacial Respiratory Group ◽  
Spontaneously Breathing ◽  
Long Term Facilitation

Abdominal expiratory activity is absent at rest and is evoked during metabolic challenges, such as hypercapnia and hypoxia, or after the exposure to intermittent hypoxia (IH). The mechanisms engaged during this process are not completely understood. In this study, we hypothesized that serotonin (5-HT), acting in the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG), is able to generate active expiration. In anesthetized (urethane, ip), tracheostomized, spontaneously-breathing adult male Holtzman rats we microinjected a serotoninergic agonist and antagonist bilaterally in the RTN/pFRG and recorded diaphragm and abdominal muscle activities. We found that episodic (3 times, 5 min apart), but not single microinjections of 5-HT (1 mM) in the RTN/pFRG elicited an enduring (>30 min) increase in abdominal activity. This response was amplified in vagotomized rats and blocked by previous 5-HT receptor antagonism with ketanserin (10 µM). Episodic 5-HT microinjections in the RTN/pFRG also potentiated the inspiratory and expiratory reflex responses to hypercapnia. The antagonism of 5-HT receptors in the RTN/pFRG also prevented the long-term facilitation (>30 min) of abdominal activity in response to acute IH exposure (10 × 6–7% O for 45 s every 5 min). Our findings indicate the activation of serotoninergic mechanisms in the RTN/pFRG is sufficient to increase abdominal expiratory activity at resting conditions and required for the emergence of active expiration after IH in anesthetized animals.

scholarly journals The hypoxic ventilatory response and ventilatory long-term facilitation are altered by time of day and repeated daily exposure to intermittent hypoxia

2011 ◽  
Vol 110 (1) ◽  
pp. 15-28 ◽  
Author(s):  
David G. Gerst ◽  
Sanar S. Yokhana ◽  
Laura M. Carney ◽  
Dorothy S. Lee ◽  
M. Safwan Badr ◽  
...  
Keyword(s):  
Sleep Apnea ◽  
Intermittent Hypoxia ◽  
Ventilatory Response ◽  
Arterial Oxygen Saturation ◽  
Time Of Day ◽  
Arterial Oxygen ◽  
Hypoxic Ventilatory Response ◽  
Daily Exposure ◽  
Long Term Facilitation

This study examined whether time of day and repeated exposure to intermittent hypoxia have an impact on the hypoxic ventilatory response (HVR) and ventilatory long-term facilitation (vLTF). Thirteen participants with sleep apnea were exposed to twelve 4-min episodes of isocapnic hypoxia followed by a 30-min recovery period each day for 10 days. On days 1 (initial day) and 10 (final day) participants completed the protocol in the evening (PM); on the remaining days the protocol was completed in the morning (AM). The HVR was increased in the morning compared with evening on the initial (AM 0.83 ± 0.08 vs. PM 0.64 ± 0.11 l·min−1·%SaO2−1; P ≤ 0.01) and final days (AM 1.0 ± 0.08 vs. PM 0.81 ± 0.09 l·min−1·%SaO2−1; P ≤ 0.01, where %SaO2 refers to percent arterial oxygen saturation). Moreover, the magnitude of the HVR was enhanced following daily exposure to intermittent hypoxia in the morning (initial day 0.83 ± 0.08 vs. final day 1.0 ± 0.08 l·min−1·%SaO2−1; P ≤ 0.03) and evening (initial day 0.64 ± 0.11 vs. final day 0.81 ± 0.09 l·min−1·%SaO2−1; P ≤ 0.03). vLTF was reduced in the morning compared with the evening on the initial (AM 19.03 ± 0.35 vs. PM 22.30 ± 0.49 l/min; P ≤ 0.001) and final (AM 20.54 ± 0.32 vs. PM 23.11 ± 0.54 l/min; P ≤ 0.01) days. Following daily exposure to intermittent hypoxia, vLTF was enhanced in the morning (initial day 19.03 ± 0.35 vs. final day 20.54 ± 0.32 l/min; P ≤ 0.01). We conclude that the HVR is increased while vLTF is decreased in the morning compared with the evening in individuals with sleep apnea and that the magnitudes of these phenomena are enhanced following daily exposure to intermittent hypoxia.

Selected Contribution: Chronic intermittent hypoxia enhances respiratory long-term facilitation in geriatric female rats

2003 ◽  
Vol 95 (6) ◽  
pp. 2614-2623 ◽  
Author(s):  
A. G. Zabka ◽  
G. S. Mitchell ◽  
E. B. Olson ◽  
M. Behan
Keyword(s):  
Intermittent Hypoxia ◽  
Young Female ◽  
Time Dependent ◽  
Female Rats ◽  
Chronic Intermittent Hypoxia ◽  
Middle Aged ◽  
Short Term ◽  
Hypoxic Response ◽  
Long Term Facilitation

Age and the estrus cycle affect time-dependent respiratory responses to episodic hypoxia in female rats. Respiratory long-term facilitation (LTF) is enhanced in middle-aged vs. young female rats ( 72 ). We tested the hypothesis that phrenic and hypoglossal (XII) LTF are diminished in acyclic geriatric rats when fluctuating sex hormone levels no longer establish conditions that enhance LTF. Chronic intermittent hypoxia (CIH) enhances LTF ( 41 ); thus we further predicted that CIH would restore LTF in geriatric female rats. LTF was measured in young (3-4 mo) and geriatric (20-22 mo) female Sasco Sprague-Dawley rats and in a group of geriatric rats exposed to 1 wk of nocturnal CIH (11 vs. 21% O2 at 5-min intervals, 12 h/night). In anesthetized, paralyzed, vagotomized, and ventilated rats, time-dependent hypoxic phrenic and XII responses were assessed. The short-term hypoxic response was measured during the first of three 5-min episodes of isocapnic hypoxia (arterial Po2 35-45 Torr). LTF was assessed 15, 30, and 60 min postepisodic hypoxia. Phrenic and XII short-term hypoxic response was not different among groups, regardless of CIH treatment ( P > 0.05). LTF in geriatric female rats was smaller than previously reported for middle-aged rats but comparable to that in young female rats. CIH augmented phrenic and XII LTF to levels similar to those of middle-aged female rats without CIH ( P < 0.05). The magnitude of phrenic and XII LTF in all groups was inversely related to the ratio of progesterone to estradiol serum levels ( P < 0.05). Thus CIH and sex hormones influence the magnitude of LTF in geriatric female rats.

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