scholarly journals Induction of sensory long-term facilitation in the carotid body by intermittent hypoxia: Implications for recurrent apneas

2003 ◽  
Vol 100 (17) ◽  
pp. 10073-10078 ◽  
Author(s):  
Y.-J. Peng ◽  
J. L. Overholt ◽  
D. Kline ◽  
G. K. Kumar ◽  
N. R. Prabhakar
Keyword(s):  
Carotid Body ◽  
Intermittent Hypoxia ◽  
Long Term Facilitation

Time-dependent modulation of carotid body afferent activity during and after intermittent hypoxia

2005 ◽  
Vol 288 (6) ◽  
pp. R1571-R1580 ◽  
Author(s):  
Kevin J. Cummings ◽  
Richard J. A. Wilson
Keyword(s):  
Carotid Body ◽  
Intermittent Hypoxia ◽  
Current Data ◽  
Time Dependent ◽  
Severe Hypoxia ◽  
Afferent Activity ◽  
Direct Role ◽  
Long Term Facilitation

The ventilatory response to several minutes of hypoxia consists of various time-dependent phenomena, some of which occur during hypoxia (e.g., short-term depression), whereas others appear on return to normoxia (e.g., posthypoxic frequency decline). Additional phenomena can be elicited by acute, intermittent hypoxia (e.g., progressive augmentation, long-term facilitation). Current data suggest that these phenomena originate centrally. We tested the hypothesis that carotid body afferent activity undergoes time-dependent modulation, consistent with a direct role in these ventilatory phenomena. Using an in vitro rat carotid body preparation, we found that 1) afferent activity declined during the first 5 min of severe (40 Torr Po2), moderate (60 Torr Po2), or mild (80 Torr Po2) hypoxia; 2) after return to normoxia (100 Torr Po2) and after several minutes of moderate or severe hypoxia, afferent activity was transiently reduced compared with prehypoxic levels; and 3) with successive 5-min bouts of mild, moderate, or severe hypoxia, afferent activity during bouts increased progressively. We call these phenomena sensory hypoxic decline, sensory posthypoxic decline, and sensory progressive augmentation, respectively. These phenomena were stimulus specific: similar phenomena were not seen with 5-min bouts of normoxic hypercapnia (100 Torr Po2 and 50–60 Torr Pco2) or hypoxic hypocapnia (60 Torr Po2 and 30 Torr Pco2). However, bouts of either normoxic hypercapnia or hypocapnic hypoxia resulted in sensory long-term facilitation. We suggest time-dependent carotid body activity acts in parallel with central mechanisms to shape the dynamics of ventilatory responses to respiratory chemostimuli.

Intermittent hypoxia: cell to system

2001 ◽  
Vol 281 (3) ◽  
pp. L524-L528 ◽  
Author(s):  
Nanduri R. Prabhakar ◽  
R. Douglas Fields ◽  
Tracy Baker ◽  
Eugene C. Fletcher
Keyword(s):  
Carotid Body ◽  
Intermittent Hypoxia ◽  
De Novo ◽  
Hypoxia Inducible Factor ◽  
Chronic Intermittent Hypoxia ◽  
Cellular Mechanisms ◽  
Hypoxia Inducible Factor 1 ◽  
Arterial Blood ◽  
Long Term Facilitation

This symposium was organized to present research dealing with the effects of intermittent hypoxia on cardiorespiratory systems and cellular mechanisms. The pattern of neural impulse activity has been shown to be critical in the induction of genes in neuronal cells and involves distinct signaling pathways. Mechanisms associated with different patterns of intermittent hypoxia might share similar mechanisms. Chronic intermittent hypoxia selectively augments carotid body sensitivity to hypoxia and causes long-lasting activation of sensory discharge. Intermittent hypoxia also activates hypoxia-inducible factor-1. Reactive oxygen species are critical in altering carotid body function and hypoxia-inducible factor-1 activation caused by intermittent hypoxia. Blockade of serotonin function in the spinal cord prevents long-term facilitation in respiratory motor output elicited by episodic hypoxia and requires de novo protein synthesis. Chronic intermittent hypoxia leads to sustained elevation in arterial blood pressure and is associated with upregulation of catecholaminergic and renin-angiotensin systems and downregulation of nitric oxide synthases.

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.

Mechanisms of severe acute intermittent hypoxia-induced phrenic long-term facilitation

2021 ◽  
Vol 125 (4) ◽  
pp. 1146-1156
Author(s):  
Nicole L. Nichols ◽  
Gordon S. Mitchell
Keyword(s):  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Intermittent Hypoxia ◽  
Nadph Oxidase Activity ◽  
Complex Interactions ◽  
Long Term Facilitation ◽  
Erk Activity

Distinct mechanisms give rise to pLTF induced by moderate and severe AIH. We demonstrate that, unlike moderate AIH, severe AIH-induced pLTF requires EPAC and PI3K/Akt and is marginally constrained by NADPH oxidase activity. Surprisingly, sAIH-induced pLTF requires MEK/ERK activity similar to moderate AIH-induced pLTF and is reduced by PKA inhibition. We suggest sAIH-induced pLTF arises from complex interactions between dominant mechanisms characteristic of moderate versus severe AIH-induced pLTF.

scholarly journals Enhancement of phrenic long-term facilitation following repetitive acute intermittent hypoxia is blocked by the glycolytic inhibitor 2-deoxyglucose

2018 ◽  
Vol 314 (1) ◽  
pp. R135-R144 ◽  
Author(s):  
P. M. MacFarlane ◽  
S. Vinit ◽  
G. S. Mitchell
Keyword(s):  
Intermittent Hypoxia ◽  
Therapeutic Modality ◽  
Glycolytic Flux ◽  
Vegf Mrna ◽  
Clinical Disorders ◽  
Glycolytic Inhibitor ◽  
Oxide Synthase ◽  
Long Term Facilitation ◽  
Serotonin 2A

Moderate acute intermittent hypoxia (mAIH) elicits a form of respiratory motor plasticity known as phrenic long-term facilitation (pLTF). Preconditioning with modest protocols of chronic intermittent hypoxia enhances pLTF, demonstrating pLTF metaplasticity. Since “low-dose” protocols of repetitive acute intermittent hypoxia (rAIH) show promise as a therapeutic modality to restore respiratory (and nonrespiratory) motor function in clinical disorders with compromised breathing, we tested 1) whether preconditioning with a mild rAIH protocol enhances pLTF and hypoglossal (XII) LTF and 2) whether the enhancement is regulated by glycolytic flux. In anesthetized, paralyzed, and ventilated adult male Lewis rats, mAIH (three 5-min episodes of 10% O2) elicited pLTF (pLTF at 60 min post-mAIH: 49 ± 5% baseline). rAIH preconditioning (ten 5-min episodes of 11% O2/day with 5-min normoxic intervals, 3 times per week, for 4 wk) significantly enhanced pLTF (100 ± 16% baseline). XII LTF was unaffected by rAIH. When glycolytic flux was inhibited by 2-deoxy-d-glucose (2-DG) administered via drinking water (~80 mg·kg−1·day−1), pLTF returned to normal levels (58 ± 8% baseline); 2-DG had no effect on pLTF in normoxia-pretreated rats (59 ± 7% baseline). In ventral cervical (C4/5) spinal homogenates, rAIH increased inducible nitric oxide synthase mRNA vs. normoxic controls, an effect blocked by 2-DG. However, there were no detectable effects of rAIH or 2-DG on several molecules associated with phrenic motor plasticity, including serotonin 2A, serotonin 7, brain-derived neurotrophic factor, tropomyosin receptor kinase B, or VEGF mRNA. We conclude that modest, but prolonged, rAIH elicits pLTF metaplasticity and that a drug known to inhibit glycolytic flux (2-DG) blocks pLTF enhancement.

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.

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