Time-dependent hypoxic ventilatory responses in rats:  effects of ketanserin and 5-carboxamidotryptamine

We hypothesized that the 5-hydroxytryptamine (5-HT) active drugs ketanserin and 5-carboxamidotryptamine (5-CT) would modulate time-dependent hypoxic phrenic and hypoglossal responses, including 1) short-term hypoxic response, 2) posthypoxia frequency decline (PHFD), and 3) long-term facilitation (LTF) of respiratory motor output. Phrenic and hypoglossal nerve activities were recorded in urethan-anesthetized, paralyzed, vagotomized, and artificially ventilated rats pretreated either with ketanserin (5-HT2A/C antagonist; 2 mg/kg iv), 5-CT (5-HT1A/B agonist; 10 μg/kg iv), or saline (sham). Rats were exposed to three 5-min episodes of hypoxia [fractional inspired O2([Formula: see text]) = 0.11], separated by 5 min of hyperoxia ([Formula: see text] = 0.5). During hypoxia, ketanserin augmented phrenic but not hypoglossal burst amplitude; 5-CT had no effect. Both drugs accentuated PHFD. Ketanserin blocked phrenic LTF; hypoglossal LTF was not apparent, even in sham-treated rats. 5-CT reversed LTF, resulting in a long-lasting depression of phrenic burst frequency and amplitude without effect on hypoglossal burst amplitude. The data suggest that 1) 5-HT2A/C receptor activation modulates the short-term hypoxic phrenic response and PHFD and is necessary for LTF; and 2) 5-CT may affect time-dependent hypoxic ventilatory responses by reducing serotonin release via 5-HT1A/Bautoreceptor activation.

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

Journal of Applied Physiology ◽

10.1152/japplphysiol.00476.2003 ◽

2003 ◽

Vol 95 (6) ◽

pp. 2614-2623 ◽

Cited By ~ 37

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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Differences in time-dependent hypoxic phrenic responses among inbred rat strains

Journal of Applied Physiology ◽

10.1152/japplphysiol.00984.2004 ◽

2005 ◽

Vol 98 (3) ◽

pp. 838-844 ◽

Cited By ~ 21

Author(s):

Francis J. Golder ◽

Andrea G. Zabka ◽

Ryan W. Bavis ◽

Tracy Baker-Herman ◽

David D. Fuller ◽

...

Keyword(s):

Phrenic Nerve ◽

Strain Differences ◽

Time Dependent ◽

Brown Norway ◽

Multiple Time ◽

Burst Frequency ◽

Hypoxic Response ◽

Ventilatory Responses ◽

Burst Amplitude ◽

Inbred Rat

Hypoxic ventilatory responses differ between rodent strains, suggesting a genetic contribution to interindividual variability. However, hypoxic ventilatory responses consist of multiple time-dependent mechanisms that can be observed in different respiratory motor outputs. We hypothesized that strain differences would exist in discrete time-dependent mechanisms of the hypoxic response and, furthermore, that there may be differences between hypoglossal and phrenic nerve responses to hypoxia. Hypoglossal and phrenic nerve responses were assessed during and after a 5-min hypoxic episode in anesthetized, vagotomized, and ventilated rats from four inbred strains: Brown Norway (BN), Fischer 344 (FS), Lewis (LW), and Piebald-viral-Glaxo (PVG). During baseline, burst frequency was higher in PVG than LW rats ( P < 0.05), phrenic burst amplitude was higher in PVG vs. other strains ( P < 0.05), and hypoglossal burst amplitude was higher in PVG and BN vs. FS and LW ( P < 0.05). During hypoxia, burst frequency did not change in BN or LW rats, but it increased in PVG and FS rats. The phrenic amplitude response was smallest in PVG vs. other strains ( P < 0.05), and the hypoglossal response was similar among strains. Short-term potentiation posthypoxia was slowest in FS and fastest in LW rats ( P < 0.05). Posthypoxia frequency decline was absent in PVG, but it was observed in all other strains. Augmented breaths were observed during hypoxia in FS rats only. Thus genetic differences exist in the time domains of the hypoxic response, and these are differentially expressed in hypoglossal and phrenic nerves. Furthermore, genetic diversity observed in hypoxic ventilatory responses in unanesthetized rats may arise from multiple neural mechanisms.

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Baseline Arterial CO2 Pressure Regulates Acute Intermittent Hypoxia-Induced Phrenic Long-Term Facilitation in Rats

Frontiers in Physiology ◽

10.3389/fphys.2021.573385 ◽

2021 ◽

Vol 12 ◽

Author(s):

Raphael R. Perim ◽

Mohamed El-Chami ◽

Elisa J. Gonzalez-Rothi ◽

Gordon S. Mitchell

Keyword(s):

Motor Neurons ◽

Intermittent Hypoxia ◽

Progressive Increase ◽

Serotonin Release ◽

Serotonergic Neurons ◽

Burst Amplitude ◽

Experimental Protocols ◽

End Tidal ◽

Long Term Facilitation

Moderate acute intermittent hypoxia (mAIH) elicits a progressive increase in phrenic motor output lasting hours post-mAIH, a form of respiratory motor plasticity known as phrenic long-term facilitation (pLTF). mAIH-induced pLTF is initiated by activation of spinally-projecting raphe serotonergic neurons during hypoxia and subsequent serotonin release near phrenic motor neurons. Since raphe serotonergic neurons are also sensitive to pH and CO2, the prevailing arterial CO2 pressure (PaCO2) may modulate their activity (and serotonin release) during hypoxic episodes. Thus, we hypothesized that changes in background PaCO2 directly influence the magnitude of mAIH-induced pLTF. mAIH-induced pLTF was evaluated in anesthetized, vagotomized, paralyzed and ventilated rats, with end-tidal CO2 (i.e., a PaCO2 surrogate) maintained at: (1) ≤39 mmHg (hypocapnia); (2) ∼41 mmHg (normocapnia); or (3) ≥48 mmHg (hypercapnia) throughout experimental protocols. Although baseline phrenic nerve activity tended to be lower in hypocapnia, short-term hypoxic phrenic response, i.e., burst amplitude (Δ = 5.1 ± 1.1 μV) and frequency responses (Δ = 21 ± 4 bpm), was greater than in normocapnic (Δ = 3.6 ± 0.6 μV and 8 ± 4, respectively) or hypercapnic rats (Δ = 2.0 ± 0.6 μV and −2 ± 2, respectively), followed by a progressive increase in phrenic burst amplitude (i.e., pLTF) for at least 60 min post mAIH. pLTF in the hypocapnic group (Δ = 4.9 ± 0.6 μV) was significantly greater than in normocapnic (Δ = 2.8 ± 0.7 μV) or hypercapnic rats (Δ = 1.7 ± 0.4 μV). In contrast, although hypercapnic rats also exhibited significant pLTF, it was attenuated versus hypocapnic rats. When pLTF was expressed as percent change from maximal chemoreflex stimulation, all pairwise comparisons were found to be statistically significant (p < 0.05). We conclude that elevated PaCO2 undermines mAIH-induced pLTF in anesthetized rats. These findings contrast with well-documented effects of PaCO2 on ventilatory LTF in awake humans.

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1993.265.4.r811 ◽

1993 ◽

Vol 265 (4) ◽

pp. R811-R819 ◽

Cited By ~ 65

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.

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

Journal of Applied Physiology ◽

10.1152/jappl.2001.90.5.2001 ◽

2001 ◽

Vol 90 (5) ◽

pp. 2001-2006 ◽

Cited By ~ 137

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.

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Glucocorticoids Decrease the Conversion of Thyroxine into 3,5,3′-Tri-Iodothyronine by Isolated Rat Renal Tubules

Clinical Science ◽

10.1042/cs0620215 ◽

1982 ◽

Vol 62 (2) ◽

pp. 215-220 ◽

Cited By ~ 5

Author(s):

P. Heyma ◽

R. G. Larkins

Keyword(s):

Strong Evidence ◽

Glucocorticoid Receptors ◽

Actinomycin D ◽

Time Dependent ◽

Renal Tubules ◽

Short Term ◽

Collagenase Digestion ◽

Isolated Rat

1. The effect of glucocorticoids on the deiodination of thyroxine (T4) to 3,5,3′-tri-iodothyronine (T3) was studied in rat renal tubules prepared by collagenase digestion. 2. In short-term (6 h) experiments, cortisol and dexamethasone inhibited the conversion of T4 into T3 at concentrations of 2 × 10-4 mol/l and 2 × 10-5 mol/l respectively. The inhibition by cortisol and dexamethasone was time dependent and was prevented by actinomycin D and progesterone, suggesting that the inhibition is mediated by an effect on nuclear transcription dependent on binding to glucocorticoid receptors. 3. In long-term (16 h) experiments, cortisol and dexamethasone inhibited T4 to T3 conversion by the tubules at concentrations of 1 × 10-12 mol/l and above. In addition, physiological concentrations of corticosterone (1 × 10-8 mol/l) were able to decrease T3 generation from T4. 4. Our data provide strong evidence that physiological concentrations of glucocorticoids are able to affect T3 production from T4 directly and suggest that they may be important regulators of T4 deiodination.

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

Journal of Applied Physiology ◽

10.1152/japplphysiol.01113.2018 ◽

2019 ◽

Vol 127 (2) ◽

pp. 432-443 ◽

Cited By ~ 5

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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Seasonal to multi-annual speedup and slowdown of Greenland outlet glaciers inferred from time-dependent remote sensing observations

10.5194/egusphere-egu2020-12679 ◽

2020 ◽

Author(s):

Lizz Ultee ◽

Bryan Riel ◽

Brent Minchew

Keyword(s):

Time Series ◽

Flow Velocity ◽

Ice Sheet ◽

Surface Air Temperature ◽

Greenland Ice Sheet ◽

Time Dependent ◽

Surface Velocity ◽

Short Term ◽

Ice Flow

<p>The rate of ice flux from the Greenland Ice Sheet to the ocean depends on the ice flow velocity through outlet glaciers. Ice flow velocity, in turn, evolves in response to multiple geographic and environmental forcings at different timescales. For example, velocity may vary daily in response to ocean tides, seasonally in response to surface air temperature, and multi-annually in response to long-term trends in climate. The satellite observations processed as part of the NASA MEaSUREs Greenland Ice Sheet Velocity Map allow us to analyse variations in ice surface velocity at multiple timescales. Here, we decompose short-term and long-term signals in time-dependent velocity fields for Greenland outlet glaciers based on the methods of Riel et al. (2018). Patterns found in short-term signals can constrain basal sliding relations and ice rheology, while the longer-term signals hint at decadal in/stability of outlet glaciers. We present example velocity time series for outlets including Sermeq Kujalleq (Jakobshavn Isbrae) and Helheim Glacier, and we highlight features indicative of dynamic drawdown or advective restabilization. Finally, we comment on the capabilities of a time series analysis software under development for glaciological applications.</p>

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

Journal of Applied Physiology ◽

10.1152/japplphysiol.00904.2013 ◽

2014 ◽

Vol 116 (11) ◽

pp. 1345-1352 ◽

Cited By ~ 19

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.

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