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.

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.

scholarly journals Ampakine pretreatment enables a single brief hypoxic episode to evoke phrenic motor facilitation

2020 ◽  
Vol 123 (3) ◽  
pp. 993-1003 ◽  
Author(s):  
L. B. Wollman ◽  
K. A. Streeter ◽  
D. D. Fuller
Keyword(s):  
Ampa Receptor ◽  
Low Dose ◽  
Motor Output ◽  
Hypoxic Exposure ◽  
Receptor Function ◽  
Sprague Dawley ◽  
Hypoxic Episode ◽  
Burst Amplitude ◽  
Vehicle Injection ◽  
Long Term Facilitation

Phrenic long-term facilitation (LTF) is a sustained increase in phrenic motor output occurring after exposure to multiple (but not single) hypoxic episodes. Ampakines are a class of drugs that enhance AMPA receptor function. Ampakines can enhance expression of neuroplasticity, and the phrenic motor system is fundamentally dependent on excitatory glutamatergic currents. Accordingly, we tested the hypothesis that combining ampakine pretreatment with a single brief hypoxic exposure would result in phrenic motor facilitation lasting well beyond the period of hypoxia. Phrenic nerve output was recorded in urethane-anesthetized, ventilated, and vagotomized adult Sprague-Dawley rats. Ampakine CX717 (15 mg/kg iv; n = 8) produced a small increase in phrenic inspiratory burst amplitude and frequency, but values quickly returned to predrug baseline. When CX717 was followed 2 min later by a 5-min exposure to hypoxia ( n = 8; [Formula: see text] ~45 mmHg), a persistent increase in phrenic inspiratory burst amplitude (i.e., phrenic motor facilitation) was observed up to 60 min posthypoxia (103 ± 53% increase from baseline). In contrast, when hypoxia was preceded by vehicle injection (10% 2-hydroxypropyl-β-cyclodextrin; n = 8), inspiratory phrenic bursting was similar to baseline values at 60 min. Additional experiments with another ampakine (CX1739, 15 mg/kg) produced comparable results. We conclude that pairing low-dose ampakine treatment with a single brief hypoxic exposure can evoke sustained phrenic motor facilitation. This targeted approach for enhancing respiratory neuroplasticity may have value in the context of hypoxia-based neurorehabilitation strategies. NEW & NOTEWORTHY A single brief episode of hypoxia (e.g., 3–5 min) does not evoke long-lasting increases in respiratory motor output after the hypoxia is concluded. Ampakines are a class of drugs that enhance AMPA receptor function. We show that pairing low-dose ampakine treatment with a single brief hypoxic exposure can evoke sustained phrenic motor facilitation after the acute hypoxic episode.

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.

EXCRETION OF CATECHOL AMINES BY WHITE RATS IN THE COLD

1964 ◽  
Vol 42 (4) ◽  
pp. 567-577 ◽  
Author(s):  
Lorraine C. Smith ◽  
L.-P. Dugal
Keyword(s):  
The Other ◽  
Sprague Dawley ◽  
White Rats ◽  
Sprague Dawley Rats ◽  
Old Rats ◽  
Catechol Amines ◽  
Sustained Increase

Exposure of white rats to 2 °C for 20 weeks caused an immediate and sustained increase in the excretion of catechol amines as compared to controls kept at 23 °C. Adrenaline excretion increased approximately three to four times while noradrenaline excretion increased about eight times. There were no marked differences between Wistar and Sprague–Dawley rats in the amounts of adrenaline and noradrenaline excreted at 23 °C or 2 °C. 'Old' rats kept in activity cages excreted much more of the catechol amines both at 23 °C and 2 °C than did the other rats and they showed a peak for adrenaline excretion after 1 week and for noradrenaline excretion after 3 to 4 weeks in the cold.

scholarly journals Increased blood pressure, aldosterone activity, and regional differences in renal ENaC protein during vasopressin escape

2004 ◽  
Vol 287 (5) ◽  
pp. F1076-F1083 ◽  
Author(s):  
Jian Song ◽  
Xinqun Hu ◽  
Osman Khan ◽  
Ying Tian ◽  
Joseph G. Verbalis ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Regional Differences ◽  
Water Retention ◽  
Urine Volume ◽  
Hydroxysteroid Dehydrogenase ◽  
Plasma Aldosterone ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Sustained Increase

The syndrome of inappropriate antidiuretic hormone (SIADH) is associated with water retention and hyponatremia. The kidney adapts via a transient natriuresis and persistent diuresis, i.e., vasopressin escape. Previously, we showed an increase in the whole kidney abundance of aldosterone-sensitive proteins, the α- and γ (70-kDa-band)-subunits of the epithelial Na+ channel (ENaC), and the thiazide-sensitive Na-Cl cotransporter (NCC) in our rat model of SIADH. Here we examine mean arterial pressure via radiotelemetry, aldosterone activity, and cortical vs. medullary ENaC subunit and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2) protein abundances in escape. Eighteen male Sprague-Dawley rats (300 g) were sham operated ( n = 6) or infused with desmopressin (dDAVP; n = 12, a V2 receptor-selective analog of AVP). After 4 days, one-half of the rats receiving dDAVP were switched to a liquid diet, i.e., water loaded (WL) for 5–7 additional days. The WL rats had a sustained increase in urine volume and blood pressure (122 vs. 104 mmHg, P < 0.03, at 7 days). Urine and plasma aldosterone levels were increased in the WL group to 844 and 1,658% of the dDAVP group, respectively. NCC and α- and γ-ENaC (70-kDa band) were increased significantly in the WL group (relative to dDAVP), only in the cortex. β- and γ-ENaC (85-kDa band) were increased significantly by dDAVP in cortex and medulla relative to control. 11β-HSD-2 was increased by dDAVP in the cortex and not significantly affected by water loading. These changes may serve to attenuate Na+ losses and ameliorate hyponatremia in vasopressin escape.

scholarly journals Solifenacin/Mirabegron Induces an Acute Compliance Increase in the Filling Phase of the Capacity-Reduced Urinary Bladder: A Pressure-Volume Analysis in Rats

2021 ◽  
Vol 12 ◽  
Author(s):  
Hsien-Yu Peng ◽  
Cheng-Yuan Lai ◽  
Ming-Chun Hsieh ◽  
Tzer-Bin Lin
Keyword(s):  
Dependent Manner ◽  
Sprague Dawley ◽  
Volume Analysis ◽  
Sprague Dawley Rats ◽  
Bladder Compliance ◽  
Data Points ◽  
Filling Phase ◽  
Acute Increase ◽  
Urine Storage ◽  
Mean Compliance

Aims: Pressure in the bladder, which is a high compliance organ, is only slightly elevated to a considerable filling volume during storage. Although cystometry off-line offers mean compliance, no protocol is available for real-time assays of the dynamics of bladder compliance, and the potential impact of solifenacin and mirabegron on dynamic bladder compliance has not been established.Methods: Along with constantly infused cystometry, a pressure-volume analysis (PVA) was performed by plotting intra-vesical volume against pressure in Sprague-Dawley rats. The instant compliance was assayed as the slope of the trajectory, and the mean compliance (Cm) was determined by the slope of the line produced by regression of the data points at the end of the first, second, and third quarters of the filling phase.Results: Under a steady-state, the PVA trajectory moved clockwise which shaped coincident enclosed loops with stable compliance. Though administering to naïve animals solifenacin, but not mirabegron (both 1 × 10−5−1 × 10−1 mg/kg, i.a.) decreased the peak pressure, both of these reagents exhibited acute increments in the trajectory slope and Cm of the filling phase in a dose-dependent manner (ED50 = 1.4 × 10−4 and 2.2 × 10−5 mg/kg, respectively). Resembling urine frequency/urgency in OAB patients, the voiding frequency of a capacity-reduced bladder was increased in association with decreased compliance which was ameliorated by both acute solifenacin and mirabegron injections (both 1 × 10−1 mg/kg).Conclusion: In addition to their well-known anti-inotropic/relaxative effects, solifenacin, and mirabegron induce an acute increase in bladder compliance to ameliorate OAB-like syndromes. Together with time-domain cystometry, PVA offers a platform for investigating the physiology/pathophysiology/pharmacology of bladder compliance which is crucial for urine storage.

Selective activation of norepinephrine- and epinephrine-secreting chromaffin cells in rat adrenal medulla

1992 ◽  
Vol 263 (3) ◽  
pp. R716-R721 ◽  
Author(s):  
R. R. Vollmer ◽  
A. Baruchin ◽  
S. S. Kolibal-Pegher ◽  
S. P. Corey ◽  
E. M. Stricker ◽  
...  
Keyword(s):  
Cold Exposure ◽  
Chromaffin Cells ◽  
Statistical Significance ◽  
Significant Rise ◽  
Significant Decline ◽  
Synthetic Activity ◽  
Sprague Dawley ◽  
Selective Activation ◽  
Sprague Dawley Rats ◽  
Contrast Exposure

The differential effects of insulin-induced hypoglycemia and cold exposure on adrenal medullary epinephrine (Epi) and norepinephrine (NE) cells were investigated in male Sprague-Dawley rats. In rats fasted overnight, insulin produced a marked hypoglycemia that resulted in a 70% decrease in adrenal medullary Epi content 3 h after the insulin was administered. No change in NE content was observed. Plasma Epi concentration was increased markedly after insulin, with a smaller increment in NE. In contrast, exposure to a 4 degrees C environment selectively reduced adrenal NE content, with the effect reaching statistical significance at 18 h. Cold exposure also led to a significant rise in plasma NE but not Epi. Both insulin-induced hypoglycemia and cold exposure significantly elevated adrenal dopamine, indicating that catecholamine synthesis was stimulated. Further evidence of enhanced catecholamine formation was the observation that inhibition of synthesis with alpha-methyl-p-tyrosine (AMT) greatly augmented the ability of insulin-induced hypoglycemia to selectively reduce adrenal medullary Epi content. Similarly, in cold-exposed animals, AMT pretreatment accelerated the NE depletion so that a significant decline was observed at 3 h. These results support the conclusion that the two major populations of adrenal catecholamine-secreting cells may be preferentially stimulated by different stressors. Moreover, augmented synthetic activity functions to maintain catecholamine stores in both Epi- and NE-secreting cells.

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