Effects of Halothane and Sevoflurane on Inhibitory Neurotransmission to Medullary Expiratory Neurons in a Decerebrate Dog Model

2002 ◽  
Vol 96 (4) ◽  
pp. 955-962 ◽  
Author(s):  
Astrid G. Stucke ◽  
Eckehard A. E. Stuth ◽  
Viseslav Tonkovic-Capin ◽  
Mislav Tonkovic-Capin ◽  
Francis A. Hopp ◽  
...  
Keyword(s):  
Spontaneous Activity ◽  
Gabaa Receptor ◽  
Neuronal Activity ◽  
Neuronal Response ◽  
Inhibitory Input ◽  
Gamma Aminobutyric Acid ◽  
Receptor Function ◽  
Presynaptic Site ◽  
Gabaa Receptor Antagonist ◽  
Expiratory Neurons

Background In canine expiratory bulbospinal neurons, 1 minimum alveolar concentration (MAC) halothane and sevoflurane reduced the glutamatergic excitatory drive at a presynaptic site and enhanced the overall gamma-aminobutyric acid (GABA)-mediated inhibitory input. The authors investigated if this inhibitory enhancement was mainly caused by postsynaptic effects. Methods Two separate anesthetic studies were performed in two sets of decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 MAC halothane or sevoflurane on extracellularly recorded neuronal activity was measured during localized picoejection of the GABAA receptor agonist muscimol and the GABAA receptor antagonist bicuculline. Complete blockade of GABAA-mediated inhibition with bicuculline was used to assess the prevailing overall inhibitory input to the neuron. The neuronal response to muscimol was used to estimate the anesthetic effect on postsynaptic GABAA receptor function. Results Halothane at 1 MAC depressed the spontaneous activity of 12 expiratory neurons 22.2 +/- 14.8% (mean +/- SD) and overall glutamatergic excitation 14.5 +/- 17.9%. Overall GABA-mediated inhibition was enhanced 14.1 +/- 17.9% and postsynaptic GABAA receptor function 74.2 +/- 69.2%. Sevoflurane at 1 MAC depressed the spontaneous activity of 23 neurons 20.6 +/- 19.3% and overall excitation 10.6 +/- 21.7%. Overall inhibition was enhanced 15.4 +/- 34.0% and postsynaptic GABAA receptor function 65.0 +/- 70.9%. The effects of halothane and sevoflurane were not statistically different. Conclusion Halothane and sevoflurane at 1 MAC produced a small increase in overall inhibition of expiratory premotor neuronal activity. The increase in inhibition results from a marked enhancement of postsynaptic GABAA receptor function that is partially offset by a reduction in presynaptic inhibitory input by the anesthetics.

Sevoflurane Enhances γ-Aminobutyric Acid Type A Receptor Function and Overall Inhibition of Inspiratory Premotor Neurons in a Decerebrate Dog Model

2005 ◽  
Vol 103 (1) ◽  
pp. 57-64 ◽  
Author(s):  
Astrid G. Stucke ◽  
Edward J. Zuperku ◽  
Mirko Krolo ◽  
Ivo F. Brandes ◽  
Francis A. Hopp ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Neuronal Activity ◽  
Type A ◽  
Aminobutyric Acid ◽  
Inhibitory Input ◽  
Receptor Function ◽  
Acid Type ◽  
Gabaa Receptor Antagonist ◽  
Premotor Neurons ◽  
Excitatory Drive

Background Inspiratory premotor neurons in the caudal ventral medulla relay excitatory drive to phrenic and inspiratory intercostal motoneurons in the spinal cord. These neurons are subject to tonic gamma-aminobutyric acid type A (GABAA)ergic inhibition. In a previous study, 1 minimum alveolar concentration (MAC) sevoflurane depressed overall glutamatergic excitatory drive and enhanced overall GABAAergic inhibitory drive to the neurons. This study investigated in further detail the effects of sevoflurane on GABAAergic inhibition by examining postsynaptic GABAA receptor activity in these neurons. Methods Studies were performed in decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 MAC sevoflurane on extracellularly recorded neuronal activity was measured during localized picoejection of the GABAA receptor antagonist bicuculline and the GABAA agonist muscimol. Complete blockade of GABAAergic inhibition by bicuculline allowed estimation of the prevailing overall inhibition of the neuron. The neuronal response to muscimol was used to assess the anesthetic effect on the postsynaptic GABAA receptor function. Results One MAC sevoflurane depressed the spontaneous activity of 21 inspiratory premotor neurons by (mean +/- SD) 32.6 +/- 20.5% (P < 0.001). Overall excitatory drive was depressed 17.9 +/- 19.8% (P < 0.01). Overall GABAAergic inhibition was enhanced by 18.5 +/- 18.2% (P < 0.001), and the postsynaptic GABAA receptor function was increased by 184.4 +/- 121.8% (n = 20; P < 0.001). Conclusion One MAC sevoflurane greatly enhanced GABAA receptor function on inspiratory premotor neurons and increased overall synaptic inhibition but to a smaller extent, indicating that the presynaptic inhibitory input was also reduced. Therefore, the anesthetic depression of spontaneous inspiratory premotor neuronal activity by 1 MAC sevoflurane in vivo is due to a combined effect on the two major ionotropic synaptic neurotransmitter systems with a decrease in overall glutamatergic excitation and a strong enhancement of postsynaptic GABAA receptor function.

Effects of Sevoflurane on Excitatory Neurotransmission to Medullary Expiratory Neurons and on Phrenic Nerve Activity in a Decerebrate Dog Model

2001 ◽  
Vol 95 (2) ◽  
pp. 485-491 ◽  
Author(s):  
Astrid G. Stucke ◽  
Eckehard A. E. Stuth ◽  
Viseslav Tonkovic-Capin ◽  
Mislav Tonkovic-Capin ◽  
Francis A. Hopp ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Phrenic Nerve ◽  
Minimum Alveolar Concentration ◽  
Neuronal Response ◽  
Gamma Aminobutyric Acid ◽  
Nerve Activity ◽  
Gaba A ◽  
Phrenic Nerve Activity ◽  
Synaptic Neurotransmission ◽  
Expiratory Neurons

Background Sevoflurane is a new volatile anesthetic with a pronounced respiratory depressant effect. Synaptic neurotransmission in canine expiratory bulbospinal neurons is mainly mediated by excitatory N-methyl-D-aspartatic acid (NMDA) receptor input and modulated by inhibitory gamma-aminobutyric acid type A (GABA(A)) receptors. The authors investigated the effect of sevoflurane on these mechanisms in decerebrate dogs. Methods Studies were performed in decerebrate, vagotomized, paralyzed and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 minimum alveolar concentration (MAC; 2.4%) sevoflurane on extracellularly recorded neuronal activity was measured during localized picoejection of the glutamate agonist NMDA and the GABA(A) receptor blocker bicuculline in a two-part protocol. First, complete blockade of the GABA(A)ergic mechanism by bicuculline allowed differentiation between the effects of sevoflurane on overall GABA(A)ergic inhibition and on overall glutamatergic excitation. In a second step, the neuronal response to exogenous NMDA was used to estimate sevoflurane's effect on postsynaptic glutamatergic neurotransmission. Results One minimum alveolar concentration sevoflurane depressed the spontaneous activity of 16 expiratory neurons by 36.7+/-22.4% (mean +/- SD). Overall glutamatergic excitation was depressed 19.5+/-16.2%, and GABA(A)ergic inhibition was enhanced 18.7+/-20.6%. However, the postsynaptic response to exogenous NMDA was not significantly altered. In addition, 1 MAC sevoflurane depressed peak phrenic nerve activity by 61.8+/-17.7%. Conclusions In the authors' in vivo expiratory neuronal model, the depressive effect of sevoflurane on synaptic neurotransmission was caused by a reduction of presynaptic glutamatergic excitation and an enhancement of GABA(A)ergic inhibition. The effects on expiratory neuronal activity were similar to halothane, but sevoflurane caused a stronger depression of phrenic nerve activity than halothane.

GABA stimulation of gonadotropin-II release in goldfish: involvement of GABAA receptors, dopamine, and sex steroids

1993 ◽  
Vol 265 (2) ◽  
pp. R348-R355 ◽  
Author(s):  
V. L. Trudeau ◽  
B. D. Sloley ◽  
R. E. Peter
Keyword(s):  
Receptor Antagonist ◽  
Gabaa Receptor ◽  
Receptor Agonist ◽  
Gabab Receptor ◽  
Dependent Manner ◽  
Gamma Aminobutyric Acid ◽  
Turnover Rates ◽  
Pharmacological Agents ◽  
Gabaa Receptor Antagonist ◽  
Gonadotropin Ii

The involvement of gamma-aminobutyric acid (GABA) in regulation of pituitary gonadotropin-II (GTH-II) release was studied in the goldfish. Intraperitoneal injection of GABA (300 micrograms/g) stimulated an increase in serum GTH-II levels at 30 min postinjection. The GABAA receptor agonist muscimol (0.1-10 micrograms/g) stimulated GTH-II in a dose-dependent manner. Baclofen, a GABAB receptor agonist, had a small but significant stimulatory effect at 1 and 10 micrograms/g; the amount of GTH-II released in response to baclofen was significantly less (P < 0.05) than that released by muscimol. Pretreatment of goldfish with bicuculline, a GABAA receptor antagonist, but not saclofen, a GABAB receptor antagonist, blocked the stimulatory effect of GABA on serum GTH-II. Elevation of brain and pituitary GABA levels with the GABA transaminase inhibitor, gamma-vinyl-GABA (GVG), decreased hypothalamic and pituitary dopamine (DA) turnover rates, indicating that GABA may stimulate GTH-II release in the goldfish by decreasing dopaminergic inhibition of GTH-II release. The release of GTH-II stimulated by muscimol and GVG was potentiated by pharmacological agents that decrease inhibitory dopaminergic tone, indicating that DA may also inhibit GABA-stimulated GTH-II release. Based on the linear 24-h accumulation of GABA in brain and pituitary after GVG injection, implantation of testosterone, estradiol, or progesterone, previously shown to regulate the serum GTH-II release response to gonadotropin-releasing hormone and GABA, was also found to modulate GABA synthesis in the brain and pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)

Diverse neuronal populations mediate local circuit excitation in area CA3 of developing hippocampus

1995 ◽  
Vol 74 (2) ◽  
pp. 650-672 ◽  
Author(s):  
K. L. Smith ◽  
D. H. Szarowski ◽  
J. N. Turner ◽  
J. W. Swann
Keyword(s):  
Confocal Microscopy ◽  
Gabaa Receptor ◽  
Action Potentials ◽  
Lucifer Yellow ◽  
Single Cells ◽  
Pyramidal Cells ◽  
Gamma Aminobutyric Acid ◽  
Gabaa Receptor Antagonist ◽  
Fast Spiking ◽  
Area Ca3

1. Studies were undertaken to better understand why the developing hippocampus has a marked capacity to generate prolonged synchronized discharges when exposed to gamma-aminobutyric acid-A (GABAA) receptor antagonists. 2. Excitatory synaptic interactions were studied in small microdissected segments of hippocampal area CA3. Slices were obtained from 10- to 16-day-old rats. Application of the GABAA receptor antagonist penicillin produced prolonged synchronized discharges in minislices that were very similar, if not identical, to those recorded in intact slices. The sizes of minislices were systematically varied. Greater than 90% of those that measured 600 microns along the cell body layer produced prolonged synchronized discharges, whereas most minislices measuring 300 microns produced only brief interictal spikes. 3. Action potentials in the majority (75%, 158 of 254) of cells impaled with microelectrodes were able to entrain the entire CA3 population. They were also able to increase (on average 26%) the frequency of spontaneous population discharges. The population discharges were followed by a refractory period that lasted 5–60 s, during which single cells were unable to initiate a population discharge. 4. The majority (87%) of neurons with intrinsic burst properties were found to entrain the CA3 population. The electrophysiological characteristics of these cells were reminiscent of recordings obtained from more mature rats. Action potentials were quite prolonged and demonstrated a secondary shoulder or hump on the down-slope of the spike. 5. When bursting cells were filled with Lucifer yellow and imaged during recording sessions by videomicroscopy and later using confocal microscopy, they showed the anatomic features of CA3 hippocampal pyramidal cells. Confocal microscopy permitted detailed characterization of individual neurons and showed substantial variation in cellular microanatomy. 6. Another class of cells that were found to entrain the CA3 population but did not demonstrate intrinsic bursts were termed regular-firing cells. These cells possessed many of the anatomic and physiological features of bursting cells with the exception of burst firing. They were rarely encountered in intracellular recordings. 7. The third physiological class of cells was termed fast-spiking cells. These had action potentials that were shorter in duration than the other two cell types. They were distinct in the rapid rate of spike repolarization. They demonstrated modest degrees of spike frequency adaptation and fired repeatedly and at relatively high frequencies. Compared with reports on fast-spiking cells in mature hippocampus and neocortex, action potentials appear to be slower and repetitive discharging appeared to be of a lower frequency.(ABSTRACT TRUNCATED AT 400 WORDS)

Modulation of GABAA receptor function by neuroactive steroids: evidence for heterogeneity of steroid sensitivity of recombinant GABAA receptor isoforms

1998 ◽  
Vol 76 (9) ◽  
pp. 909-920 ◽  
Author(s):  
Rajatavo Maitra ◽  
James N Reynolds
Keyword(s):  
Gabaa Receptor ◽  
Membrane Current ◽  
Neuroactive Steroids ◽  
Maximal Response ◽  
Gamma Aminobutyric Acid ◽  
Receptor Function ◽  
Gamma Subunit ◽  
Receptor Isoforms ◽  
Analgesic Agents ◽  
Gabaa Receptor Isoforms

Neuroactive steroids are potent, selective allosteric modulators of gamma-aminobutyric acid type A (GABAA) receptor function in the central nervous system, and may serve as endogenous anxiolytic and analgesic agents. In order to study the influence of subunit subtypes of the GABAA receptor on modulation of receptor function by neuroactive steroids, we expressed human recombinant GABAA receptors in Xenopus oocytes. GABA-activated membrane current, and the modulatory effects of the endogenous neurosteroid 5alpha-pregnan-3alpha-ol-20-one (allopregnanolone) and the synthetic steroid anesthetic 5alpha-pregnan-3alpha-ol-11,20-dione (alphaxalone) were measured using two-electrode voltage-clamp recording techniques. Allopregnanolone had similar effects to potentiate GABA-activated membrane current in the alpha1beta1gamma2L and alpha1beta2gamma2L receptor isoforms. In contrast, alphaxalone was much more effective as a positive allosteric modulator on the alpha1beta1gamma2L receptor isoform. In the absence of the gamma2L subunit subtype, allopregnanolone had much greater efficacy, but its potency was decreased. Allopregnanolone was much more effective on the alpha1beta1 receptor isoform compared with the alpha1beta2 receptor isoform. The potency for alphaxalone to potentiate the GABA response was not altered in the absence of the gamma2L subunit subtype, although its efficacy was greatly enhanced. Both allopregnanolone and alphaxalone produced nonparallel leftward shifts in the GABA concentration-response relationship in the absence of the gamma2L subunit, decreasing the EC50 concentration of GABA and increasing the maximal response. Only alphaxalone increased the maximal GABA response when the gamma2L subunit subtype was present. The 3beta-pregnane isomers epipregnanolone and isopregnanolone both inhibited the ability of allopregnanolone and alphaxalone to potentiate GABAA receptor function. However, the degree of block produced by the 3beta-pregnane steroid isomers was dependent on the type of receptor isoform studied and the neuroactive steroid tested. Isopregnanolone, the 3beta-isomer of allopregnanolone, was significantly more effective as a blocker of potentiation caused by allopregnanolone compared with alphaxalone in all receptor isoforms tested. Epipregnanolone had a greater efficacy as a blocker at the alpha1beta2gamma2L receptor isoform compared with the alpha1beta1gamma2L receptor isoform, and also produced a greater degree of block of potentiation caused by allopregnanolone compared with alphaxalone. Our results support the hypothesis that the heteromeric assembly of different GABAA receptor isoforms containing different subunit subtypes results in multiple steroid recognition sites on GABAA receptors, which in turn produces distinctly different modulatory interactions between neuroactive steroids acting at the GABAA receptor. The alpha and gamma subunit subtypes may have the greatest influence on allopregnanolone modulation of GABAA receptor function, whereas the beta and gamma subunit subtypes appear to be most important for the modulatory effects of alphaxalone.Key words: GABAA receptor, neurosteroid, allopregnanolone, alphaxalone, Xenopus oocyte.

scholarly journals Dynorphin and GABAA Receptor Signaling Contribute to Progesterone’s Inhibition of the LH Surge in Female Mice

Endocrinology ◽  
2020 ◽  
Vol 161 (5) ◽  
Author(s):  
Yali Liu ◽  
Xiaofeng Li ◽  
Xi Shen ◽  
Deyana Ivanova ◽  
Geffen Lass ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Gabaa Receptor ◽  
Gabab Receptor ◽  
Gaba Release ◽  
Estradiol Benzoate ◽  
Receptor Signaling ◽  
Gamma Aminobutyric Acid ◽  
Lh Surge ◽  
Female Mice ◽  
Gabaa Receptor Antagonist

Abstract Progesterone can block estrogen-induced luteinising hormone (LH) surge secretion and can be used clinically to prevent premature LH surges. The blocking effect of progesterone on the LH surge is mediated through its receptor in the anteroventral periventricular nucleus (AVPV) of the hypothalamus. However, the underlying mechanisms are unclear. The preovulatory LH surge induced by estrogen is preceded by a significant reduction in hypothalamic dynorphin and gamma-aminobutyric acid (GABA) release. To test the detailed roles of dynorphin and GABA in an LH surge blockade by progesterone, ovariectomized and 17β-estradiol capsule-implanted (OVX/E2) mice received simultaneous injections of estradiol benzoate (EB) and progesterone (P) or vehicle for 2 consecutive days. The LH level was monitored from 2:30 pm to 8:30 pm at 30-minute intervals. Progesterone coadministration resulted in the LH surge blockade. A continuous microinfusion of the dynorphin receptor antagonist nor-BNI or GABAA receptor antagonist bicuculline into the AVPV from 3:00 pm to 7:00 pm reversed the progesterone-mediated blockade of the LH surge in 7 of 9 and 6 of 10 mice, respectively. In addition, these LH surges started much earlier than the surge induced by estrogen alone. However, 5 of 7 progesterone-treated mice did not show LH surge secretion after microinfusion with the GABAB receptor antagonist CGP-35348. Additionally, peripheral administration of kisspeptin-54 promotes LH surge-like release in progesterone treated mice. These results demonstrated that the progesterone-mediated suppression of the LH surge is mediated by an increase in dynorphin and GABAA receptor signaling acting though kisspeptin neurons in the AVPV of the hypothalamus in female mice.

Halothane Enhances γ-Aminobutyric Acid Receptor Type A Function but Does Not Change Overall Inhibition in Inspiratory Premotor Neurons in a Decerebrate Dog Model

2003 ◽  
Vol 99 (6) ◽  
pp. 1303-1312 ◽  
Author(s):  
Astrid G. Stucke ◽  
Edward J. Zuperku ◽  
Viseslav Tonkovic-Capin ◽  
Mirko Krolo ◽  
Francis A. Hopp ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Minimum Alveolar Concentration ◽  
Type A ◽  
Aminobutyric Acid ◽  
Inhibitory Input ◽  
Gabaergic Inhibition ◽  
Receptor Function ◽  
Gaba A ◽  
Premotor Neurons ◽  
Excitatory Drive

Background Inspiratory premotor neurons in the caudal ventral medulla relay excitatory drive to phrenic and inspiratory intercostal motoneurons in the spinal cord. These neurons are subject to tonic gamma-aminobutyric acid type A (GABA(A))-mediated (GABA(A)ergic) inhibition. In a previous study, 1 minimum alveolar concentration (MAC) halothane depressed overall glutamatergic excitatory drive but did not change overall inhibitory drive to the neurons. This study investigated in further detail the effects of halothane on GABA(A)ergic inhibition by examining postsynaptic GABA(A) receptor activity in these neurons. Methods Studies were performed in decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 MAC halothane on extracellularly recorded neuronal activity was measured during localized picoejection of the GABA(A) receptor antagonist bicuculline and the GABA(A) agonist muscimol. Complete blockade of GABAergic inhibition by bicuculline allowed estimation of the prevailing overall inhibition of the neuron. The neuronal response to muscimol was used to assess the anesthetic effect on the postsynaptic GABA(A) receptor function. Results One minimum alveolar concentration halothane depressed the spontaneous activity of 19 inspiratory premotor neurons by 22.9 +/- 29.1% (mean +/- SD; P &lt; 0.01). Overall excitatory drive was depressed 23.6 +/- 16.9% (P &lt; 0.001). Overall GABAergic inhibition was not changed (+8.7 +/- 27.5%; P = 0.295), but the postsynaptic GABA(A) receptor function was increased by 110.3 +/- 97.5% (P &lt; 0.001). Conclusion One minimum alveolar concentration halothane greatly enhanced GABA(A) receptor function on inspiratory premotor neurons but did not change overall synaptic inhibition, indicating that the presynaptic inhibitory input was reduced. Therefore, the anesthetic depression of spontaneous inspiratory premotor neuronal activity in the intact brainstem respiratory network is mainly due to a decrease in overall glutamatergic excitation.

Neurotransmitters in the parabrachial nucleus mediating visceral input to the thalamus in rats

1994 ◽  
Vol 266 (4) ◽  
pp. R1287-R1296 ◽  
Author(s):  
T. M. Saleh ◽  
D. F. Cechetto
Keyword(s):  
Neuronal Activity ◽  
Vagal Stimulation ◽  
Neuronal Response ◽  
Evoked Response ◽  
Parabrachial Nucleus ◽  
Gamma Aminobutyric Acid ◽  
Spontaneous Firing ◽  
Thalamic Neurons ◽  
Adrenergic Antagonist ◽  
Before And After

The putative neurotransmitters in ascending visceral pathways were investigated by recording changes in the response of thalamic neuronal activity evoked by vagal stimulation before and after neurotransmitter antagonist injections into the parabrachial nucleus (PB). Male Wistar rats (n = 39) were anesthetized with chloral hydrate and alpha-chloralose, ventilated, and blood pressure and heart rate were continuously monitored. The left cervical vagus nerve was stimulated to elicit changes in single and multiunit activity in the visceral thalamus. Peristimulus-time histograms of thalamic activity were made before and after 200-nl injections of antagonist or control solution into the PB. Synaptic blockade using cobalt (10 mM) injections into the PB inhibited both the thalamic response evoked by vagal stimulation (86-100%) and the spontaneous firing of thalamic neurons (88-92%). Injections of kynurenate (250 mM) or the N-methyl-D-aspartate (NMDA) antagonist, DL-2-amino-5-phosphonopentanoic acid (AP-5; 200 microM), inhibited (87-94% and 92-100%) the thalamic neuronal response evoked by vagal stimulation. The alpha-adrenergic antagonist, phentolamine (0.1 microM), or the specific alpha 2-adrenergic antagonist, yohimbine (0.1 microM), inhibited the spontaneous firing of thalamic units (42-56% and 64-77%) but had no effect on the vagally evoked response. Bicuculline [gamma-aminobutyric acid (GABA) A-subtype antagonist] significantly enhanced spontaneous thalamic neuronal activity (108-125%) without effect on the vagally evoked response. Atropine (0.1 microM) had no significant effect on either the vagally evoked response or the spontaneous firing of thalamic neurons. These results suggest that the relay of visceral afferent sensory information through the PB is mediated by NMDA receptors and that alpha 2 and GABAA receptors contribute to the tonic activity of ventral basal thalamic neurons receiving visceral input.

Additive Effects of Sevoflurane and Propofol on γ-Aminobutyric Acid Receptor Function

2006 ◽  
Vol 104 (6) ◽  
pp. 1176-1183 ◽  
Author(s):  
Luke E. Sebel ◽  
James E. Richardson ◽  
Sunil P. Singh ◽  
Shannon V. Bell ◽  
Andrew Jenkins
Keyword(s):  
Gabaa Receptor ◽  
Aminobutyric Acid ◽  
Dependent Manner ◽  
Gamma Aminobutyric Acid ◽  
Receptor Function ◽  
Human Embryonic Kidney Cells ◽  
Gaba A ◽  
Apparent Affinity ◽  
Acid Type ◽  
Transfection Method

Background Previous studies have shown that propofol and sevoflurane enhance the function of gamma-aminobutyric acid type A (GABAA) receptors. However, it is not known whether these two drugs modulate the same molecular pathways. In addition, little is known about receptor function in the presence of both propofol and sevoflurane. The aim of this study was to better understand the interactions of propofol and sevoflurane with the GABAA receptor. Methods Wild-type alpha1, beta(2), gamma(2s) GABA(A) receptor subunit complementary DNAs were transfected into human embryonic kidney cells grown on glass coverslips using a calcium phosphate transfection method. After transfection (36-72 h), cells were whole cell patch clamped and exposed to combinations of the following: 0.3-1,000 microm gamma-aminobutyric acid (GABA), 0-10 microm propofol, and 0-1,650 microm sevoflurane. Chemicals were delivered to the cells using two 10-channel infusion pumps and a rapid solution exchanger. Results Both propofol and sevoflurane alone enhanced the amplitude of GABA(A) receptor responses to submaximal concentrations of GABA in a dose-dependent manner. The enhancement was underpinned by an increase in the apparent affinity of the receptor for GABA. Coapplication of both anesthetics further enhanced the apparent affinity of the receptor for GABA. Conclusions Response surface modeling of the potentiation of GABA responses (0.3-1,000 microm) by sevoflurane and propofol revealed that the two anesthetics modulated receptor function in an additive manner. These results are consistent with recent mutagenesis studies, suggesting that these two drugs have separate binding sites and converging pathways of action on the GABAA receptor.

Gamma-aminobutyric acid (GABAA) receptor-function in a rat model of hepatic encephalopathy

1990 ◽  
Vol 5 (4) ◽  
pp. 185-193 ◽  
Author(s):  
Bennie L. Baker ◽  
A. Leslie Morrow ◽  
John Vergalla ◽  
Steven M. Paul ◽  
E. Anthony Jones
Keyword(s):  
Hepatic Encephalopathy ◽  
Gabaa Receptor ◽  
Rat Model ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Receptor Function
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