scholarly journals Hypnotic Hypersensitivity to Volatile Anesthetics and Dexmedetomidine in Dopamine β-Hydroxylase Knockout Mice

2012 ◽  
Vol 117 (5) ◽  
pp. 1006-1017 ◽  
Author(s):  
Frances Y. Hu ◽  
George M. Hanna ◽  
Wei Han ◽  
Feras Mardini ◽  
Steven A. Thomas ◽  
...  
Keyword(s):  
General Anesthesia ◽  
Volatile Anesthetic ◽  
Volatile Anesthetics ◽  
Genetically Engineered ◽  
Adrenergic System ◽  
Adrenergic Signaling ◽  
Loss Of Righting Reflex ◽  
Volatile Anesthesia ◽  
Righting Reflex ◽  
Adrenergic Neurotransmission

Background Multiple lines of evidence suggest that the adrenergic system can modulate sensitivity to anesthetic-induced immobility and anesthetic-induced hypnosis as well. However, several considerations prevent the conclusion that the endogenous adrenergic ligands norepinephrine and epinephrine alter anesthetic sensitivity. Methods Using dopamine β-hydroxylase knockout (Dbh) mice genetically engineered to lack the adrenergic ligands and their siblings with normal adrenergic levels, we test the contribution of the adrenergic ligands upon volatile anesthetic induction and emergence. Moreover, we investigate the effects of intravenous dexmedetomidine in adrenergic-deficient mice and their siblings using both righting reflex and processed electroencephalographic measures of anesthetic hypnosis. Results We demonstrate that the loss of norepinephrine and epinephrine and not other neuromodulators co-packaged in adrenergic neurons is sufficient to cause hypersensitivity to induction of volatile anesthesia. However, the most profound effect of adrenergic deficiency is retarding emergence from anesthesia, which takes two to three times as long in Dbh mice for sevoflurane, isoflurane, and halothane. Having shown that Dbh mice are hypersensitive to volatile anesthetics, we further demonstrate that their hypnotic hypersensitivity persists at multiple doses of dexmedetomidine. Dbh mice exhibit up to 67% shorter latencies to loss of righting reflex and up to 545% longer durations of dexmedetomidine-induced general anesthesia. Central rescue of adrenergic signaling restores control-like dexmedetomidine sensitivity. A novel continuous electroencephalographic analysis illustrates that the longer duration of dexmedetomidine-induced hypnosis is not due to a motor confound, but occurs because of impaired anesthetic emergence. Conclusions Adrenergic signaling is essential for normal emergence from general anesthesia. Dexmedetomidine-induced general anesthesia does not depend on inhibition of adrenergic neurotransmission.

scholarly journals Mutation of α1GT-type Calcium Channels in Mice Does Not Change Anesthetic Requirements for Loss of the Righting Reflex and Minimum Alveolar Concentration but Delays the Onset of Anesthetic Induction

2007 ◽  
Vol 106 (6) ◽  
pp. 1177-1185 ◽  
Author(s):  
Andrey B. Petrenko ◽  
Mika Tsujita ◽  
Tatsuro Kohno ◽  
Kenji Sakimura ◽  
Hiroshi Baba
Keyword(s):  
Calcium Channels ◽  
Minimum Alveolar Concentration ◽  
Volatile Anesthetics ◽  
Effective Concentration ◽  
Mutant Mice ◽  
Neuronal Membrane ◽  
Normal Functioning ◽  
Anesthetic Agents ◽  
Loss Of Righting Reflex ◽  
Righting Reflex

Background T-type calcium channels regulate neuronal membrane excitability and participate in a number of physiologic and pathologic processes in the central nervous system, including sleep and epileptic activity. Volatile anesthetics inhibit native and recombinant T-type calcium channels at concentrations comparable to those required to produce anesthesia. To determine whether T-type calcium channels are involved in the mechanisms of anesthetic action, the authors examined the effects of general anesthetics in mutant mice lacking alpha1G T-type calcium channels. Methods The hypnotic effects of volatile and intravenous anesthetics administered to mutant and C57BL/6 control mice were evaluated using the behavioral endpoint of loss of righting reflex. To investigate the immobilizing effects of volatile anesthetics in mice, the minimum alveolar concentration (MAC) values were determined using the tail-clamp method. Results The 50% effective concentration for loss of righting reflex and MAC values for volatile anesthetics were not altered after alpha1G channel knockout. However, mutant mice required significantly more time to develop anesthesia/hypnosis after exposure to isoflurane, halothane, and sevoflurane and after intraperitoneal administration of pentobarbital. Conclusions The 50% effective concentration for loss of righting reflex and MAC values for the volatile anesthetics were not altered after alpha1G calcium channel knockout, indicating that normal functioning of alpha1G calcium channels is not required for the maintenance of anesthetic hypnosis and immobility. However, the timely induction of anesthesia/hypnosis by volatile anesthetic agents and some intravenous anesthetic agents may require the normal functioning of these channel subunits.

Heteromeric Nicotinic Inhibition by Isoflurane Does Not Mediate MAC or Loss of Righting Reflex

2002 ◽  
Vol 97 (4) ◽  
pp. 902-905 ◽  
Author(s):  
Pamela Flood ◽  
James M. Sonner ◽  
Diane Gong ◽  
Kristen M. Coates
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Genetically Engineered ◽  
Neuronal Nicotinic Acetylcholine Receptors ◽  
General Anesthetics ◽  
Nicotinic Acetylcholine ◽  
Loss Of Righting Reflex ◽  
Righting Reflex ◽  
Surgical Setting

Background Neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated in the mechanism of action of isoflurane as they are inhibited at subanesthetic concentrations. Despite clear evidence for nicotinic inhibition at relevant isoflurane concentrations, it is unclear what behavioral result ensues, if any. Methods The authors have modeled two behaviors common to all general anesthetics, immobility and hypnosis, as minimum alveolar concentration that prevents movement in response to a supramaximal stimulus (MAC) and loss of righting reflex (LORR). They have tested the ability of nicotinic pharmacologic modulators and congenital absence of most heteromeric nAChRs to affect concentration of isoflurane required for these behaviors. Results Neither mecamylamine, 5 mg/kg, nor chlorisondamine, 10 mg/kg, affected isoflurane MAC. Nicotine caused a small decrease in MAC. None of the above agents had any effect on the concentration of isoflurane required for LORR. Mice genetically engineered to lack the beta 2 nicotinic gene product were not different in MAC or LORR from controls. Conclusions Nicotinic antagonists do not cause MAC or LORR. Inhibition of nicotinic acetylcholine receptors by isoflurane is not likely related to its ability to provide immobility and hypnosis in a surgical setting. This is perhaps not surprising as the inhibition of nAChRs in vitro is complete at an isoflurane concentration equal to one half of MAC. Nicotinic inhibition may, however, be involved in anesthetic behaviors such as amnesia and analgesia, which occur at lower anesthetic concentrations.

Absence of Bronchodilation during Desflurane Anesthesia

2000 ◽  
Vol 93 (2) ◽  
pp. 404-408 ◽  
Author(s):  
Mitchell J. Goff ◽  
Shahbaz R. Arain ◽  
David J. Ficke ◽  
Toni D. Uhrich ◽  
Thomas J. Ebert
Keyword(s):  
General Anesthesia ◽  
Elective Surgery ◽  
Volatile Anesthetics ◽  
Smoking History ◽  
Respiratory Resistance ◽  
Volatile Anesthesia ◽  
History Of ◽  
Respiratory System Resistance ◽  
American Society ◽  
American Society Of Anesthesiologists

Background Bronchospasm is a potential complication in anyone undergoing general anesthesia. Because volatile anesthetics relax bronchial smooth muscle, the effects of two newer volatile anesthetics, desflurane and sevoflurane, on respiratory resistance were evaluated. The authors hypothesized that desflurane would have greater bronchodilating effects because of its ability to increase sympathetic nervous system activity. Methods Informed consent was obtained from patients undergoing elective surgery with general anesthesia. We recorded airway flow and pressure after thiopental induction and tracheal intubation (baseline) and for 10 min after beginning volatile anesthesia ( approximately 1 minimum alveolar concentration inspired). Respiratory system resistance was determined using the isovolume technique. Results Fifty subjects were randomized to receive sevoflurane (n = 20), desflurane (n = 20), or thiopental infusion (n = 10, 0.25 mg. kg-1. h-1). There were no differences between groups for age, height, weight, smoking history, and American Society of Anesthesiologists physical class. On average, sevoflurane reduced respiratory resistance 15% below baseline, whereas both desflurane (+5%) and thiopental (+10%) did not decrease respiratory resistance. The respiratory resistance changes did not differ in patients with and without a history of smoking during sevoflurane or thiopental. In contrast, administration of desflurane to smokers resulted in the greatest increase in respiratory resistance. Conclusions Sevoflurane causes moderate bronchodilation that is not observed with desflurane or sodium thiopental. The bronchoconstriction produced by desflurane was primarily noted in patients who currently smoked. (Key words: Bronchospasm; respiratory resistance; volatile anesthetics.)

scholarly journals Does Equi–Minimum Alveolar Concentration Value Ensure Equivalent Analgesic or Hypnotic Potency?

2018 ◽  
Vol 128 (6) ◽  
pp. 1092-1098 ◽  
Author(s):  
Kyoung-Ho Ryu ◽  
Keulame Song ◽  
Tae-Young Lim ◽  
Won-Jun Choi ◽  
Yun-Hong Kim ◽  
...  
Keyword(s):  
Primary Outcome ◽  
Minimum Alveolar Concentration ◽  
Single Agent ◽  
Volatile Anesthetic ◽  
Volatile Anesthetics ◽  
Tetanic Stimulation ◽  
Sevoflurane Group ◽  
Nociceptive Stimulus ◽  
Spinal Mechanism ◽  
Volatile Anesthesia

Abstract Background Minimum alveolar concentration (MAC) has traditionally been used to compare the potency of volatile anesthetics. However, as it reflects the spinal mechanism of immobility rather than the cerebral mechanism of analgesia and hypnosis, it is doubtful that equi-MAC connotes equivalent analgesic or hypnotic potency. The level of analgesia and hypnosis can be assessed using surgical pleth index and bispectral index (BIS) values, respectively. This study was designed to compare the surgical pleth index and BIS values produced by equi-MAC of desflurane and sevoflurane in patients undergoing single-agent volatile anesthesia. Methods Eighty-nine patients were randomly allocated to two groups receiving either desflurane (n = 44) or sevoflurane (n = 45). Anesthesia was only maintained with assigned volatile anesthetic of age-corrected 1.0 MAC. Surgical pleth index values as an analgesic estimate and BIS values as a hypnotic estimate were obtained under standard tetanic stimulation. Results Post-stimulation surgical pleth index values (mean ± SD), the primary outcome, were significantly lower for the desflurane group than those for the sevoflurane group (49 ± 10 vs. 64 ± 14, difference, 15 [95% CI, 10 to 20], P < 0.001). The desflurane group showed significantly lower poststimulation BIS values (median [interquartile range]) than the sevoflurane group (36 [31 to 41] vs. 41 [38 to 47], difference, 6 [95% CI, 2 to 9], P = 0.001). Conclusions During a steady-state of 1.0 MAC, desflurane and sevoflurane did not cause similar surgical pleth index and BIS values under the standardized nociceptive stimulus. These findings suggest that equi-MAC of desflurane and sevoflurane may not ensure equivalent analgesic or hypnotic potency.

scholarly journals Mitochondrial Function in Astrocytes Is Essential for Normal Emergence from Anesthesia in Mice

2019 ◽  
Vol 130 (3) ◽  
pp. 423-434 ◽  
Author(s):  
Renjini Ramadasan-Nair ◽  
Jessica Hui ◽  
Leslie S. Itsara ◽  
Philip G. Morgan ◽  
Margaret M. Sedensky
Keyword(s):  
Mitochondrial Function ◽  
Fluorescent Protein ◽  
Volatile Anesthetic ◽  
Glutamatergic Neurons ◽  
Excitatory Transmission ◽  
Loss Of Righting Reflex ◽  
Righting Reflex ◽  
Green Fluorescent ◽  
And Control

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background In mice, restriction of loss of the mitochondrial complex I gene Ndufs4 to glutamatergic neurons confers a profound hypersensitivity to volatile anesthetics similar to that seen with global genetic knockout of Ndufs4. Astrocytes are crucial to glutamatergic synapse functioning during excitatory transmission. Therefore, the authors examined the role of astrocytes in the anesthetic hypersensitivity of Ndufs4(KO). Methods A tamoxifen-activated astrocyte-specific Ndufs4(KO) mouse was constructed. The specificity of the astrocyte-specific inducible model was confirmed by using the green fluorescent protein reporter line Ai6. Approximately 120 astrocyte-specific knockout and control mice were used for the experiments. Mice were anesthetized with varying concentrations of isoflurane or halothane; loss of righting reflex and response to a tail clamp were determined and quantified as the induction and emergence EC50s. Because norepinephrine has been implicated in emergence from anesthesia and astrocytes respond to norepinephrine to release gliotransmitters, the authors measured norepinephrine levels in the brains of control and knockout Ndufs4 animals. Results The induction EC50s for tail clamp in both isoflurane and halothane were similar between the control and astrocyte-specific Ndufs4(KO) mice at 3 weeks after 4-hydroxy tamoxifen injection (induction concentration, EC50(ind)—isoflurane: control = 1.27 ± 0.12, astrocyte-specific knockout = 1.21 ± 0.18, P = 0.495; halothane: control = 1.28 ± 0.05, astrocyte-specific knockout = 1.20 ± 0.05, P = 0.017). However, the emergent concentrations in both anesthetics for the astrocyte-specific Ndufs4(KO) mice were less than the controls for tail clamp; (emergence concentration, EC50(em)—isoflurane: control = 1.18 ± 0.10, astrocyte-specific knockout = 0.67 ± 0.11, P < 0.0001; halothane: control = 1.08 ± 0.09, astrocyte-specific knockout = 0.59 ± 0.12, P < 0.0001). The induction EC50s for loss of righting reflex were also similar between the control and astrocyte-specific Ndufs4(KO) mice (EC50(ind)—isoflurane: control = 1.02 ± 0.10, astrocyte-specific knockout = 0.97 ± 0.06, P = 0.264; halothane: control = 1.03 ± 0.05, astrocyte-specific knockout = 0.99 ± 0.08, P = 0.207). The emergent concentrations for loss of righting reflex in both anesthetics for the astrocyte-specific Ndufs4(KO) mice were less than the control (EC50(em)—isoflurane: control = 1.0 ± 0.07, astrocyte-specific knockout = 0.62 ± 0.12, P < 0.0001; halothane: control = 1.0 ± 0.04, astrocyte-specific KO = 0.64 ± 0.09, P < 0.0001); N ≥ 6 for control and astrocyte-specific Ndufs4(KO) mice. For all tests, similar results were seen at 7 weeks after 4-hydroxy tamoxifen injection. The total norepinephrine content of the brain in global or astrocyte-specific Ndufs4(KO) mice was unchanged compared to control mice. Conclusions The only phenotype of the astrocyte-specific Ndufs4(KO) mouse was a specific impairment in emergence from volatile anesthetic-induced general anesthesia. The authors conclude that normal mitochondrial function within astrocytes is essential for emergence from anesthesia.

Anesthesia Sensitivity in Mice that Lack the β3 Subunit of the γ-Aminobutyric Acid Type A Receptor 

1998 ◽  
Vol 88 (3) ◽  
pp. 775-780 ◽  
Author(s):  
Joseph J. Quinlan ◽  
Gregg E. Homanics ◽  
Leonard L. Firestone
Keyword(s):  
Null Allele ◽  
Volatile Anesthetic ◽  
Aminobutyric Acid ◽  
Wild Type ◽  
Gaba A ◽  
Anesthetic Agents ◽  
Loss Of Righting Reflex ◽  
Acid Type ◽  
Beta3 Subunit ◽  
Righting Reflex

Background The mammalian gamma-aminobutyric acid type A (GABA(A)) receptor, a likely target of anesthetic action, exhibits remarkable subunit heterogeneity. In vitro expression studies suggest that there is subunit specificity to anesthetic responses at the GABA(A) receptor. The authors tested whether genetically engineered mice that lack the beta3 subunit of the GABA(A) receptor differed in their sensitivities to several general anesthetic agents. Methods Median effective concentrations for loss-of-righting reflex and tail clamp/withdrawal for enflurane and halothane were determined in mice with and without the beta3 gene and gene product. Sleep time was measured after intraperitoneal injection of pentobarbital, ethanol, etomidate, and midazolam. Results Null allele mice (beta3 -/-) did not differ from wild-type mice (beta3 +/+) in the obtunding response to enflurane and halothane but were significantly more resistant to enflurane (null allele half-effect concentrations [EC50] of 2.59 +/- 0.10 vs. wild-type EC50 of 2.06 +/- 0.12 atm %, P < 0.001) and halothane (null allele EC50 of 1.73 +/- 0.04 vs. wild-type EC50 of 1.59 +/- 0.05 atm %, P = 0.01) as determined by tail clamp response. Wild-type and null allele mice exhibited divergent responses to other sedative agents active at the GABA(A) receptor. No differences were noted in sleep times after administration of pentobarbital and ethanol, but null allele mice were more resistant to etomidate (null allele EC50 of 17.8 +/- 1.9 min vs. wild-type EC50 of 26.2 +/- 2.4 min, P < 0.02) and midazolam (null allele EC50 of 14.2 +/- 7.8 min vs. wild-type EC50 of 41.3 +/- 10.4 min, P < 0.05). Conclusions The beta3 subunit of the GABA(A) receptor appears to be important in the mediation of the immobilizing (tail clamp) but not obtunding (loss-of-righting reflex) effects of the volatile anesthetic agents enflurane and halothane. These data support the hypotheses that separate components of the anesthetic state are mediated via different central nervous system loci; that the GABA(A) receptor is a likely target for the immobilizing response to volatile anesthetic agents; and that the beta3 subunit plays a direct or indirect role in the mediation of this response. Absence of the beta3 subunit appears to attenuate the obtunding effect of midazolam and etomidate but appears not to alter the obtunding effect of pentobarbital, enflurane, and halothane, suggesting that these anesthetic agents produce hypnosis by different specific molecular mechanisms.

Volatile Anesthetics Affect Nutrient Availability in Yeast

Genetics ◽  
2002 ◽  
Vol 161 (2) ◽  
pp. 563-574
Author(s):  
Laura K Palmer ◽  
Darren Wolfe ◽  
Jessica L Keeley ◽  
Ralph L Keil
Keyword(s):  
Amino Acids ◽  
Nutrient Availability ◽  
Wild Type Strain ◽  
Volatile Anesthetic ◽  
Volatile Anesthetics ◽  
Wild Type ◽  
Anesthetic Exposure ◽  
Sites Of Action ◽  
Insight Into ◽  
Lines Of Evidence

Abstract Volatile anesthetics affect all cells and tissues tested, but their mechanisms and sites of action remain unknown. To gain insight into the cellular activities of anesthetics, we have isolated genes that, when overexpressed, render Saccharomyces cerevisiae resistant to the volatile anesthetic isoflurane. One of these genes, WAK3/TAT1, encodes a permease that transports amino acids including leucine and tryptophan, for which our wild-type strain is auxotrophic. This suggests that availability of amino acids may play a key role in anesthetic response. Multiple lines of evidence support this proposal: (i) Deletion or overexpression of permeases that transport leucine and/or tryptophan alters anesthetic response; (ii) prototrophic strains are anesthetic resistant; (iii) altered concentrations of leucine and tryptophan in the medium affect anesthetic response; and (iv) uptake of leucine and tryptophan is inhibited during anesthetic exposure. Not all amino acids are critical for this response since we find that overexpression of the lysine permease does not affect anesthetic sensitivity. These findings are consistent with models in which anesthetics have a physiologically important effect on availability of specific amino acids by altering function of their permeases. In addition, we show that there is a relationship between nutrient availability and ubiquitin metabolism in this response.

Behavioral Effects of Volatile Anesthetics in Caenorhabditis elegans

1996 ◽  
Vol 85 (4) ◽  
pp. 901-912 ◽  
Author(s):  
Michael C. Crowder ◽  
Laynie D. Shebester ◽  
Tim Schedl
Keyword(s):  
Nervous System ◽  
Caenorhabditis Elegans ◽  
Time Course ◽  
Model Organism ◽  
Volatile Anesthetic ◽  
Volatile Anesthetics ◽  
Effective Concentration ◽  
Forward Genetics ◽  
C Elegans ◽  
Median Effective Concentration

Background The nematode Caenorhabditis elegans offers many advantages as a model organism for studying volatile anesthetic actions. It has a simple, well-understood nervous system; it allows the researcher to do forward genetics; and its genome will soon be completely sequenced. C. elegans is immobilized by volatile anesthetics only at high concentrations and with an unusually slow time course. Here other behavioral dysfunctions are considered as anesthetic endpoints in C. elegans. Methods The potency of halothane for disrupting eight different behaviors was determined by logistic regression of concentration and response data. Other volatile anesthetics were also tested for some behaviors. Established protocols were used for behavioral endpoints that, except for pharyngeal pumping, were set as complete disruption of the behavior. Time courses were measured for rapid behaviors. Recovery from exposure to 1 or 4 vol% halothane was determined for mating, chemotaxis, and gross movement. All experiments were performed at 20 to 22 degrees C. Results The median effective concentration values for halothane inhibition of mating (0.30 vol%-0.21 mM), chemotaxis (0.34 vol%-0.24 mM), and coordinated movement (0.32 vol% - 0.23 mM) were similar to the human minimum alveolar concentration (MAC; 0.21 mM). In contrast, halothane produced immobility with a median effective concentration of 3.65 vol% (2.6 mM). Other behaviors had intermediate sensitivities. Halothane's effects reached steady-state in 10 min for all behaviors tested except immobility, which required 2 h. Recovery was complete after exposure to 1 vol% halothane but was significantly reduced after exposure to immobilizing concentrations. Conclusions Volatile anesthetics selectively disrupt C. elegans behavior. The potency, time course, and recovery characteristics of halothane's effects on three behaviors are similar to its anesthetic properties in vertebrates. The affected nervous system molecules may express structural motifs similar to those on vertebrate anesthetic targets.

Investigation of Potassium Chloride for Euthanasia of Anesthetized Marine Toads (Rhinella marina)

2021 ◽  
Author(s):  
Meghan M. Louis ◽  
Gregory Scott ◽  
Dustin Smith ◽  
Brigid V. Troan ◽  
Larry J. Minter ◽  
...  
Keyword(s):  
Potassium Chloride ◽  
Potassium Concentration ◽  
Plasma Potassium ◽  
Post Treatment ◽  
Spontaneous Movement ◽  
Limits Of Detection ◽  
Rhinella Marina ◽  
Loss Of Righting Reflex ◽  
Righting Reflex ◽  
Technique Failure

Euthanasia techniques in amphibians are poorly described and sparsely validated. This study investigated potassium chloride (KCl) for euthanasia of anesthetized marine toads ( Rhinella marina ). Twenty three toads were immersed in buffered MS-222 (2 g/L) for five minutes (min) beyond loss of righting reflex, manually removed, and randomly administered KCl (n = 6/group) via one of three routes: intracardiac at 10 mEq/kg (IC), intracoelomic at 100 mEq/kg (ICe), or immersion at 4500 mEq/L (IMS) or no treatment (C) (n = 5/group). Doppler sounds were assessed continuously from prior to treatment until two min post-treatment and every five min thereafter until sound cessation or resumption of spontaneous movement. Plasma potassium concentration (K+) was measured at the time of Doppler sound cessation in ICe and IMS. In IC, ICe, IMS, and C, Doppler sound cessation occurred in 4/6, 6/6, 6/6, and 1/5 toads with median (range) or mean + SD times of 0.23 (0-4.65), 17.5 + 9.0, 40.6 + 10.9, and >420 min, respectively. Nonsuccess in 2/6 toads in IC was suspected due to technique failure. Plasma K+ exceeded the limits of detection (>9 mmol/L) in 12/12 toads in ICe and IMS. Five of six toads in C resumed spontaneous movement at median (range) times of 327 (300-367) min. KCl delivered via an intracardiac, intracoelomic, or immersion routes resulted in Doppler sound cessation in 16 of 18 toads and may be appropriate for euthanasia of anesthetized marine toads.

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