Anesthesia. Lv. The Pharmacologic Response to Hexafluorodiethyl Ether

Krantz, John C.; Truitt, Edward B.; Ling, Alfred S. C.; Speers, Louise; Little, David M.

doi:10.1097/00132586-195902000-00011

Cited by 7 publications

(10 citation statements)

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“…The fact that flurothyl evokes convulsive seizures in laboratory animals when inhaled has been known for some time Krantz, Truitt, Ling & Speers, 1957). It is an ether with a pleasant ethereal odour and is excreted unchanged through the Table 1 Effect of (7) 0.43 ± 0.02 (7) 0.45 ± 0.02 (7) 2.11 ± 0.13 (7) 0.30 ± 0.02 (7) 1.17 ± 0.14 (6) 6.88 ± 0.82 (6) 0.57 ± 0.03 (6) 4.79 ± 0.25 (8) Rats were convulsed daily for 10 days by exposure to flurothyl as described in Methods.…”

Section: Discussionmentioning

confidence: 99%

Repeated Exposure of Rats to the Convulsant Agent Flurothyl Enhances 5‐hydroxytryptamine‐ and Dopamine‐mediated Behavioural Responses

Green

1978

British J Pharmacology

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1 Rats were convulsed once daily for 7 days by exposure to the inhalant convulsant agent, flurothyl (Indoklon, bis (2,2,2-trifluouroethyl)ether). Twenty four hours after the final convulsion the rats were injected with tranylcypromine (20 mg/kg) followed 30 min later by L-DOPA (50 mg/kg), a procedure which increases brain dopamine concentrations. The flurothyl-treated rats showed a greater locomotor activity response than rats that had not been convulsed. 2 This enhanced response appears to be due to increased postsynaptic dopamine receptor sensitivity since flurothyl-treated rats also showed enhanced locomotor responses to methamphetamine (2 mg/kg) and apomorphine (2 mg/kg). 3 Enhanced 5-hydroxytryptamine-induced activity responses following administration of tranylcypromine (20 mg/kg) and L-tryptophan (50 mg/kg) were also seen 24 h after the last of 10 daily flurothylinduced convulsions. 4 The increased 5-hydroxytryptamine response also appears to be due to increased postsynaptic sensitivity since the flurothyl-treated rats showed increased hyperactivity following administration of tranylcypromine (20mg/kg) and the suggested 5-hydroxytryptamine agonist, 5-methoxy N,Ndimethyltryptamine (2 mg/kg). 5 No change in the brain concentration of 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, tryptophan, dopamine or noradrenaline was observed 24h after the last of 10 daily flurothyl-induced convulsions. compared to untreated rats. The rate of 5-hydroxytryptamine accumulation after tranylcypromine/L-tryptophan treatment and of dopamine and noradrenaline accumulation after tranylcypromine/L-DOPA treatment was similar in both groups. 6 Repeated flurothyl convulsion has the same effects on these behavioural tests as repeated electroconvulsive shock. Since both treatments have been used successfully to treat depression, it is suggested that the mechanism of action of electroconvulsive therapy may be by increasing postsynaptic responses to the monoamine neurotransmitters.

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Section: Discussionmentioning

confidence: 99%

Repeated Exposure of Rats to the Convulsant Agent Flurothyl Enhances 5‐hydroxytryptamine‐ and Dopamine‐mediated Behavioural Responses

Green

1978

British J Pharmacology

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“…Staphylococcus aureus glutamic-C endopeptidase (EndoGlu-C) was from Princeton Separations, and Lyso-FIGURE 1. Locations of binding sites for GABA, benzodiazepines, R-mTFD-MPAB, and etomidate in an (␣1) 2 (␤3) 2 ␥ GABA A R. GABA-binding sites are in the ECD at the interface between the ␤ and ␣ subunit referred to as the ␤ ϩ -␣ Ϫ subunit interface, and with that nomenclature continued in a counterclockwise direction, the benzodiazepine site is at the ␣ ϩ -␥ Ϫ subunit interface. Depicted in the TMD are the locations of the four transmembrane helices (M1-M4) in each subunit, the etomidate-binding sites at the ␤ ϩ -␣ Ϫ subunit interfaces that contain the GABA-binding sites in the ECD, and the R-mTFD-MPAB sites at the ␣ ϩ -␤ Ϫ and ␥ ϩ -␤ Ϫ subunit interfaces.…”

Section: Materials-r-and S-mtfd-mpabmentioning

confidence: 99%

“…In the process of identifying novel anesthetics, comparison of the actions of geometric isomers of certain volatile fluorinated ethers and barbiturate stereoisomers sometimes revealed that one isomer acted as an anesthetic and the other as a convulsant (2)(3)(4)(5). Anesthetic barbiturates and other intravenous anesthetics (propofol, etomidate, and steroids), as well as volatile ethers, potentiate inhibitory GABA type A receptors (GABA A R) 2 in vitro at concentrations producing anesthesia in vivo (6 -8), and the importance of GABA A Rs for anesthesia is demonstrated by the decreased sensitivity of "knock-in" mice bearing a single amino acid substitution in a GABA A R ␤ subunit to the immobilizing and hypnotic effects of pentobarbital, etomidate, and propofol (9 -12).…”

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confidence: 99%

Positive and Negative Allosteric Modulation of an α1β3γ2 γ-Aminobutyric Acid Type A (GABAA) Receptor by Binding to a Site in the Transmembrane Domain at the γ+-β− Interface

Jayakar

Zhou

Savechenkov

et al. 2015

Journal of Biological Chemistry

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Background: For some chiral barbiturates, one isomer potentiates and the other inhibits GABA responses by binding to unknown sites. Results: A photoreactive convulsant barbiturate identifies a transmembrane intersubunit-binding site between the ␥ and ␤ subunits. Conclusion: Positive and negative allosteric modulators can bind to a common intersubunit site. Significance: This study defines a novel mode of regulation of GABA A R responses.

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“…These values correspond to aqueous equivalents at 20°C of 100 μM (chicks) and 28 μM (mice). Concentrations of saturated aqueous solutions of flurothyl and iso-flurothyl at room temperature are 7.7 and 5.8 mM, respectively (Krantz et al, 1957b;Eger et al, 1999).…”

Section: Conversion Of Flurothyl and Iso-flurothyl Concentrations Expmentioning

confidence: 99%

“…1), which is a potent volatile convulsant (Krantz et al, 1957a). Flurothyl was discovered inadvertently during the search for novel inhaled anesthetics (Krantz et al, 1957b). The convulsant properties of flurothyl at one time were used clinically as a chemical replacement for electroconvulsive therapy in patients with psychiatric disorders (Krantz et al, 1957a).…”

Section: Introductionmentioning

confidence: 99%

Differential modulatory actions of the volatile convulsant flurothyl and its anesthetic isomer at inhibitory ligand-gated ion channels

Krasowski

2000

Neuropharmacology

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A challenge for theories of general anesthesia is the existence of compounds predicted to be anesthetics but which, instead, do not produce anesthesia and often elicit other behavioral effects such as convulsions. This study focused on flurothyl (bis[2,2,2-trifluoroethyl] ether), a potent volatile convulsant, and its anesthetic isomer, 'iso-flurothyl' (1,1,1,3,3,3-hexafluoro-2-methoxypropane). The effects of flurothyl and iso-flurothyl were studied using the whole-cell patch-clamp technique on agonist activated chloride currents in human GABA A , glycine, and GABA c ρ 1 receptors expressed in HEK 293 cells. GABA A and glycine receptors are promising molecular targets for the actions of inhaled ether general anesthetics. Flurothyl acted as a non-competitive antagonist at GABA A α 2 β 1 and α 2 β 1 γ 2s receptors, but had no effect at glycine α 1 receptors. Flurothyl had biphasic actions on GABA responses at GABA C ρ 1 receptors. In contrast, iso-flurothyl enhanced ('potentiated') submaximal agonist responses at GABA A and glycine receptors, but had no effect on GABA responses at GABA C ρ 1 receptors. Point mutations in GABA A and glycine receptor subunits, which have been previously shown to abolish potentiation of agonist responses by the ether anesthetics enflurane and isoflurane, also ablated potentiation of agonist responses by iso-flurothyl. These same mutations in the GABA A receptor had only modest effects on the inhibitory actions of flurothyl. GABA A receptors with mutations conferring insensitivity to antagonism by picrotoxin were still inhibited by flurothyl, suggesting that picrotoxin and flurothyl antagonize GABA responses by distinct sites or mechanisms of action. In summary, antagonism of GABA A receptors is likely to account for the convulsant effects of flurothyl, while the general anesthetic actions of iso-flurothyl, like those of other ether anesthetics, may be related to positive modulation of GABA A and/or glycine receptors.

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Anesthesia. Lv. The Pharmacologic Response to Hexafluorodiethyl Ether

Cited by 7 publications

References 0 publications

Repeated Exposure of Rats to the Convulsant Agent Flurothyl Enhances 5‐hydroxytryptamine‐ and Dopamine‐mediated Behavioural Responses

Repeated Exposure of Rats to the Convulsant Agent Flurothyl Enhances 5‐hydroxytryptamine‐ and Dopamine‐mediated Behavioural Responses

Positive and Negative Allosteric Modulation of an α1β3γ2 γ-Aminobutyric Acid Type A (GABAA) Receptor by Binding to a Site in the Transmembrane Domain at the γ+-β− Interface

Differential modulatory actions of the volatile convulsant flurothyl and its anesthetic isomer at inhibitory ligand-gated ion channels

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