What Solvent Best Represents the Site of Action of Inhaled Anesthetics in Humans, Rats, and Dogs?

Taheri, Shahram; Halsey, Michael J.; Liu, Jin; Eger, Edmond I.; Koblin, Donald D.; Laster, Michael J.

doi:10.1213/00000539-199105000-00010

Cited by 169 publications

(79 citation statements)

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“…Significant inhibition occurred at subanaesthetic isoflurane concentrations [35 (9)% at 0.18 mM, P¼0.002] based on its minimum alveolar concentration (MAC) for immobilization in response to a noxious stimulus in rats (0.35 mM). 20 Isoflurane at concentrations .0.4 mM produced sustained increases in basal NE release (Fig. 2B, inset), as described previously for halothane.…”

Section: Resultssupporting

confidence: 78%

Nicotinic receptor-evoked hippocampal norepinephrine release is highly sensitive to inhibition by isoflurane

Westphalen

Gomez²,

Hemmings

2009

British Journal of Anaesthesia

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Background. Inhaled anaesthetics (IAs) produce multiple dose-dependent behavioural effects including amnesia, hypnosis, and immobility in response to painful stimuli that are mediated by distinct anatomical, cellular, and molecular mechanisms. Amnesia is produced at lower anaesthetic concentrations compared with hypnosis or immobility. Nicotinic acetylcholine receptors (nAChRs) modulate hippocampal neural network correlates of memory and are highly sensitive to IAs. Activation of hippocampal nAChRs stimulates the release of norepinephrine (NE), a neurotransmitter implicated in modulating hippocampal synaptic plasticity. We tested the hypothesis that IAs disrupt hippocampal synaptic mechanisms critical to memory by determining the effects of isoflurane on NE release from hippocampal nerve terminals.

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Section: Resultssupporting

confidence: 78%

Nicotinic receptor-evoked hippocampal norepinephrine release is highly sensitive to inhibition by isoflurane

Westphalen

Gomez²,

Hemmings

2009

British Journal of Anaesthesia

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“…After each experiment, remaining solutions from each syringe containing anesthetic were drawn through the perfusion system and sampled upon immediate exit from the synaptosome chamber into a gas tight glass syringe and then extracted into n-heptane (1:10, v/v) for analysis by gas chromatography (Ratnakumari and Hemmings, 1998). Solution anesthetic concentrations were compared with their potencies as defined by minimum alveolar concentration (MAC) in rat: 0.35 mM for isoflurane, 0.75 mM enflurane, and 0.35 mM halothane (Taheri et al, 1991).…”

Section: Methodsmentioning

confidence: 99%

“…Prelabeled synaptosomes were exposed to 2-min pulses of high [K ϩ ] (20 mM KCl replacing equivalent NaCl), a K ϩ channel blocker (1 mM 4AP), or to H 2 O for 1 min using the perfusion technique described above at a flow rate of 0.2 ml/min. Anesthetic effects were examined using 6-min pulses of 2, 4, and 8ϫ MAC of isoflurane, enflurane, or halothane (Taheri et al, 1991). Perfusate was collected in one 20-min fraction (encompassing the entire release pulse) followed by a 20-min fraction collecting remaining synaptosomal contents after lysis with H 2 O.…”

Section: Methodsmentioning

confidence: 99%

Volatile Anesthetic Effects on Glutamate versus GABA Release from Isolated Rat Cortical Nerve Terminals: Basal Release

Westphalen¹,

Hemmings²

2005

J Pharmacol Exp Ther

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The effects of three volatile anesthetics (isoflurane, enflurane, and halothane) on basal release of glutamate and GABA from isolated rat cerebrocortical nerve terminals (synaptosomes) were compared using a dual isotope superfusion method. Concentration-dependent effects on basal release differed between anesthetics and transmitters. Over a range of clinical concentrations (0.5-2ϫ minimum alveolar concentration), basal glutamate release was inhibited by all three anesthetics, whereas basal GABA release was enhanced (isoflurane) or unaffected (enflurane and halothane). These effects may represent a balance of stimulatory and inhibitory mechanisms between transmitters and anesthetics. There were no significant differences between anesthetic effects on basal release in the absence or presence of external Ca 2ϩ , whereas intracellular Ca 2ϩ buffering limited volatile anesthetic inhibition of basal glutamate release. Although these results demonstrate fundamental differences in anesthetic effects on basal release between glutamatergic and GABAergic nerve terminals, all three volatile anesthetics at clinical concentrations consistently reduced the ratio of basal glutamate to GABA release. These actions may contribute to the net depression of glutamatergic excitation and potentiation of GABAergic inhibition characteristic of general anesthesia.

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“…17] significantly slowed exocytosis kinetics of the total recycling pool (TRP) (mean exocytosis time constants: τ control = 29 ± 3 s, n = 12; τ isoflurane = 44 ± 3 s, n = 12, 95% CI [4.6, 25]; Fig. 1B).…”

Section: Significancementioning

confidence: 99%

Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca ²⁺ influx, not Ca ²⁺ -exocytosis coupling

Baumgart

Zhou

Hara

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

106

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Identifying presynaptic mechanisms of general anesthetics is critical to understanding their effects on synaptic transmission. We show that the volatile anesthetic isoflurane inhibits synaptic vesicle (SV) exocytosis at nerve terminals in dissociated rat hippocampal neurons through inhibition of presynaptic Ca 2+ influx without significantly altering the Ca 2+ sensitivity of SV exocytosis. A clinically relevant concentration of isoflurane (0.7 mM) inhibited changes in [Ca 2+ ] i driven by single action potentials (APs) by 25 ± 3%, which in turn led to 62 ± 3% inhibition of single AP-triggered exocytosis at 4 mM extracellular Ca 2+ ([Ca 2+ ] e ). Lowering external Ca 2+ to match the isoflurane-induced reduction in Ca 2+ entry led to an equivalent reduction in exocytosis. These data thus indicate that anesthetic inhibition of neurotransmitter release from small SVs occurs primarily through reduced axon terminal Ca 2+ entry without significant direct effects on Ca 2+ -exocytosis coupling or on the SV fusion machinery. Isoflurane inhibition of exocytosis and Ca 2+ influx was greater in glutamatergic compared with GABAergic nerve terminals, consistent with selective inhibition of excitatory synaptic transmission. Such alteration in the balance of excitatory to inhibitory transmission could mediate reduced neuronal interactions and network-selective effects observed in the anesthetized central nervous system. GCaMP3 | pHlourin | mechanisms of anesthesia | live cell imaging | presynaptic T he molecular and cellular mechanisms of anesthetic-induced amnesia, unconsciousness and immobilization are incompletely understood, particularly for the modern halogenated ether derivatives like isoflurane. General anesthetics, which are essential to both medical practice and experimental neuroscience, have potent and selective effects on neurotransmission (1), including both presynaptic actions (reduced neurotransmitter release) and postsynaptic actions (modulation of receptor function). These effects contribute to anesthetic-induced reductions in neuronal interactions, which are critical to information processing and consciousness (2-4). Knowledge of the fundamental synaptic effects of anesthetics is therefore essential to a molecular and physiological understanding of anesthetic mechanisms, and to development of more selective and safer anesthetics.Although postsynaptic electrophysiological effects of anesthetics can be assessed directly using whole cell recordings and heterologous expression of putative molecular targets, their presynaptic actions have been difficult to resolve by conventional approaches that do not clearly discriminate between presynaptic and postsynaptic contributions. Direct evidence for presynaptic effects of volatile anesthetics includes selective inhibition of glutamate release from isolated nerve terminals (5, 6) and of synaptic vesicle (SV) exocytosis in intact hippocampal neurons (7). However, it remains controversial whether these effects involve direct inhibition of SV exocytosis itself or of upstrea...

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What Solvent Best Represents the Site of Action of Inhaled Anesthetics in Humans, Rats, and Dogs?

Cited by 169 publications

References 0 publications

Nicotinic receptor-evoked hippocampal norepinephrine release is highly sensitive to inhibition by isoflurane

Nicotinic receptor-evoked hippocampal norepinephrine release is highly sensitive to inhibition by isoflurane

Volatile Anesthetic Effects on Glutamate versus GABA Release from Isolated Rat Cortical Nerve Terminals: Basal Release

Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca ²⁺ influx, not Ca ²⁺ -exocytosis coupling

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What Solvent Best Represents the Site of Action of Inhaled Anesthetics in Humans, Rats, and Dogs?

Cited by 169 publications

References 0 publications

Nicotinic receptor-evoked hippocampal norepinephrine release is highly sensitive to inhibition by isoflurane

Nicotinic receptor-evoked hippocampal norepinephrine release is highly sensitive to inhibition by isoflurane

Volatile Anesthetic Effects on Glutamate versus GABA Release from Isolated Rat Cortical Nerve Terminals: Basal Release

Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca 2+ influx, not Ca 2+ -exocytosis coupling

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Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca ²⁺ influx, not Ca ²⁺ -exocytosis coupling