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Edmond I. Eger - One of the best experts on this subject based on the ideXlab platform.

  • Alpha 1 subunit-containing GABA type A receptors in forebrain contribute to the effect of Inhaled Anesthetics on conditioned
    2016
    Co-Authors: James M Sonner, Mike Cascio, Yilei Xing, Michael S. Fanselow, Jason E. Kralic, Esa R. Korpi, Steven Hardy, Brian Sloat, Leslie A. Morrow, Edmond I. Eger
    Abstract:

    Inhaled Anesthetics are believed to produce anesthesia by their actions on ion channels. Because Inhaled Anesthetics robustly enhance GABA A receptor (GABAA-R) responses to GABA, these receptors are considered prime targets of anesthetic action. However, the importance of GABAA-Rs and individual GABAA-R subunits to specific anesthetic-induced behavioral effects in the intact animal is unknown. We hypothesized that Inhaled Anesthetics produce amnesia, as assessed by loss of fear conditioning, by acting on the forebrain GABAA-Rs that harbor the 1 subunit. To test this, we used global knockout mice that completely lack the 1 subunit and forebrain-specific, conditional knockout mice that lack the 1 subunit only in the hippocampus, cortex, and amygdala. Both knockout mice were 75 to 145 % less sensitive to the amnestic effects of the inhale

  • Is a New Paradigm Needed to Explain How Inhaled Anesthetics Produce Immobility
    Anesthesia & Analgesia, 2008
    Co-Authors: Edmond I. Eger, Douglas E Raines, Steven L. Shafer, Hugh C. Hemmings, James M Sonner
    Abstract:

    A paradox arises from present information concerning the mechanism(s) by which Inhaled Anesthetics produce immobility in the face of noxious stimulation. Several findings, such as additivity, suggest a common site at which Inhaled Anesthetics act to produce immobility. However, two decades of focused investigation have not identified a ligand- or voltage-gated channel that alone is sufficient to mediate immobility. Indeed, most putative targets provide minimal or no mediation. For example, opioid, 5-HT3, gamma-aminobutyric acid type A and glutamate receptors, and potassium and calcium channels appear to be irrelevant or play only minor roles. Furthermore, no combination of actions on ligand- or voltage-gated channels seems sufficient. A few plausible targets (e.g., sodium channels) merit further study, but there remains the possibility that immobilization results from a nonspecific mechanism.

  • Inhaled Anesthetics do not combine to produce synergistic effects regarding minimum alveolar anesthetic concentration in rats
    Anesthesia & Analgesia, 2008
    Co-Authors: Edmond I. Eger, Douglas E Raines, Ken Solt, Jan F. A. Hendrickx, Michael J. Laster, Pamela Flood, Andrew Jenkins, Michael Tang, Mark Liao, Steven L. Shafer
    Abstract:

    BACKGROUND: We hypothesized that pairs of Inhaled Anesthetics having divergent potencies [one acting weakly at minimum alveolar anesthetic concentration (MAC); one acting strongly at MAC] on specific receptors/channels might act synergistically, and that such deviations from additivity would support the notion that Anesthetics act on multiple sites to produce anesthesia. METHODS: Accordingly, we studied the additivity of MAC for 11 anesthetic pairs divergently (one weakly, one strongly) affecting a specific receptor/channel at MAC. By “divergently,” we usually meant that at MAC the more strongly acting anesthetic enhanced or blocked the in vitro receptor or channel at least twice (and usually more) as much as did the weakly acting anesthetic. The receptors/channels included: TREK-1 and TASK-3 potassium channels; and -aminobutyric acid type A, glycine, N-methyl-d-aspartic acid, and acetylcholine receptors. We also studied the additivity of cyclopropane-benzene because the N-methyl-d-aspartic acid blocker MK-801 had divergent effects on the MACs of these Anesthetics. We also studied four pairs that included nitrous oxide because nitrous oxide had been reported to produce infraadditivity (antagonism) when combined with isoflurane. RESULTS: All combinations produced a result within 10% of that which would be predicted by additivity except for the combination of isoflurane with nitrous oxide where infraadditivity was found. CONCLUSIONS: Such results are consistent with the notion that Inhaled Anesthetics act on a single site to produce immobility in the face of noxious stimulation. (Anesth Analg 2008;107:479‐85)

  • do n methyl d aspartate receptors mediate the capacity of Inhaled Anesthetics to suppress the temporal summation that contributes to minimum alveolar concentration
    Anesthesia & Analgesia, 2006
    Co-Authors: Robert C. Dutton, Douglas E Raines, James M Sonner, Ken Solt, Michael J. Laster, Yilei Xing, Edmond I. Eger
    Abstract:

    Antagonism of N-methyl-d-aspartate (NMDA) receptors markedly decreases the minimum alveolar concentration (MAC) of Inhaled Anesthetics. To assess the importance of suppression of the temporal summation NMDA receptor component of MAC, we stimulated the tail of rats with trains of electrical pulses of varying interstimulus intervals (ISIs) and determined the Inhaled anesthetic concentrations (crossover concentrations) that suppressed movement at different ISIs. The slopes of crossover concentrations versus ISIs provided a measure of temporal summation for each anesthetic. We studied five Anesthetics that differ widely in their in vitro capacity to block NMDA receptors. To block NMDA receptor transmission and reveal the NMDA receptor component, the NMDA receptor antagonist, MK801, was separately added during each anesthetic. Halothane, isoflurane, and hexafluorobenzene did not appreciably suppress the NMDA receptor components of temporal summation, which contributed to 21% to 29% of MAC (P < 0.05 for each). Xenon and o-difluorobenzene suppressed these components to 8% to 0%, respectively, of MAC (neither significant), consistent with their greater NMDA receptor blocking action in vitro. NMDA receptor blockade may contribute to the MAC produced by Inhaled Anesthetics that potently inhibit NMDA receptors in vitro but not those that have a limited in vitro effect.

  • tutorial context sensitive decrement times for Inhaled Anesthetics
    Anesthesia & Analgesia, 2005
    Co-Authors: Edmond I. Eger, Steven L. Shafer
    Abstract:

    Context-sensitive decrement times for Inhaled Anesthetics connect two values: a) the duration of anesthesia (nominally at a constant alveolar concentration)-the "context" and b) the time to decrease the alveolar or vital tissue (e.g., brain, heart, kidney, and liver, collectively called the vessel-rich group of tissues) concentration by some fractional "decrement" of the starting concentration. Increasing duration of anesthesia increases the time to a given decrement in a nonlinear manner that may considerably delay recovery. In the present report we use a commercially available simulation program (Gas Man) to confirm and enlarge on these concepts. In this simulation, increasing duration of anesthesia can markedly delay complete awakening for isoflurane. Increasing anesthesia duration imposes considerably less delay in awakening from sevoflurane compared with isoflurane. For desflurane, only prolonged anesthesia or decrements of 95% and more should delay awakening from anesthesia. These changes are shown to be the result of the relative solubility of each anesthetic in blood and tissue. An increase in cardiac output is also shown to delay awakening.

James M Sonner - One of the best experts on this subject based on the ideXlab platform.

  • Alpha 1 subunit-containing GABA type A receptors in forebrain contribute to the effect of Inhaled Anesthetics on conditioned
    2016
    Co-Authors: James M Sonner, Mike Cascio, Yilei Xing, Michael S. Fanselow, Jason E. Kralic, Esa R. Korpi, Steven Hardy, Brian Sloat, Leslie A. Morrow, Edmond I. Eger
    Abstract:

    Inhaled Anesthetics are believed to produce anesthesia by their actions on ion channels. Because Inhaled Anesthetics robustly enhance GABA A receptor (GABAA-R) responses to GABA, these receptors are considered prime targets of anesthetic action. However, the importance of GABAA-Rs and individual GABAA-R subunits to specific anesthetic-induced behavioral effects in the intact animal is unknown. We hypothesized that Inhaled Anesthetics produce amnesia, as assessed by loss of fear conditioning, by acting on the forebrain GABAA-Rs that harbor the 1 subunit. To test this, we used global knockout mice that completely lack the 1 subunit and forebrain-specific, conditional knockout mice that lack the 1 subunit only in the hippocampus, cortex, and amygdala. Both knockout mice were 75 to 145 % less sensitive to the amnestic effects of the inhale

  • Is a New Paradigm Needed to Explain How Inhaled Anesthetics Produce Immobility
    Anesthesia & Analgesia, 2008
    Co-Authors: Edmond I. Eger, Douglas E Raines, Steven L. Shafer, Hugh C. Hemmings, James M Sonner
    Abstract:

    A paradox arises from present information concerning the mechanism(s) by which Inhaled Anesthetics produce immobility in the face of noxious stimulation. Several findings, such as additivity, suggest a common site at which Inhaled Anesthetics act to produce immobility. However, two decades of focused investigation have not identified a ligand- or voltage-gated channel that alone is sufficient to mediate immobility. Indeed, most putative targets provide minimal or no mediation. For example, opioid, 5-HT3, gamma-aminobutyric acid type A and glutamate receptors, and potassium and calcium channels appear to be irrelevant or play only minor roles. Furthermore, no combination of actions on ligand- or voltage-gated channels seems sufficient. A few plausible targets (e.g., sodium channels) merit further study, but there remains the possibility that immobilization results from a nonspecific mechanism.

  • A hypothesis on the origin and evolution of the response to Inhaled Anesthetics.
    Anesthesia and analgesia, 2008
    Co-Authors: James M Sonner
    Abstract:

    In this article, I present an evolutionary explanation for why organisms respond to Inhaled Anesthetics. It is conjectured that organisms today respond to Inhaled Anesthetics owing to the sensitivity of ion channels to Inhaled Anesthetics, which in turn has arisen by common descent from ancestral, anesthetic-sensitive ion channels in one-celled organisms (i.e., that the response to Anesthetics did not arise as an adaptation of the nervous system, but rather of ion channels that preceded the origin of multicellularity). This sensitivity may have been refined by continuing selection at synapses in multicellular organisms. In particular, it is hypothesized that 1) the beneficial trait that was selected for in one-celled organisms was the coordinated response of ion channels to compounds that were present in the environment, which influenced the conformational equilibrium of ion channels; 2) this coordinated response prevented the deleterious consequences of entry of positive charges into the cell, thereby increasing the fitness of the organism; and 3) these compounds (which may have included organic anions, cations, and zwitterions as well as uncharged compounds) mimicked Inhaled Anesthetics in that they were interfacially active, and modulated ion channel function by altering bilayer properties coupled to channel function. The proposed hypothesis is consistent with known properties of Inhaled Anesthetics. In addition, it leads to testable experimental predictions of nonvolatile compounds having anesthetic-like modulatory effects on ion channels and in animals, including endogenous compounds that may modulate ion channel function in health and disease. The latter included metabolites that are increased in some types of end-stage organ failure, and genetic metabolic diseases. Several of these predictions have been tested and proved to be correct.

  • do n methyl d aspartate receptors mediate the capacity of Inhaled Anesthetics to suppress the temporal summation that contributes to minimum alveolar concentration
    Anesthesia & Analgesia, 2006
    Co-Authors: Robert C. Dutton, Douglas E Raines, James M Sonner, Ken Solt, Michael J. Laster, Yilei Xing, Edmond I. Eger
    Abstract:

    Antagonism of N-methyl-d-aspartate (NMDA) receptors markedly decreases the minimum alveolar concentration (MAC) of Inhaled Anesthetics. To assess the importance of suppression of the temporal summation NMDA receptor component of MAC, we stimulated the tail of rats with trains of electrical pulses of varying interstimulus intervals (ISIs) and determined the Inhaled anesthetic concentrations (crossover concentrations) that suppressed movement at different ISIs. The slopes of crossover concentrations versus ISIs provided a measure of temporal summation for each anesthetic. We studied five Anesthetics that differ widely in their in vitro capacity to block NMDA receptors. To block NMDA receptor transmission and reveal the NMDA receptor component, the NMDA receptor antagonist, MK801, was separately added during each anesthetic. Halothane, isoflurane, and hexafluorobenzene did not appreciably suppress the NMDA receptor components of temporal summation, which contributed to 21% to 29% of MAC (P < 0.05 for each). Xenon and o-difluorobenzene suppressed these components to 8% to 0%, respectively, of MAC (neither significant), consistent with their greater NMDA receptor blocking action in vitro. NMDA receptor blockade may contribute to the MAC produced by Inhaled Anesthetics that potently inhibit NMDA receptors in vitro but not those that have a limited in vitro effect.

  • the effect of three Inhaled Anesthetics in mice harboring mutations in the glur6 kainate receptor gene
    Anesthesia & Analgesia, 2005
    Co-Authors: James M Sonner, Michael S. Fanselow, Neil L Harrison, Bryce Vissel, Gordon Royle, Anya J Maurer, Diane Gong, Nicole V Baron, Edmond I. Eger
    Abstract:

    Combinations of GluR5-GluR7, KA1, and KA2 subunits form kainate receptors, a subtype of excitatory ionotropic glutamate receptors. Isoflurane enhances the action of kainate receptors comprising GluR6 subunits expressed in oocytes. To test whether alterations of the GluR6 subunit gene affect the actions of Inhaled Anesthetics in vivo, we measured the minimum alveolar concentration of desflurane, isoflurane, and halothane in mice lacking the kainate receptor subunit GluR6 (GluR6 knockout mice) and mice with a dominant negative glutamine/arginine (Q/R) editing mutation in membrane domain 2 of the GluR6 receptor (GluR6 editing mutants), which increases the calcium permeability of kainate receptors containing GluR6Q. We also measured the capacity of isoflurane to interfere with Pavlovian fear conditioning to a tone and to context. Absence of the GluR6 subunit did not change the minimum alveolar concentration of isoflurane, desflurane, or halothane. Possibly, kainate receptors assembled from the remaining kainate receptor subunits compensate for the absent subunits and thereby produce a normal minimum alveolar concentration. A Q/R mutation that dominantly affects kainate receptors containing the GluR6 subunit in mice increased isoflurane minimum alveolar concentration (by 12%; P < 0.01), decreased desflurane minimum alveolar concentration (by 18%; P < 0.001), and did not change halothane minimum alveolar concentration (P = 0.25). These data may indicate that kainate receptors containing GluR6Q subunits differently modulate, directly or indirectly, the mechanism by which Inhaled Anesthetics cause immobility. The mutations of GluR6 that were studied did not affect the capacity of isoflurane to interfere with fear conditioning.

Michael J. Laster - One of the best experts on this subject based on the ideXlab platform.

  • Inhaled Anesthetics do not combine to produce synergistic effects regarding minimum alveolar anesthetic concentration in rats
    Anesthesia & Analgesia, 2008
    Co-Authors: Edmond I. Eger, Douglas E Raines, Ken Solt, Jan F. A. Hendrickx, Michael J. Laster, Pamela Flood, Andrew Jenkins, Michael Tang, Mark Liao, Steven L. Shafer
    Abstract:

    BACKGROUND: We hypothesized that pairs of Inhaled Anesthetics having divergent potencies [one acting weakly at minimum alveolar anesthetic concentration (MAC); one acting strongly at MAC] on specific receptors/channels might act synergistically, and that such deviations from additivity would support the notion that Anesthetics act on multiple sites to produce anesthesia. METHODS: Accordingly, we studied the additivity of MAC for 11 anesthetic pairs divergently (one weakly, one strongly) affecting a specific receptor/channel at MAC. By “divergently,” we usually meant that at MAC the more strongly acting anesthetic enhanced or blocked the in vitro receptor or channel at least twice (and usually more) as much as did the weakly acting anesthetic. The receptors/channels included: TREK-1 and TASK-3 potassium channels; and -aminobutyric acid type A, glycine, N-methyl-d-aspartic acid, and acetylcholine receptors. We also studied the additivity of cyclopropane-benzene because the N-methyl-d-aspartic acid blocker MK-801 had divergent effects on the MACs of these Anesthetics. We also studied four pairs that included nitrous oxide because nitrous oxide had been reported to produce infraadditivity (antagonism) when combined with isoflurane. RESULTS: All combinations produced a result within 10% of that which would be predicted by additivity except for the combination of isoflurane with nitrous oxide where infraadditivity was found. CONCLUSIONS: Such results are consistent with the notion that Inhaled Anesthetics act on a single site to produce immobility in the face of noxious stimulation. (Anesth Analg 2008;107:479‐85)

  • do n methyl d aspartate receptors mediate the capacity of Inhaled Anesthetics to suppress the temporal summation that contributes to minimum alveolar concentration
    Anesthesia & Analgesia, 2006
    Co-Authors: Robert C. Dutton, Douglas E Raines, James M Sonner, Ken Solt, Michael J. Laster, Yilei Xing, Edmond I. Eger
    Abstract:

    Antagonism of N-methyl-d-aspartate (NMDA) receptors markedly decreases the minimum alveolar concentration (MAC) of Inhaled Anesthetics. To assess the importance of suppression of the temporal summation NMDA receptor component of MAC, we stimulated the tail of rats with trains of electrical pulses of varying interstimulus intervals (ISIs) and determined the Inhaled anesthetic concentrations (crossover concentrations) that suppressed movement at different ISIs. The slopes of crossover concentrations versus ISIs provided a measure of temporal summation for each anesthetic. We studied five Anesthetics that differ widely in their in vitro capacity to block NMDA receptors. To block NMDA receptor transmission and reveal the NMDA receptor component, the NMDA receptor antagonist, MK801, was separately added during each anesthetic. Halothane, isoflurane, and hexafluorobenzene did not appreciably suppress the NMDA receptor components of temporal summation, which contributed to 21% to 29% of MAC (P < 0.05 for each). Xenon and o-difluorobenzene suppressed these components to 8% to 0%, respectively, of MAC (neither significant), consistent with their greater NMDA receptor blocking action in vitro. NMDA receptor blockade may contribute to the MAC produced by Inhaled Anesthetics that potently inhibit NMDA receptors in vitro but not those that have a limited in vitro effect.

  • blockade of 5 ht2a receptors may mediate or modulate part of the immobility produced by Inhaled Anesthetics
    Anesthesia & Analgesia, 2003
    Co-Authors: Yi Zhang, Edmond I. Eger, Michael J. Laster, Caroline R. Stabernack, James M Sonner
    Abstract:

    UNLABELLED Many Inhaled Anesthetics block the in vitro effect of the excitatory neurotransmitter serotonin on the 5-HT2A receptor, supporting the view that this receptor might mediate the capacity of Inhaled Anesthetics to produce immobility during noxious stimulation (i.e., would underlie MAC, the minimum alveolar concentration required to suppress movement in response to a noxious stimulus in 50% of subjects). In the present investigation in rats, we found that intrathecal administration of the 5HT-2A blocker, ketanserin, can decrease isoflurane MAC. This effect, presumably mediated by blockade of serotonin transmission in the spinal cord, reaches a maximum of 20%-25%. An additional decrease (to 60%) may be obtained by IV infusion of ketanserin, and presumably this decrease results from ketanserin's actions on supraspinal centers. The IV doses of ketanserin that decreased MAC were approximately 100 microg. kg(-1). min(-1) in rats, compared with usual clinical doses of 1.25 microg. kg(-1). min(-1) in humans. These results indicate that 5HT2A receptors are in the neural circuitry influencing isoflurane MAC. These results, together with the blocking action of isoflurane on expressed 5HT2A receptors, strengthen the case for a role for 5HT2A receptors to isoflurane-induced immobility. However, because MAC for isoflurane is predominantly determined in the spinal cord, this result is consistent at most with a minor contribution of these receptors to the immobilizing action of isoflurane. IMPLICATIONS A subset of serotonin receptors, 5HT2A receptors, may mediate or modulate a minor portion of the immobility produced by Inhaled Anesthetics.

  • Glycine receptors mediate part of the immobility produced by Inhaled Anesthetics.
    Anesthesia and analgesia, 2003
    Co-Authors: Yi Zhang, Edmond I. Eger, Michael J. Laster, Koji Hara, R. Adron Harris, Caroline R. Stabernack, James M Sonner
    Abstract:

    UNLABELLED Many Inhaled Anesthetics potentiate the effect of glycine on inhibitory strychnine-sensitive glycine receptors in vitro, supporting the view that this receptor could mediate the immobility produced by Inhaled Anesthetics during noxious stimulation (i.e., would underlie minimum alveolar anesthetic concentration [MAC]). There are quantitative differences between Anesthetics in their capacity to potentiate glycine's effect in receptor expression systems: halothane (most potentiation), isoflurane (intermediate), and cyclopropane (minimal). If glycine receptors mediate MAC, then their blockade in the spinal cord should increase the MAC of halothane more than that of isoflurane and isoflurane MAC more than cyclopropane MAC; the increases in MAC should be proportional to the receptor potentiation produced in vitro. Rats with chronically implanted intrathecal catheters were anesthetized with halothane, isoflurane, or cyclopropane. During intrathecal infusion of artificial cerebrospinal fluid, MAC was determined. Then MAC was re-determined during an infusion of 3, 12, 24, or 48 (isoflurane only) micro g/min of strychnine (strychnine blocks glycine receptors) in artificial cerebrospinal fluid. Strychnine infusion increased MAC in proportion to the enhancement of glycine receptors found in vitro. The maximum effect was with an infusion of 12 micro g/min. For the combined results at 12 and 24 micro g/min of strychnine, the increase in MAC correlated with the extent of in vitro potentiation (r(2) = 0.82). These results support the hypothesis that glycine receptors mediate part of the immobilization produced by Inhaled Anesthetics. IMPLICATIONS In vitro, halothane potentiates glycine's effect on strychnine-sensitive glycine receptors more than isoflurane and isoflurane more than cyclopropane. The present in vivo work indicates that antagonism of the glycine receptor with strychnine increases minimum alveolar anesthetic concentration for halothane more than isoflurane and isoflurane more than cyclopropane. Such results support the notion that glycine receptors may mediate part of the immobility produced by Inhaled Anesthetics.

  • 2 Adrenoreceptors Probably Do Not Mediate the Immobility Produced by Inhaled Anesthetics
    Anesthesia and analgesia, 2003
    Co-Authors: Edmond I. Eger, Michael J. Laster, Yilei Xing, James M Sonner
    Abstract:

    UNLABELLED Agonism of alpha-adrenoreceptors has a powerful anesthetic result mediated, in part, by effects on the spinal cord. Alpha-adrenoreceptor agonists (e.g., dexmedetomidine) can decrease the minimum alveolar anesthetic concentration (MAC) of Inhaled Anesthetics (e.g., halothane) to zero, with an apparently additive interaction between halothane and dexmedetomidine. We tested whether the capacity of the Inhaled anesthetic isoflurane to produce immobility in the face of noxious stimulation resulted from agonism of alpha-adrenoreceptors. MAC (the concentration required to eliminate movement in response to a noxious stimulus in 50% of subjects) of isoflurane was determined before and after intraperitoneal administration of the alpha-adrenoreceptor antagonists yohimbine and atipamezole. The doses of yohimbine and atipamezole equaled or exceeded those that reverse the ability of agonism of alpha-adrenoreceptors to decrease MAC. Smaller doses of yohimbine or atipamezole slightly increased (by 10%) the MAC of isoflurane, an increase we interpret as the result of blockade of a small amount of tonically active alpha-adrenoreceptor activity. Doses five-fold larger did not change MAC. Doses 10-fold larger decreased MAC. We conclude that alpha-adrenoreceptors do not or minimally mediate the capacity of Inhaled Anesthetics to produce immobility. IMPLICATIONS Although stimulation (agonism) of alpha-2 adrenoreceptors can decrease the Inhaled anesthetic concentration required to produce immobility in the face of noxious stimulation, blockade of alpha-2 adrenoreceptors minimally affects the concentration. Thus, augmentation of the effect of alpha-2 adrenoreceptors is not an appreciable part of the mechanism whereby Inhaled Anesthetics produce immobility.

Roderic G. Eckenhoff - One of the best experts on this subject based on the ideXlab platform.

  • Taxane modulation of anesthetic sensitivity in surgery for nonmetastatic breast cancer
    Journal of Clinical Anesthesia, 2015
    Co-Authors: Regina E. Linganna, Roderic G. Eckenhoff, Warren J. Levy, Ivan J. Dmochowski, Rebecca M. Speck
    Abstract:

    Abstract Study objective and design The mechanism of action of commonly used general Anesthetics is largely unknown. One hypothesized mechanism is through modulation of microtubule stability. Taxanes, a subset of chemotherapeutic drugs known to alter microtubule stability and commonly used to treat breast cancer, offer a natural experiment to test our hypothesis that patients exposed to taxanes prior to surgery, as compared to after surgery, would have a partial resistance to general Anesthetics. Setting, patients, and measurements The anesthetic record of adult women with nonmetastatic breast cancer was used to obtain changes in heart rate and blood pressure surrounding incision, and the amount of Inhaled anesthetic agent, induction, and rescue drugs administered. Main results Change in blood pressure in response to incision was significantly higher in the neoadjuvant group ( P = .03), whereas change in heart rate was not ( P = .53). A greater amount of morphine was administered in the neoadjuvant group (26.3 vs 15.5 mg, P = .02), although not a higher concentration of Inhaled Anesthetics ( P = .15). Conclusion These results suggest that the alteration of microtubule stability is one of a number of mechanisms of Inhaled Anesthetics.

  • Inhaled Anesthetics elicit region specific changes in protein expression in mammalian brain
    Proteomics, 2008
    Co-Authors: Jonathan Z Pan, Maryellen F Eckenhoff, Roderic G. Eckenhoff
    Abstract:

    Inhaled Anesthetics bind specifically to many proteins in the mammalian brain. Within the subgroup of proteins whose activity is substantially modulated by anesthetic binding, it is reasonable to expect anesthetic-induced alterations in host expression level. Thus, in an attempt to define the group of functional targets for these commonly used drugs, we examined changes in protein expression after anesthetic exposure in both intact rodent brains and in neuronal cell culture. Differential in-gel electrophoresis was used to minimize variance, in order to detect small changes. Quantitative analysis shows that 5 h exposures to 1 minimum alveolar concentration (1 MAC) halothane caused changes in the expression of approximately 2% of detectable proteins, but only at 2-24 h after awakening, and only in the cortex. An equipotent concentration of isoflurane altered the expression of only approximately 1% of detectable proteins, and only in the hippocampus. Primary cortical neurons were exposed to three-fold higher concentrations of Anesthetics with no evidence of cytotoxicity. Small changes in protein expression were elicited by both drugs. Despite the fact that Anesthetics produce profound changes in neurobiology and behavior, we found only minor changes in brain protein expression. A pronounced degree of regional selectivity was noted, indicating an under appreciated degree of specificity for these promiscuous drugs.

  • Inhaled Anesthetic Modulation of Amyloid β 1-40 Assembly and Growth
    Current Alzheimer research, 2007
    Co-Authors: Anna Carnini, J.d. Lear, Roderic G. Eckenhoff
    Abstract:

    Anesthesia and surgery have been reported to produce long-term cognitive problems, and to accelerate neurodegenerative disorders in the elderly. In previous work, we found that Inhaled Anesthetics enhance fibril formation and cytotoxicity of amyloid β peptide. In this work we show that the Inhaled Anesthetics halothane (2-bromo-2-chloro-1,1,1- trifluoroethane) and isoflurane (1-chloro-2,2,2-trifluoroethyl difluoromethyl ether) also favor intermediate oligomers of amyloid β1-40, and reduce solubility of amyloid β1-40 monomer. Size-exclusion chromatography, analytical ultracentrifugation and photo-induced cross-linking experiments indicate halothane enhancement of oligomeric species having molecular weight ∼44-100 kDa. Bis-ANS fluorescence experiments revealed that halothane stabilizes a population of diffusible oligomers relative to the monomer or the mature fibril. These data show that Inhaled Anesthetics lower the amyloid β1-40 concentration necessary to initiate oligomer formation, probably by preferential binding to intermediate oligomers en route to fibril formation.

  • Inhaled Anesthetic Enhancement of Amyloid-β Oligomerization and Cytotoxicity
    Anesthesiology, 2004
    Co-Authors: Roderic G. Eckenhoff, Jonas S. Johansson, Ravindernath Pidikiti, Anna Carnini, Huafeng Wei, Baobin Kang, Wenlin Wei, Jason M. Keller, Maryellen F Eckenhoff
    Abstract:

    Background: The majority of surgical patients receive Inhaled Anesthetics, principally small haloalkanes and haloethers. Long-term cognitive problems occur in the elderly subsequent to anesthesia and surgery, and previous surgery might also be a risk factor for neurodegenerative disorders like Alzheimer and Parkinson disease. The authors hypothesize that Inhaled Anesthetics contribute to these effects through a durable enhancement of peptide oligomerization. Methods: Light scattering, filtration assays, electron microscopy, fluorescence spectroscopy and size-exclusion chromatography was used to characterize the concentration-dependent effects of halothane, isoflurane, propofol, and ethanol on amyloid β peptide oligomerization. Pheochromocytoma cells were used to characterize cytotoxicity of amyloid oligomers with and without the above Anesthetics. Results: Halothane and isoflurane enhanced amyloid beta oligomerization rates and pheochromocytoma cytotoxicity in vitro through a preference for binding small oligomeric species. Ethanol and propofol inhibited oligomerization at low concentration but enhanced modestly at very high concentration. Neither ethanol nor propofol enhanced amyloid β toxicity in pheochromocytoma cells. Conclusions: Inhaled Anesthetics enhance oligomerization and cytotoxicity of Alzheimer disease-associated peptides. In addition to the possibility of a general mechanism for anesthetic neurotoxicity, these results call for further evaluation of the interaction between neurodegenerative disorders, dementia, and inhalational anesthesia.

  • G protein-coupled receptors as direct targets of Inhaled Anesthetics.
    Molecular pharmacology, 2002
    Co-Authors: Yumiko Ishizawa, Paul A Liebman, Ravindernath Pidikiti, Roderic G. Eckenhoff
    Abstract:

    The molecular pharmacology of inhalational Anesthetics remains poorly understood. Despite accumulating evidence suggesting that neuronal membrane proteins are potential targets of Inhaled Anesthetics, most currently favored membrane protein targets lack any direct evidence for anesthetic binding. We report herein the location of the binding site for the Inhaled anesthetic halothane at the amino acid residue level of resolution in the ligand binding cavity in a prototypical G protein-coupled receptor, bovine rhodopsin. Tryptophan fluorescence quenching and direct photoaffinity labeling with [14C]halothane suggested an interhelical location of halothane with a stoichiometry of 1 (halothane/rhodopsin molar ratio). Radiosequence analysis of [14C]halothane-labeled rhodopsin revealed that halothane contacts an amino acid residue (Trp265) lining the ligand binding cavity in the transmembrane core of the receptor. The predicted functional consequence, competition between halothane and the ligand retinal, was shown here by spectroscopy and is known to exist in vivo. These data suggest that competition with endogenous ligands may be a general mechanism of the action of halothane at this large family of signaling proteins.

Jhi J Wang - One of the best experts on this subject based on the ideXlab platform.