Chirality in Anesthesia II: Stereoselective Modulation of Ion Channel Function by Secondary Alcohol Enantiomers

Brosnan, Robert J; Gong, Diane; Cotten, Joseph F.; Keshavaprasad, Bharat; Yost, C. Spencer; Eger, Edmond I.; Sonner, James M.

doi:10.1213/01.ane.0000221437.87338.af

Cited by 23 publications

(14 citation statements)

References 19 publications

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“…Methods for measuring whole-cell GABA A receptor currents have been described (Brosnan et al 2006; Yang et al 2007a, b; Brosnan & Pham 2014). Pairs of identical concentrations of hydrocarbon mixtures were prepared in glass syringes containing Frog Ringer’s (FR) solution (115 mM NaCl, 2.5 mM KCl, 1.8 mM CaCl 2 , and 10 mM HEPES in 18.2 MΩ H 2 O, filtered and adjusted to pH = 7.4) or frog Ringer’s + agonist (FR-GABA; FR plus 20–40μM, 4-aminobutanoic acid, equal to an EC 10–20 ).…”

Section: Methodsmentioning

confidence: 99%

“…Methods for measuring whole-cell NMDA receptor currents have been described (Brosnan et al 2006; Yang et al 2007b; Brosnan & Pham 2008, 2011, 2014). Baseline perfusion solutions were the same as for GABA A with the substitution of equimolar BaCl 2 for calcium salts and the addition of 0.1 mM EGTA; this constituted barium frog Ringer’s solution (BaFR).…”

Section: Methodsmentioning

confidence: 99%

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Anesthetic synergy between two n-alkanes

Brosnan

Fukushima

Pham

2017

Veterinary Anaesthesia and Analgesia

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Objective N-butane and n-pentane each can produce general anesthesia. Both compounds potentiate GABAA receptor function, but only butane inhibits NMDA receptors. It was hypothesized that butane and pentane would exhibit anesthetic synergy due to their different actions on ligand-gated ion channels. Study design Prospective experimental study. Animals Four Xenopus laevis frogs and 43 Sprague Dawley rats. Methods Alkane concentrations for all studies were determined via gas chromatography. Using a Xenopus oocyte expression model, standard two-electrode voltage clamp techniques were used to measure NMDA and GABAA receptor responses in vitro as a function of butane and pentane concentrations relevant to anesthesia. The minimum alveolar concentration (MAC) of butane and pentane were measured separately in rats, and then pentane MAC was measured during co-administration of 0.25, 0.50, or 0.75 times MAC of butane. An isobole with 95% confidence intervals was constructed using regression analysis. A sum of butane and pentane that was statistically less than the lower-end confidence bound isobole indicated a synergistic interaction. Results Both butane and pentane dose-dependently potentiated GABAA receptor currents over the study concentration range. Butane dose-dependently inhibited NMDA receptor currents, but pentane did not modulate NMDA receptors. Butane and pentane MAC in rats was 39.4 ± 0.7 and 13.7 ± 0.4 %, respectively. A small but significant (p < 0.03) synergistic anesthetic effect with pentane was observed during administration of either 0.50 or 0.75 × MAC butane. Conclusion Butane and pentane show synergistic anesthetic effects in vivo consistent with their different in vitro receptor effects. Clinical relevance Findings support the relevance of NMDA receptors in mediating anesthetic actions for some, but not all, inhaled agents.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Anesthetic synergy between two n-alkanes

Brosnan

Fukushima

Pham

2017

Veterinary Anaesthesia and Analgesia

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“…The authors finally opined that enantioselectivity should not be used as a test of relevance for inhaled anaesthetic targets. [63]…”

Section: Basic Conceptsmentioning

confidence: 99%

Chirality and anaesthetic drugs: A review and an update

Mitra¹,

Chopra²

2011

Indian J Anaesth

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Many molecules can exist as right-handed and left-handed forms that are non-superimposable mirror images of each other. They are known as enantiomers or substances of opposite shape. Such compounds are also said to be chiral (Greek chiros meaning ‘hand’). Such chiral molecules are of great relevance to anaesthetic theory and practice. This review summarizes the basic concepts, pharmacokinetic and pharmacodynamic aspects of chirality, and some specific examples of their application in anaesthesia, along with recent advances to elucidate the anaesthetic mechanisms. Chirality is relevant to anaesthesia, simply because more than half of the synthetic agents used in anaesthesia practice are chiral drugs. Almost all these synthetic chiral drugs are administered as racemic mixture, rather than as single pure enantiomers. These mixtures are not drug formulations containing two or more therapeutic substances, but combination of isomeric substances, with the therapeutic activity residing mainly in one of the enantiomer. The other enantiomer can have undesirable properties, have different therapeutic activities or be pharmacologically inert. Specific examples of application of chirality in anaesthetic drugs include inhalational general anaesthetics (e.g. isoflurane), intravenous anaesthetics (e.g. etomidate, thiopentone), neuromuscular blocking agents (e.g. cisatracurium), local anaesthetics (e.g. ropivacaine and levobupivacaine) and other agents (e.g. levosimendan, dexmedetomidine, L-cysteine). In the recent advances, chirality study has not only helped new drug development as mentioned above, but has also contributed in a more profound way to the understanding of the mechanism of anaesthesia and anaesthetic drugs.

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“…The weak stereoselective actions of inhaled anesthetics in animals (60, 61) and on ion channels (62, 63) is said to indicate inhaled anesthetics bind to proteins. However, this finding is as consistent with a bilayer as with a protein site of action, because cholesterol and phospholipids are chiral.…”

Section: Introductionmentioning

confidence: 99%

A Hypothesis on the Origin and Evolution of the Response to Inhaled Anesthetics

Sonner

2008

Anesthesia &Amp; Analgesia

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An evolutionary narrative explaining why organisms respond to inhaled anesthetics is proposed. It is conjectured that organisms today respond to inhaled anesthetics because their ion channels are sensitive to inhaled anesthetics by virtue of 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 ongoing 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) that this coordinated response prevented the deleterious consequences of entry of positive charges into the cell, thereby increasing the fitness of the organism (3) that 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 that of endogenous compounds that may modulate ion channel function in health and disease. The latter included metabolites which are elevated in some types of end stage organ failure, and genetic metabolic diseases. Several of these predictions have been tested and proved to be correct. Implications A hypothesis for the origin and evolution of the response to inhaled anesthetics is offered, and experimental predictions of this theory are made.

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Chirality in Anesthesia II: Stereoselective Modulation of Ion Channel Function by Secondary Alcohol Enantiomers

Cited by 23 publications

References 19 publications

Anesthetic synergy between two n-alkanes

Anesthetic synergy between two n-alkanes

Chirality and anaesthetic drugs: A review and an update

A Hypothesis on the Origin and Evolution of the Response to Inhaled Anesthetics

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