Toxicology letters
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(1) Considerable evidence has accumulated that the molecular target of general anesthetics in the central nervous system is the GABA(A) receptor, the major mediator of inhibitory synaptic transmission. This receptor is actually a family of ligand-gated chloride channel proteins, each a heteropentameric membrane-spanning structure. (2) Regional variation in anesthetic actions on the central nervous system may parallel a corresponding regional variation in pharmacological subtypes of GABA(A) receptors. These result from differential regional expression of approximately 18 subunit genes. (3) Receptors of varying subunit composition show differential sensitivity to GABA, modulatory drugs, and biological regulatory mechanisms. Regional variation in allosteric modulation of GABA(A) receptor binding and function can be reconstituted in certain recombinant receptor subunit combinations expressed in heterologous cells. (5) Differential sensitivity to anesthetics for various GABA(A) receptor subunits also allows the use of the chimeric and site-directed mutagenesis approach in attempting to define domains of the protein which participate in the binding and actions of anesthetics.
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A large body of evidence has accumulated in recent years pointing towards the GABA(A) receptor as a primary determinant of volatile anesthetic action (Franks and Lieb, 1994). Nevertheless, our understanding of the function of the central nervous system (CNS) remains sufficiently incomplete that other mechanisms of CNS depression remain to be examined. We have studied a new family of potassium (K+) channels which function as regulators of the baseline excitability of neuronal tissue. As such they must be considered potential targets for volatile anesthetic action and as a possible mechanism by which volatile anesthetics act to allow patients to undergo noxious surgical stimulation.
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1. The intravenous anaesthetic etomidate augments GABA-gated chloride currents (indirect action) and, at higher concentrations, evokes chloride currents in the absence of GABA (direct action). 2. ⋯ In contrast, the indirect effect of etomidate was retained, though its potency was reduced. 5. These findings indicate that there are distinct requirements for these dual actions of etomidate at GABA(A) receptors.
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1. The effects of volatile and intravenous anesthetics were studied on evoked field potentials in rat hippocampal CA1 neurons in vitro to determine the role of GABAergic mechanisms in the action of general anesthetics. 2. It was observed that both volatile (halothane, isoflurane, sevoflurane) and intravenous (thiopental, pentobarbital, propofol) anesthetics decreased population spike (PS) amplitudes. 3. ⋯ Use-dependent effects on PS amplitudes were observed following application of the intravenous anesthetics, whereas volatile agents did not show use-dependency. The effects of the intravenous anesthetics were blocked by the GABA(A) receptor antagonist, bicuculline. 4. It is suggested that agent specific actions of general anesthetics are a result of differential effects on GABAergic mechanisms that modulate synaptic transmission.
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The pulmonary damage caused by prolonged exposure to high oxygen concentrations is accompanied by lung inflammation, which may contribute to the expression of hyperoxic lung injury. In turn, adhesion molecules are crucial for initiating inflammatory responses. The goal of the present study was to investigate the association of contents of soluble adhesion molecules in plasma or alveolar fluids of hyperoxic rats with lung expression of adhesion molecules, lung inflammation and lung injury. ⋯ Lung ICAM-I expression was more than doubled at 48 h, although soluble ICAM-I contents were not elevated in plasma or lavage. Soluble E-Selectin was increased by more than 50% at 24 h of hyperoxia-exposure, while lung expressions of E-Selectin were not increased until 48 h. The sequence of the events observed in the present studies suggests that E-Selectin contributes to lung inflammation in hyperoxia and the acceleration of lung injury immediately following the inflammatory response suggests a pivotal role for inflammation in this injury.