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PubMed2000

Differential effects of anesthetic and nonanesthetic cyclobutanes on neuronal voltage-gated sodium channels.

BACKGROUND: Despite their key role in the generation and propagation of action potentials in excitable cells, voltage-gated sodium (Na+) channels have been considered to be insensitive to general anesthetics. The authors tested the sensitivity of neuronal Na+ channels to structurally similar anesthetic (1-chloro-1,2,2-trifluorocyclobutane; F3) and nonanesthetic (1,2-dichlorohexafluorocyclobutane; F6) polyhalogenated cyclobutanes by neurochemical and electrophysiologic methods. METHODS: Synaptosomes (pinched-off nerve terminals) from adult rat cerebral cortex were used to determine the effects of F3 and F6 on 4-aminopyridine- or veratridine-evoked (Na+ channel-dependent) glutamate release (using an enzyme-coupled spectrofluorimetric assay) and increases in intracellular Ca2+ ([Ca2+]i) (using ion-specific spectrofluorimetry). Effects of F3 and F6 on Na+ currents were evaluated directly in rat lumbar dorsal root ganglion neurons by whole-cell patch-clamp recording. RESULTS: F3 inhibited glutamate release evoked by 4-aminopyridine (inhibitory concentration of 50% [IC50] = 0.77 mM [approximately 0.8 minimum alveolar concentration (MAC)] or veratridine (IC50 = 0.42 mM [approximately 0.4 MAC]), and veratridine-evoked increases in [Ca2+]i (IC50 = 0.5 mM [approximately 0.5 MAC]) in synaptosomes; F6 had no significant effects up to 0.05 mM (approximately twice the predicted MAC). F3 caused reversible membrane potential-independent inhibition of peak Na+ currents (70+/-9% block at 0.6 mM [approximately 0.6 MAC]), and a hyperpolarizing shift in the voltage-dependence of steady state inactivation in dorsal root ganglion neurons (-21+/-9.3 mV at 0.6 mM). F6 inhibited peak Na+ currents to a lesser extent (16+/-2% block at 0.018 mM [predicted MAC]) and had minimal effects on steady state inactivation. CONCLUSIONS: The anesthetic cyclobutane F3 significantly inhibited Na+ channel-mediated glutamate release and increases in [Ca2+]i. In contrast, the nonanesthetic cyclobutane F6 had no significant effects at predicted anesthetic concentrations. F3 inhibited dorsal root ganglion neuron Na+ channels with a potency and by mechanisms similar to those of conventional volatile anesthetics; F6 was less effective and did not produce voltage-dependent block. This concordance between anesthetic activity and Na+ channel inhibition supports a role for presynaptic Na+ channels as targets for general anesthetic effects and suggests that shifting the voltage-dependence of Na+ channel inactivation is an important property of volatile anesthetic compounds.

Anesthetics, Inhalation↗

PubMed2000

Volatile anesthetics differentially affect immunostimulated expression of inducible nitric oxide synthase: role of intracellular calcium.

BACKGROUND: Nitric oxide released by inducible nitric oxide synthase (iNOS) plays an important role in immune responses and systemic vasodilation in septic shock. Volatile anesthetics have been reported to interfere with signal transduction and gene expression. We studied the effect of volatile anesthetics on activity and expression of iNOS and potential mechanisms of action. METHODS: Nitrite release and iNOS expression were determined using the Griess reaction and Western and Northern blot techniques, respectively, in J774 murine macrophages stimulated with lipopolysaccharide and gamma-interferon in the absence and presence of various concentrations (0.25-2.0 minimum alveolar concentration [MAC]) of volatile anesthetics (i.e., halothane, enflurane, isoflurane, desflurane). Furthermore, potential interference of volatile anesthetics with specific signal transduction pathways was investigated. RESULTS: All volatile anesthetics, studied in a time- and dose-dependent manner, suppressed nitrite production and iNOS expression in J774 macrophages stimulated by lipopolysaccharide or gamma-interferon at clinically relevant concentrations. The inhibition was completely antagonized by ionomycin but unaffected by diacylglycerol, phorbol myristate acetate, and C2-ceramide. In contrast, in cells costimulated by lipopolysaccharide plus gamma-interferon, volatile anesthetics significantly increased nitrite production and iNOS expression independent of ionomycin and other mediators studied. CONCLUSIONS: Volatile anesthetics strongly reduced the mRNA and protein levels of iNOS and NOS activity after a single stimulation with lipopolysaccharide or gamma-interferon, most likely by attenuating intracellular calcium increase. Costimnulation with lipopolysaccharide plus gamma-interferon, however, results in maximum iNOS expression and activity, which are no longer inhibited but are potentiated by volatile anesthetics by unidentified mechanisms.

Adjuvants, Immunologic↗

PubMed2001

Absence of direct antioxidant effects from volatile anesthetics in primary mixed neuronal-glial cultures.

BACKGROUND: Volatile anesthetics decrease ischemic brain injury. Mechanisms for this protection remain under investigation. The authors hypothesized that volatile anesthetics serve as antioxidants in a neuronal-glial cell culture system. METHODS: Primary cortical neuronal-glial cultures were prepared from fetal rat brain. Cultures were exposed to iron, H2O2, or xanthine-xanthine oxidase for 30 min in serum-free media containing dissolved isoflurane (0-3.2 mm), sevoflurane (0-3.6 mm), halothane (0-4.1 mm), n-hexanol, or known antioxidants. Cell damage was assessed by release of lactate dehydrogenase (LDH) and trypan blue exclusion 24 h later. Lipid peroxidation was measured by the production of thiobarbituric acid-reactive substances in a cell-free lipid system. Iron and calcium uptake and mitochondrial depolarization were measured after exposure to iron in the presence or absence of isoflurane. RESULTS: Deferoxamine reduced LDH release caused by H2O2 or xanthine-xanthine oxidase, but the volatile anesthetics had no effect. Iron-induced LDH release was prevented by the volatile anesthetics (maximum effect for halothane = 1.2 mm, isoflurane = 1.2 mm, and sevoflurane = 2.1 mm aqueous phase). When corrected for lipid solubility, the three volatile anesthetics were equipotent against iron-induced LDH release. In the cell-free system, there was no effect of the anesthetics on thiobarbituric acid-reactive substance formation in contrast to Trolox, which provided complete inhibition. Isoflurane (1.2 mm) reduced mean iron uptake by 46% and inhibited mitochondrial depolarization but had no effect on calcium uptake. CONCLUSIONS: Volatile anesthetics reduced cell death induced by oxidative stress only in the context of iron challenge. The likely reason for protection against iron toxicity is inhibition of iron uptake and therefore indirect reduction of subsequent intracellular oxidative stress caused by this challenge. These data argue against a primary antioxidant effect of volatile anesthetics.

Anesthetics, Inhalation↗

PubMed2001

Nonhalogenated alkane anesthetics fail to potentiate agonist actions on two ligand-gated ion channels.

BACKGROUND: Although ether, alcohol, and halogenated alkane anesthetics potentiate agonist actions or increase the apparent agonist affinity of ligand-gated ion channels at clinically relevant concentrations, the effects of nonhalogenated alkane anesthetics on ligand-gated ion channels have not been studied. The current study assessed the abilities of two representative nonhalogenated alkane anesthetics (cyclopropane and butane) to potentiate agonist actions or increase the apparent agonist affinity of two representative ligand-gated ion channels: the nicotinic acetylcholine receptor and y-aminobutyric acid type A (GABA(A)) receptor. METHODS: Nicotinic acetylcholine receptors were obtained from the electroplax organ of Torpedo nobiliana, and human GABA(A) receptors (alpha1beta2gamma2L) were expressed in human embryonic kidney 293 cells. The Torpedo nicotinic acetylcholine receptors apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the apparent rates of desensitization induced by a range of acetylcholine concentrations. The GABA(A) receptor's apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the peak currents induced by a range of GABA concentrations. RESULTS: Neither cyclopropane nor butane potentiated agonist actions or increased the apparent agonist affinity (reduced the apparent agonist dissociation constant) of the Torpedo nicotinic acetylcholine receptor or GABA(A) receptor. At clinically relevant concentrations, cyclopropane and butane reduced the apparent rate of Torpedo nicotinic acetylcholine receptor desensitization induced by low concentrations of agonist. CONCLUSIONS: Our results suggest that the in vivo central nervous system depressant effects of nonhalogenated alkane anesthetics do not result from their abilities to potentiate agonist actions on ligand-gated ion channels. Other targets or mechanisms more likely account for the anesthetic activities of nonhalogenated alkane anesthetics.

Algorithms↗

PubMed2002

Inhibitory effects of volatile anesthetics on K+ and Cl- channel currents in porcine tracheal and bronchial smooth muscle.

BACKGROUND: K+ and Ca2+-activated Cl- (ClCa) channel currents have been shown to contribute to the alteration of membrane electrical activity in airway smooth muscle. This study was conducted to investigate the effects of volatile anesthetics, which are potent bronchodilators, on the activities of these channels in porcine tracheal and bronchial smooth muscles. METHODS: Whole-cell patch clamp recording techniques were used to investigate the effects of superfused isoflurane (0-1.5 minimum alveolar concentration) or sevoflurane (0-1.5 minimum alveolar concentration) on K+ and ClCa channel currents in dispersed smooth muscle cells. RESULTS: Isoflurane and sevoflurane inhibited whole-cell K+ currents to a greater degree in tracheal versus bronchial smooth muscle cells. More than 60% of the total K+ currents in tracheal smooth muscle appeared to be mediated through delayed rectifier K+ channels compared with less than 40% in bronchial smooth muscle. The inhibitory effects of the anesthetics were greater on the delayed rectifier K+ channels than on the remaining K+ channels. Cl- currents through ClCa channels were significantly inhibited by the anesthetics. The inhibitory potencies of the anesthetics on the ClCa channels were not different in tracheal and bronchial smooth muscle cells. CONCLUSIONS: Volatile anesthetics isoflurane and sevoflurane significantly inhibited Cl- currents through ClCa channels, and the inhibitory effect is consistent with the relaxant effect of volatile anesthetics in airway smooth muscle. Different distributions and different anesthetic sensitivities of K+ channel subtypes could play a role in the different inhibitory effects of the anesthetics on tracheal and bronchial smooth muscle contractions.

4-Aminopyridine↗

PubMed2002

Extracellular magnesium ion modifies the actions of volatile anesthetics in area CA1 of rat hippocampus in vitro.

BACKGROUND: Magnesium ion (Mg2+) is involved in important processes as modulation of ion channels, receptors, neurotransmitter release, and cell excitability in the central nervous system. Although extracellular Mg2+ concentration ([Mg2+]o) can be altered during general anesthesia, there has been no evidence for [Mg2+]o-dependent modification of anesthetic actions on neural excitability in central nervous system preparations. The purpose of current study was to determine whether the effects of volatile anesthetics are [Mg2+]o-dependent in mammalian central nervous system. METHODS: Extracellular electrophysiologic recordings from CA1 neurons in rat hippocampal slices were used to investigate the effects of [Mg2+]o and anesthetics on population spike amplitude and excitatory postsynaptic potential slope. RESULTS: The depression of population spike amplitudes and excitatory postsynaptic potential slopes by volatile anesthetics were significantly dependent on [Mg2+]o. The effects were attenuated in the presence of a constant [Mg2+]o/extracellular Ca2+ concentration ratio. However, neither N-methyl-d-aspartate receptor antagonists nor a non-N-methyl-d-aspartate receptor antagonist altered the [Mg2+]o-dependent anesthetic-induced depression of population spikes. Volatile anesthetics produced minimal effects on input-output (excitatory postsynaptic potential-population spike) relations or the threshold for population spike generation. The effects were not modified by changes in [Mg2+]o. In addition, the population spike amplitudes, elicited via antidromic (nonsynaptic) stimulation, were not influenced by [Mg2+]o in the presence of volatile anesthetics. CONCLUSIONS: These results provide support that alteration of [Mg2+]o modifies the actions of volatile anesthetics on synaptic transmission and that the effects could be, at least in part, a result of presynaptic Ca2+ channel-related mechanisms.

2-Amino-5-phosphonovalerate↗

PubMed2002

Preparation of the Siemens KION anesthetic machine for patients susceptible to malignant hyperthermia.

BACKGROUND: Preparation of anesthetic machines for use with malignant hyperthermia-susceptible (MHS) patients requires that the machines be flushed with clean fresh gas. We investigated the washout of inhalational anesthetics from the KION anesthetic machine. METHODS: In part 1, halothane was circulated through KION anesthetic machines for either 2 or 12 h using a test lung. The times to washout halothane (to 10 parts per million [ppm]) first, from the internal circuitry and second, from the ventilator-patient cassette (without the carbon dioxide absorber) were determined at 5 and 10 l/min fresh gas flow (FGF). In part 2, the rates of washout of halothane or isoflurane from either the KION or Ohmeda Excel 210 machines were compared. The effluent gases were analyzed using calibrated Datex Capnomac Ultima (Helsinki, Finland) and a Miran LB2 Portable Ambient Air Analyzer (Foxboro, Norwalk, CT). RESULTS: Halothane was washed out of the internal circuitry of the KION within 5 min at 10 l/min FGF. Halothane was eliminated from the ventilator-patient cassette in 22 min at the same FGF. The times to reach 10 ppm concentration of halothane and isoflurane in the KION at 10 l/min FGF, 23 to 25 min, was four-fold greater than those in the Ohmeda Excel 210, 6 min. CONCLUSIONS: To prepare the KION anesthetic machine for MHS patients, the machine without the carbon dioxide absorber must be flushed with 10 l/min FGF for at least 25 min to achieve 10 ppm anesthetic concentration. This FGF should be maintained throughout the anesthetic to avoid increases in anesthetic concentration in the FGF.

Anesthesiology↗

PubMed2002

Effects of volatile anesthetics on glutamate transporter, excitatory amino acid transporter type 3: the role of protein kinase C.

BACKGROUND: Glutamate transporters play an important role in maintaining extracellular glutamate homeostasis. The authors studied the effects of volatile anesthetics on one type of glutamate transporters, excitatory amino acid transporter type 3 (EAAT3), and the role of protein kinase C in mediating these effects. METHODS: Excitatory amino acid transporter type 3 was expressed in Xenopus oocytes by injection of EAAT3 mRNA. Using two-electrode voltage clamp, membrane currents were recorded before, during, and after application of L-glutamate. Responses were quantified by integrating the current trace and are reported as microcoulombs. Data are mean +/- SEM. RESULTS: L-Glutamate-induced responses were increased gradually with the increased concentrations of isoflurane, a volatile anesthetic. At 0.52 and 0.70 mm isoflurane, the inward current was significantly increased compared with control. Isoflurane (0.70 mm) significantly increased Vmax (maximum velocity) (3.6 +/- 0.4 to 5.1 +/- 0.4 microC; P < 0.05) but not Km (Michoelis-Menten Constant) (55.4 +/- 17.0 vs. 61.7 +/- 13.6 microm; P > 0.05) of EAAT3 for glutamate compared with control. Treatment of the oocytes with phorbol-12-myrisate-13-acetate, a protein kinase C activator, caused a significant increase in transporter current (1.7 +/- 0.2 to 2.5 +/- 0.2 microC; P < 0.05). Responses in the presence of the combination of phorbol-12-myrisate-13-acetate and volatile anesthetics (isoflurane, halothane, or sevoflurane) were not greater than those when volatile anesthetic was present alone. Oocytes pretreated with any of the three protein kinase C inhibitors alone (chelerythrine, staurosporine, or calphostin C) did not affect basal transporter current. Although chelerythrine did not change the anesthetic effects on the activity of EAAT3, staurosporine or calphostin C abolished the anesthetic-induced increase of EAAT3 activity. CONCLUSIONS: These data suggest that volatile anesthetics enhance EAAT3 activity and that protein kinase C is involved in mediating these anesthetic effects.

Amino Acid Transport System X-AG↗

PubMed2006

Store-operated Ca2+ influx in airway smooth muscle: Interactions between volatile anesthetic and cyclic nucleotide effects.

BACKGROUND: Volatile anesthetics produce bronchodilation in part by depleting sarcoplasmic reticulum Ca stores in airway smooth muscle (ASM). Other bronchodilatory drugs are known to act via cyclic nucleotides (cyclic adenosine 3',5'-cyclic monophosphate, cyclic guanosine 3',5'-cyclic monophosphate). Intracellular Ca regulation in ASM involves plasma membrane Ca influx, including that triggered by sarcoplasmic reticulum Ca depletion (store-operated Ca entry [SOCE]). The authors hypothesized that anesthetics and bronchodilatory agents interact in inhibiting SOCE, thus enhancing ASM relaxation. METHODS: In enzymatically dissociated porcine ASM cells imaged using fluorescence microscopy, sarcoplasmic reticulum Ca was depleted by 1 microm cyclopiazonic acid in 0 extracellular Ca, nifedipine, and potassium chloride (preventing Ca influx through L-type channels and SOCE). Extracellular Ca was rapidly reintroduced to selectively activate SOCE in the presence or absence of 1 minimum alveolar concentration (MAC) halothane, isoflurane, or sevoflurane. Anesthetic interference with SOCE regulation by cyclic nucleotides was examined by activating SOCE in the presence of (1) 1 microm acetylcholine, (2) 100 microm dibutryl cyclic adenosine 3',5'-cyclic monophosphate, or (3) 100 microm 8-bromo-cyclic guanosine 3',5'-cyclic monophosphate. RESULTS: SOCE was enhanced by acetylcholine, whereas volatile anesthetics and both cyclic nucleotides partially inhibited Ca influx. Preexposure to 1 or 2 MAC anesthetic (halothane > isoflurane > sevoflurane) inhibited SOCE. Only halothane and isoflurane inhibited acetylcholine-induced augmentation of Ca influx, and significantly potentiated cyclic nucleotide inhibition such that no influx was observed in the presence of anesthetics and cyclic nucleotides. CONCLUSIONS: These data indicate that volatile anesthetics prevent sarcoplasmic reticulum refilling by inhibiting SOCE and enhancing cyclic nucleotide blunting of Ca influx in ASM. Such interactions likely result in substantial airway relaxation in the presence of both anesthetics and bronchodilatory agents such as beta agonists or nitric oxide.

Acetylcholine↗

PubMed1998

Effect of topical anesthetic use on initial patient satisfaction and overall success with rigid gas permeable contact lenses.

BACKGROUND: Rigid gas permeable (RGP) contact lenses have numerous benefits; however, RGP lens use is not increasing in the United States. An important factor for this trend has been initial comfort. Studies have demonstrated that how RGPs are presented to patients, in addition to lens design, can play an important role in the initial comfort process. Another important factor could be the use of a topical anesthetic during the fitting and dispensing visits. The purpose of this study was to use a multicenter format to determine if topical anesthetic use increased the likelihood of patient satisfaction and success. METHODS: A total of 80 subjects, with no previous rigid lens wear experience, was entered into this 1-month study, including 20 subjects from each of 4 institutions. Subjects were randomly divided into the following two groups: (A) anesthetic or (B) placebo, with the former group receiving one drop of a topical anesthetic before lens insertion at both the diagnostic fitting and dispensing visits, whereas the latter group received a placebo. Subjects completed a questionnaire on their perception of rigid lens wear both immediately before fitting and at the 1-month visit. After diagnostic fitting with rigid lenses, subjects completed an adaptation questionnaire after 15 min, 1 week, 2 weeks, and 1 month of lens wear. RESULTS: Seventy of the 80 subjects completed the study and, of the 10 subjects who discontinued, 8 were in the placebo group. In all categories evaluated, the anesthetic group experienced a more optimum adaptation experience at each visit vs. the placebo group. Specifically, overall comfort was rated significantly higher at both dispensing and 2 weeks. In addition, the anesthetic group exhibited significantly greater overall satisfaction with rigid lens wear at 2 and 4 weeks. Also, the anesthetic group perceived their adaptation, sensitivity, and adaptation time to be significantly better at the 1-month visit. There was no significant difference in corneal staining between these two groups at each visit, with the exception of a greater amount of staining in the central quadrant for the placebo group at the 1-month visit. CONCLUSIONS: The use of a topical anesthetic at the fitting and dispensing visits for first-time wearers of RGP lenses resulted in significantly fewer dropouts, improved initial comfort, an enhanced perception of the adaptation process, and greater overall satisfaction after 1 month of lens wear as compared to the use of a nonanesthetizing placebo at those visits. This result, in combination with both presenting RGP lenses in a nonthreatening manner and optimizing the lens design and fitting relationship, should result in a positive adaptation process and successful wear of RGP contact lenses.

Adaptation, Physiological↗

PubMed1979

Fast kinetic studies on the allosteric interactions between acetylcholine receptor and local anesthetic binding sites.

Preincubation of receptor-rich membrane fragments from Torpedo marmorata with tertiary amine local anesthetics and several toxins such as histrionicotoxin, crotoxin and cerulotoxin, modifies the amplitude and time course of the relaxation processes monitored upon rapid mixing of the membrane fragments with the fluorescent agonist, Dns-C6-Cho. In particular, the amplitude of the rapid relaxation process, which is proportional to the fraction of acetylcholine receptor sites in a high-affinity state, increases; accordingly, the rate constant of the 'slow' and 'intermediate' relaxation processes also increases up to ten times (except with histrionicotoxin) whereas in a higher range of local anesthetic concentrations the rate constant of the 'rapid' relaxation process decreases. The data are accounted for by a two-state model of the acetylcholine regulator, assuming distinct binding sites for cholinergic agonists and local anesthetics and allosteric interactions between these two classes of sites; local anesthetics stabilize the regulator in a high-affinity state for agonists even in the absence of agonist, and modify the rate constants for th interconversions between the low-affinity and high-affinity states. The model accounts for the 'slow' fluorescence increase monitored upon addition of local anesthetics to a suspension of receptor-rich membranes supplemented with trace amounts of Dns-C6-Cho. The effect of local anesthetics on the apparent rate constant of the 'rapid' relaxation process can be accounted for on the basis of an additional low-affinity binding of local anesthetics to the acetylcholine receptor site. Finally the increase of the apparent rate constant of the 'intermediate' relaxation process can be simply accounted for by assuming the existence of a third state, corresponding to the 'active' state, to which local anesthetics bind and block ionic transport.

Amphibian Venoms↗

PubMed2004

The local anesthetic activity of Aconitum alkaloids can be explained by their structural properties: a QSAR analysis.

Alkaloids isolated from Aconitum roots exhibit anesthetic effects at peripheral nerves. We performed the present quantitative structure-activity relationship (QSAR) analysis in order to understand the mechanism of action as local anesthetics of 11 Aconitum alkaloids. The alkaloids with the highest anesthetic activity had an aroyl/aroyloxy group at R14 position while the weaker anesthetic alkaloids had the aroyloxy group at R4. The stable compounds exhibited a higher local anesthetic activity than the unstable compounds. In relation to the reactivity indexes of atoms on the aromatic ring, C2' was more reactive while C3' and C5' were less reactive in the compounds with the highest anesthetic activity. Reactivity of N, C1', C4' and C6' was similar between the two groups of alkaloids. The pKa was approximately 7.3 in both groups. The local anesthetic ED50 of alkaloids was significantly inversely related to molecular weight, core-core repulsion energy, steric energy and RI-C2', and directly related to electronic energy, total energy, RI-C5' and to the heat of formation. In conclusion, we identified a set of structural parameters that are related to the local anesthetic activity of Aconitum alkaloids. Our findings are useful to understand the mechanism of action of these alkaloids and to provide a rational for chemical manipulation of the compounds in order to obtain potent derivates with minor toxicity.

Acetic Acid↗

PubMed2005

Modulation of human 5-hydroxytryptamine type 3AB receptors by volatile anesthetics and n-alcohols.

Functional 5-hydroxytryptamine type 3 (5-HT3) receptors can be formed by 5-HT3A subunits alone or in combination with the 5-HT3B subunit, but only the 5-HT3A receptor has been previously studied with respect to the modulation by volatile anesthetics and n-alcohols. Using two-electrode voltage-clamp, we show for the first time the modulation of heteromeric human (h)5-HT3AB receptors, expressed in Xenopus oocytes, by a series of n-alcohols and halogenated volatile anesthetics. At twice their anesthetic concentration, compounds having a molecular volume of less than 110 A3 enhanced submaximal 5-HT-evoked current. Compounds larger than 110 A3 inhibited submaximal 5-HT-evoked current. In experiments examining 5-HT concentration-response relationships, chloroform and butanol caused a slight decrease in the 5-HT EC50. Sevoflurane and octanol inhibited 5-HT-evoked current at all 5-HT concentrations tested but had no effect upon the 5-HT EC50. Compared with previous data on homomeric h5-HT3A receptors, the presence of the h5-HT3B subunit reduces the enhancement of h5-HT3 receptors by smaller halogenated volatile anesthetics and n-alcohols. In summary, these results suggest that heteromeric h5-HT3AB receptors are modulated by halogenated volatile anesthetics at clinically relevant concentrations, in addition to n-alcohols, suggesting that these receptors may be another physiological target for these compounds. The modulation is dependent upon the molecular volume of the compound, further supporting the concept of an anesthetic binding pocket of limited volume common on other Cys-loop ligand-gated ion channels. Incorporation of the 5-HT3B subunit alters either the anesthetic binding site or the allosteric interactions between anesthetic binding and channel opening.

Alcohols↗

PubMed2005

Volatile anesthetic effects on glutamate versus GABA release from isolated rat cortical nerve terminals: basal release.

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 (0.5-2x 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(2+), whereas intracellular Ca(2+) 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.

Algorithms↗

PubMed2003

Local anesthetics worsen renal function after ischemia-reperfusion injury in rats.

Local anesthetics are widely used during the perioperative period, even in patients with preexisting renal disease. However, local anesthetics have been shown to cause cell death in multiple cell lines, including human kidney proximal tubule cells. We questioned whether local anesthetics potentiate renal dysfunction after ischemia-reperfusion (I/R) injury in vivo. Rats were implanted with subcutaneous miniosmotic pumps that continuously delivered lidocaine (2 mg.kg-1.h-1), bupivacaine (0.4 mg.kg-1.h-1), tetracaine (1 mg.kg-1.h-1), or saline vehicle, and 6 h later the rats were subjected to 30 min of renal ischemia or to sham operation. Renal function was assessed by measurement of plasma creatinine at 24 and 48 h after renal I/R injury in the presence or absence of chronic infusions of local anesthetics and correlated to histological changes indicative of necrosis. The degree of renal apoptosis was assessed by three methods: 1) DNA fragmentation detected by terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling staining, 2) DNA laddering detected after agarose gel electrophoresis, and 3) morphological identification of apoptotic tubules at the corticomedullary junction. We also measured the expression of the proinflammatory markers ICAM-1 and TNF-alpha. Continuous local anesthetic infusion with renal I/R injury resulted in an increased magnitude and duration of renal dysfunction compared with the saline-infused I/R group. Additionally, both apoptotic and necrotic renal cell death as well as inflammatory changes were significantly potentiated in local anesthetic-treated rat kidneys. Local anesthetic infusion alone without I/R injury had no effect on renal function. We conclude that local anesthetics potentiated renal injury after I/R by increasing necrosis, apoptosis, and inflammation.

Anesthetics, Local↗

PubMed1993

Effects of volatile anesthetics on the kinetics of inhibitory postsynaptic currents in cultured rat hippocampal neurons.

1. The effects of the volatile anesthetics enflurane, halothane, and isoflurane on gamma-aminobutyric acid (GABA) receptor-mediated inhibitory postsynaptic currents (IPSCs) were studied in cultured rat hippocampal neurons. The experimental concentrations of anesthetics were measured directly using gas chromatography. All three anesthetics increased the overall duration of IPSCs, measured as the time to half-decay (T1/2). Clinically effective concentrations of anesthetics [between 0.5 and 1.5 times MAC (minimum alveolar concentration)] produced between 100 and 400% increases in T1/2. These effects were fully reversible, and did not involve alterations in the reversal potential for the IPSC (EIPSC). 2. The decay of the IPSC was fitted as a sum of two exponential functions, yielding a fast component (tau fast = 20 ms), and a slow component (tau slow = 77 ms), such that the fast component accounted for 79% of the IPSC amplitude and 52% of the total charge transfer. All three anesthetics produced concentration-related increases in the amplitude and charge transfer of the slow component, while simultaneously decreasing the amplitude and charge transfer of the fast component. Thus T1/2 approximated tau fast under control conditions, but approximated tau slow in the presence of the anesthetics. 3. Varying the calcium chelating agents in the recording pipettes had no effect on the quality or magnitude of alterations in IPSC kinetics produced by halothane, suggesting that variations in intracellular calcium levels are not required for the effect of halothane on the time course of the IPSC. 4. The (+)-stereoisomer of isoflurane produced greater increases in the duration of the IPSC than the (-)-isomer when applied at approximately equal concentrations, suggesting that there is a structurally selective site of interaction for isoflurane that modulates the GABAA receptor. 5. These results suggest that the previously shown abilities of volatile anesthetics to potentiate responses to exogenously applied GABA and to prolong the duration of GABA-mediated synaptic inhibition may be due to an alteration in the gating kinetics of the GABAA receptor/channel complex. Prolongation of synaptic inhibition in the CNS is consistent with the physiological effects that accompany anesthesia and may contribute to the mechanism of anesthetic action.

Anesthetics↗

PubMed1986

Manipulation of rat brain fatty acid composition alters volatile anesthetic potency.

The molecular mechanism of volatile anesthetic action remains unknown. Attempts to elucidate this mechanism have been complicated by the absence of models in which changes in neuronal cellular properties can be correlated with changes in whole animal anesthetic effect. In this study we describe a model where diet-induced alterations in rat brain fatty acid composition are correlated with alterations in volatile anesthetic potency. Rats maintained on a fat-free diet showed significant depletion of arachidonic acid (20:4 omega 6; 5,8,11,14-eicosatetraenoic acid) and docosahexaenoic acid (22:6 omega 3; 4,7,10,13,16,19,-docosahexaenoic acid) in brain, and a corresponding increase in Mead acid (20: 3 omega 9; 5,8,11-eicosatrienoic acid). These fat-deprived rats were significantly more sensitive to all volatile anesthetics tested than were age-controlled rats on a normal diet. Parenteral supplementation of the fat-deprived animals with linolenic acid (18: 3 omega 3, 9,12,15-octadecatrienoic acid) completely reconstituted the docosahexaenoic acid content of brain without affecting anesthetic sensitivity. In contrast, supplementation of the fat-deprived rats with linoleic acid (18: omega 6; 9,12-octadecadienoic acid) caused a dramatic decrease in anesthetic sensitivity, but only a small change in whole brain arachidonate content. Further analysis revealed that linoleate supplementation of fat-deprived animals resulted in a preferential normalization of the arachidonate content of brain phosphatidylinositol as compared with other brain phosphoglycerides. These results demonstrate for the first time a correlation between changes in membrane composition and anesthetic effect, and indicate that the precise fatty acid composition (perhaps in specific phospholipids) of brain is important in the mechanism of volatile anesthetic action.

Anesthetics↗

PubMed1991

Breathing pattern and occlusion pressure waveform in humans anesthetized with halothane or sevoflurane.

To examine the ventilatory effects of sevoflurane, breathing pattern, airway occlusion pressure waveform, and the mechanical variables of the respiratory system were determined in seven subjects anesthetized with sevoflurane and in an additional seven subjects anesthetized with halothane. All patients breathed 1 MAC of anesthetic using oxygen as the carrier gas, and the measurements were performed in the absence of surgical stimulation. The durations of inspiration and expiration were significantly longer during sevoflurane than during halothane administration. Tidal volumes were larger in the sevoflurane group than in the halothane group. Occlusion pressure waveforms were also markedly different between the two groups. Occlusion pressure during the initial 300-400 ms tended to be less in the sevoflurane-anesthetized than in the halothane-anesthetized subjects. There was no evidence of an active Hering-Breuer reflex with either anesthetic. Mechanical variables of the respiratory system were essentially identical between the two anesthetics. We conclude that (a) the ventilatory effects of halothane and sevoflurane are different, (b) the difference in the respiratory timing and depth of breathing originates from the action of the anesthetics on the central respiratory neural network, and (c) the different shape of the tracheal occlusion pressure may be largely due to the different effects of halothane and sevoflurane on the muscles of the rib cage.

Airway Resistance↗