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PubMed1990

Volatile anesthetic effects on left ventricular relaxation in swine.

The effects of halothane (0.5, 1.0, and 1.5%; n = 10), enflurane (1.0, 2.0, and 3.0%; n = 8), and isoflurane (0.75, 1.5, and 2.25%; n = 8) on isovolumic relaxation were studied in open-chest swine. The time constant for isovolumic left ventricular pressure decline, T, was determined at each anesthetic concentration at the intrinsic heart rate and during atrial pacing to 150 beats per min. The effect of increased left ventricular afterload on T was investigated by partial occlusion of the thoracic aorta to raise the left ventricular systolic pressure to baseline in the presence of volatile anesthetics, and 20% above baseline in the absence of volatile anesthetics. Heart rate and left ventricular systolic pressure decreased substantially with all three anesthetics, whereas left ventricular end-diastolic pressure increased (by 3-4 mmHg). Relaxation time constants increased with all three anesthetics at the intrinsic heart rate; when the heart rate was controlled by pacing, T increased in the halothane and enflurane, but not in the isoflurane, experiments. T was significantly prolonged (by 30-100%) by partial aortic occlusion in the presence of anesthetic, but not in the control measurements. T did not change significantly in the isoflurane experiments when atrial pacing was employed with partial aortic occlusion. The volatile anesthetics, particularly halothane, seem to impair the relaxation process of the left ventricle; further investigation of the mechanisms of this interference, such as anesthetic effects on intracellular calcium movement and total left ventricular load, is warranted.

Animals↗
PubMed1992

The effects of volatile anesthetics on calcium regulation by malignant hyperthermia-susceptible sarcoplasmic reticulum.

To clarify the mechanism by which volatile anesthetics initiate malignant hyperthermia (MH), we examined the effect of halothane, isoflurane, and enflurane on Ca2+ uptake and release by sarcoplasmic reticulum vesicles isolated from MH-susceptible (MHS) and normal pig muscle. Clinical concentrations of these anesthetics (0.1-0.5 mM) stimulated sarcoplasmic reticulum ATP-dependent Ca2+ uptake (maximal at approximately 4 mM), whereas 10-20 times the clinical anesthetic concentration inhibited Ca2+ uptake. There was no significant difference between MHS and normal sarcoplasmic reticulum in any aspect of Ca2+ uptake. Ca2+ release from 45Ca(2+)-filled sarcoplasmic reticulum vesicles in a 10(-8) M Ca(2+)-containing medium (pH 7.0) was significantly stimulated at clinical concentrations of all three volatile anesthetics (anesthetic concentration for the 50% stimulation of Ca2+ release = 0.096-0.22 mM); however, the rate constant for Ca2+ release from MHS sarcoplasmic reticulum was in all cases significantly greater than that from normal sarcoplasmic reticulum. Furthermore, 0.5 mM halothane had no effect on Ca2+ release from normal sarcoplasmic reticulum at pH values less than 6.8, although it could still significantly stimulate Ca2+ release from MHS sarcoplasmic reticulum even at pH 6.4; similar results were obtained for isoflurane and enflurane. These studies thus demonstrate that the interaction of volatile anesthetics with the sarcoplasmic reticulum Ca(2+)-release channel is altered in MHS porcine muscle such that the channel may be activated even at a Ca2+ concentration or pH that would be expected to maintain the channel in the closed state.

Animals↗
PubMed1993

Reversal of volatile anesthetic-induced depression of myocardial contractility by extracellular calcium also enhances left ventricular diastolic function.

BACKGROUND: Volatile anesthetics depress global left ventricular function by altering intracellular calcium (Ca2+) homeostasis at several sites within the myocyte. Although extracellular Ca2+ partially reverses the negative inotropic effects of volatile anesthetics, the actions of extracellular Ca2+ on anesthetic-induced diastolic dysfunction are unexplored. This investigation examined and compared the direct effects of extracellular Ca2+ on left ventricular systolic and diastolic function in conscious and anesthetized dogs. METHODS: Experiments were conducted in the presence of pharmacologic blockade of the autonomic nervous system because autonomic nervous activity may significantly influence the hemodynamic actions of anesthetics and Ca2+ in vivo. Three groups comprised a total of 27 experiments conducted using nine dogs chronically instrumented for measurement of aortic and left ventricular pressure, left ventricular dP/dt, subendocardial segment length, and cardiac output. Myocardial contractility was evaluated using the preload recruitable stroke work relationship slope (Mw). Diastolic function was assessed using a time constant of isovolumic relaxation (tau), a regional chamber stiffness constant (Kp), and maximum segment lengthening velocity during rapid ventricular filling (dL/dtE) and atrial systole (dL/dtA). On 3 separate days, a CaCl2 infusion at 1.25, 2.5, or 5 mg.kg-1 x min-1 was administered. Hemodynamics and ventricular pressure-length loops were recorded after a 20-min equilibration at each dose in the conscious state or during halothane or isoflurane anesthesia. RESULTS: In conscious dogs, CaCl2 produced a significant (P < .05) and dose-dependent increase in contractility as evaluated by Mw. In the presence of halothane anesthesia, CaCl2 increased contractility (Mw of 26 +/- 5 mmHg to 78 +/- 10 mmHg during the high dose of CaCl2), enhanced isovolumic relaxation (tau of 57.9 +/- 4.2 ms to 41.1 +/- 1.9 ms during the high dose of CaCl2), improved rapid ventricular filling (dL/dtE of 11.8 +/- 1.4 mm/s to 20.2 +/- 1.6 mm/s during the high dose of CaCl2), and reduced regional chamber stiffness (Kp of 0.70 +/- 0.18 mm-1 to 0.38 +/- 0.04 mm-1 during the high dose of CaCl2). Similar findings were observed when CaCl2 was administered to dogs anesthetized with isoflurane. CONCLUSIONS: Although CaCl2 produced positive inotropic effects in both the conscious and anesthetized states, CaCl2 did not alter diastolic function in conscious dogs. In contrast, CaCl2 reversed halothane- and isoflurane-induced negative lusitropic actions. The results of the present investigation suggest that improvement of left ventricular performance by CaCl2 during volatile anesthesia may be related to actions in diastole as well as systole.

Anesthesia, Inhalation↗
PubMed1993

Inhibition of dopamine transport in rat brain synaptosomes by volatile anesthetics.

BACKGROUND: Volatile anesthetics may depress transmission by altering synaptic concentrations of neurotransmitter. Microdialysis studies have found an increase in brain extracellular dopamine concentration on exposure to volatile anesthetics. We investigated the possibility that synaptosomal dopamine transport is reversibly inhibited by the halothane and isoflurane. METHODS: Rat brain synaptosomes were incubated with 5 nM 3H-DA and increasing concentrations of anesthetic in Teflon-sealed microvials. Cocaine (100 microM) was used to quantify non-specific binding/uptake. Uptake was stopped by vacuum filtration and washing; label incorporation into synaptosomes was determined by liquid scintillation counting. 3H-DA release from preloaded synaptosomes also was studied in the presence of the anesthetic to allow distinction between uptake inhibition and release stimulation in the synaptosomes. RESULTS: Both halothane and isoflurane inhibited the specific 3H-DA uptake in a concentration-dependent fashion with an IC50 of 0.72 +/- 0.14 mM for halothane and 2.24 +/- 0.85 mM for isoflurane. No stereoselectivity of isoflurane's action on Dopamine (DA) uptake was observed. The inhibition produced by halothane and isoflurane was kinetically characterized as noncompetitive, but full reversal was demonstrated after removal of the anesthetic from the incubation mixture. The anesthetics did not stimulate 3H-DA release from preloaded synaptosomes. CONCLUSIONS: These results demonstrate volatile anesthetic-induced inhibition of the dopamine transporter in this preparation of synaptosomes. The calculated IC50S suggest this inhibition occurs with clinically relevant concentrations of halothane but not with isoflurane. The results are consistent with and may explain the increase in extracellular dopamine concentrations demonstrated by microdialysis.

Animals↗
PubMed1993

Factors influencing the direct actions of volatile anesthetics on airway smooth muscle.

BACKGROUND: The authors hypothesized that the ability of volatile anesthetics to relax airway smooth muscle (AWSM) depends on: 1) the agonist used to produce muscle contraction, 2) the preexisting level of contraction, and 3) the volatile anesthetic used. METHODS: To test the first hypothesis, isolated strips of canine trachealis muscle were precontracted with acetylcholine (ACh), McN-A-343 (McN, another muscarinic agonist), 5-hydroxytryptamine (5HT, a different receptor agonist), or potassium chloride (KCl, which induces contraction by cell depolarization) to 50% of maximal force, then exposed to halothane (0.2-1.6 MAC). To test the second and third hypotheses, other strips were precontracted to 25, 50, 75, and 100% of maximal force with ACh, or to 10, 30, or 50% of maximal force with KCl, and were then exposed to halothane or isoflurane (0.2-1.6 MAC). RESULTS: For AWSM contracted to 50% of maximal force, the amount of relaxation produced by halothane depended on the agonist used to elicit contraction in the following manner: 5HT = McN > ACh; the muscles contracted with KCL did not relax. For ACh-induced contractions, the absolute amount of relaxation produced by halothane did not depend on the level of precontraction. In muscles contracted with KCl, the volatile anesthetics caused significant relaxation only in muscles contracted to 10% of maximal force. Overall, halothane had a significantly greater relaxing effect as compared with isoflurane during ACh-mediated contractions; the effects of the two agents did not differ significantly during KCl-mediated contractions. CONCLUSIONS: When canine AWSM tone is increased by contractile agonists in vitro, the absolute amount of relaxation produced by halothane depends on the agonist used to elicit contraction, but not the degree of precontraction. In addition, there are small but significant differences between the effects of halothane and isoflurane on ACh-mediated contractions.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1994

Volatile anesthetic effects on sarcoplasmic reticulum Ca content and sarcolemmal Ca flux in isolated rat cardiac cell suspensions.

BACKGROUND: Cardiac cellular Ca metabolism is central to the control of the inotropic state of the heart and is altered in various ways by the volatile anesthetics halothane, enflurane and isoflurane. Specifically, differences among the agents regarding their effect on the uptake and release of Ca from the sarcoplasmic reticulum (SR) have been found, but the nature of such differences is not yet certain. At the sarcolemma, the effects of the anesthetics on the peak Ca current generally are believed to be similar among the three agents, but their impact on other aspects of sarcolemmal Ca transport is less understood. The authors sought to measure the direct action of these agents on SR Ca content and, in the same preparation, to provide a measure of Ca transfer across the sarcolemma during sustained depolarizations. METHODS: In stirred suspensions of quiescent rat cardiac cells, the effects were measured of halothane, enflurane, and isoflurane on changes in quin2Ca fluorescence produced by the addition of caffeine (10 mM) and by depolarization with increased extracellular K+. The peak of the fluorescence response to caffeine, which is due to a sudden release of Ca from the SR into the cytoplasm, was used as an index of SR Ca content. Analysis of the fluorescence increase that occurred after increasing extracellular K+ from 5 mM to 30 mM in the presence of caffeine provided a measure of net Ca influx across the sarcolemma during sustained depolarizations. RESULTS: The Ca channel blocker nitrendipine maximally inhibited 77% of the initial net Ca influx during 30 mM K+ depolarization, indicating that most of this influx involves L-type Ca channels. Of the volatile anesthetics, isoflurane (2.6 vol% or 0.57 mM) and enflurane (4.3 vol% or 1.25 mM) inhibited initial net Ca influx during K depolarization significantly more than halothane (1.7 vol% or 0.50 mM), which had no apparent effect. Isoflurane caused no transient change in cytoplasmic Ca concentration and had no effect on the SR Ca content of these quiescent cells. Enflurane (4.3 vol%) caused a significant reduction in SR Ca content. CONCLUSIONS: As previously reported, halothane depleted the SR of Ca in quiescent rat cardiac cells, and the present results indicate that enflurane had a similar effect. However, isoflurane did not produce any SR Ca depletion and thus must not significantly alter the balance between SR Ca efflux and uptake in these quiescent cells. The different effects of the three volatile anesthetics on a Ca influx largely carried by L-type Ca channels stand in contrast to the reported findings of similar inhibition of peak L-channel current among the three agents. This result may indicate a differential action (at least in the case of halothane) on peak and steady-state Ca currents.

Animals↗
PubMed1994

Volatile anesthetics inhibit dihydropyridine binding to malignant hyperthermia-susceptible and normal pig skeletal muscle membranes.

BACKGROUND: Surface membrane dihydropyridine receptor Ca2+ channels may play a role in the response of malignant hyperthermia-susceptible skeletal muscle to volatile anesthetics. METHODS: We determined the effect of halothane, enflurane, and isoflurane on the binding of the Ca2+ channel blocker PN200-110 to skeletal muscle membranes isolated from malignant hyperthermia-susceptible and normal pigs. RESULTS: In the presence of 0.4 mM halothane, the maximal [3H]PN200-110 binding to both normal and malignant hyperthermia membranes was reduced by 37-43% (P < 0.05). There was no difference in the equilibrium constant for the halothane-dependent inhibition of [3H]PN200-110 binding to these two types of membranes. There also was no significant difference among halothane, enflurane, or isoflurane in their ability to inhibit [3H]PN200-110 binding to either normal or malignant hyperthermia membranes. CONCLUSIONS: Volatile anesthetics inhibit the binding of PN200-110 to skeletal muscle membranes by decreasing the number of functionally active dihydropyridine receptor proteins. This inhibition is similar for membranes isolated from both normal and malignant hyperthermia-susceptible muscle, thus providing no evidence for a halothane-induced functional defect in this protein in malignant hyperthermia-susceptible muscle. However, the results of this study also indicate that the mechanism by which volatile anesthetics decrease surface membrane Ca2+ currents in skeletal muscle is by reducing the number of functional dihydropyridine receptor Ca2+ channels.

Anesthetics↗
PubMed1994

Mutations conferring new patterns of sensitivity to volatile anesthetics in Caenorhabditis elegans.

BACKGROUND: We previously described the use of the nematode Caenorabditis elegans as a genetic model for studying the mechanism of action of volatile anesthetics. All previous strains of C. elegans with altered responses to anesthetics have been identified by screening the response to halothane. The current study was designed to identify classes of mutations by screening for alterations in sensitivity to enflurane, isoflurane, and diethylether. METHODS: Nematodes were mutated and the resulting mutant strains were screened for immobility in low doses of enflurane, isoflurane, or diethylether. Concentrations of halothane, enflurane, isoflurane, and diethylether that anesthetized 50% of the animals were determined in all mutations. Interactions of some new mutations with previously identified mutations were determined by construction of double mutants. RESULTS: Mutations in six genes were identified and were divided into two classes. One class primarily affected sensitivity to enflurane and isoflurane; a second class affected sensitivity to all of the volatile anesthetics studied. The effects of the latter group dominated the effects of previously identified mutations. CONCLUSIONS: The interaction of these mutations indicates that multiple sites of anesthetic action exist and that there are at least three such sites. A pathway for control of sensitivity to volatile anesthetics is proposed.

Anesthetics↗
PubMed1995

Hypoxic contraction of isolated rabbit mesenteric veins. Contribution of endothelium and attenuation by volatile anesthetics.

BACKGROUND: Acute systemic hypoxia induces mesenteric venoconstriction in intact rabbits in part because of an increase in chemoreflex-mediated sympathetic efferent nerve activity. Inhaled anesthetics attenuate this reflex response. The direct effects of hypoxia on mesenteric veins are unknown. The purpose of the current study was to examine the effects of hypoxia on isolated rabbit mesenteric capacitance veins and to determine the effects of halothane, isoflurane, and enflurane on the responses to hypoxia. METHODS: Isometric tension was measured before, during, and after 10 min of hypoxia in the rings of either quiescent or norepinephrine contracted veins, with or without endothelium. Effects of various pharmacologic agents and volatile anesthetics on the responses to hypoxia were examined. RESULTS: Hypoxia augmented contractions to norepinephrine and phenylephrine only in endothelium-intact veins. The hypoxic response was inhibited by phentolamine (alpha-adrenoceptor antagonist) and abolished in the absence of extracellular Ca2+. There were no effects of propranolol (beta-adrenoceptor antagonist), ryanodine (a sarcoplasmic reticulum Ca2+ depleter), indomethacin (cyclooxygenase inhibitor), or nordihydroguaiaretic acid (lipoxygenase inhibitor). L-NAME (an inhibitor of nitric oxide synthase) enhanced basal sensitivity of veins to norepinephrine but had no effect on the response to hypoxia. Nicardipine (a blocker of voltage-gated calcium channels) depressed the hypoxic contraction by 86 +/- 5%, phosphoramidon (an inhibitor of endothelin-converting enzyme) by 82 +/- 8%, and BQ-123 (a specific endothelin-1 receptor antagonist) by 47 +/- 10%. Volatile anesthetics (1.0 MAC) inhibited responses to hypoxia in the absence as well as presence of L-NAME. CONCLUSIONS: These results suggest that in mesenteric capacitance veins of rabbits an intrinsic vascular mechanism contributes to endothelium-dependent hypoxic augmentation of contraction to alpha-adrenergic agonists that involve activation of endothelin-1, an endothelium-derived constricting factor. Inhibition of hypoxic contraction by volatile anesthetics is not mediated by endothelium relaxing factor.

Acetylcholine↗
PubMed1995

Volatile anesthetic actions on contractile proteins in membrane-permeabilized small mesenteric arteries.

BACKGROUND: Volatile anesthetics have been shown to have vasodilating or vasoconstricting actions in vitro that may contribute to their cardiovascular effects in vivo. However, the precise mechanisms of these actions in vitro have not been fully elucidated. Moreover, there are no data regarding the mechanisms of volatile anesthetic action on small resistance arteries, which play a critical role in the regulation of blood pressure and blood flow. METHODS: With the use of isometric tension recording methods, volatile anesthetic actions were studied in intact and beta-escin-membrane-permeabilized smooth muscle strips from rat small mesenteric arteries. In experiments with intact muscle, the effects of-halothane (0.25-5.0%), isoflurane (0.25-5.0%), and enflurane (0.25-5.0%) were investigated on high K(+)-induced contractions at 22 degrees C and 35 degrees C. All experiments were performed on endothelium-denuded strips in the presence of 3 microM guanethidine and 0.3 microM tetrodotoxin to minimize the influence of nerve terminal activities. In experiments with membrane-permeabilized muscle, the effects of halothane (0.5-4.0%), isoflurane (0.5-4.0%), and enflurane (0.5-4.0%) on the half-maximal and maximal Ca(2+)-activated contractions were examined at 22 degrees C in the presence of 0.3 microM ionomycin to eliminate intracellular Ca2+ stores. RESULTS: In the high K(+)-stimulated intact muscle, all three anesthetics generated transient contractions, which were followed by sustained vasorelaxation. The IC50 values for this vasorelaxing action of halothane, isoflurane, and enflurane were 0.47 vol% (0.27 mM), 0.66 vol% (0.32 mM), and 0.53 vol% (0.27 mM), respectively, at 22 degrees C and were 3.36 vol% (0.99 mM), 3.07 vol% (0.69 mM), and 3.19 vol% (0.95 mM), respectively, at 35 degrees C. Ryanodine (10 microM) eliminated the anesthetic-induced contractions but had no significant effect on the anesthetic-induced vasorelaxation in the presence of high K+. In addition, no significant differences were observed in the dose dependence of the direct vasodilating action among these anesthetics with or without ryanodine at either the low or the high temperature. However, significant differences were observed in the vasoconstricting actions among the anesthetics, and the order of potency was halothane > enflurane > isoflurane. The Ca(2+)-tension relation in the membrane-permeabilized muscle yielded a half-maximal effective Ca2+ concentration (EC50) of 2.02 microM. Halothane modestly but significantly inhibited 3 microM (approximately the EC50) and 30 microM (maximal) Ca(2+)-induced contractions. Enflurane slightly but significantly inhibited 3 microM but not 30 microM Ca2+ contractions. Isoflurane did not significantly inhibit either 3 microM or 30 microM Ca2+ contractions. CONCLUSIONS: Halothane, isoflurane, and enflurane have both vasoconstricting and vasodilating actions on isolated small splanchnic resistance arteries. The direct vasoconstricting action appears to result from Ca2+ release from the ryanodine-sensitive intracellular Ca2+ store. The vasodilating action of isoflurane in the presence of high K+ appears to be attributable mainly to a decrease in intracellular Ca2+ concentration, possibly resulting from inhibition of voltage-gated Ca2+ channels. In contrast, the vasodilating actions of halothane and enflurane in the presence of high K+ appears to involve inhibition of Ca2+ activation of contractile proteins as well as a decrease in intracellular Ca2+ concentration in smooth muscle.

Animals↗
PubMed1995

Inhibition by volatile anesthetics of endogenous glutamate release from synaptosomes by a presynaptic mechanism.

BACKGROUND: Synaptic transmission is more sensitive than axonal conduction to the effects of general anesthetics. Previous studies of the synaptic effects of general anesthetics have focused on postsynaptic sites of action. We now provide direct biochemical evidence for a presynaptic effect of volatile anesthetics on neurotransmitter release. METHODS: Rat cerebrocortical synaptosomes (isolated presynaptic nerve terminals) were used to determine the effects of general anesthetics on the release of endogenous L-glutamate, the major fast excitatory neurotransmitter. Basal and evoked (by 4-aminopyridine, veratridine, increased KCl, or ionomycin) glutamate release were measured by continuous enzyme-coupled fluorometry. RESULTS: Clinical concentrations of volatile halogenated anesthetics, but not of pentobarbital, inhibited 4-aminopyridine-evoked Ca(2+)-dependent glutamate release. Halothane also inhibited veratridine-evoked glutamate release but not basal, KCl-evoked, or ionomycin-evoked glutamate release. Halothane inhibited both the 4-aminopyridine-evoked and the KCl-evoked increase in free intrasynaptosomal [Ca2+]. CONCLUSIONS: Inhibition of glutamate release from presynaptic nerve terminals is a potential mechanism of volatile anesthetic action. Comparison of the sensitivity of glutamate release evoked by secretogogues that act at various steps in the neurotransmitter release process suggests that halothane does not affect Ca(2+)-secretion coupling or vesicle exocytosis but inhibits glutamate release at a step proximal to Ca2+ influx, perhaps by blocking presynaptic Na+ channels. Synaptosomal glutamate release evoked by 4-aminopyridine should provide a useful system for further characterization of the presynaptic effects of anesthetics.

4-Aminopyridine↗
PubMed1996

Effect of volatile anesthetics on hydrogen peroxide-induced injury in aortic and pulmonary arterial endothelial cells.

BACKGROUND: Oxidant damage to endothelial cells occurs during inflammation and reperfusion after ischemia, mediated in part by endogenously produced hydrogen peroxide (H2O2). Previous studies have established a role for increased cytosolic calcium in the mechanism of endothelial oxidant injury, and have suggested that volatile anesthetics may exacerbate oxidant injury in pulmonary endothelium. However, the effect of volatile anesthetics on oxidant injury to systemic arterial endothelial cells, and their effect on oxidant-related changes in cytosolic calcium homeostasis, have not been reported previously. METHODS: Primary cultures of human aortic and pulmonary arterial endothelial cells were studied. The rate of cell death after H2O2 exposure was determined in cell suspension by propidium iodide fluorimetry and lactate dehydrogenase release. The final extent of cell death 24 h after H2O2 exposure was determined in monolayer cultures by methyl thiazolyl tetrazolium reduction. Cytosolic calcium and cell death were determined in single cells using fura-2 and propidium iodide imaging with digitized, multiparameter, fluorescent video microscopy. RESULTS: In aortic endothelial cells, clinical concentrations of halothane (1.0%) and isoflurane (1.5%) decreased both the rate of cell death and the final extent of cell death after H2O2 exposure, with halothane being more protective. Supraclinical concentrations of halothane (2.7%) and isoflurane (4.0%) were less protective. In pulmonary arterial endothelial cells, halothane and isoflurane had essentially no effect on H2O2-mediated cell death. The protective effect of anesthetic in aortic endothelial cells was not due to an enhanced removal of H2O2 by endogenous enzymes. Hydrogen peroxide exposure caused a large increase in cytosolic calcium well before cell death, and this was moderated by anesthetic treatment. CONCLUSIONS: The effect of volatile anesthetics on oxidant injury to endothelial cells may differ between cells derived from systemic and pulmonary vascular beds. Halothane, and to a lesser extent, isoflurane, protects against oxidant injury in aortic endothelial cells. The mechanism of protection may involve modulation of the interaction of H2O2 with vital cellular constituents, and/or amelioration of the toxic increase in cytosolic calcium that follows such interaction.

Anesthetics, Inhalation↗
PubMed1996

Anesthetic and nonanesthetic halogenated volatile compounds have dissimilar activities on nicotinic acetylcholine receptor desensitization kinetics.

BACKGROUND: The Meyer-Overton rule predicts that an anesthetic's potency will correlate with its oil solubility. A group of halogenated volatile compounds that disobey this rule has been characterized. These compounds do not induce anesthesia in rats at partial pressures exceeding those predicted by the Meyer-Overton rule to be anesthetic. The observation that potentiation of GABA(A) receptor responses by anesthetic and nonanesthetic halogenated volatile compounds correlates with their abilities to induce general anesthesia suggests that this receptor is involved in the mechanism of general anesthesia. However, the GABA(A) receptor is only one member of a superfamily of structurally similar ligand-gated ion channels. This study compares the actions of both anesthetic and nonanesthetic halogenated volatile compounds on another member of this super family of receptors, the nicotinic acetylcholine receptor (nAcChoR). METHODS: The actions of both anesthetic and nonanesthetic compounds on desensitization kinetics were characterized from the time-dependent binding of the fluorescent acetylcholine analogue, Dns-C6-Cho, to the nAcChoR. RESULTS: At concentrations predicted by the Meyer-Overton rule to be equianesthetic, the anesthetics isoflurane and enflurane were significantly more effective than the nonanesthetics 1,2-dichlorohexafluorocyclobutane and 2, 3-dichlorooctafluorobutane in enhancing the fraction of receptors preexisting in the slow desensitized state and increasing the apparent rates of agonist-induced fast and slow desensitization. CONCLUSIONS: The potencies with which anesthetic and nonanesthetic compounds enhance desensitization kinetics in the nAcChoR parallel their in vivo anesthetic potencies. These results support the use of desensitization of the nAcChoR as a mechanistic model for studies of general anesthesia and suggest that an insensitivity to nonanesthetic compounds may be a feature common to members of the superfamily of ligand-gated ion channels.

Anesthetics, Inhalation↗
PubMed1996

Temperature dependence of the potency of volatile general anesthetics: implications for in vitro experiments.

BACKGROUND: When performing experiments at room temperature with volatile general anesthetics and in vitro mammalian preparations (such as isolated neurons), the question arises as to which concentrations of anesthetics are "clinically relevant." Different choices can lead to different interpretations of the anesthetic sensitivities of putative target sites. METHODS: Published data on the temperature dependence of minimum alveolar concentration were analyzed. RESULTS: Although gas-phase potencies of volatile anesthetics increase markedly with decreasing temperature, the corresponding aqueous-phase potencies are relatively constant. Changes in minimum alveolar concentration with temperature can be accounted for, on physical grounds, in terms of the temperature dependencies of anesthetics binding to their central nervous system target sites. CONCLUSION: When performing room-temperature in vitro experiments on simple mammalian preparations with a volatile anesthetic, the aqueous-phase (but not the gas- phase) minimum alveolar concentration calculated at normal body temperature is, to a first approximation, the appropriate choice for a clinically relevant anesthetic concentration. Recommended aqueous-phase minimum alveolar concentration values (in MM) for desflurane, enflurane, halothane, isoflurane, and sevoflurane have have been calculated.

Anesthetics, Inhalation↗
PubMed1996

Volatile anesthetics reduce low-voltage-activated calcium currents in a thyroid C-cell line.

BACKGROUND: Volatile anesthetics may act in part by inhibiting voltage-dependent calcium channels. The effects of several volatile agents on three types of calcium channels in a thyroid C-cell line were examined. METHODS: Whole-cell calcium currents were recorded using standard patch clamp techniques. Current-voltage relationships were derived before, during, and after application of isoflurane, enflurane, or halothane. Low-voltage-activated (LVA; T type) calcium currents were isolated based on the voltage range of activation. High-voltage-activated (HVA) calcium currents were separated into L and N types using omega-conotoxin GVIA (omega-CTX) and nicardipine. RESULTS: All three agents reversibly decreased both LVA and HVA currents at clinically relevant concentrations. Isoflurane and enflurane both reduced peak LVA current more than peak HVA current: -33 +/- 6% (mean +/- SE) versus -22 +/- 4% for 0.71 mM isoflurane (n = 6), and -46 +/- 6% versus -35 +/- 5% for 1.21 mM enflurane (n = 6). In contrast, halothane depressed LVA and HVA currents to a similar extent: -22 +/- 4% versus -29 +/- 3% for 0.65 mM halothane (n = 6). Isoflurane had no effect on LVA whole-cell current kinetics. Pretreatment with either omega-CTX (400 nM) or nicardipine (1 microM) did not change the sensitivity of HVA current to isoflurane. CONCLUSIONS: Isoflurane and enflurane block LVA calcium channels more potently than either L-type or N-type calcium channels, but halothane shows no such preferential effect. These results may have implications for the mechanism action of volatile anesthetics.

Anesthetics, Inhalation↗
PubMed1997

Volatile anesthetics protect the ischemic rabbit myocardium from infarction.

BACKGROUND: The influence of anesthetic agents on the infarction process in the ischemic myocardium is unclear. This study evaluated the effects of three intravenous and three inhalational anesthetic agents on myocardial infarction within a quantified ischemic risk zone in rabbit hearts subjected to a standardized regional ischemia-reperfusion insult. METHODS: Both in vitro and in situ rabbit models were used to investigate the effects of anesthetic agents on infarct size. In all rabbits the heart was exposed and a coronary artery surrounded with a suture to form a snare for subsequent occlusion. In in situ preparations, both intravenous and inhalational agents were tested, whereas only the latter were used in isolated hearts. Infarct size was determined by triphenyltetrazolium chloride staining. To determine whether an adenosine-mediated protective mechanism was involved, 8-(p-sulfophenyl)theophylline, an adenosine receptor blocker, was added to halothane-treated isolated hearts. Adenosine concentration in the coronary effluent was also measured in isolated hearts exposed to halothane. In other protocols, chelerythrine, a highly selective protein kinase C inhibitor, was administered to both halothane-treated and untreated isolated hearts. RESULTS: Infarcts in the three in situ groups anesthetized with halothane, enflurane, and isoflurane were about one half as large as infarcts in rabbits that underwent anesthesia with pentobarbital, ketamine-xylazine, or propofol. Volatile anesthetics also protected isolated hearts by a similar amount. Both adenosine receptor blockade and chelerythrine abolished cardioprotection from halothane in isolated hearts. Halothane treatment did not increase adenosine release. CONCLUSIONS: The volatile anesthetics tested protected the ischemic rabbit heart from infarction, in contrast to the three intravenous agents tested. Protection was independent of the hypotensive effect of the inhalational agents because halothane also protected isolated hearts, in which changing vascular tone is not an issue and coronary perfusion pressure is constant. Cardioprotection by volatile anesthetics depended on both adenosine receptors and protein kinase C, and thus is similar to the mechanism of protection seen with ischemic preconditioning.

Adenosine↗
PubMed1997

Increase of glutamate uptake in astrocytes: a possible mechanism of action of volatile anesthetics.

BACKGROUND: Glutamate is the most ubiquitous excitatory neurotransmitter in the vertebrate central nervous system. Astrocytes play an important role in terminating glutamatergic neurotransmission by removing released glutamate from the synaptic cleft. The authors examined the effects of several anesthetics on the glutamate uptake activity of astrocytes. METHODS: Cultured astrocytes from hippocampi of rat embryos were incubated with solution containing [3H]glutamate, which was pre-equilibrated with 0-4% halothane at 37 degrees C. The uptake activity was evaluated as the amount of radioactivity per cell of protein. RESULTS: When the reaction solution was equilibrated with 4% halothane, glutamate uptake increased to about 165% of the control. The effect of halothane was dose-dependent, and a significant augmentation (30-50%) of glutamate uptake was observed at a range in clinical use concentrations (1-2%). On the other hand, the uptake of gamma-aminobutyric acid, an inhibitory transmitter, was hardly affected by 1-4% halothane. The effect of halothane on glutamate uptake was also examined in neuron-rich culture, and similar augmentation was observed, although the extent was less than that in astrocyte culture. Biochemical subcellular fractions (i.e., glial plasmalemmal vesicles and synaptosomes) were also examined, however, only slight (not significant) increase was detected in the glutamate uptake activity. Other volatile anesthetics, such as enflurane, isoflurane, and sevoflurane, also enhanced glutamate uptake, whereas the intravenous anesthetics ketamine and pentobarbital showed no effect on glutamate uptake. CONCLUSIONS: The increase of glutamate uptake by astrocytes in the presence of volatile anesthetics potentially attenuates excitatory synaptic transmission in the entire central nervous system, a finding that may explain in part the action of volatile anesthetics.

Adjuvants, Anesthesia↗
PubMed1998

Effects of small concentrations of volatile anesthetics on action potential firing of neocortical neurons in vitro.

BACKGROUND: Volatile general anesthetics depress neuronal activity in the mammalian central nervous system and enhance inhibitory Cl- currents flowing across the gamma-aminobutyric acid A (GABA(A)) receptor-ion channel complex. The extent to which an increase in GABA(A)-mediated synaptic inhibition contributes to the decrease in neuronal firing must be determined, because many further effects of these agents have been reported on the molecular level. METHODS: The actions of halothane, isoflurane, and enflurane on the firing patterns of single neurons were investigated by extracellular recordings in organotypic slice cultures derived from the rat neocortex. RESULTS: Volatile anesthetics depressed spontaneous action potential firing of neocortical neurons in a concentration-dependent manner. The estimated median effective concentration (EC50) values were about one half the EC50 values for general anesthesia. In the presence of the GABA(A) antagonist bicuculline (20 microM), the effectiveness of halothane, isoflurane, and enflurane in reducing the discharge rates were diminished by 48-65%, indicating that these drugs act via the GABA(A) receptor. CONCLUSIONS: Together with recent investigations, our results provide evidence that halothane, isoflurane, and enflurane reduced spontaneous action potential firing of neocortical neurons in cultured brain slices mainly by increasing GABA(A)-mediated synaptic inhibition. At concentrations, approximately one half the EC50 for general anesthesia, volatile anesthetics increased overall GABA(A)-mediated synaptic inhibition about twofold, thus decreasing spontaneous action potential firing by half.

2-Amino-5-phosphonovalerate↗