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PubMed1991

Modulation of the general anesthetic sensitivity of a protein: a transition between two forms of firefly luciferase.

The activities of most proteins are relatively insensitive to general anesthetics. A notable exception is firefly luciferase, whose sensitivity to a wide range of anesthetic agents closely parallels that of whole animals. We have now found that this sensitivity can be controlled by ATP. The enzyme is insensitive at low (microM) concentrations of ATP and very sensitive at high (mM) concentrations. The differential sensitivity varies from anesthetic to anesthetic, being greatest (about a 100-fold difference) for molecules with large apolar segments. This suggests that anesthetic sensitivity is modulated by changes in the hydrophobicity of the anesthetic-binding pocket. Parallel changes in the binding of the substrate firefly luciferin, for which anesthetics compete, indicate that anesthetics bind at the same site as the luciferin substrate. These changes in the nature of the binding pocket modify not only the sensitivity to anesthetics but also the position of the "cutoff" in the homologous series of primary alcohol anesthetics; the cutoff position can vary from octanol to pentadecanol, depending upon the concentration of ATP. Our results suggest that particularly sensitive anesthetic target sites in the central nervous system may possess anesthetic-binding pockets whose polarities are regulated by neuromodulatory agents.

Adenosine Triphosphate↗
PubMed2000

Comparisons of the anesthetic potency and intracellular concentrations of S(-) and R() bupivacaine and ropivacaine in crayfish giant axon in vitro.

UNLABELLED: Levobupivacaine and ropivacaine are both single S(-) enantiomers that have less severe cardiotoxic and convulsant effects than racemic bupivacaine. We compared the anesthetic actions of S(-) bupivacaine, R(+) bupivacaine, and ropivacaine in vitro by studying their effects on action potential amplitude and the maximal rate of rise of action potential in crayfish giant axon. To clarify the difference of intracellular anesthetic concentration, the intracellular ionized anesthetic concentration was measured. Desheathed crayfish axons were stimulated at a frequency of either 0. 1 or 5 Hz and perfused with 1 mM of each anesthetic at pH 7.0. Intracellular anesthetic concentration was measured by us- ing local anesthetic-sensitive glass microelectrodes. At 0.1-Hz stimulation, no differences were observed in their potency. At 5-Hz stimulation, the order of magnitude of the mean percentage decrease in maximal rate of rise of action potential was S(-) bupivacaine > R(+) bupivacaine > ropivacaine. Intracellular local anesthetic concentration did not differ among the three anesthetics at 0.1 Hz and 5 Hz. We conclude that, compared with ropivacaine, S(-) bupivacaine has a more potent phasic blocking effect in crayfish giant axon. The intracellular local anesthetic concentrations of S(-), R(+) bupivacaine and ropivacaine were not significantly different, regardless of differences in blocking effect and stimulation frequency. IMPLICATIONS: S(-) bupivacaine has a more potent phasic blocking effect than ropivacaine or R(+) bupivacaine in crayfish giant axons in vitro. An equivalent intracellular local anesthetic concentration for the three anesthetics was found, suggesting that the intracellular cationic local anesthetic concentration is not directly correlated with the intensity of block.

Action Potentials↗
PubMed1977

Biophysical mechanisms of anesthetic action: historical perspective and review of current concepts.

The large number and diversity of anesthetic agents were evident to investigators 80 years ago, and suggested a physicochemical theory of anesthesia. Meyer and Overton were the first to offer a quantitative relationship between a physicochemical property and potency of anesthetic agents. They also focused attention on the lipid phase as the site of anesthetic action. Ferguson realized that the concentration of an agent at its site of action bears a generally unknown relation to the concentration in the external phase. However, at equilibrium the activity of an agent is the same in every phase, motivating Ferguson to suggest that activities rather than concentrations be used as indices of dosage. The critical-volume theory resulted from modification of the Meyer-Overton theory to include the molal volume of the anesthetic. The allowance for molal volume resulted initially from an attempt further to regularize the experimental data. The concept of a critical-volume fraction of anesthetic being necessary for narcosis was discussed in most detail by Mullins. Subsequently, the concept of the effect of the anesthetic has changed from filling of free space to expansion and fluidization of the membrane. The ability of pressure to cause excitant phenomena and antagonize anesthetics is predictable from the critical-volume theory and is therefore highly significant evidence. K. W. Miller and associates are perhaps most prominent in the recent quantification and formalization of the critical-volume theory and HPNS. The existence of a separate convulsant site(s) is suggested by the demonstration of significantly different compressibilities associated with anesthesia and convulsions. Work corroborating a separate convulsant site involved measurement of the partial molal volumes of a series of related convulsant and anesthetic ethers and calculation of each compound's solubility parameter. Multiple convulsant sites may exist, and these two methods may not have accessed the same site. Understanding the anesthetic-convulsant duality will have important practical application to deepwater diving, and may well offer important insight into the neurophysiologic and electrophysiologic effects of anesthetics. The application of ESR and NMR allows investigation at the molecular level of effects of anesthetics on biological and model membranes. Magnetic resonance techniques have generally supported the concept of membrane fluidization by anesthetics. Some investigators have recently attempted to displace the focus of attention from the lipid phase. However, the evidence is clearly against the aqueous-phase theory of Pauling and S.L. Miller. The microtubule theory of Allison and Nunn has not accumulated supporting evidence comparable to the lipid theories. Contradictory evidence makes any evaluation of this theory speculative. Additionally, the interspecies and intracellular variability of microtubules raises questions of the relevance of many studies...

Anesthesia, General↗
PubMed1987

Anesthetic depression of myocardial contractility: a review of possible mechanisms.

The bulk of experimental evidence indicates that anesthetics do not produce their negative inotropic effect via an inhibitory action on mitochondrial electron transport. Anesthetics decrease energy need, rather than energy production. Anesthetics also decrease the rate of sequestration of Ca2+ by mitochondria, but, again, this appears not to be an important cause of reduced myocardial contractility. The role played by direct anesthetic depression of the myofibrils in reducing contractility is uncertain. Most experimental evidence now available suggests that significant myofibrillar depression, measured in terms of inhibition of actomyosin ATPase activity or inhibition of force production, occurs only at anesthetic concentrations which are high compared to concentrations employed clinically. This would seem to indicate that the myofibrils are not an important target for anesthetics in regard to the production of depressed myocardial contractility. However, the experimental act of removing myofibrils from their intracellular environment, or of removing the sarcolemma or making it hyperpermeable, appears to prevent some regulatory myofibrillar phosphorylation reactions from taking place. As stated by Winegrad, "certain forms of regulation of the cardiac myofibril are fragile and can be seen only when cellular constituents and structure are maintained." It is possible that this type of regulation is susceptible to inhibition by anesthetics. Methods for preserving this regulation are available, and will need to be employed before a depressant action of anesthetics on the myofibril can be definitely dismissed as a significant cause of the inhibition of cardiac contractility. A single study, of intracellular Ca2+ levels in the intact cell (where myofibrillar regulation was presumably preserved), has indicated that halothane may decrease myofilament Ca2+ sensitivity. However, for reasons stated above, this study cannot be taken as unequivocal proof of such an action. Despite the fact that the normal action potential is little affected by anesthetics, the sarcolemma appears to play a pivotal role in the production of anesthetic-induced contractile depression. Significant depression of the rate of upstroke of the slow (Ca2+-mediated) action potential by clinical concentrations of both inhalation and intravenous anesthetics has been demonstrated by several workers. This has been interpreted to mean that anesthetics inhibit the influx of Ca2+ through the slow channel, and such has been confirmed (to date, for halothane and thiamylal) by direct measurement of the slow inward Ca2+ current using a voltage clamp technique.(ABSTRACT TRUNCATED AT 400 WORDS)

Anesthetics↗
PubMed2001

Effects of volatile anesthetics on N-methyl-D-aspartate excitotoxicity in primary rat neuronal-glial cultures.

BACKGROUND: Volatile anesthetics are known to ameliorate experimental ischemic brain injury. A possible mechanism is inhibition of excitotoxic cascades induced by excessive glutamatergic stimulation. This study examined interactions between volatile anesthetics and excitotoxic stress. METHODS: Primary cortical neuronal-glial cultures were exposed to N-methyl-D-aspartate (NMDA) or glutamate and isoflurane (0.1-3.3 mM), sevoflurane (0.1-2.9 mM), halothane (0.1-2.9 mM), or 10 microM (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801). Lactate dehydrogenase release was measured 24 h later. In other cultures, effects of volatile anesthetics on Ca++ uptake and mitochondrial membrane potential were determined in the presence or absence of NMDA (0-200 microM). RESULTS: Volatile anesthetics reduced excitotoxin induced lactate dehydrogenase release by up to 52% in a dose-dependent manner. At higher concentrations, this protection was reversed. When corrected for olive oil solubility, the three anesthetics offered equivalent protection. MK-801 provided near-complete protection. Ca++ uptake was proportionally reduced with increasing concentrations of anesthetic but did not account for reversal of protection at higher anesthetic concentrations. Given equivalent NMDA-induced Ca++ loads, cells treated with volatile anesthetic had greater lactate dehydrogenase release than those left untreated. At protective concentrations, volatile anesthetics partially inhibited NMDA-induced mitochondrial membrane depolarization. At higher concentrations, volatile anesthetics alone were sufficient to induce mitochondrial depolarization. CONCLUSIONS: Volatile anesthetics offer similar protection against excitotoxicity, but this protection is substantially less than that provided by selective NMDA receptor antagonism. Peak effects of NMDA receptor antagonism were observed at volatile anesthetic concentrations substantially greater than those used clinically.

Anesthetics, Inhalation↗
PubMed1991

Role of signal transduction in anesthetic action. Alpha 2 adrenergic agonists.

The molecular mechanism for general anesthetic action is not known. The alpha 2 adrenergic agonists represent a novel class of "anesthetic-like" agent because of their selectivity for receptor binding sites and because the transmembrane signaling systems mediating their biologic responses in non-CNS systems are known. We have begun to characterize the signal transduction pathway involved in the anesthetic-like action of the alpha 2 adrenergic agonists. The alpha 2 adrenergic agonists potently decrease both central noradrenergic neurotransmission and halothane anesthetic requirements (MAC). Since MAC is only reduced by 30-40% when noradrenergic neurotransmission is totally abolished and since the reduction in MAC with the highly selective alpha 2 adrenergic agonists exceeds 90%, factors in addition to noradrenergic neurotransmission must be contributing to the anesthetic action of the alpha 2 agonists. Studies with the superselective alpha 2 agonist dexmedetomidine confirmed this, as the alpha 2 agonist could still reduce the MAC for halothane in rats depleted of their central norepinephrine stores. The profound reduction in anesthetic requirements with dexmedetomidine raised the possibility that alpha 2 adrenergic agonists may be considered an anesthetic hypnotic agent by itself. This sole anesthetic hypnotic response was established together with the confirmation that a central alpha 2 adrenoceptor mediated this action. Subsequently, data using molecular biologic techniques suggested that the alpha 2 C4 isoreceptor was the probable receptor that mediated the anesthetic response. We further explored the postreceptor effector mechanism for the signal transduction pathway for alpha 2 anesthetic action and identified the participation of two other molecular components, namely, a pertussis-toxin-sensitive G protein and a 4-aminopyridine-sensitive ion channel. Whether the signal transduction pathway for alpha 2 anesthetic action mediates the further response to other non-alpha 2 anesthetic agents needs to be defined.

Adrenergic alpha-Agonists↗
PubMed2005

Illustrations of inhaled anesthetic uptake, including intertissue diffusion to and from fat.

Although several mathematical and computer simulations of inhaled anesthetic pharmacokinetics have been devised, their complexity sometimes limits an intuitive appreciation of the interactions produced by the determinants of kinetics. In this essay, we illustrate the factors that govern inhaled anesthetic pharmacokinetics with drawings that consider delivery of anesthetic by ventilation to the lungs and dispersion of the anesthetic to tissue depots by the circulation. The illustrations incorporate the effects of both blood flow and blood solubility as determinants of the extent of dispersion. They incorporate tissue volume and solubility as determinants of the capacity of the tissue depots. Capacity to hold (take up) anesthetic is depicted by areas representing specific tissues, and the extent of anesthetic movement is depicted by the length and breadth of arrows to and from the areas depicting capacity. The illustrations incorporate increasingly important elements to kinetics, such as obesity. Obesity increases the depots available for storage of anesthetic, including anesthetic that reaches fat by intertissue diffusion. Such anesthetic returns to the circulation to delay recovery in healthy and obese patients, particularly with more soluble anesthetics. However, the increased anesthetic in fat occurs at a lower partial pressure and thus might not influence emergence materially. We hope that these illustrations will allow anesthesia practitioners to appreciate the interactions of the factors that govern inhaled anesthetic pharmacokinetics.

Adipose Tissue↗
PubMed2005

Preferable anesthetic conditions for echocardiographic determination of murine cardiac function.

Ketamine and xylazine are routinely used for measurement of hemodynamics of mice and rats by echocardiography. The anesthetic agents produce low heart rate (HR) in the animals, which may result in misleading data in the hemodynamic profiles of the small animals. The purpose of the present study was to select an appropriate anesthetic condition in the evaluation of mouse and rat cardiac function by echocardiography. Echocardiographic measurement was performed in male C57BL6 mice anesthetized with an intraperitoneal injection of 30 or 40 mg/kg pentobarbital (P30 or P40) or a combination of 60 mg/kg ketamine and 6 mg/kg xylazine (KX) and in male Wistar rats with an intraperitoneal injection of 40 or 50 mg/kg pentobarbital (P40 or P50) or a combination of 100 mg/kg ketamine and 10 mg/kg xylazine (KX). Basal HR of P30-anesthetized mice and P40-anesthetized were comparable to those in the conscious state, whereas KX-anesthetized mice and rats were 38% and 74% of those of the conscious animals, respectively. Fractional shortening (FS) and cardiac output index (COI) of the P30-anesthetized mice or the P40-anesthetized rats were greater than those of KX-anesthetized animals. Intraperitoneal injection of dobutamine at 0.3 and 1 mg/kg increased HR, FS, and COI of the P30-anesthetized mice and the P40-anesthetized rats, respectively, whereas the percent responses of these parameters in KX animals were greater than those in pentobarbital-anesthetized ones due to the lower basal values for the cardiac functional parameters. Anesthesia with P30 for the mouse and P40 for the rat rather than ketamine/xylazine may be relevant to the evaluation of cardiac function using echocardiography.

Adrenergic beta-Agonists↗
PubMed2004

[Critical incidents due to drug administration error in the operating room: an analysis of 4,291,925 anesthetics over a 4 year period].

BACKGROUND: Wrong drugs, overdose of drugs, and incorrect administration route remain unsolved problems in anesthetic practice. We determined the incidence and outcome of drug administration error in the operating room of Japanese Society of Anesthesiologists Certified Training Hospitals. METHODS: Data were obtained from annual surveys conducted by Japanese Society of Anesthesiologists between 1999 and 2002. There were 4,291,925 cases of anesthetic delivery for this analysis. RESULTS: Incidence of critical incidents due to drug administration error was 18.27/100,000 anesthetics. Cardiac arrest occurred in 2.21 patients per 100,000 anesthetics. Causes of these critical incidents were as follows: overdose or selection error involving non-anesthetic drugs, 42.1%; overdose of anesthetics, 28.7%; inadvertent high spinal anesthesia, 17.9%; local anesthetic intoxication, 6.4%; ampule or syringe swap, 4.3%; blood mismatch, 0.6%. Incidence of death following these incidents was 0.44/100,000. Causes of death were as follows: overdose or selection error involving non-anesthetic drugs, 47.4%; overdose of anesthetics, 26.3%; inadvertent high spinal anesthesia, 15.8%; local anesthetic intoxication, 5.3%. Ampule or syringe swap did not lead to any fatalities. Death following inadvertent high spinal anesthesia and local anesthetic intoxication was reported only in patients who had developed cardiac arrest. It should be noted that 88 percent of ampule or syringe swap occurred in patients with American Society of Anesthesiologists-Physical Status 1 or 2, who did not seem to require complex anesthetic management. CONCLUSIONS: We should increase awareness that drug administration is generally performed with limited objective monitoring, although "To error is human". Increased vigilance is required to avoid drug administration error in the operating room. Additional anesthesia resident education, adequate supervision, and improved organization are necessary. Bar-coding technology might be useful in preventing drug administration error.

Anesthetics↗
PubMed1995

The membrane lipid cholesterol modulates anesthetic actions on a human brain ion channel.

BACKGROUND: Molecular theories of general anesthesia often are divided into two categories: (1) Anesthetics may bind specifically to proteins, such as ionic channels, and alter their function directly, and (2) anesthetics may alter the functions of integral membrane proteins indirectly through modification of the physical properties of the membrane. Recent studies have provided evidence that anesthetics can bind to proteins and modify their function directly, bringing into question the role of the membrane in anesthetic interactions. To reexamine the role of membrane lipids in anesthetic interactions, an experimental approach was used in which the membrane lipid composition could be systematically altered and the impact on anesthetic interactions with potential targets examined. METHODS: Sodium channels from human brain cortex were incorporated into planar lipid bilayers with increasing cholesterol content. The anesthetic suppression of these channels by pentobarbital was quantitatively examined by single channel measurements under voltage-clamp conditions. RESULTS: Changes in cholesterol content had no effect on measured channel properties in the absence of anesthetic. In the presence of pentobarbital, however, cholesterol inhibited anesthetic suppression of channel ionic currents, with 1.9% (weight/weight, corresponding to 3.5 mol%) cholesterol decreasing anesthetic suppression of sodium channels by half. CONCLUSIONS: These results support a critical role for the lipid membrane in some anesthetic actions and further indicate that differences in lipid composition must be considered in the interpretation of results when comparing the anesthetic potencies of potential targets in model systems.

Cerebral Cortex↗
PubMed2003

Anesthetic management of dental procedures in mentally handicapped patients.

BACKGROUND: Providing dental care to a mentally handicapped patient is a challenge to both dentist and anesthesiologist. This study was aimed to describe the anesthetic methods which were used to facilitate dental treatments in mentally handicapped patients at a medical university hospital in Taiwan during a three-year period. METHODS: The data referring to anesthetic techniques to facilitate dental treatments during the period from Dec. 1, 1997 to Nov. 30, 2000 were retrospectively collected. In the period, there were four different anesthetic techniques in application: nasal mask technique combined with intravenous sedation, total intravenous anesthesia, laryngeal mask intubating general anesthesia and endotracheal intubating general anesthesia. Basic characteristics of patients were compared with student t-test between groups according to anesthetic technique used. Intraoperative and postoperative complications and complaints collected were analyzed by chi-square test between anesthetic techniques. P value less than 0.05 was considered statistically significant. RESULTS: The anesthetic records of 1201 mentally handicapped patients who underwent dental procedures over the three-year period were reviewed. Anesthesia was accomplished with nasal mask technique combined with intravenous sedation in 10 patients, with intravenous anesthesia in 112 patients, with endotracheal intubation anesthesia in 249 patients and with reinforced laryngeal mask anesthesia in 826 patients. Four patients were excluded from study because of changing of anesthetic method during the dental procedure. The use of nasal mask combined with intravenous sedation and intravenous anesthesia caused a higher incidence of intraoperative hypoxemia (P < 0.05) in comparison with the groups of endotracheal intubation anesthesia and reinforced laryngeal mask anesthesia. Although patients anesthetized by intravenous anesthetics had less postoperative complaints or complications but the difference was not statistically significant (P > 0.05) when group comparison was made. Patients who were anesthetized by volatile agents through endotracheal tube had the highest rate of postoperative complication although the difference was of no significance (P > 0.05) when comparison between groups was made. CONCLUSIONS: We provided four different anesthetic methods for 1197 mentally handicapped patients who underwent dental procedures in three years. All anesthetic methods had their advantages and disadvantages. Using reinforced laryngeal mask or endotracheal intubation for general anesthesia to facilitate dental procedures for such patients had greater intraoperative safety than other two methods. However, less postoperative complaints or complications were revealed with the methods of nasal mask combined with intravenous sedation and intravenous anesthesia.

Adolescent↗
PubMed1988

Depression of phase-transition temperature by anesthetics: nonzero solid membrane binding.

The anesthetic-induced depression of the main phase-transition temperature of phospholipid membranes is often analyzed according to the van't Hoff model on the freezing point depression. In this procedure, zero interaction between anesthetics and solid-gel membranes is assumed. Nevertheless, anesthetics bind to solid-gel membranes to a significant degree. It is necessary to analyze the difference in the anesthetic binding between the liquid-crystal and solid-gel membranes to probe the anesthetic action on the lipid membranes. This article describes a theory to estimate the anesthetic binding to each state at the phase-transition temperature. The equations derived here reveal the relation between the partition coefficients of anesthetics and the anesthetic effects on the transition characters: the change in the transition temperature, and the broadening of transition. The theory revealed that the width of transition temperature is determined primarily by the membrane/buffer partition coefficients of anesthetics. Our previous data on the local anesthetic action on the transition temperature of the dipalmitoylphosphatidylcholine vesicle membrane (Ueda, I., Tashiro, C. and Arakawa, K. (1977) Anesthesiology 46, 327-332) are analyzed by this method. The numerical values for the partition of local anesthetics into the liquid-crystal and solid-gel dipalmitoyl-phosphatidylcholine vesicle membranes at the phase-transition temperature are: procaine 8.0 x 10(3) and 4.7 x 10(3), lidocaine, 3.7 x 10(3) and 2.3 x 10(3), bupivacaine 4.1 x 10(4), and 2.6 x 10(4), and tetracaine 7.3 x 10(4) and 4.7 x 10(4), respectively.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2004

Preferential partitioning of uncharged local anesthetics into the surface-adsorbed film.

The surface tension and pH of aqueous solutions of three hydrochloric acid (HCl) - uncharged anesthetic (mepivacaine (MC), bupibacaine (BC) and dibucaine (DC)) mixtures were measured as a function of total molality and composition of local anesthetic in order to investigate the competitive surface-adsorption of uncharged and charged local anesthetics. The behavior of the surface tension versus total molality and pH versus total molality curves remarkably changed at the composition corresponding to an equimolar mixture. The pH measurements showed that uncharged and charged forms coexisted only at compositions more than the equimolar mixture. The partitioning quantities of respective uncharged and charged anesthetics into the surface-adsorbed film were estimated from their surface densities calculated thermodynamically. The greater quantity of uncharged anesthetics existed in the adsorbed film at the coexisting composition, that is, the uncharged anesthetics adsorbed more preferentially than charged ones. The relative ease with which uncharged anesthetics transferred into the surface-adsorbed film was proportional to the hydrophobicities and well correlated the anesthetic potencies. At compositions in the vicinity of physiological pH (ca. 7.4), the bulk solution is more abundant in charged anesthetics than uncharged ones, whereas the uncharged molecules is conversely more abundant in the surface region. The present results clearly imply that the surface-active molecule of local anesthetic in the physiological pH is the uncharged form and the partitioning is greatly dependent on the hydrophobicity among the anesthetics.

Adsorption↗
PubMed1988

The potency of fluorinated ether anesthetics correlates with their 19F spin-spin relaxation times in brain tissue.

In this study, four fluorinated ether anesthetics and one non-anesthetic fluorinated alkane were observed in rat brain and adipose tissue using 19F-NMR spectroscopy. Measurements of 19F spin-spin relaxation times (T2) of the anesthetics in brain revealed T2 values (0.5-4.5 msec) that correlated linearly with the anesthetic potency (ED50) of the drugs. The non-anesthetic was present at very low concentrations in brain and had a T2 value (18.5 msec) far longer than that of any of the anesthetics. All of the drugs were present at high concentration in peripheral adipose tissue. 19F T2 values for these drugs in adipose tissue (200-400 msec) were far larger than the values observed in brain and did not correlate with anesthetic potency. These results indicate that volatile anesthetic molecules have a specific affinity for neural tissue and that immobilization of anesthetic molecules in brain correlates with anesthetic potency. The results with adipose tissue suggest that the interaction of anesthetic with brain tissue cannot be explained by a simple partition of these drugs into lipid.

Adipose Tissue↗
PubMed1996

Direct inhibition of the actomyosin motility by local anesthetics in vitro.

Using a recently developed in vitro motility assay, we have demonstrated that local anesthetics directly inhibit myosin-based movement of single actin filaments in a reversible dose-dependent manner. This is the first reported account of the actions of local anesthetics on purified proteins at the molecular level. In this study, two tertiary amine local anesthetics, lidocaine and tetracaine, were used. The inhibitory action of the local anesthetics on actomyosin sliding movement was pH dependent; the anesthetics were more potent at higher pH values, and this reaction was accompanied by an increased proportion of the uncharged form of the anesthetics. QX-314, a permanently charged derivative of lidocaine, had no effect on actomyosin sliding movement. These results indicate that the uncharged form of local anesthetics is predominantly responsible for the inhibition of actomyosin sliding movement. The local anesthetics inhibited sliding movement but hardly interfered with the binding of actin filaments to myosin on the surface or with actomyosin ATPase activity at low ionic strength. To characterize the actomyosin interaction in the presence of anesthetics, we measured the binding and breaking force of the actomyosin complex. The binding of actin filaments to myosin on the surface was not affected by lidocaine at low ionic strength. The breaking force, measured using optical tweezers, was approximately 1.5 pN per micron of an actin filament, which was much smaller than in rigor and isometric force. The binding and breaking force greatly decreased with increasing ionic strength, indicating that the remaining interaction is ionic in nature. The result suggests that the binding and ATPase of actomyosin are governed predominantly by ionic interaction, which is hardly affected by anesthetics; whereas the force generation requires hydrophobic interaction, which plays a major part of the strong binding and is blocked by anesthetics, in addition to the ionic interaction.

Actins↗
PubMed1997

Role of adenosine in the ethanol-induced potentiation of the effects of general anesthetics in rats.

Acetate, derived from ethanol metabolism in the liver, is released into the circulation and utilized in many tissues including the brain. The subsequent metabolism of acetate results in the production of adenosine that has a number of effects in the central nervous system. The purpose of the present studies, therefore, was to investigate the contribution of metabolically generated adenosine to the ethanol-induced potentiation of the inhalational agents isoflurane and sevoflurane. Changes in the anesthetic requirement for isoflurane and sevoflurane were determined in rats using the tail-clamp procedure. Both ethanol and sodium acetate reduced anesthetic requirement for isoflurane and sevoflurane in a dose-dependent fashion. The effect of acetate on anesthetic requirement was completely blocked by the administration of the adenosine receptor blocker, 8-phenyltheophylline. The ethanol-induced reduction in anesthetic requirement, however, was only partially blocked by 8-phenyltheophylline. Direct intracerebroventricular (i.c.v.) administration of the water-soluble adenosine receptor blocker, 8-sulfophenyltheophylline, also completely blocked the effect of acetate and partially blocked the effect of ethanol. This i.c.v. administration demonstrates that the actions of ethanol and acetate on anesthetic requirement are a central nervous system effect. The i.c.v. administration of the adenosine A1 receptor subtype agonist, R-phenylisopropyl adenosine, potentiated the anesthetic effects of isoflurane and suggests that the A receptor mediates the observed potentiation of anesthetic effect. This is further supported by the concomitant administration of 5-N-ethylcarboxamido adenosine, a non-selective adenosine agonist, with the selective A1 antagonist, 8-cyclopentyltheophylline, showing A1 receptor potentiation of anesthetic requirements. The studies show that (1) acetate potentiates the anesthetic effects of the inhalational anesthetics, sevoflurane and isoflurane; (2) acetate contributes in part to the effect of ethanol on anesthetic potency through metabolically generated adenosine; (3) these effects are likely mediated via adenosine A1 receptor subtypes.

Acetic Acid↗
PubMed1998

Concentration measures of volatile anesthetics in the aqueous phase using calcium sensitive electrodes.

Volatile anesthetic concentrations have been difficult to measure, but are an important experimental parameter for in vitro studies of anesthetic actions. Calcium sensitive electrodes were investigated as a means of continuously monitoring anesthetic concentrations in artificial cerebrospinal fluids (ACSF). Anesthetic-induced Ca2+ electrode signals were compared at room (22 degrees C) and physiological (35 degrees C) temperatures. Electrophysiological measures of anesthetic effects on synaptic potentials provided a bioassay. Halothane and isoflurane produced negative changes in calcium electrode potentials which were linearly related to concentrations over a clinically useful range (0.5-1.5 MAC). Anesthetic-induced voltages persisted in nominally zero Ca2+ ACSF and even in deionized water. A good correlation (r>0.9) was found for calcium electrode measures of anesthetic concentration and synaptic response depression produced by halothane, at both 22 and 35 degrees C. These results support three conclusions: (1) calcium sensitive electrodes provide a useful measure of volatile anesthetic concentrations in aqueous solution. (2) Care must be taken when using these electrodes for Ca2+ concentration measurements, if a volatile anesthetic is also to be used, since the anesthetic could introduce an appreciable error (>50%). (3) A temperature change of 13 degrees C had surprisingly little effect on Ca2+ electrode responses or on synaptic depression produced by anesthetics.

Anesthetics, Inhalation↗
PubMed1999

Comparative study of the efficacy of four topical anesthetics.

BACKGROUND: With the emergence of new laser and dermatologic procedures, the need for more effective topical anesthesia continues to grow. There are now several topical anesthetics that are being used prior to laser and surgical procedures. OBJECTIVE: To compare the degree and duration of anesthesia produced by four commonly used topical anesthetics, we performed a prospective study investigating the efficacy of EMLA (eutectic mixture of local anesthetics), ELA-Max, 4% tetracaine gel, and betacaine-LA ointment (formerly eutectic-LA). METHODS: Equal amounts of the above topical anesthetics plus a control (eucerin cream) were applied to 10 test sites under occlusion on the volar forearms of 12 adult volunteers. After a 60-minute application time, the degree of anesthesia was assessed immediately by a Q-switched Nd:YAG laser at 1064 nm. Pain testing was also performed 30 minutes after the 60-minute application period. Volunteer responses to pain stimuli were recorded using an ordinal scale of 0 (no pain) to 4 (maximal pain). The mean scores for the time intervals were obtained. Analysis of the data was performed using analysis of variance (ANOVA), Newman-Keuls test, Friedman rank order test, and paired t-tests. RESULTS: ELA-Max, EMLA, and tetracaine were statistically superior to control after the 60-minute application period. Thirty minutes later, ELA-Max, EMLA, tetracaine, and betacaine-LA were all statistically superior to the control. Comparing individual anesthetics, ELA-Max and EMLA were the superior anesthetics at both time intervals. Although the mean pain scores for each anesthetic were lower 30 minutes after their removal, the differences did not reach statistical significance. CONCLUSION: This is the first prospective study comparing the efficacy of several new topical anesthetic agents. Using the methodology of this study, in which the anesthetics were applied under occlusion, ELA-Max and EMLA were the superior anesthetics after a 60-minute application time and 30 minutes later. In addition, there was a clinical increase in efficacy suggested with all of the anesthetics 30 minutes after their removal.

Administration, Topical↗