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PubMed2004

Gene "volatility" is most unlikely to reveal adaptation.

It has recently been claimed that adaptive molecular evolution can be detected within single genome sequences by use of gene "volatility" scores. However, the approach used was entirely based on the assumption that synonymous codon usage is normally shaped by selection for low volatility; this is most unlikely to be true. Furthermore, even if that assumption could be justified, the method would clearly lack power, detecting only genes where a very large number of nonsynonymous substitutions had occurred. Volatility scores are susceptible to other influences. The unusually high volatilities of the Mycobacterium tuberculosis and Plasmodium falciparum genes that were identified as putatively having undergone adaptive changes were largely the result of internally repetitive structures, in which unusual codon usage was caused by the mechanisms that generated this repetition rather than by adaptive changes.

Adaptation, Physiological↗
PubMed1993

Respiratory and irritant health effects of ambient volatile organic compounds. The Kanawha County Health Study.

Kanawha County, West Virginia, is one of the largest chemical manufacturing centers in the United States. In 1988, a survey of respiratory and irritant symptoms was administered to all third grade to fifth grade children attending 74 elementary schools in Kanawha County, and concentrations of 15 volatile organic compounds were measured at each school. Exposures were characterized by school location, by the sum of the concentrations of five petroleum-related compounds, and by the sum of the concentrations of 10 compounds more specific to industrial processes. Children enrolled in schools within the valley had higher rates of doctor-diagnosed asthma (odds ratio (OR) = 1.27, 95% confidence interval (CI) 1.09-1.48) and a higher score on a composite indicator of five chronic lower respiratory symptoms (OR = 1.13, 95% CI 1.02-1.26) than children who were enrolled in schools outside of the valley. The incidence of chronic respiratory symptoms was also positively associated with the concentrations of volatile organic compounds. The estimated change in the odds ratio for chronic lower respiratory symptoms associated with a 2-micrograms/m3 change in process-related compounds was 1.08 (95% CI 1.02-1.14). No consistent pattern was found between acute irritant symptoms in the 2 weeks preceding questionnaire administration and either proximity to industry or exposure to volatile organic compounds. The authors conclude that exposure to volatile organic compounds, including emissions from chemical manufacturing plants, is associated with increased rates of chronic respiratory symptoms characteristic of reactive airways.

Air Pollutants↗
PubMed2001

Volatiles, color, and lipid oxidation of broiler breast fillets irradiated before and after cooking.

Chicken breast fillets were equally divided into three groups. One group was vacuum packaged, cooked in a water bath (cooked-in-bag) at 82 C for 25 min, and then irradiated at 0 or 3 kGy with a linear accelerator (V-C-I). The other two groups were irradiated at 0 or 3.0 kGy in vacuum packaging (V-I-C) or aerobic packaging (A-I-C). After 3 d of storage at 4 C, the irradiated meats were cooked in a water bath (cooked-in-bag) at 82 C for 25 min. After being cooked, meats were repackaged under vacuum and stored at 4 C. Breast fillets were analyzed at 0 and 21 d after cooking and analyzed for lipid oxidation, color, and volatiles. Irradiation accelerated lipid oxidation of breast fillets. Three days of storage of raw meat in aerobic conditions after irradiation had only minor influences on lipid oxidation after cooking. However, irradiation had a significant effect on the volatile production in meat. Dimethyl disulfide, related to irradiation odor, was significantly higher in irradiated fillets than in nonirradiated fillets for V-C-I and V-I-C, whereas it was only slightly higher for A-I-C. Other volatiles, such as 3-methyl butanal and 2-methyl butanal, were also produced in significant amounts after irradiation, especially in V-C-I and V-I-C. These results showed that irradiating cooked meat induced slightly more changes in volatiles than irradiating raw meat and then cooking. The amount of dimethyl disulfide between irradiated and nonirradiated samples for A-I-C was not different, because the dimethyl disulfide produced by irradiation disappeared during the 3 d in aerobic storage before cooking. Color a* value of irradiated fillets was higher than that of nonirradiated fillets. Irradiation also induced color L* and b* value changes. After 3 d of aerobic storage after irradiation of raw meat, the influence of irradiation on color after cooking was reduced. No significant lipid oxidation occurred during storage as shown by the low values for TBA-reactive substances.

Aldehydes↗
PubMed2003

Double-packaging is effective in reducing lipid oxidation and off-odor volatiles of irradiated raw turkey meat.

The effects of double packaging on lipid oxidation, color, and volatile production were determined to establish a modified packaging method to improve quality changes in irradiated raw turkey meat. Sliced raw turkey breast and thigh meats were aerobically, vacuum- or double (vacuum and aerobic)-packaged, electron beam irradiated at 2.5 kGy, and then stored under refrigerated temperature. For the double-packaged samples, the outer vacuum bags were removed after 5, 7, or 9 d of refrigerated storage. 2-Thiobarbituric acid-reactive substances (TBARS) values, volatile compounds, and color values of the samples were determined after 10 d of storage. Irradiation and aerobic packaging promoted production of aldehydes (propanal and hexanal) related to lipid oxidation in turkey breast and thigh meats. Vacuum-packaged irradiated samples retained S-volatile compounds (methanethiol, dimethyl sulfide, dimethyl disulfide, and dimethyl trisulfide), mainly responsible for the irradiation off-odor, during storage. Exposure of double-packaged irradiated turkey meats to aerobic conditions by removing outer vacuum bags a few days before the test was effective in controlling both lipid oxidation-dependent (aldehydes) and radiolytic off-odor (S-compounds) volatiles. The a* values of raw turkey breast and thigh meats increased by irradiation regardless of packaging conditions. The a* value of double-packaged meats was lower than that of the vacuum-packaged meats but was not significant. Thus, the use of double-packaging alone was not enough to reduce the pink color of irradiated raw turkey meat. When lipid oxidation and irradiation off-odor should be minimized without any additional additives, however, double packaging is an excellent method to be used for turkey meats.

Animals↗
PubMed1992

Volatile anesthetics gate a chloride current in postnatal rat hippocampal neurons.

A volatile anesthetic-gated current was characterized in patch-clamped cultured postnatal rat hippocampal neurons. In this preparation, the major volatile anesthetics, isoflurane, halothane, and enflurane, open an anion-selective conductance. This volatile anesthetic-gated current exhibits anion selectivity with a chloride-to-acetate permeability ratio of 15, shows outward rectification well described by the constant field equation, and is activated in a dose-dependent fashion with half-maximal response to isoflurane at 0.8 mM (0.032 atm). The current persists in the absence of external Ca2+ and is not blocked by strychnine, a glycine antagonist. However, the gamma-aminobutyric acidA (GABAA) antagonists, bicuculline and picrotoxinin, and the nonspecific anion channel blocker, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), completely block the response. These observations suggest that volatile anesthetics, like several other general anesthetics such as barbiturates, steroids, and etomidate, have a GABA-mimetic effect on vertebrate central neurons in culture. It is not clear whether this GABAA-gating property is a prerequisite for all general anesthetics. However, under normal physiological conditions of low intracellular Cl-, it is likely that drugs with both direct GABA agonist and GABA modulatory properties will produce overall depression of the central nervous system by increasing the normal inhibitory synaptic influence and by directly hyperpolarizing neurons.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1999

Volatile anesthetic sensitivity of T-type calcium currents in various cell types.

UNLABELLED: We evaluated the effects of volatile anesthetics on T-type calcium current (ICa,T) present in four different cell types using the whole cell version of the patch clamp technique. In dorsal root ganglion neurons and in two neuroendocrine cells--adrenal glomerulosa cells (AG) and thyroid C-cells--ICa,T was reversibly decreased by volatile anesthetics at clinically relevant concentrations, with isoflurane and enflurane being more potent that halothane. In AG cells, the most sensitive cell type tested, ICa,T was reduced 47%+/-4% (n = 6) by isoflurane (0.7 mM) and 56%+/-2% (n = 5) by enflurane (1.2 mM), but by only 24%+/-1% (n = 5; P < 0.05) by halothane (0.7 mM). Isoflurane caused a significant increase in the rate of deactivation of ICa,T in AG cells. In ventricular myocytes, however, ICa,T was much less sensitive to both isoflurane and halothane. The differential sensitivity of ICa,T in various cell types to the anesthetics may reflect differences in the channels expressed in these tissues or differences in the cellular intermediates involved in anesthetic action. Depression of ICa,T in neuronal cells may contribute to anesthetic action through decreases in cellular excitability. IMPLICATIONS: Using the patch clamp technique, we showed that T-type calcium channels, which promote cellular excitability, are inhibited by volatile anesthetics in neuronal and neuroendocrine cells, but not in ventricular myocytes. Inhibition of neuronal T-type channels may contribute to the mechanism of action of volatile anesthetics.

Anesthetics, Inhalation↗
PubMed2002

Autoantibodies associated with volatile anesthetic hepatitis found in the sera of a large cohort of pediatric anesthesiologists.

UNLABELLED: Anesthetic-induced hepatitis is thought to have an immune-mediated basis, in part because many patients who develop hepatitis have serum autoantibodies that react with specific hepatic proteins. The present study shows that pediatric anesthesiologists also have these serum autoantibodies. Moreover, levels of these autoantibodies are higher than those of general anesthesiologists. We collected sera from 105 pediatric and 53 general anesthesiologists (including 3 nurse anesthetists), 20 halothane hepatitis patients, and 20 control individuals who were never exposed to inhaled anesthetics. Serum cytochrome P450 2E1 (P450 2E1) and 58-kd hepatic endoplasmic reticulum protein (ERp58) autoantibodies were measured by enzyme-linked immunosorbent assays. Positive values were 2 SD above median control values. Two multiple regression models were constructed. Pediatric anesthesiologists, like halothane hepatitis patients, had higher serum autoantibody levels of ERp58 and P450 2E1 than general anesthesiologists and controls, which was possibly because of their increased occupational exposures to anesthetics. Female anesthesiologists had higher levels of ERp58 autoantibodies than male anesthesiologists, whereas female pediatric anesthesiologists had higher levels of P450 2E1 autoantibodies than all other anesthesiologists. One female pediatric anesthesiologist had symptoms of hepatic injury. Because most anesthesiologists do not develop volatile anesthetic-induced hepatic injury, the findings suggest that pathogenic ERp58 and P450 2E1 autoantibodies may not directly cause volatile anesthetic hepatitis. Female anesthesiologists have high levels of these autoantibodies; however, the majority of these individuals do not develop hepatitis, suggesting that autoantibodies may not have a pathological role in volatile anesthetic-induced hepatitis. IMPLICATIONS: Environmental exposure of anesthesiology personnel to certain inhaled anesthetics can induce the formation of autoantibodies that have been associated with anesthetic hepatitis. Female anesthesiologists have high levels of these autoantibodies; however, the majority of these individuals do not develop hepatitis, suggesting that autoantibodies may not have a pathological role in volatile anesthetic-induced hepatitis.

Adult↗
PubMed2003

Volatile anesthetics reduce agonist affinity at nicotinic acetylcholine receptors in the brain.

UNLABELLED: In previous studies we and others have demonstrated that the activation of nicotinic acetylcholine receptors (nAChRs) is inhibited by subanesthetic concentrations of volatile anesthetics. The mechanism by which activation is inhibited is unknown. Studies of the evolutionarily related nAChRs from the electric fish Torpedo have suggested that volatile anesthetics alter the affinity of the agonist for the receptor. We studied the effect of two volatile anesthetics, isoflurane and sevoflurane, on equilibrium binding of the high-affinity nicotinic agonist epibatidine to nicotinic receptors from mouse brain. We studied binding to male and female brain separately, because sex differences in nicotine responses have been reported. Male and female brains have equal epibatidine binding without anesthetic. Isoflurane and sevoflurane reduce the binding of [(3)H]epibatidine to male and female nicotinic receptors, but only at concentrations at and above those required for anesthesia. The 50% inhibitory concentration for isoflurane inhibition of [(3)H]epibatidine binding to male brain was 0.58 +/- 0.07 mM and to female brain was 1.62 +/- 0.30 mM. The 50% inhibitory concentration for sevoflurane inhibition of [(3)H]epibatidine binding to male brain was 0.77 +/- 0.05 mM and to female brain was 0.77 +/- 0.04 mM. There was no statistically significant difference in the effect of either drug between sexes (P > 0.05). Although there is a slight decrease in agonist affinity at anesthetic concentrations, the marked reductions in nAChR function at subanesthetic concentrations cannot be attributed to changes in agonist affinity. IMPLICATIONS: Volatile anesthetics reduce the activation of nicotinic acetylcholine receptors by an unknown mechanism. We have demonstrated that although isoflurane and sevoflurane inhibit agonist affinity, the concentrations required are too large to be responsible for the dynamic changes observed.

Acetylcholine↗
PubMed1991

Effects of volatile anesthetics on cytoplasmic Ca2+ signaling and transmitter release in a neural cell line.

To provide new insights into the effects of volatile agents on the basic regulatory events involved in cytoplasmic free Ca2+ ([Ca2+]i) and stimulus-secretion coupling, the well-characterized clonal rat pheochromocytoma cell line PC12 was chosen as an experimental model. This cell line possesses nicotinic and muscarinic receptors, L-type voltage-operated channels (VOCs), and receptor-operated Ca2+ channels (ROCs). A PC12 variant, defective in nicotinic response, made it possible to study the influx-independent inositol trisphosphate-mediated intracellular Ca2+ release that is triggered by muscarinic receptor stimulation. [Ca2+]i was measured with the fluorescent Ca2+ indicator fura-2. Dopamine and norepinephrine secretion were determined by high-performance liquid chromatography. High K+ and nicotinic-receptor-induced [Ca2+]i increase and catecholamine secretion were inhibited by halothane, enflurane, isoflurane, and methoxyflurane in a dose-dependent manner; half-maximal inhibition (IC50) occurred within the clinically relevant concentration range. The inhibition was reversible after wash-out of anesthetic; was not restricted to dihydropyridine-sensitive L-type VOCs; and could not be overcome by increasing extracellular Ca2+. The inhibitory mechanisms of volatile anesthetics therefore differed from those of classical organic Ca2(+)-channel blockers, a difference also reflected by the differing Hill coefficients found for both substance groups. In contrast, the muscarinic-receptor-evoked internal Ca2+ release remained unimpaired, and secretion even increased under anesthetic exposure. In conclusion, the current study provides evidence that volatile anesthetics depress the Ca2+ influx through at least two independent Ca2+ channels, one of which proved insensitive to the dihydropyridine Ca2(+)-channel blocker nifedipine. This is particularly noteworthy, since dihydropyridine-insensitive N-type VOCs, so far found exclusively in neurons, are assumed to play a dominant role in synaptic transmission, which, although resistant to dihydropyridine inhibition, is effectively blocked by volatile anesthetics.

Anesthetics↗
PubMed1993

Inhibition of plasma membrane Ca(2+)-ATPase activity by volatile anesthetics.

BACKGROUND: The precise sites and mechanisms of action of volatile anesthetics remain unknown. Recently, several integral membrane proteins have been suggested as potential targets to which anesthetics can bind at hydrophobic regions. Impairment of cell Ca2+ homeostasis has been postulated as one of the possible mechanisms of anesthetic action. To test these hypotheses, the authors selected the human erythrocyte Ca(2+)-ATPase as a model membrane protein. This enzyme is an integral membrane protein that is instrumental in maintaining Ca2+ homeostasis in the cell in which it is the sole Ca(2+)-transporting system. Thus, any functional alteration of the Ca(2+)-ATPase by anesthetics may lead to serious perturbations in Ca(2+)-regulated processes in the cell. METHODS: The Ca(2+)-ATPase activity was measured as a function of increased concentration of four volatile anesthetics: halothane, isoflurane, enflurane, and desflurane. RESULTS: All four anesthetics significantly inhibited the Ca(2+)-ATPase activity in a dose-dependent manner. The half-maximal inhibition occurred at anesthetic concentrations from 0.3 to 0.7 vol% at 37 degrees C, which, except for desflurane, is a clinically relevant concentration range. The greater the clinical potency of the volatile anesthetics studied, the less was the concentration required to inhibit the Ca(2+)-ATPase activity. The inhibition was less at 25 degrees C than at 37 degrees C, which is consistent with direct interactions of the nonpolar interfaces of the enzyme with the nonpolar of the portions of the anesthetics. CONCLUSIONS: The authors' findings indicate that the Ca(2+)-ATPase is a suitable model for investigating the mechanism of action of volatile anesthetics on the integral membrane protein, and that this inhibition may be specific.

Administration, Inhalation↗
PubMed1994

The electrophysiologic effects of volatile anesthetics and sufentanil on the normal atrioventricular conduction system and accessory pathways in Wolff-Parkinson-White syndrome.

BACKGROUND: The effects of volatile agents and sufentanil anesthesia on the electrophysiologic properties of the accessory pathway and on the incidence of intraoperative tachyarrhythmias in patients with Wolff-Parkinson-White syndrome are unknown. Therefore, we studied these agents for their use in patients undergoing ablative procedures or requiring a general anesthetic for other surgeries. METHODS: Twenty-one patients with Wolff-Parkinson-White syndrome undergoing surgical ablation were anesthetized with sufentanil (20 micrograms/kg), lorazepam (0.06 mg/kg), and vecuronium (20 mg). After sternotomy, the electrophysiologic study during antegrade stimulation consisted of the effective refractory period of the right atrium, atrioventricular node, and accessory pathway; the shortest cycle length of the atrioventricular node and accessory pathway; and the coupling interval. During retrograde stimulation, the effective refractory period of the right ventricle and accessory pathway and the shortest cycle length of the accessory pathway were measured and compared to preoperative electrophysiologic values. Patients then were randomized to receive 1 MAC of halothane, isoflurane, or enflurane, and the electrophysiologic study was repeated. RESULTS: Sufentanil-lorazepam caused mild prolongation (P < 0.05) of the effective refractory period of the accessory pathway and the shortest cycle length of the atrioventricular node. Enflurane and isoflurane significantly prolonged all parameters related to refractoriness during antegrade conduction, with enflurane having the largest effect. During retrograde conduction, isoflurane prolonged the effective refractory period of the right ventricle and accessory pathway and the shortest cycle length of the accessory pathway, whereas enflurane prolonged only the accessory pathway effective refractory period and shortest cycle length. Halothane had the least effect on refractoriness, causing significant prolongation of the atrioventricular node effective refractory period and the shortest cycle length of the accessory pathway only during antegrade conduction. The coupling interval, a measure of the period of vulnerability to supraventricular tachycardia, was prolonged only by halothane and isoflurane. Supraventricular tachycardia was still obtainable in all patients. CONCLUSIONS: Sufentanil-lorazepam has no clinically significant effect on the electrophysiologic expression of the accessory pathway. Of the volatile agents, enflurane most, isoflurane next, and halothane least increased refractoriness within the accessory and atrioventricular pathways. Therefore, administration of these volatile agents during ablative procedures may confound interpretation of postablative studies used to determine the success of ablation treatment. Conversely, in patients with preexcitation syndrome requiring general anesthesia for nonablative procedures, volatile agents may reduce the incidence of perioperative tachyarrhythmias because of their effects on refractoriness. Enflurane would be the agent of choice because it increases refractoriness the most without prolonging the coupling interval.

Adolescent↗
PubMed1994

Effects of volatile anesthetics, thiopental, and ketamine on spontaneous and depolarization-evoked dopamine release from striatal synaptosomes in the rat.

BACKGROUND: Recent experimental data indicate that anesthesia is often associated with significant changes in brain concentrations of dopamine (DA), an inhibitory neurotransmitter located in restricted, but functionally important, areas such as the striatum. Whether the presynaptic DA nerve endings represent potential targets for anesthetics remains unknown. Therefore, the current study was designed to investigate the effects of volatile anesthetics, thiopental, and ketamine on both spontaneous and depolarization-evoked DA release from striatal synaptosomes in the rat. METHODS: Purified striatal synaptosomes preloaded with 3H-DA were superfused with artificial cerebrospinal fluid (1 ml/min). Radioactivity obtained from 1-ml fractions was measured over 15 min; first, in the absence of any treatment (spontaneous release), then in either the absence (time-dependent control) or presence (evoked-release) of anesthetic and pharmacologic agents, and finally, again, without any pharmacologic stimulation. The compounds tested were: potassium chloride (15 and 50 mM), glutamate, N-methyl-D-aspartate (NMDA) and kainate (10(-4) M and 10(-3) M), MK-801 (10(-4) M, an antagonist of NMDA receptors) and 6-cyano-7-nitro-quinoxaline-2,3-dione (10(-4) M, an antagonist of D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate [AMPA] receptors), halothane, enflurane, isoflurane (1, 1.5, and 2 minimum alveolar concentrations), ketamine (10(-5) and 10(-4) M), and thiopental (10(-5) and 10(-4) M). RESULTS: Volatile anesthetics induced a significant, concentration-related increase in spontaneous 3H-DA release, but thiopental and ketamine were ineffective. The effect of 2 minimum alveolar concentration enflurane (but not halothane or isoflurane) was significantly enhanced when a Mg(2+)-free cerebrospinal fluid was used, and was reduced by MK-801 application. Nomifensine (10(-5) M, a blocker of monoamine transporter) did not affect the 3H-DA release evoked by volatile anesthetics. Glutamate, kainate, NMDA, and potassium chloride induced a significant, dose-related, Ca(2+)-dependent 3H-DA release. Halothane and isoflurane produced a significant and concentration-related decrease in the 3H-DA peaks evoked by glutamate, kainate, and NMDA; however, enflurane significantly attenuated the glutamate- and kainate-mediated release, but enhanced that evoked by NMDA. Thiopental and ketamine (10(-4), but not 10(-5) M) significantly reduced the glutamate- and NMDA-stimulated release, but only thiopental decreased the kainate-induced effect. Furthermore, the effect of potassium chloride (15 mM) was significantly reduced by all anesthetics examined, whereas that of potassium chloride (50 mM) was unaffected. CONCLUSION: The authors conclude that: (1) volatile anesthetics, thiopental, and ketamine exert significant changes in both spontaneous and depolarization-evoked 3H-DA release in the rat striatum; (2) enflurane uniquely enhances NMDA-receptor mediated dopamine release; and (3) the results obtained from these receptor-mediated effects (AMPA and NMDA) may apply to postsynaptic, as well as presynaptic, glutamate receptors.

Anesthesia, Inhalation↗
PubMed1994

Thermogenesis in brown adipocytes is inhibited by volatile anesthetic agents. A factor contributing to hypothermia in infants?

BACKGROUND: In infants, nonshivering thermogenesis from brown adipose tissue provides an important source of heat for thermoregulation. Infants are known to have a high susceptibility to hypothermia during anesthesia. To investigate whether this could be due to an inhibition of nonshivering thermogenesis by anesthetics, the effect of preincubation with volatile anesthetics on the norepinephrine-induced heat production of brown adipocytes was investigated. METHODS: Brown adipocytes from hamsters were isolated with a collagenase digestion method and preincubated with volatile anesthetics. The cells were stimulated with norepinephrine, and heat production, measured as oxygen consumption, was monitored polarographically. RESULTS: Norepinephrine addition led to a 20-fold increase in the rate of oxygen consumption (thermogenesis). However, preincubation of cells with 3% halothane reduced the response to norepinephrine by more than 70%. The potency of norepinephrine (the median effective concentration) was not affected by halothane. Full effect of halothane was reached quickly, and after halothane withdrawal, the thermogenic response recovered, although rather slowly. Halothane, isoflurane, and enflurane were approximately equipotent inhibitors of thermogenesis, with concentrations of approximately 0.7% resulting in 50% inhibition. The inhibitory effect of 1% halothane was unaffected by the presence of 74% nitrous oxide, but nitrous oxide alone also reduced thermogenesis. CONCLUSIONS: Volatile anesthetics severely attenuated the thermogenic response to norepinephrine of isolated brown-fat cells. It is inferred that brown-adipose-tissue heat production is reduced during (and probably also some time after) anesthesia. Because infants are dependent on brown-fat-derived nonshivering thermogenesis for thermal balance, the inhibition by volatile anesthetic agents of brown-adipocyte heat production may at least partly explain the susceptibility of infants to hypothermia during and after anesthesia.

Adipocytes↗
PubMed1996

Volatile anesthetics selectively inhibit the Ca(2+)-transporting ATPase in neuronal and erythrocyte plasma membranes.

BACKGROUND: The activity of the plasma membrane Ca(2+)-transporting adenosine triphosphatase (PMCA) is inhibited by volatile anesthetics at clinical concentrations. The goal of the current study was to determine whether the inhibition is selective as compared to other adenosine triphosphatases (ATPases) and another group of general anesthetics, barbiturates. In addition, the authors determined whether the response to anesthetics of the enzymes in neuronal membranes is similar to that in erythrocyte membranes. METHODS: The effects of halothane, isoflurane, and sodium pentobarbital on four different ATPase activities were studied at 37 degrees C in two distinct plasma membrane preparations, human red blood cells and synaptosomal membranes from rat cerebellum. RESULTS: Inhibition patterns of the PMCA by halothane and isoflurane at anesthetic concentrations were vary similar in red blood cells and synaptosomal membranes. The half-maximal inhibition (I50) occurred at 0.25-0.30 mM halothane and 0.30-0.32 mM isoflurane. The PMCA in both membranes was significantly more sensitive to the inhibitory action of volatile anesthetics (I50 = 0.75-1.15 minimum alveolar concentration) than were other ATPases, such as the Na+,K+-ATPase (I50 approximately 3 minimum alveolar concentration) or Mg(2+)-ATPase (I50 > or = 5 minimum alveolar concentration). In contrast, sodium pentobarbital inhibited the PMCA in both membranes only at approximately 100-200-fold above its anesthetic concentrations. The other ATPases were inhibited at similar pentobarbital concentrations (I50 = 11-22 mM). CONCLUSIONS: The findings demonstrate analogous response of the PMCA of neuronal and erythrocyte cells to two groups of general anesthetics. The PMCA activity is selectively inhibited by volatile anesthetics at their clinical concentrations. The enzyme in vivo may then be a pharmacologic target for volatile anesthetics but not for barbiturates.

Anesthetics, Inhalation↗
PubMed1996

Volatile general anesthetics produce hyperpolarization of Aplysia neurons by activation of a discrete population of baseline potassium channels.

BACKGROUND: The mechanism by which volatile anesthetics act on neuronal tissue to produce reversible depression is unknown. Previous studies have identified a potassium current in invertebrate neurons that is activated by volatile anesthetics. The molecular components generating this current are characterized here in greater detail. METHODS: The cellular and biophysical effects of halothane and isoflurane on neurons of Aplysia californica were studied. Isolated abdominal ganglia were perfused with anesthetic-containing solutions while membrane voltage changes were recorded. These effects were also studied at the single-channel level by patch clamping cultured neurons from the abdominal and pleural ganglia. RESULTS: Clinically relevant concentrations of halothane and isoflurane produced a slow hyperpolarization in abdominal ganglion neurons that was sufficient to block spontaneous spike firings. Single-channel studies revealed specific activation by volatile anesthetics of a previously described potassium channel. In pleural sensory neurons, halothane and isoflurane increased the open probability of the outwardly rectifying serotonin-sensitive channel (S channel). Halothane also inhibited a smaller noninactivating channel with a linear slope conductance of approximately 40 pS. S channels were activated by halothane with a median effective concentration of approximately 500 microM (0.013 atm), which increased channel activity about four times. The mechanism of channel activation involved shortening the closed-time durations between bursts and apparent recruitment of previously silent channels. CONCLUSIONS: The results demonstrate a unique ability of halothane and isoflurane to activate a specific class of potassium channels. Because potassium channels are important regulators of neuronal excitability within the mammalian central nervous system, background channels such as the S channel may be responsible in part for mediating the action of volatile anesthetics.

Anesthetics, Inhalation↗
PubMed1996

Behavioral effects of volatile anesthetics in Caenorhabditis elegans.

BACKGROUND: The nematode Caenorhabditis elegans offers many advantages as a model organism for studying volatile anesthetic actions. It has a simple, well-understood nervous system; it allows the researcher to do forward genetics; and its genome will soon be completely sequenced. C. elegans is immobilized by volatile anesthetics only at high concentrations and with an unusually slow time course. Here other behavioral dysfunctions are considered as anesthetic endpoints in C. elegans. METHODS: The potency of halothane for disrupting eight different behaviors was determined by logistic regression of concentration and response data. Other volatile anesthetics were also tested for some behaviors. Established protocols were used for behavioral endpoints that, except for pharyngeal pumping, were set as complete disruption of the behavior. Time courses were measured for rapid behaviors. Recovery from exposure to 1 or 4 vol% halothane was determined for mating, chemotaxis, and gross movement. All experiments were performed at 20 to 22 degrees C. RESULTS: The median effective concentration values for halothane inhibition of mating (0.30 vol%-0.21 mM), chemotaxis (0.34 vol%-0.24 mM), and coordinated movement (0.32 vol% - 0.23 mM) were similar to the human minimum alveolar concentration (MAC; 0.21 mM). In contrast, halothane produced immobility with a median effective concentration of 3.65 vol% (2.6 mM). Other behaviors had intermediate sensitivities. Halothane's effects reached steady-state in 10 min for all behaviors tested except immobility, which required 2 h. Recovery was complete after exposure to 1 vol% halothane but was significantly reduced after exposure to immobilizing concentrations. CONCLUSIONS: Volatile anesthetics selectively disrupt C. elegans behavior. The potency, time course, and recovery characteristics of halothane's effects on three behaviors are similar to its anesthetic properties in vertebrates. The affected nervous system molecules may express structural motifs similar to those on vertebrate anesthetic targets.

Anesthetics, Inhalation↗
PubMed1997

Region-specific and agent-specific dilation of intracerebral microvessels by volatile anesthetics in rat brain slices.

BACKGROUND: Volatile anesthetics are potent cerebral vasodilators. Although the predominant site of cerebrovascular resistance is attributed to intracerebral arterioles, no studies have compared the actions of volatile anesthetics on intraparenchymal microvessels. The authors compared the effects of halothane and isoflurane on intracerebral arteriolar responsiveness in hippocampal and neocortical microvessels using a brain slice preparation. METHOD: After Institutional Review Board approval, hippocampal or neocortical brain slices were prepared from anesthetized Sprague-Dawley rats and placed in a perfusion-recording chamber, superfused with artificial cerebrospinal fluid. Arteriolar diameters were monitored with videomicroscopy before, during, and after halothane or isoflurane were equilibrated in the perfusate. PGF2alpha preconstricted vessels before anesthetic administration. A blinded observer using a computerized videomicrometer analyzed diameter changes. RESULTS: Baseline microvessel diameter and the degree of preconstriction were not different between groups. In the hippocampus, the volatile agents produced similar, concentration-dependent dilation (expressed as percent of preconstricted control +/- SEM) of 68 +/- 6% and 79 +/- 9% (1 MAC) and 120 +/- 3% and 109 +/- 5% (2 MAC) (P < 0.05) during halothane and isoflurane, respectively. In the cerebral cortex, isoflurane caused significantly less vasodilation than did similar MAC levels of halothane (84 +/- 9% vs. 42 +/- 5% dilation at 1 MAC; 121 +/- 4% vs. 83 +/- 5% dilation at 2 MAC halothane vs. isoflurane, respectively). CONCLUSION: Halothane and isoflurane differentially produce dose-dependent dilation of intraparenchymal cerebral microvessels. These findings suggest that local effects of the volatile anesthetics on intracerebral microvessel diameter contribute significantly to alterations in cerebrovascular resistance and support previously described heterogeneous actions on cerebral blood flow produced by these agents.

Anesthetics, Inhalation↗
PubMed1998

Nonanesthetic volatile drugs obey the Meyer-Overton correlation in two molecular protein site models.

BACKGROUND: Nonanesthetic volatile compounds fail to inhibit movement in response to noxious stimulation at concentrations predicted to induce anesthesia from their oil-water partitioning. Thus they represent tools to determine whether molecular models behave like the targets that mediate in vivo anesthetic actions. The effects of volatile anesthetics and nonanesthetics were examined in two experimental models in which anesthetics interact directly with proteins: the pore of the nicotinic acetylcholine receptor and human serum albumin. METHODS: Wild-type mouse muscle nicotinic receptors and receptors containing pore mutations (alphaS252I + betaT263I) were studied electrophysiologically in membrane patches from Xenopus oocytes. Patch currents evoked by brief pulses of acetylcholine were measured in the presence of enflurane and two nonanesthetics, 1,2-dichlorohexafluorocyclobutane and 2,3-dichlorooctafluorobutane. Nonanesthetic interactions with human serum album were assessed by quenching of intrinsic protein fluorescence. RESULTS: Both anesthetic and nonanesthetic volatile compounds inhibited wild-type and alphaS252I + betaT263I mutant nicotinic channels but displayed different selectivity for open versus resting receptor states. Median inhibitory concentrations (IC50s) in wild-type nicotinic receptors were 870+/-20 microM for enflurane, 37+/-3 microM for 1,2-dichlorohexafluorocylcobutane, and 11.3+/-5.6 microM for 2,3-dichlorooctafluorobutane. For all three drugs, ratios of wild-type IC50s to mutant IC50mut ranged from 7-10, and ratios of wild-type IC50s to predicted anesthetic median effective concentrations (EC50s) ranged from 1.8-2.3. 1,2-Dichlorohexafluorocyclobutane quenched human serum albumin with an apparent dissociation constant (Kd) of 160+/-11 microM. The ratios of dissociation constants to predicted EC50s for the nonanesthetics were within a factor of two of the dissociation constant:EC50 ratios calculated for halothane and chloroform from previous published results. CONCLUSIONS: In two models in which anesthetics bind to protein sites, both anesthetic and nonanesthetic volatile drugs cause similar steady state effects with potencies that are predicted by hydrophobicity. These protein sites do not sterically discriminate between anesthetic and nonanesthetic drugs. However, differential state-selective actions on ion channel targets may underlie the distinct in vivo effects of anesthetics and nonanesthetics.

Anesthetics, Inhalation↗