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PubMed1983

Osmolarity determines the solubility of anesthetics in aqueous solutions at 37 degrees C.

The authors determined whether they could predict accurately the solubility of anesthetics in aqueous solutions at 37 degrees C, knowing the osmolarity and the pH of the solution and the solute composition. The partition coefficients of the four volatile anesthetics, isoflurane, enflurane, halothane, and methoxyflurane, were determined concurrently at 37 degrees C between air and aqueous solutions containing sodium chloride, dextrose, mannitol, or heparin. The osmolarities of these solutions ranged from 0 to 7,000 mOsm/l. The partition coefficients decreased linearly with increasing osmolarity when plotted on a semilogarithmic scale. The effect of osmolarity on the partition coefficient of the alkane anesthetic, halothane, was 20% less (P less than 0.001) than the effect of osmolarity on the partition coefficients of the three methyl-ethyl ether anesthetics, isoflurane, enflurane, and methoxyflurane. The solubility of anesthetics in aqueous solutions did not depend on either the molecular structure of the solute or the pH of the solution. The solubility of volatile anesthetics in aqueous solutions at 37 degrees C is inversely and predictably dependent on the osmolarity of the solutions.

Anesthetics↗

PubMed1985

Inhalation anesthetics augment oxidant-induced pulmonary vasoconstriction: evidence for a membrane effect.

Inhalational anesthetics "fluidize" biologic membranes. Since arachidonate metabolism also occurs in cell membranes, anesthetic agents may modify arachidonic acid mediator production. The authors used the isolated perfused rabbit lung preparation to examine the effects of inhalational anesthetics on the production of arachidonate mediators. The oxidant tert-butyl-hydroperoxide (t-bu-OOH) is known to cause pulmonary vasoconstriction by causing increased production of thromboxane A2 (TxA2). The authors administered three anesthetics (halothane, cyclopropane, and nitrous oxide) of widely different potencies, at different dosages, each to three different groups of preparations and challenged the lungs at each anesthetic dose with t-bu-OOH. They found a dose-related augmentation of the pulmonary vasopressor response to t-bu-OOH. Preparations given t-bu-OOH alone showed no change in response over time. Lungs perfused with indomethacin (5 micrograms . ml-1 in Krebs-Henseleit buffer), ventilated with cyclopropane (2 MAC), and challenged with t-bu-OOH showed almost complete inhibition of the response to t-bu-OOH. Indomethacin at this concentration is a specific inhibitor of cyclooxygenase. The authors also have demonstrated significantly increased perfusate levels of thromboxane B2 (TxB2), the inactive metabolite of TxA2, after oxidant challenge during exposure to 2% halothane compared with TxB2 levels before halothane exposure. The authors believe that the augmented pressor response and mediator production occur because of increased substrate (arachidonic acid) availability induced by anesthetic agent.

6-Ketoprostaglandin F1 alpha↗

PubMed1988

The effect of two genes on anesthetic response in the nematode Caenorhabditis elegans.

The authors studied the wild type strain, N2, and three mutant strains of the nematode, Caenorhabditis elegans, in order to measure genetically produced changes in responses to nine volatile anesthetics. They determined the anesthetic ED50s of N2 for thiomethoxyflurane, methoxyflurane, chloroform, halothane, enflurane, isoflurane, fluroxene, flurothyl, and diethylether. The log-log relationship of the oil-gas partition coefficients (O/G) and the ED50s of these agents for N2 yields a straight line with a slope of -.997 with a R2 of .98 over a range of O/G (at 37 degrees C) from 48 to 7230. When the O/Gs are corrected to 22 degrees C, the slope is -.964 with an R2 of .98. This relationship is similar to that found in other animals. Two mutant strains, unc-79 and unc-80, show altered responses to these anesthetics. These strains are two to three times more sensitive than N2 to anesthetics with an O/G greater than that of halothane (220 at 37 degrees C), yet they differ little from N2 in response to anesthetics with lower O/Gs. unc-79 and unc-80 are about 30% more sensitive than N2 to diethylether. The double mutant unc-79; unc-80 is more sensitive to halothane, isoflurane, and fluroxene than is either mutant alone. The authors believe these data indicate an alteration at the site of action of volatile anesthetics in unc-79 and unc-80. They also postulate that the interaction of unc-79 and unc-80 indicate these genes code for enzymes in a common pathway, and that unc-79 precedes unc-80 in this pathway.

Anesthetics↗

PubMed1992

Effect of K+ channel blockade with tetraethylammonium on anesthetic-induced relaxation in canine cerebral and coronary arteries.

The mechanism by which volatile anesthetics produce their direct effects on vascular smooth muscle remains unknown. The authors previously reported that volatile anesthetics decrease both Ca2+ and K+ currents, however the role of Ca(2+)-activated K+ channels during the vasorelaxation by anesthetics has not been investigated. The purpose of this study was to determine whether blockade of the K+ channel alters the response to volatile anesthetics. Responses were studied in canine middle cerebral arteries and proximal and distal canine coronary arteries. Vascular rings (2-mm length) were suspended in tissue baths, and isometric tension was recorded. Rings were constricted with 40 mM KCl and prostaglandin F2 alpha (middle cerebral arteries only) and subsequently exposed to enflurane (3.25%), halothane (1.35%), and isoflurane (2.1%). Volatile anesthetics produced vasorelaxation with relative potency in order: enflurane > halothane > isoflurane. The procedure was repeated in the presence of the K+ channel blocker tetraethylammonium chloride (TEA, 20 mM). In all groups of vessels TEA alone elicited either no increase or only a transient increase in tension, however constrictions to both agonists were augmented in the presence of TEA. The presence of TEA significantly augmented anesthetic-induced vasorelaxation in small and large coronary vessels and in middle cerebral arteries. However, this effect was more pronounced in the cerebral as compared to coronary arteries. Constrictions produced in cerebral vessels by 15 microM prostaglandin F2 alpha were comparable with constrictions produced by 5 microM prostaglandin F2 alpha in the presence of TEA. The subsequent relaxant response of these vessels to enflurane was also comparable in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics↗

PubMed1994

Left ventricular mechanical consequences of dihydropyridine calcium channel modulation in conscious and anesthetized chronically instrumented dogs.

BACKGROUND: Volatile anesthetics depress left ventricular contractile function by altering voltage-dependent slow calcium (Ca2+) channel activity in the sarcolemmal membrane. This investigation examined the left ventricular systolic and diastolic mechanical effects of the dihydropyridine Ca2+ channel antagonist nifedipine and agonist Bay k 8644 (Bay k) in dogs in the conscious state and during anesthesia. METHODS: Forty-eight experiments were conducted using 16 chronically instrumented dogs during autonomic nervous system blockade. Myocardial contractility was evaluated with the slope (Mw) of the regional preload recruitable stroke work relationship. 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/dtmax). On 3 separate days (24 experiments), a nifedipine infusion at 0.5, 1.0, 2.0, or 4.0 micrograms.kg-1.min-1 was administered. Hemodynamics and left ventricular pressure-segment length diagrams were recorded after a 10-min equilibration at each dose in the conscious state or during isoflurane or halothane anesthesia (0.8 MAC). In 24 parallel experiments, a Bay k infusion at 0.5, 1.0, 2.0, or 4.0 micrograms.kg-1.min-1 was administered, and hemodynamics and left ventricular function parameters were assessed after a 10-min equilibration in the conscious state or during isoflurane or halothane administration (1.2 MAC). RESULTS: In conscious dogs, nifedipine significantly (P < 0.05) decreased Mw (71 +/- 5 to 42 +/- 4 mmHg during the high dose) and increased tau (35 +/- 1 to 48 +/- 3 ms during the high dose) without changes in dL/dtmax or Kp. In anesthetized dogs, nifedipine decreased Mw and dL/dtmax) (31 +/- 4 during isoflurane to 27 +/- 3 mm/s during the high dose) and increased tau and Kp (0.43 +/- 0.05 during isoflurane to 0.53 +/- 0.04 mm-1 during the high dose). Administration of Bay k increased Mw, decreased tau, and increased dL/dtmax in conscious dogs. In contrast, no changes in tau were observed in dogs anesthetized with isoflurane or halothane during infusions of Bay k despite concomitant increases in Mw. Bay k also enhanced dL/dtmax and decreased Kp during isoflurane but not halothane anesthesia. CONCLUSIONS: Nifedipine caused direct negative inotropic actions in conscious and anesthetized dogs and worsened volatile anesthetic-induced negative lusitropic effects. Bay k improved left ventricular systolic and diastolic function in the conscious state. Bay k also improved contractility during anesthesia; however, Bay k only partially reversed volatile anesthetic-induced abnormalities in indexes of left ventricular diastolic function in dogs during autonomic nervous system blockade.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

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↗

PubMed1996

Volatile anesthetics depress spinal motor neurons.

BACKGROUND: Depression of spinal alpha-motor neurons apparently plays a role in the surgical immobility induced by isoflurane. Using the noninvasive technique of F-wave analysis, the authors tested the hypothesis that depressed motor neuron excitability is an effect common to other clinically relevant inhaled anesthetics. METHODS: The authors measured F-wave amplitude in rats anesthetized with desflurane, enflurane, halothane, or sevoflurane. Each animal received one anesthetic at five equipotent anesthetic concentrations (0.6, 0.8, 1.2, and 1.6 minimum alveolar concentration [MAC] and 0.8 MAC with 65% N2O). F waves were detected as late potentials in electromyographic responses evoked in the intrinsic muscles of the hind paw after monopolar stimulation of the ipsilateral posterior tibial nerve. RESULTS: All tested inhaled anesthetics depressed F-wave amplitude but not M-wave (orthodromic, early muscle activation) amplitude, and increased M-F latency in a dose-dependent manner. At 1.0 MAC, the estimated F/M ratio was 70 +/- 13% SD of that at baseline (0.6 MAC). Nitrous oxide added to 0.8 MAC of the potent vapors depressed F/M ratio by 63 +/- 17%. CONCLUSIONS: All anesthetics tested appeared to depress the excitability of spinal motor neurons. This effect may contribute to surgical immobility, and its magnitude is comparable at equipotent concentrations of agents. The authors hypothesize that this effect is due to hyperpolarization, although, currently, there is insufficient information to discriminate between pre- and postsynaptic mechanisms.

Anesthetics, Inhalation↗

PubMed1996

Volatile anesthetics depress glutamate transmission via presynaptic actions.

BACKGROUND: Recent evidence for a presynaptic depression of glutamate release produced by volatile anesthetics prompted the current study of isoflurane and halothane effects on glutamate-mediated transmission in the mammalian central nervous system. METHODS: Electrophysiologic recordings from CA1 neurons in rat hippocampal brain slices were used to measure anesthetic effects on glutamate-mediated excitatory postsynaptic potential (EPSP) amplitudes and paired pulse facilitation. Paired pulse facilitation is known to be altered when the calcium-dependent release of glutamate is depressed, but not when EPSP amplitudes are depressed by postsynaptic mechanisms. RESULTS: Isoflurane depressed EPSP amplitudes over a concentration range of 0.35-2.8 vol %, with a 50% depression (EC50) occurring at 1.0 vol % (0.71 rat minimum alveolar concentration). This depression was accompanied by an increase in paired-pulse facilitation of approximately 30% at 1.7 vol %, using interpulse intervals of 120 ms. Halothane depressed EPSP amplitudes in a concentration-dependent manner (0.3-2.4 vol %, EC50 = 1.1 minimum alveolar concentration; 1.3 vol %) and also increased facilitation by approximately 20% at 1.2 vol %. These effects persisted in the presence of 10 microM bicuculline, indicating that enhanced gamma-aminobutyric acid-mediated inhibition was not involved. The anesthetic-induced increase in facilitation and EPSP depression was mimicked by lowering extracellular calcium, which is known to depress glutamate release at these synapses. The postsynaptic glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione depressed EPSP amplitudes with no change in facilitation. CONCLUSIONS: Our results confirm earlier findings that clinically relevant concentrations of volatile anesthetics depress glutamate-mediated synaptic transmission. The observed increases in synaptic facilitation support recent findings from biochemical and electrophysiologic studies indicating presynaptic sites of action contribute to anesthetic-induced depression of excitatory transmission. This anesthetic-induced reduction in glutamate release would contribute to the central nervous system depression associated with anesthesia by adding to postsynaptic depressant actions on glutamate receptors.

Anesthetics, Inhalation↗

PubMed1996

Volatile anesthetics affect calcium mobilization in bovine endothelial cells.

BACKGROUND: The site where volatile anesthetics inhibit endothelium-dependent, nitric oxide-mediated vasodilation is unclear. To determine whether anesthetics could limit endothelium-dependent nitric oxide production by inhibiting receptor-mediated increases in cytosolic Ca2+, experiments were performed to see if the inhalational anesthetics halothane, isoflurane, and enflurane affect intracellular Ca2+ ([Ca2+]i) transients induced by the agonists bradykinin and adenosine triphosphate in cultured bovine aortic endothelial cells. METHODS: Bovine aortic endothelial cells, which had been loaded with the fluorescent Ca2+ indicator Fura-2, were added to medium preequilibrated with volatile anesthetic (1.25% and 2.5% for isoflurane, 1.755 and 3.5% for enflurane, and 0.75% and 1.5% for halothane). In Ca(2+)-containing medium, intracellular Ca2+ transients were elicited in response to bradykinin (10 nM and 1 microM) or adenosine triphosphate (1 microM and 100 microM). RESULTS: Both bradykinin and adenosine triphosphate triggered a rapid rise to peak [Ca2+]i followed by a gradual decline to a plateau above the resting level. Although basal [Ca2+]i was unaltered by the anesthetics, both halothane and enflurane, in a dose-dependent manner, depressed the peak and plateau of the [Ca2+]i transient elicited by 10 nM bradykinin, whereas isoflurane had no effect. When [Ca2+]i transients were elicited by 1 microM bradykinin, halothane (1% and 5%) did not alter peak and plateau levels. Halothane and enflurane also decreased [Ca2+]i transients evoked by 1 microM and 100 microM adenosine triphosphate, whereas isoflurane also had no effect in this setting. CONCLUSIONS: Halothane and enflurane, but not isoflurane, inhibit bradykinin- and adenosine triphosphate-stimulated Ca2+ transients in endothelial cells. Limitations of Ca2+ availability to activate constitutive endothelial nitric oxide synthase could allow for part, but not all, of the inhibition of endothelium-dependent nitric oxide-mediated vasodilation by inhalational anesthetics.

Adenosine Triphosphate↗

PubMed1997

Local anesthetic administration for awake direct laryngoscopy. Are glossopharyngeal nerve blocks superior?

BACKGROUND: Glossopharyngeal nerve (GPN) blocks may provide reliable analgesia for awake direct laryngoscopy, although this has not been evaluated prospectively. This study was designed to determine if GPN blocks provide a superior route of local anesthetic administration for awake direct laryngoscopy as measured by hemodynamic, gag, and subjective pain responses. METHODS: A prospective, randomized, single-blinded, crossover design was used. All participants (n = 11) were anesthesiologists. Three routes of local anesthetic administration were evaluated: 2 min of 2% viscous lidocaine swish and gargle (S&G); S&G combined with 10% lidocaine spray (S&G/spray); and S&G combined with 1% lidocaine bilateral GPN blocks (S&G/block; anterior tonsillar pillar method). Five minutes after the local anesthetic was administered, laryngoscopy was performed and sustained for 20 s. Noninvasive hemodynamic measurements and serum lidocaine concentrations were determined. Visual analogue scale scores and a poststudy questionnaire were used to assess participants' ability to tolerate local anesthetic administration and laryngoscopy and their choice for use in clinical practice. RESULTS: No significant hemodynamic changes were observed, although there was a modest increase (< 15%) in heart rate in the S&G/block group in the first minute after laryngoscopy. Serum lidocaine concentrations were higher (P < 0.05) in the S&G/block group at 5 and 10 min (0.5 +/- 0.1 and 1.0 +/- 0.2 microgram/ml) compared with the S&G group. Participants' visual analogue scale scores, which assessed their ability to tolerate laryngoscopy, showed that S&G (5.4 +/- 0.9) resulted in more discomfort (P < 0.05) than either S&G/spray (3.5 +/- 0.9) or S&G/block (3.3 +/- 0.7). The laryngoscopist's visual analogue scale scores, which assessed the ease of visualization, revealed a trend (P < 0.08) toward less coughing and gagging with S&G/spray (1.8 +/- 0.9) compared with S&G (4.0 +/- 1.3) and S&G/block (3.7 +/- 1.1). Oropharyngeal discomfort lasting 24 h or more was reported by 91% of participants after S&G/block, whereas no participant reported oropharyngeal discomfort after S&G or S&G/spray. Significantly more participants (73%) indicated their preference for using S&G/spray in future clinical practice compared with S&G (P < 0.01) and S&G/block (P < 0.05). CONCLUSIONS: Glossopharyngeal nerve blocks do not provide a superior route of local anesthetic administration for awake direct laryngoscopy. Two minutes of 2% viscous lidocaine S&G followed by 10% lidocaine spray was the anesthetic route preferred by participants and laryngoscopists.

Anesthetics, Local↗

PubMed1997

Titration of volatile anesthetics using bispectral index facilitates recovery after ambulatory anesthesia.

BACKGROUND: The bispectral (BIS) index has previously been shown to be a quantifiable measure of the sedative and hypnotic effects of anesthetic drugs. This study was designed to assess the effect of BIS monitoring on the utilization of volatile anesthetics and their recovery profiles after ambulatory surgery. METHODS: Sixty consenting women undergoing outpatient laparoscopic tubal ligation procedures were randomly assigned to one of four treatment groups. After a standardized induction, anesthesia was maintained with either desflurane (Groups I and II) or sevoflurane (Groups III and IV) in combination with nitrous oxide, 65%, and fentanyl. In the control groups (Groups I and III), the anesthesiologists were blinded to the BIS value, and the volatile anesthetics were administered according to standard clinical practice. In Groups II and IV, the volatile anesthetics were titrated to maintain the BIS value at 60. The volatile anesthetic usage and the times from discontinuation of anesthesia to verbal response, orientation, and home-readiness were recorded. RESULTS: During the maintenance period, the BIS values were significantly lower in the control groups (mean, 42) compared with the BIS-titrated groups (mean, 60). The volatile anesthetic usage in the BIS-titrated groups was 30-38% lower (P < 0.05) compared with the control groups. Similarly, the times to verbal responsiveness were 30-55% shorter in the BIS-titrated (vs. control) groups. CONCLUSIONS: Titrating desflurane and sevoflurane using the BIS monitor decreased their utilization and contributed to a faster emergence from anesthesia in outpatients undergoing laparoscopic tubal ligation procedures.

Adult↗

PubMed1998

Treatment of incomplete analgesia after placement of an epidural catheter and administration of local anesthetic for women in labor.

BACKGROUND: Approximately 15% of women still have pain after placement of an epidural catheter and administration of local anesthetic for labor analgesia. Two techniques frequently used to treat this pain were compared: (1) withdrawal of the catheter 1 cm and repeated dosing with additional local anesthetic, and (2) repeated dosing with additional local anesthetic without any catheter manipulation. METHODS: Fifteen minutes after placement of a multiple-orifice epidural catheter 5 cm into the epidural space and administration of 13 ml 0.25% bupivacaine to the parturient in labor, the adequacy of analgesia was assessed. All women who had incomplete analgesia were randomized (first intervention) to receive an additional 5 ml 0.25% bupivacaine (local-anestheticonly group) or to receive 5 ml 0.25% bupivacaine after first withdrawing the epidural catheter 1 cm (catheter-manipulation group). If after 15 min the woman still had pain, then (second intervention) the catheter was withdrawn 1 cm and an additional 5 ml 0.25% bupivacaine was administered to the local-anesthetic-only group, whereas 5 ml 0.25% bupivacaine was given to the catheter-manipulation group without further catheter manipulation. The success rate of the second intervention was assessed 15 min later. RESULTS: Seventy-eight women were enrolled in the study, 39 to each group. In the local-anesthetic-only group, 29 (74%) women were successfully treated with the first intervention and the remaining 10 (100%) were successfully treated with the second intervention. In the catheter-manipulation group, 30 (77%) were successfully treated with the first intervention and 7 (100%; 2 patients were not studied because of investigator error) were successfully treated with the second intervention (P=NS). CONCLUSIONS: Administration of additional local anesthetic without first withdrawing the epidural catheter will effectively treat most women for whom analgesia is incomplete after the placement of an epidural catheter during labor.

Analgesia, Epidural↗

PubMed1998

The effects of extracellular pH with and without bicarbonate on intracellular procaine concentrations and anesthetic effects in crayfish giant axons.

BACKGROUND: The potentiating effect of sodium bicarbonate on local anesthetic action is attributed to two mechanisms: (1) an increase in the un-ionized local anesthetic due to extracellular alkalinization, and (2) an accelerated conversion of local anesthetic from un-ionized to ionized form with intracellular acidification caused by bicarbonate. To evaluate these hypotheses, the intracellular pH, intracellular ionized procaine concentration, and evoked action potentials were measured in crayfish giant axons. METHODS: In all measurements, axon preparations from crayfish were perfused extracellularly for 15 min with either bicarbonate-containing solution at pH 7.6 (bicarb/7.6) or bicarbonate-free solution at pH 7.6 (nonbicarb/7.6) or pH 8.0 (nonbicarb/8.0). Intracellular pH was measured using a pH-sensitive microelectrode. Intracellular anesthetic concentration was measured using a specially designed procaine-sensitive microelectrode with each of three solutions containing 1 mM procaine hydrochloride. Membrane potential was measured and, as an index of anesthetic action, the dV/dt of evoked action potential was calculated during perfusion with procaine. RESULTS: Mean intracellular pH was significantly lower in the bicarb/7.6 (7.16+/-0.07) group than in the nonbicarb/7.6 (7.33+/-0.09) and nonbicarb/8.0 (7.33+/-0.12) groups (P < 0.01). The mean intracellular ionized procaine concentration was significantly higher in the bicarb/7.6 (0.53+/-0.08 mM; P < 0.05) and nonbicarb/8.0 (0.58+/-0.13 mM; P < 0.01) than in nonbicarb/7.6 (0.32+/-0.14 mM) group but did not differ between the bicarb/7.6 and nonbicarb/8.0 groups. The mean percentage decrease in dV/dtmax was approximately coincident with the mean intracellular procaine concentration in each solution. CONCLUSION: The presence of bicarbonate or extracellular alkalinization increased the intracellular concentration of ionized procaine and the anesthetic effect.

Action Potentials↗

PubMed1998

Effects of intravenous general anesthetics on [3H]GABA release from rat cortical synaptosomes.

BACKGROUND: Potentiation by general anesthetics of gamma-aminobutyric acid (GABA)-mediated inhibitory transmission in the central nervous system is attributed to GABA(A) receptor-mediated postsynaptic effects. However, the role of presynaptic mechanisms in general anesthetic action is not well characterized, and evidence for anesthetic effects on GABA release is controversial. The effects of several intravenous general anesthetics on [3H]GABA release from rat cerebrocortical synaptosomes (isolated nerve terminals) were investigated. METHODS: Purified synaptosomes were preloaded with [3H]GABA and superfused with buffer containing aminooxyacetic acid and nipecotic acid to inhibit GABA metabolism and reuptake, respectively. Spontaneous and elevated potassium chloride depolarization-evoked [3H]GABA release were evaluated in the superfusate in the absence or presence of various anesthetics, extracellular Ca2+, GABA receptor agonists and antagonists, and 2,4-diaminobutyric acid. RESULTS: Propofol, etomidate, pentobarbital, and alphaxalone, but not ketamine, potentiated potassium chloride-evoked [3H]GABA release (by 1.3 to 2.9 times) in a concentration-dependent manner, with median effective concentration values of 5.4 +/- 2.8 microM (mean +/- SEM), 10.1 +/- 2.1 microM, 18.8 +/- 5.8 microM, and 4.4 +/- 2.0 microM. Propofol also increased spontaneous [3H]GABA release by 1.7 times (median effective concentration = 7.1 +/- 3.4 microM). Propofol facilitation of [3H]GABA release was Ca2+ dependent and inhibited by bicuculline and picrotoxin, but was insensitive to pretreatment with 2,4-diaminobutyric acid, which depletes cytoplasmic GABA pools. CONCLUSIONS: Low concentrations of propofol, etomidate, pentobarbital, and alphaxalone facilitated [3H]GABA release from cortical nerve terminals. General anesthetics may facilitate inhibitory GABA-ergic synaptic transmission by a presynaptic mechanism in addition to their well-known postsynaptic actions.

Aminobutyrates↗

PubMed1998

Mechanistic aspects of carbon monoxide formation from volatile anesthetics.

BACKGROUND: Desflurane, enflurane and isoflurane can be degraded to carbon monoxide (CO) by carbon dioxide absorbents, whereas sevoflurane and halothane form negligible amounts of CO. Carbon monoxide formation is greater with drier absorbent, and with barium hydroxide, than with soda lime. The mechanism, role of absorbent composition and water, and anesthetic structures determining CO formation are unknown. This investigation examined sequential steps in anesthetic degradation to CO. METHODS: Carbon monoxide formation from anesthetics and desiccated barium hydroxide lime or soda lime was determined at equimole and equiMAC concentrations. Carbon monoxide formation from deuterium-substituted anesthetics was also quantified. Proton abstraction from anesthetics by strong base was determined by deuterium isotope exchange. A reactive chemical intermediate was trapped and identified by gas chromatography-mass spectrometry. The source of the oxygen in CO was identified by 18O incorporation. RESULTS: Desflurane,enflurane,andisoflurane(difluoromethylethyl ethers), but not sevoflurane (monofluoromethyl ether), methoxyflurane (methy-ethyl ether), or halothane (alkane) were degraded to CO. The amount of CO formed was desflurane > or = enflurane > isoflurane at equiMAC and enflurane > desflurane > isoflurane at equimole concentrations. Proton abstraction from the difluoromethoxy carbon was greater with potassium than with sodium hydroxide, but unmeasurable with barium hydroxide. Carbon monoxide formation was correlated (r = 0.95-1.00) with difluoromethoxy (enflurane > desflurane > isoflurane > or = methoxyflurane = sevoflurane = 0) but not ethyl carbon proton abstraction. Deuterium substitution on enflurane and desflurane diminished CO formation. Chemical trapping showed formation of a difluorocarbene intermediate from enflurane and desflurane. Incorporation of H2(18)O in barium hydroxide lime resulted in C18O formation from unlabeled enflurane and desflurane. CONCLUSIONS: A difluoromethoxy group is a structural requirement for haloether degradation to CO. Results are consistent with initial base-catalyzed difluoromethoxy proton abstraction (potassium > sodium hydroxide, thus greater CO formation with barium hydroxide lime vs. soda lime) forming a carbanion (reprotonated by water to regenerate the anesthetic, hence requirements for relatively dry absorbent), carbanion decomposition to a difluorocarbene, and subsequent difluorocarbene reaction to form CO.

Absorption↗

PubMed1998

Effect of intravenous anesthetics on spontaneous and endotoxin-stimulated cytokine response in cultured human whole blood.

BACKGROUND: Various anesthetics have been suggested to interfere with the immune system. The ability of leukocytes to express surface receptors and mediators is fundamental to a successful host defense. Therefore, the effects of intravenous anesthetics on cytokine release by leukocytes and expression of surface molecules known to modulate this response were determined. METHODS: Concentration-dependent effects of thiopentone, etomidate, propofol, ketamine, midazolam, and fentanyl on spontaneous and endotoxin (lipopolysaccharide; 1 microg/ml)-stimulated cytokine release were studied in whole blood from volunteers (n = 6) cultured for 25 h. In addition, expression of the lipopolysaccharide-recognition molecule CD14 and the major histocompatibility complex class II molecule human leukocyte locus A system-DR (HLA-DR) on monocytes were assessed using flow cytometry. RESULTS: All anesthetics studied elicited only minor effects on spontaneous cytokine release even at pharmacologic concentrations. However, expression density of CD14 was reduced in the presence of thiopentone, etomidate, and propofol, whereas HLA-DR was unaffected. Lipopolysaccharide-stimulated tumor necrosis factor response was inhibited by thiopentone (12.8% [median]; 7.6-18.8 [25-75 percentile]) of control, and ketamine (46.4% [median]; 44.4-56.4 [25-75 percentile]), at pharmacologic concentrations, whereas it was augmented even in the presence of low concentrations of propofol (172.3% [median]; 120.5-200.7 [25-75 percentile]). Ketamine additionally decreased the concentration of interleukin (IL)-1beta (14.8% [median]; 12.0-18.0 [25-75 percentile]). Release of IL-1 receptor antagonist (IL-1ra) was inhibited by thiopentone, etomidate, and propofol, whereas the same anesthetics increased IL-10 concentration simultaneously. Midazolam and fentanyl did not alter the concentrations of any cytokine. CONCLUSIONS: These results suggest a complex modulation of the cytokine response by the studied anesthetics in cultured whole blood. Although effects on spontaneous cytokine release by leukocytes were negligible, some anesthetics affected their ability to respond to lipopolysaccharide.

Anesthetics, Intravenous↗

PubMed1999

Bound volatile general anesthetics alter both local protein dynamics and global protein stability.

BACKGROUND: Recent studies have demonstrated that volatile general anesthetic agents such as halothane and isoflurane may bind to discrete sites on protein targets. In the case of bovine serum albumin, the sites of halothane and chloroform binding have been identified as being located in the IB and IIA subdomains. This structural information provides a foundation for more detailed studies into the potential mechanisms of anesthetic action. METHODS: The effect of halothane and isoflurane and the nonimmobilizer 1,2-dichlorohexafluorocyclobutane on the mobility of the indole ring in the tryptophan residues of albumin was investigated using measurements of fluorescence anisotropy. Myoglobin served as a negative control. In addition, the effect of bound anesthetic agents on global protein stability was determined by thermal denaturation experiments using near-ultraviolet circular dichroism spectroscopy. RESULTS: The fluorescence anisotropy measurements showed that halothane and isoflurane decreased the mobility of the indole rings in a concentration-dependent manner. The calculated dissociation constants were 1.6+/-0.4 and 1.3+/-0.3 mM for isoflurane and halothane, respectively. In contrast, both agents failed to increase the fluorescence anisotropy of the tryptophan residues in myoglobin, compatible with lack of binding. The nonimmobilizer 1,2-dichlorohexafluorocyclobutane caused no change in the fluorescence anisotropy of albumin. Binding of the anesthetic agents stabilized the native folded form of albumin to thermal denaturation. Analysis of the thermal denaturation data yielded dissociation constant values of 0.98+/-0.10 mM for isoflurane and 1.0+/-0.1 mM for halothane. CONCLUSIONS: Attenuation of local side-chain dynamics and stabilization of folded protein conformations may represent fundamental modes of action of volatile general anesthetic agents. Because protein activity is crucially dependent on inherent flexibility, anesthetic-induced stabilization of certain protein conformations may explain how these important clinical agents change protein function.

Algorithms↗

PubMed1999

Local anesthetic inhibition of baseline potassium channels with two pore domains in tandem.

BACKGROUND: Recently, a new structural family of potassium channels characterized by two pore domains in tandem within their primary amino acid sequence was identified. These tandem pore domain potassium channels are not gated by voltage and appear to be involved in the control of baseline membrane conductances. The goal of this study was to identify mechanisms of local anesthetic action on these channels. METHODS: Oocytes of Xenopus laevis were injected with cRNA from five cloned tandem pore domain baseline potassium channels (TASK, TREK-1, TOK1, ORK1, and TWIK-1), and the effects of several local anesthetics on the heterologously expressed channels were assayed using two-electrode voltage-clamp and current-clamp techniques. RESULTS: Bupivacaine (1 mM) inhibited all studied tandem pore potassium channels, with TASK inhibited most potently. The potency of inhibition was directly correlated with the octanol: buffer distribution coefficient of the local anesthetic, with the exception of tetracaine, to which TASK is relatively insensitive. The approximate 50% inhibitory concentrations of TASK were 709 microM mepivacaine, 222 microM lidocaine, 51 microM R(+)-ropivacaine, 53 microM S(-)-ropivacaine, 668 microM tetracaine, 41 microM bupivacaine, and 39 microM etidocaine. Local anesthetics (1 mM) significantly depolarized the resting membrane potential of TASK cRNA-injected oocytes compared with saline-injected control oocytes (tetracaine 22+/-6 mV rs. 7+/-1 mV, respectively, and bupivacaine 31+/-7 mV vs. 6+/-4 mV). CONCLUSIONS: Local anesthetics inhibit tandem pore domain baseline potassium channels, and they could depolarize the resting membrane potential of cells expressing these channels. Whether inhibition of these channels contributes to conduction blockade or to the adverse effects of local anesthetics remains to be determined.

Anesthetics, Local↗