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PubMed2000

Rapid induction of anesthesia with high concentrations of halothane or sevoflurane in children.

STUDY OBJECTIVE: To compare the characteristics of the rapid induction of anesthesia in pediatric patients with high concentrations of sevoflurane or halothane, and to determine the ability of anesthesiologists to correctly identify the anesthetic drug when administered in this fashion. DESIGN: Randomized, prospective, open-label study. SETTING: Academic university hospital. PATIENTS: 78 ASA physical status I and II healthy children scheduled for brief surgical procedures with general anesthesia and medicated with midazolam. INTERVENTIONS: Assessments were made by 5 pediatric anesthesiologists and 18 anesthesiology residents. Sevoflurane or halothane was randomly selected for anesthetic induction. The anesthetic circuit was primed with the drug (8% sevoflurane or 4% halothane) in 50% nitrous oxide and oxygen. The anesthesiologists were blinded as to the anesthetics being administered. After completion of anesthetic induction, the anesthesiologists were asked to identify the anesthetic and to assess the quality and speed of induction. MEASUREMENT AND MAIN RESULTS: The pediatric anesthesiologists correctly identified the anesthetic in 55 of 78 assessments (70.5%). This figure is statistically better than what could be achieved by random guessing (p < 0.001). The residents correctly identified the anesthetic in only 46 of 78 assessments (60.0%). Statistically, this figure is no better than what could be achieved by random guessing (p = 0.06). Speed of induction was subjectively felt to be faster with sevoflurane than halothane but there were no differences in actual induction time (sevoflurane group, 3.7 +/- 2.7 min; halothane group, 3.7 +/- 2.6 min). There were no differences in the quality of induction or the incidence of airway complications. The perceived incidence of tachycardia was significantly higher with sevoflurane than halothane(sevoflurane group, 74%; halothane group 20%). CONCLUSION: The induction of anesthesia with high concentrations of either halothane or sevoflurane can be safely accomplished. Pediatric anesthesiologists can differentiate between halothane and sevoflurane when either drug is given in high initial concentrations. The presence of tachycardia may have served as the primary clue in determining which drug was being used.

Anesthesia↗
PubMed1993

Molecular mechanism of Ca-ATPase activation by halothane in sarcoplasmic reticulum.

We have studied the molecular mechanism of Ca-ATPase activation in sarcoplasmic reticulum (SR) by the volatile anesthetic halothane. Using time-resolved phosphorescence anisotropy, we determined the rotational correlation times and mole fractions of different oligomeric states of the enzyme, as a function of halothane and temperature. Lipid fluidity was measured independently, using EPR of spin-labeled lipids. At 4 and 7 degrees C, the principal effects of halothane were to increase the activity of the Ca-ATPase and to promote the formation of monomers and dimers of the enzyme from larger aggregates. At higher temperatures (up to 25 degrees C), halothane activated the enzyme, but to a lesser extent than observed at lower temperatures. While the functional effects of halothane were temperature dependent, the effects of halothane on lipid fluidity and protein aggregation state were similar at all temperatures tested. We conclude that at low temperatures Ca-ATPase activity is dominated by aggregation state, so halothane activates the enzyme primarily by promoting the formation of monomers and dimers of the enzyme from larger aggregates. At higher temperatures, the activity of the enzyme is dominated by lipid fluidity, so halothane activates the enzyme by increasing the lipid fluidity. The physical mechanism of Ca-ATPase activation, dominated by aggregation state at low temperature and lipid fluidity at higher temperature, provides an explanation for the break in the Arrhenius plot of Ca-ATPase activity (in the absence of halothane) at approximately 20 degrees C.

Animals↗
PubMed1999

The direct effect of halothane on myocardial contraction in rat myocytes with poorly developed gap junctional intercellular communication.

BACKGROUND: The gap junction channel plays an important role in synchronous beating in the heart, and the reduction in the amount of gap junctional intercellular communication (GJIC) is thought to be the main arrhythmogenic factor in diseased heart. However, the effect of halothane on myocardial contraction in heart tissue with less GJIC is not well known. The purpose of the present study is to examine the direct effect of halothane on myocardium with poorly expressed GJIC. METHODS: Ventricular myocytes were obtained from neonatal rats by enzymatic digestion with collagenase and then cultured for 3 or 7 d. We have previously reported that the number of gap junctions at 3 d is approximately 10% of that at 7 d (1). The myocytes were stabilized in serum-free medium, and the spontaneous beating rate and amplitude were measured by a fiberoptic sensor. RESULTS: Heptanol (2 mM), an inhibitor of GJIC, abolished synchronized beating in myocytes cultured for 7 d. Halothane decreased the beating rate and amplitude in both groups of myocytes in a concentration-dependent manner (P < 0.05). Halothane at 1 and 2 MAC (adult rat MAC) decreased the beating rate more in myocytes cultured for 3 d than in myocytes cultured for 7 d (P < 0.05). Halothane reduced beating amplitude equally in both groups. Asynchronous contraction developed more frequently among myocytes cultured for 3 d than for those at 7 d. CONCLUSION: Halothane may block the GJIC channels, and when the number of these channels is reduced, exposure to halothane may cause asynchronous beating and decrease the beating rate. However, the halothane-induced decrease in amplitude is probably not due to blockade of GJIC because reducing the number of GJIC channels did not alter halothane's depressant effect.

Anesthetics, Inhalation↗
PubMed2003

Concordance between trifluoroacetic acid and hepatic protein trifluoroacetylation after disulfiram inhibition of halothane metabolism in rats.

BACKGROUND: Cytochrome P4502E1(CYP2E1)-mediated oxidation of halothane to a reactive intermediate (trifluoroacyl chloride) that covalently binds to hepatic proteins forming trifluoroacetylated neoantigens is believed to be the initiating event in a complex immunologic cascade culminating in antibody formation and severe hepatic necrosis ('halothane hepatitis') in susceptible patients. Trifluoroacyl chloride may also hydrolyze to the stable metabolite trifluoroacetic acid (TFA). CYP2E1 inactivation by disulfiram or its primary metabolite, diethyldithiocarbamate, inhibits human halothane oxidation to TFA in vitro and in vivo. Nevertheless, disulfiram effects on hepatic protein trifluoroacetylation by halothane in vivo are unknown. This investigation tested the hypotheses that disulfiram prevents halothane-dependent protein trifluoroacetylation in vivo, and that TFA represents a biomarker for hepatic protein trifluoroacetylation. METHODS: Rats were pretreated with isoniazid (CYP2E1 induction), isoniazid followed by disulfiram (CYP2E1 inhibition), or nothing (controls), then anesthetized with halothane or nothing (controls). Plasma and urine TFA were quantified by ion HPLC; hepatic microsomal TFA-proteins were analyzed by Western blot. RESULTS: CYP2E1 induction increased both TFA and TFA-protein formation compared with uninduced halothane-treated rats. Disulfiram, even after CYP2E1 induction, nearly abolished both TFA and TFA-protein formation. Pretreatments similarly affected both TFA and TFA-protein formation across all groups. CONCLUSIONS: Disulfiram inhibition of CYP2E1-mediated halothane oxidation prevents hepatic protein trifluoroacetylation. Based on the concordance between TFA and TFA-protein formation, TFA appears to be a valid biomarker for TFA-protein formation. Disulfiram inhibition of human halothane oxidation in vivo, previously assessed by diminished TFA formation, probably also confers inhibition of hepatic TFA-protein formation.

Anesthetics, Inhalation↗
PubMed1998

Presynaptic and postsynaptic actions of halothane at glutamatergic synapses in the mouse hippocampus.

Whole-cell patch-clamp recordings in adult mouse hippocampal slices were used to test the mechanism by which the volatile anesthetic halothane inhibits glutamate receptor-mediated synaptic transmission. Non-N-methyl-D-aspartate (nonNMDA) and NMDA receptor-mediated currents in CA1 pyramidal cells were pharmacologically isolated by bath application of D,L-2-amino-5-phosphonovaleric acid (APV; 100 microM) or 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX; 5 microM), respectively. Halothane blocked both nonNMDA and NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) to a similar extent (IC50 values of 0.66 and 0.57 mM, respectively). Partial blockade of the EPSCs by lowering the extracellular concentration of calcium ([Ca2+]o), but not by application of CNQX (1 microM), was accompanied by an increase in paired-pulse facilitation (PPF). Halothane-induced blockade of the EPSCs also was associated with an increase in PPF. The effects of halothane on alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and NMDA receptor-mediated currents induced by agonist iontophoresis, were compared. AMPA-induced currents were blocked with an IC50 of 1.7 mM. NMDA-induced currents were significantly less sensitive to halothane (IC50 of 5.9 mM). The effect of halothane on iontophoretic AMPA dose-response curves was tested. Halothane suppressed the maximal response to AMPA without affecting its EC50, suggesting a noncompetitive mechanism of inhibition. All effects of halothane were reversible upon termination of the exposure to the drug. These data suggest that halothane blocks central glutamatergic synaptic transmission by presynaptically inhibiting glutamate release and postsynaptically blocking the AMPA subtype of glutamate receptors.

Anesthetics, Inhalation↗
PubMed2001

Halothane differentially decreases 5-hydroxytryptamine-induced contractions in normal and chronic hypoxic rat pulmonary arteries.

The mechanism of action of halothane is not fully understood in pulmonary circulation and especially in chronic hypertension models. As the 5-hydroxytryptamine (5-HT) pulmonary vasoconstrictor response increases in chronic hypoxic rat, halothane could differentially attenuate this vasoconstriction response on normoxic and chronic hypoxic rats. The effect of halothane on 5-HT-induced contractions on pulmonary arteries isolated from normoxic and chronic hypoxic rats was compared. Rings dissected from proximal pulmonary artery without endothelium were attached to a force transducer to record tone and placed in an organ chamber gassed either by air or air + halothane (1-5%). Contractions induced by (10(-4) M) 5-HT were used to test the effect of halothane on rings isolated from normoxic and chronic hypoxic rats. 5-Hydroxytryptamine-mediated contractions were more sensitive to external calcium in normoxic than chronic hypoxic rings. In calcium-free solution, with verapamil or cadmium the amplitude of remaining 5-HT-induced contractions were greater in chronic hypoxic rings. Halothane (1-5%) decreased 5-HT-mediated contractions in normoxic and chronic hypoxic rings. The effect occurred with no change of pD2 for 5-HT and was more pronounced in normoxic rings. The effect of halothane on both rings was abolished in the absence of external calcium or in the presence of verapamil. In the presence of cadmium, 5% halothane had no effect on normoxic rings but still decreased the remaining 5-HT contraction on chronic hypoxic rings. The findings suggested that halothane decreased sarcolemmal calcium entry in pulmonary artery rings by a cadmium-sensitive pathway in normoxic rats and by a cadmium-insensitive pathway in chronic hypoxic rats.

Anesthetics, Inhalation↗
PubMed1995

[Hemo- and cardiodynamic effect of nifedipine in halothane or isoflurane anesthesia. An animal experiment study].

OBJECTIVE: The present experimental study on 16 acutely instrumented dogs was designed to determine the haemo- and cardiodynamic changes after an intravenous infusion of nifedipine during halothane or isoflurane anaesthesia. METHODS: General anaesthesia was induced with ketamine (10 mg/kg) and fentanyl (0.02 mg/kg) and maintained with fentanyl (0.3 micrograms/kg/min), 3:1 N2O/O2 inhalation mixture, and pancuronium (300 micrograms/kg/h). A left thoracotomy was performed and a needle force probe was placed in the left ventricular wall to measure myocardial force of contraction. A Widney gauge was placed around the left ventricle to measure left ventricular circumference changes. The animals were also monitored with left ventricular tip manometers, pulmonary arterial thermodilution catheters, and femoral arterial and venous catheters. Three hours after instrumentation baseline haemodynamic measurements were performed and repeated 30 min after either halothane 0.8 vol.% (n = 8) or isoflurane 1.5 vol.% (n = 8). Then nifedipine (10 micrograms/kg i.v.) was administered and haemodynamic measurements were repeated. RESULTS: Both volatile anaesthetic agents caused a decrease in MAP, CO, LVP, LVFS, and dP/dtmax. Heart rate, CVP, PAOP, and the diastolic diameter of the heart did not change with halothane and isoflurane. Isoflurane led to a decrease of SVR that was not seen with the administration of halothane. Nifedipine during halothane anaesthesia caused a further decrease in MAP, SVR, LVP, dP/dtmax, and LVFS compared to the already reduced values with halothane alone. However, SV did not decrease any further. If nifedipine was added to isoflurane a further decrease in CO and SV was observed despite a constant SVR. CONCLUSION: Halothane, isoflurane and nifedipine are cardiac depressant drugs. Isoflurane induces vasodilation and appears to be less cardiodepressant than halothane in the clinical situation. However, if nifedipine is added, the vasodilation caused by nifedipine offsets its own negative inotropic effect and in parts the cardiac depression of halothane. Combined with isoflurane the vasodilatory effect of nifedipine is insignificant and the negative inotropic effects of both drugs are additive resulting in a profound decrease in SV and CO.

Anesthesia, General↗
PubMed1997

Quantitative trait loci controlling halothane sensitivity in Caenorhabditis elegans.

Genetic analysis is an essential tool for defining the molecular mechanisms whereby volatile anesthetics (VA) disrupt nervous system function. However, the degree of natural variation of the genetic determinants of VA sensitivity has not been determined nor have mutagenesis approaches been very successful at isolating significantly resistant mutant strains. Thus, a quantitative genetic approach was taken toward these goals. Recombinant-inbred strains derived from two evolutionarily distinct lineages of the nematode Caenorhabditis elegans were tested for sensitivity to clinically relevant concentrations (0.3-0.5 mM) of the VA halothane. The halothane sensitivities of coordinated movement and male mating behavior were highly variant among the recombinant-inbred strains with a range of EC50 values of 13- and 4-fold, respectively. Both traits were highly heritable (H2 = 0.82, 0.87, respectively). Several strains were found to be significantly resistant to halothane when compared with the wild-type strain N2. A major locus or loci mapping to the middle of chromosome V accounted for more than 40% of the phenotypic variance for both traits. Five weaker loci, four of which interact, explained most of the remaining variance. None of the halothane-sensitivity quantitative trait loci significantly affected behavior in the absence of halothane or halothane's potency for C. elegans immobilization, which requires 5-fold higher drug concentrations. Thus, the quantitative trait loci are unlikely to result from differences in halothane-independent (native) behavior or differences in halothane metabolism or permeability. Rather, these loci may code for targets and/or downstream effectors of halothane in the C. elegans nervous system or for modifiers of such gene products.

Anesthetics, Inhalation↗
PubMed1999

Influence of halothane on phospholipase A2 and enzymatic methylations in the rat retinal membranes.

Phospholipase A2 (PLA2) and phospholipid methylases (PLM) play significant roles in transmitter release and membrane signal transduction, respectively. Previous studies have indicated that PLMs occur in the rat brain synaptosomal and retinal membranes, and they are activated under halothane anesthesia. The influence of halothane on PLA2 is not known. Therefore, we have investigated the effect of halothane on retinal PLA2 activity. Rat retinal sonicates were assayed for PLA2 activity using 1-palmitoyl-2[1-14C]arachidonyl-phosphatidylethanolamine (PE, 2.2 nmol) in Tris buffer (10 mM, pH 7.4) at 37 degrees C with and without halothane (0.25-2.0 mM) in the assay medium. These studies gave the following results: (1) Rat retinal sonicates contained PLA2 activity of 4.2+/-0.8 pmol PE hydrolyzed/100 ng protein/hr; (2) Halothane (0.25-2.0 mM) increased PLA2 activity by 20 to 150% depending upon concentration; (3) The lower concentration of halothane (0.25 mM) exhibited high activation of PLA2 (150%); (4) High concentrations of halothane (1.0-2.0 mM) caused a low degree of activation of PLA2 (20%); and (5) During phospholipid methylation of retinal membranes with S-adenosyl-L-methionine in the presence of halothane, increased amounts of fatty acid methyl esters (FAME) were formed. This increase in FAME (45%) was possibly due to the hydrolysis of phospholipids by activated PLA2, liberating fatty acids which were methylated. This increase in FAME (45%) was inhibited by mepacrine (quinacrine) (10 microM), an inhibitor of PLA2. These observations suggest that the release of retinal transmitters (dopamine, acetylcholine and others) is affected during halothane anesthesia, due to activation of PLA2 and enhanced fusogenic activity of vesicular membranes with plasma membrane and depletion of vesicles.

Anesthetics, Inhalation↗
PubMed1982

Mechanisms of halothane adsorption by dry soda-lime.

Using fresh soda-lime (15% water by weight) the soda lime/air partition coefficient of halothane was found to decrease as a function of vapour phase halothane concentration from 2.40 at 0.3% halothane by volume to 1.15 at 2.6%, but adsorption generally followed Henry's law. However, soda-lime dried to a constant weight and subsequently exposed to various concentrations of halothane adsorbed approximately 320 microlitre of vaporized liquid halothane per 100 g before a measurable concentration of halothane was detected in the vapour phase. Adding additional halothane then caused a linear increase in vapour concentration. We conclude that dry soda-lime can absorb large quantities of halothane by a mechanism which is similar to that of a molecular sieve. After these "high affinity" sites are satisfied, additional halothane is absorbed by a mechanism following Henry's law.

Adsorption↗
PubMed1985

Diltiazem inhibits halothane-induced contractions in malignant hyperthermia-susceptible muscles in vitro.

The ability of diltiazem to suppress halothane and halothane-caffeine induced contractures in malignant hyperthermia (MH) susceptible pig muscle, was tested in vitro. Muscle specimens were divided into two groups and tested with a modified halothane-caffeine contracture test. One group acted as the control; the other group was pretreated with diltiazem 20 mumol litre-1. The control muscles developed contractures attributable to halothane and halothane-caffeine, whereas the diltiazem-treated specimens did not. Increases in muscle twitch tension as a result of halothane or halothane-caffeine exposure occurred in treated and untreated specimens, but were significantly delayed in the presence of diltiazem. Muscle exhaustion observed after halothane and halothane-caffeine exposure in the control specimens did not occur in the diltiazem treated muscles.

Animals↗
PubMed1986

In vitro muscle contractures induced by halothane and suxamethonium. II: Human skeletal muscle from normal and malignant hyperthermia susceptible patients.

The role of lipolysis in halothane-induced contractures of human skeletal muscle was examined using three inhibitors of phospholipase A2 (PLA2) activity (quinacrine, spermine and indomethacin) and exogenously administered PLA2. In addition, we examined the effects of the same PLA2 inhibitors on contractures induced by halothane in combination with suxamethonium. The studies were conducted on directly stimulated muscle strips isolated from biopsies from patients diagnosed as MH susceptible, or not susceptible, by the halothane contracture test. The liberation of fatty acids from skeletal muscle homogenates was examined to determine whether PLA2 activity might be increased in MH susceptible patients. The three PLA2 inhibitors antagonized halothane-induced contractures of muscle from MH susceptible patients as well as induction of contractures by suxamethonium and halothane. Pre-exposing preparations that were previously unresponsive to halothane to bee venom PLA2 caused the muscle strips to respond with contractures upon subsequent challenge with halothane, but not with suxamethonium. Free fatty acid production during an in vitro incubation of skeletal muscle homogenates was greater in preparations from MH susceptible patients than in those from patients who were not susceptible. These results suggest that excess liberation of fatty acids may be involved in halothane-induced contractures of muscle from MH susceptible individuals, in the synergism observed between halothane and suxamethonium, and in human MH.

Disease Susceptibility↗
PubMed1990

Halothane metabolism in children.

Halothane (1% v/v inspired) was administered for 60 min to six children of mean age 74 months (range 14-119 months). Uptake of halothane was measured from the difference in the concentration in inspired and expired gas and varied from 176 to 310 mg kg-1, depending on minute ventilation. After administration of halothane ceased, its elimination in expired gas was measured in four patients until the conclusion of anaesthesia; 32-37% of the absorbed halothane was expired 90 min after halothane administration ceased. Urinary excretion of trifluoroacetic acid, fluoride and bromide was measured for up to 1 week. Of the absorbed halothane, 11.4% (range 6.3-18.2%) was excreted in urine as trifluoroacetic acid and 0.37% (range 0.10-0.64%) as inorganic fluoride. The urinary half-life of trifluoracetic acid was 41.8 h (range 10.4-59.1 h). The quantitative and qualitative metabolism of halothane via the reductive and oxidative pathways in children are comparable to values found in adults. No differences in the metabolism of halothane by children were found which would explain the different incidence of halothane-associated hepatitis compared with adults.

Anesthesia, Inhalation↗
PubMed1990

Effect of halothane on hypoxic and hypercapnic ventilatory responses of goats.

We have measured the ventilatory responses to increased inspired carbon dioxide and to hypoxia in four goats awake and at 0.5%, 1.0% and 1.25% end-tidal halothane concentration. While maintaining PE'CO2 constant at each of three values (means 5.86, 6.45 and 7.2 kPa), PE'O2 was reduced rapidly from more than 25 kPa to 5.3-6 kPa for 3 min to record the increase in ventilation. Eleven sets of these 24 steady state points were obtained (2 PO2 x 3 PCO2 x 4 anaes. = 24). The mean isocapnic hypoxic ventilatory response (HVR) was 6.52 (SD 2.58) litre min-1 (n = 33) when awake, 5.62 (3.48) litre min-1 at 0.5% end-tidal halothane (ns), 3.05 (2.02) litre min-1 at 1% and 2.91 (2.12) litre min-1 at 1.25%, the last two being reduced significantly from awake and 0.5% halothane (P less than 0.05). With 1.25% halothane, HVR was reduced to 44.5 (18.6)% of the awake HVR. However, when HVR was expressed as % increase in ventilation produced by isocapnic hypoxia, it was 71 (19)% awake but 124 (65)% with 1.25% halothane, a significant increase with halothane (P less than 0.05). With 1.25% halothane, the carbon dioxide response slope decreased to 36.4 (26.4)% of control; hypoxia did not increase the slope significantly. Whereas previous studies in man have shown that halothane preferentially depresses hypoxic chemosensitivity and has a significant effect at 0.1 MAC, in the goat the hypoxic and carbon dioxide chemosensitivities were depressed equally. At 0.5% end-tidal concentration (about 0.5 MAC), halothane did not significantly depress hypoxic response.

Anesthesia, Inhalation↗
PubMed1995

Uptake of halothane and isoflurane by mother and baby during caesarean section.

Twenty-three patients undergoing Caesarean section received either 0.5% halothane or 0.8% isoflurane to supplement nitrous oxide-oxygen anaesthesia. We studied the rate of uptake of the agents by the mother and fetus by measuring partial pressures in maternal arterial (Pa) and fetal umbilical venous (Puv) blood. Mean induction-delivery interval did not differ between the halothane (10.8 min) and isoflurane (11.7 min) groups. There were no differences in maternal heart rate, arterial pressure, pH and blood-gas tensions and fetal pH, blood-gas tensions or Apgar scores between the two groups. Isoflurane uptake by the mother was more rapid than halothane; at delivery, mean Pa of isoflurane as a fraction of the inspired partial pressure (Pl) was 0.44 compared with 0.35 for halothane (P < 0.05). Mean Puv as a fraction of maternal Pa at delivery was 0.71 for both agents; thus placental transfer was the same for both agents. Consequently mean Puv/Pl was greater for isoflurane (0.32) than halothane (0.26) (P < 0.05). We conclude that both halothane and isoflurane are suitable agents for general anaesthesia for Caesarean section. The rate of uptake of isoflurane by the mother during Caesarean section was more rapid than halothane. The rate of uptake by the fetus from the mother was the same for halothane and isoflurane, so that fetal partial pressure as a fraction of the inspired partial pressure was greater for isoflurane than halothane.

Adult↗
PubMed1996

Halothane and potassium channels in airway smooth muscle.

Earlier studies have suggested that halothane may relax smooth muscle in part by opening adenosine triphosphate-sensitive potassium (KATP) channels. We tested this hypothesis in vitro by examining the interaction of halothane with glibenclamide, a KATP channel blocker, and YM934, a KATP channel opener, in strips of canine tracheal smooth muscles mounted in an organ bath system. To examine the specificity of any effects of halothane on the KATP channel, we assessed the interaction of halothane with tetraethylammonium (TEA), an antagonist of the large-conductance, calcium-activated potassium channel. Experiments were conducted with drugs added before exposure to increasing concentrations of acetylcholine (ACh), and with drugs added after stable increases in force produced by ACh were achieved (ACh precontraction). Exposure to halothane 0.62 mmol litre-1 (equivalent to approximately 2 MAC) increased significantly the ED50 for ACh-induced contractions (by 0.24 (SEM 0.07) mumol litre-1). TEA 1 mmol litre-1 but not glibenclamide 10 mumol litre-1 significantly augmented this increase in ED50 (by an additional 0.17 (0.06) mumol litre-1). In strips precontracted with ACh, TEA, but not glibenclamide, potentiated concentration-dependent relaxation induced by halothane. Incubation with YM934 0.32 mumol litre-1 increased significantly the ED50 for ACh-induced contractions (from 0.12 (0.02) to 0.55 (0.11) mumol litre-1), an increase not affected by exposure to halothane 0.72 mmol litre-1. When added to strips precontracted with approximately ACh 0.3 mumol litre-1, YM934 produced concentration-dependent relaxation; halothane had little effect on this relaxation. These results do not support the hypothesis that halothane relaxes canine tracheal smooth muscle in part by opening KATP channels.

Acetylcholine↗
PubMed1996

Effect of halothane on myocardial reoxygenation injury in the isolated rat heart.

Several studies have reported a protective effect of halothane on myocardial injury in an ischaemia-reperfusion situation. It is unclear if the protection is a result of the haemodynamic effects of halothane or if halothane has a specific action on ischaemia or reperfusion pathomechanisms. To examine this question, we have used an isolated rat heart model where heart rate (300 beat min-1), ventricular volume and coronary flow are constant. Left ventricular developed pressure (LVDP) and release of creatine kinase (CK) were measured as variables of myocardial performance and cellular injury, respectively. Five control hearts were subjected to 35 min of low-flow (2 ml min-1) anoxic and substrate-free perfusion and were then perfused for 1 h with the oxygenated buffer. In the treatment groups, halothane 0.4 mmol litre-1 was added during the first 30 min of anoxic perfusion (n = 5) or during the first 30 min of reoxygenation (n = 5). In five additional hearts, the effect of halothane 0.4 mmol litre-1 was tested under normoxic conditions. Mean basal CK release was 0.29 (SEM 0.13) iu g-1 min-1 and LVDP was 105.5 (4.0) mm Hg. Under normoxic conditions, halothane reduced LVDP to 52.0 (2.6) mm Hg. In control hearts, the major cell injury occurred at the onset of reoxygenation (CK release increased to 149.1 (9.1) iu g-1 min-1) and functional recovery after 1 h of reoxygenation was poor (control LVDP, 14.2(2.)% of baseline). Halothane during anoxia attenuated myocardial injury only moderately (CK release 50.2(5.7) iu g-1 min-1) and LVDP recovered to 30.8(3.0)% (each P < 0.05 vs control). When halothane was administered at reoxygenation, CK release was reduced to 10.1 (0.9) iu g-1 min-1 and LVDP recovered to 69.4(4.9)% (each P < .05 vs control). We conclude that halothane not only attenuated ischaemic injury but had a specific protective action against reoxygenation injury.

Anesthetics, Inhalation↗
PubMed1997

Effect of halothane on conventional protein kinase C translocation and down-regulation in rat cerebrocortical synaptosomes.

Protein kinase C (PKC) is a key regulatory enzyme that has been implicated as a molecular target for the action of general anaesthetics. We have determined the effects of halothane on the translocation and down-regulation of conventional PKC (cPKC) by analysing the subcellular distribution of PKC activity, [3H]phorbol-12,13-dibutyrate ([3H]PDBu) binding and PKC immunoreactivity in intact rat cerebrocortical synaptosomes, a subcellular fraction that contains functional nerve terminals. Halothane alone (2.4 vol%) reduced membrane-associated (P < 0.05) and increased cytosol (P < 0.01) PKC activity, while phorbol-12-myristate, 13-acetate (PMA) 0.1 mumol litre-1, a metabolically stable activator of PKC, reduced membrane (P < 0.01) without altering cytosol PKC activity. Halothane and PMA in combination reduced membrane PKC activity to undetectable levels and reduced cytosol PKC activity (P < 0.01). Halothane alone had no significant effects on the distribution of [3H]PDBu binding, while PMA alone significantly reduced both membrane and cytosol [3H]PDBu binding (P < 0.01). Halothane and PMA in combination reduced membrane and cytosol [3H]PDBu binding further, but this effect was not significantly different from the effect of PMA alone. Experiments using isoform-selective antibodies to PKC alpha, PKC beta or PKC gamma demonstrated synergistic interactions between halothane and PMA in promoting translocation of the three conventional PKC isoforms from the cytosol to the membrane fraction of synaptosomes and down-regulation of their immunoreactivity. Halothane and PMA together reduced cytosol PKC alpha/beta/gamma immunoreactivity significantly more (P < 0.05) than PMA alone. Halothane thus has two distinct actions on PKC in synaptosomes: activation of endogenous PKC activity and potentiation of activation-induced cPKC translocation and down-regulation. These potentially competing effects may underlie some of the conflicting results obtained with halothane on PKC-mediated processes in intact cells.

Anesthetics, Inhalation↗