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PubMed1984

The crucial role of hypoxia in halothane-induced lipid peroxidation.

Halothane-induced lipid peroxidation in NADPH-reduced liver microsomes from phenobarbital-pretreated male rats was studied under defined steady state oxygen partial pressures (Po2). Under anaerobic conditions, as well as at a Po2 above 10 mm Hg no halothane-induced formation of malondialdehyde was detected. At a Po2 below 10 mm Hg, however, with a maximum near 1 mm Hg oxygen, significant halothane-induced malondialdehyde formation was found. This evidence supports the hypothesis that halothane can induce lipid peroxidation. The Po2 (i) must be low enough to permit the reductive formation of . CF3 CHCl-radicals but (ii), it must be high enough to promote formation of lipid peroxides.

Animals↗
PubMed1988

Reductive metabolism of halothane by purified cytochrome P-450.

The reductive metabolism of halothane was determined using purified RLM2, PBRLM4 and PBRLM5 forms of rat liver microsomal cytochrome P-450. The metabolites, 2-chloro-1,1,1-trifluoroethane (CTE) and 2-chloro-1,1-difluoroethylene (CDE), were determined. All three forms of cytochrome P-450 produced CTE with relatively small differences in its production among the various forms. There were major differences, however, in the production of CDE, with PBRLM5 being the most active. PBRLM5 was also the only form to show the development of a complex between halothane and cytochrome P-450. This complex absorbed light maximally at 470 nm. The complex formation and the production of CDE by PBRLM5 were stimulated by the addition of cytochrome b5. Cytochrome b5 had no effect on CDE production by PBRLM4 and inhibited the production of both CTE and CDE by RLM2. These results show that the two-electron reduction of halothane by cytochrome P-450 was catalyzed by the PBRLM5 form and that cytochrome b5 stimulated the transfer of the second electron to halothane through PBRLM5, but not RLM2 or PBRLM4.

Animals↗
PubMed1991

Influence of halothane on the interactions of serotonin1A and adenosine A1 receptors with G proteins in rat brain membranes.

The influence of halothane on the interactions of 5-HT1A and adenosine A1 receptors with G proteins was determined by monitoring the guanine nucleotide sensitivity of agonist binding to these receptors. Halothane inhibited the binding of radiolabeled agonists to 5-HT1A and adenosine A1 receptors by up to 30%, but only at concentrations considerably greater than those necessary for the maintenance of the anesthetic state. The sensitivity of high-affinity agonist binding to a guanine nucleotide (guanylyl-5'-imidodiphosphate) was not affected by halothane, indicating no disruption of receptor-G protein coupling. Thus, it appears that the ability of halothane to disrupt receptor-mediated signal transduction by interference with receptor-G protein interactions is receptor specific.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

The topography of trifluoroacetylated protein antigens in liver microsomal fractions from halothane treated rats.

Sera from patients with halothane hepatitis contain immunoglobulin G (IgG) antibodies to trifluoroacetylated liver microsomal proteins of 100, 76, 59, 57 and 54 kDa, which are produced as a consequence of metabolism of halothane to trifluoroacetyl halide by cytochrome(s) P450. In the present study, the membrane topographies of the various antigens in rat liver microsomal fractions were investigated. Liver microsomal fractions from rats treated with halothane in vivo, and rat liver microsomal fractions which had been incubated with halothane in vitro, were used as the source of trifluoroacetyl antigens. The antigens were detected by immunoblotting. Whereas the 100, 76, 59 and 57 kDa antigens were solubilized from the microsomal membrane by either 0.1 M sodium carbonate or 0.1% (w/v) sodium deoxycholate, the 54 kDa antigen was not solubilized by 0.1% (w/v) sodium deoxycholate. In intact microsomal fractions, the 100, 76, 59 and 57 kDa antigens were not degraded appreciably by trypsin unless detergent was added to permeabilize the microsomal membrane. These results indicate that the 54 kDa antigen is an integral membrane protein, whereas the 100, 76, 59 and 57 kDa antigens are peripheral membrane proteins situated within the lumen of microsomal vesicles, and hence presumably located within the lumen of the endoplasmic reticulum in vivo.

Animals↗
PubMed1991

Halothane enhances tonic neuronal inhibition by elevating intracellular calcium.

Whether the major action of anesthetics is to depress the central nervous system (CNS) by reducing excitation or enhancing inhibition remains unknown. Using whole cell patch-clamp recording in hippocampal slices, halothane and pentobarbital were found to prolong the decay time constant (TAU(D)) of GABAA-mediated spontaneous inhibitory postsynaptic currents (sIPSCs). Intracellular administration of the Ca2+ chelator BAPTA or the Ca2+ release inhibitor dantrolene significantly (ANOVA, P less than 0.005) reduced halothane's effect; in contrast, the pentobarbital effect was unchanged. Halothane induced depression of population spike amplitude was blocked by the GABAA antagonist bicuculline. Together, these findings suggest that a major depressant effect of halothane involves enhancement of GABAA-mediated inhibition through release of intraneuronally stored Ca2+.

Animals↗
PubMed1980

Quantum chemical studies of anaerobic reductive metabolism of halothane by cytochrome P-450.

Proposed pathways for anaerobic reductive metabolism of the widely used anesthetic halothane by cytochrome P-450s have been investigated using two all-valence semiempirical molecular orbital methods. Molecular conformations and electronic structure of halothane and intermediates in proposed one- and two-electron reductive metabolism were were calculated and results used to explore the feasibility of each step in the pathway to observed metabolites. The results suggest facile bromide ion elimination with formation of a CHClCF3 radical as a consequence of single electron reduction of halothane. Characterization of this radical species and its carbanion which would be formed by a second electron reduction suggests that either species could undergo reasonable nonenzymatic transformations leading to the formation of the two volatile metabolic products observed and the proposed trifluoroethylcarbene intermediate. This carbene, rather than CF3CCl, is predicted to be preferentially formed by either a radical or ionic halide elimination reaction. Moreover, when bound as an axial ligand to the iron atom at the heme site in cytochrome P-450, a carbene complex is formed which gives calculated spectral characteristics consistent with those observed when excess halothane is added to reduced cytochrome P-450 or rat liver microsomes under anaerobic conditions.

Anaerobiosis↗
PubMed1983

The metabolism of halothane by hepatocytes: a comparison between free radical spin trapping and lipid peroxidation in relation to cell damage.

The technique of free radical spin trapping has been applied to demonstrate the formation of free radicals produced during the metabolism of halothane by rat liver hepatocytes under hypoxic conditions. The results obtained support previous findings that reported sex differences in the metabolic activation of halothane by rats in vivo. Cell viability under hypoxic conditions, as judged by trypan blue staining and lactate dehydrogenase release, shows a correlation with the extent of metabolism of halothane as measured by electron spin resonance spectroscopy. The extent of lipid peroxidation was measured by diene conjugation, malondialdehyde production and chemiluminescence. The latter technique allowed the demonstration of lipid peroxidation during incubations of hepatocytes under aerobic conditions. The magnitude of the aerobic chemiluminescence showed a similar sex dependency to the extent of free radical formation under hypoxic conditions. Cell viability measurements show that halothane metabolism in both hypoxic and aerobic conditions can lead to cell death. Consequently, oxidative lipid damage could be a cause of cell damage, as judged by cell viability, additional to covalent binding.

Animals↗
PubMed1983

Cytochrome P-450 and halothane metabolism. Decrease in rat liver microsomal P-450 in vitro.

Anaerobic in vitro incubation of microsomes from phenobarbital(PB)-induced rats with halothane results in an irreversible decrease of measurable cytochrome P-450. There is a parallel decrease in heme content under the same incubation conditions. However, microsomes from 3-methylcholanthrene(3-MC)-induced or untreated animals do not show a reduction in cytochrome P-450 content. Aerobic incubation with halothane results in a decrease of cytochrome P-450 which can be completely reversed by dialysis or the addition of potassium ferricyanide. These latter treatments only partially restore the cytochrome P-450 levels following anaerobic incubations. The decrease in cytochrome caused by halothane is not associated with measureable heme N-alkyl adduct formation; lipid peroxidation does not play a role as indicated by the lack of effect of 1 mM EDTA or a decrease in glucose-6-phosphatase activity. Halothane metabolites are bound irreversibly to microsomal protein as determined by gel electrophoresis only when the oxygen concentration is very low. The mechanism of cytochrome P-450 decrease is consistent with the formation of a reactive metabolite which binds to the protein portion and also destroys heme.

Animals↗
PubMed1981

EEG and clinical features in epileptic children during halothane anaesthesia.

Clinical and EEG changes were studied in 12 children affected by infantile cerebral palsy and generalized or focal epilepsy, during and after halothane anaesthesia induced by orthopaedic surgery. The anaesthesia was induced by inhalation of halothane 1.5%, and maintained with halothane 0.5%. During anaesthesia a decrease of the incidence of epileptic abnormalities was observed in 10 patients. In the other 2 children no changes were seen. At the end of surgery, when the anaesthetic was gradually suspended, there was a notable increase of epileptic abnormalities in 4 children. Clinical seizures were never observed during or shortly after surgery. In the majority of the cases, the EEGs performed 1 week later did not show modifications of epileptic abnormalities, as compared to the preoperative EEGs. Only in a few patients the epileptic activity was modified. The data show that halothane anaesthesia can be used in epileptic children without risking activation of seizures.

Anesthesia↗
PubMed1980

Halothane effect on cAMP generation and hydrolysis in rat brain.

The volatile anesthetic halothane increased the rate of cAMP generation and decreased the rate of cAMP hydrolysis in rat cerebral cortex and cerebellum. The effect of halothane on the enzymes was reflected in a two-fold rise in cAMP content of cerebral cortical tissue exposed to the anesthetic at 3 vol% for 15 and 30 min. The action of halothane on adenylate cyclase is calcium-independent and different from the action of guanine nucleotides, sodium fluoride and specific transmitters. The Vmax of the enzyme is higher in the presence of the anesthetic. It is suggested that halothane, through conformational changes of the enzyme, renders more catalytic sites operative.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Differential inotropic effects of halothane and isoflurane in dog ventricular tissues.

The differential effects of halothane (0.25-0.75%) and isoflurane (0.5-1.25%) on the electromechanical activity of canine ventricular tissues were compared in vitro. In Purkinje fibres, halothane but not isoflurane could induce an initial increase of contractile force which was not blocked by diltiazem or propranolol. In ventricular muscles, halothane decreased the resting state contraction more markedly than isoflurane. The results suggest that halothane induces a greater negative inotropy than isoflurane through a differential alteration of intracellular Ca2+ stores.

Action Potentials↗
PubMed1990

Interaction between halothane and morphine on isolated heart muscle.

The present study describes the effects of halothane on morphine activity in the isolated left atria of the rat. Concentration-response curves were obtained for the negative inotropic effects of morphine on electrically stimulated left atria. Morphine significantly decreased the contractile force, with an inhibitory concentration 16 (IC16) of 3.130.698 +/- 22.5 X 10(-9) M. The opiate agonist was more potent in reserpinized rats, causing a consistent negative inotropic action over a wide range (10(-8)-10(-4) M) or morphine concentrations. The IC16 of morphine was significantly (P less than 0.001) decreased in the presence of 1.5% v/v halothane. The administration of L-naloxone (3 X 10(-7)-10(-6) M) but not D-naloxone (10(-6) M) antagonized the inhibitory effects of morphine in the presence of halothane. These results demonstrate that halothane increases the potency of morphine on the isolated left atria and suggest that this effect is mediated by opioid receptors.

Animals↗
PubMed1993

Effect of the general anesthetic halothane on the activity of the transverse tubule Ca(2+)-activated K+ channel.

The effect of the general anesthetic halothane on the activity of the rat skeletal muscle Ca(2+)-activated K+ channel in planar lipid bilayers was investigated. Halothane concentrations in the clinical range (1.0-0.2 mM) alter the regulation of the channel by both Ca2+ and membrane potential. At Ca2+ concentrations between 10 and 250 microM and membrane potentials between 0 and -30 mV, halothane significantly decreases the open state probability without changing the channel conductance. The results demonstrate that halothane can act directly on the Ca(2+)-activated K+ channel or its lipid environment to alter the channel gating kinetics.

Animals↗
PubMed1989

Effects of halothane on contractile properties of skinned fibers from cardiomyopathic animals.

The effects of clinical concentrations of halothane (1 and 2% v/v) on detergent treated cardiac fibers were studied in two different models of cardiomyopathic animals, the Syrian hamster UM-X7.1, and the streptozotocin-induced diabetic rat. The changes of contractile properties in cardiac muscle observed on cardiomyopathic animals, although of moderate importance, were different in these two models. The cardiomyopathic hamsters exhibited macroscopic structural changes in cardiac muscle responsible for a significant decrease in maximal activated tension, but myocardial calcium sensitivity was unchanged. On the other hand, in diabetic rats, maximal activated tension was unchanged, while a slight but significant increase in myocardial calcium sensitivity was observed. Addition of halothane produced a similar dose-dependent decrease in myocardial calcium sensitivity, in both the controls and the two groups of cardiomyopathic animals. Halothane exposure was also associated with a dose-dependent decrease in maximal calcium activated tension in all groups, an effect that was more pronounced in cardiomyopathic hamsters than in their control at the lowest anesthetic concentration. These results indicate that the negative inotropic effects of halothane are additive to the myocardial depression observed in these cardiomyopathies.

Animals↗
PubMed1982

Elevated ornithine decarboxylase activity in the rat liver following exposure to halothane, enflurane and isoflurane.

Exposure of rats to the volatile anesthetics, halothane, enflurane and isoflurane and low FIO2 (0.8%) for two hours results in a transient induction of ODC appearing maximally four hours after exposure. Without the low oxygen accompanying the anesthetic or the low oxygen alone, no significant induction of ODC occurred. The concentration of anesthetic used to produce the ODC induction were 0.5% halothane, 1.5% enflurane and 1.4% isoflurane. Except for halothane, reducing the anesthetic concentration only slightly reduced the effect on ODC levels to control values. Reduction of halothane concentrations to 0.1% was required to reduce the values to control levels. Pretreatment of the animals with either cycloheximide or actinomycin D delayed the onset of ODC induction. The data support the fact that liver damage can occur in the absence of metabolism of the drug.

Aerobiosis↗
PubMed1984

In vivo spin-trap study on anaerobic dehalogenation of halothane.

Radical formation in vivo by anaerobic dehalogenation of halothane is described in this paper. The radicals were stabilized by spin-trapping and assayed by electron spin resonance spectrometry. The radical adducts were formed by inhalation of halothane in vivo and increased with decrease in inspired oxygen concentration. Following administration of the spin-trap, the expired concentration of CF2CHCl and CF3CH2Cl which are the anaerobic metabolites of halothane decreased, but bilious trifluoroacetate which are aerobic did not change. These results strongly suggest that radical intermediates are produced in anaerobic dehalogenation of halothane to CF2CHCl and CF3CH2Cl.

Anaerobiosis↗
PubMed1995

Inhibition of plasma membrane Ca(2+)-ATPase pump activity in cultured C6 glioma cells by halothane and xenon.

We have compared the effect of two inhalational anesthetics, halothane and xenon, on Ca(2+)-ATPase (PMCA) pumping activity in plasma membrane vesicles prepared from cultured rat C6 glioma cells. Halothane, at concentrations ranging from 0.5 to 1.75 vol% (equivalent to 0.5 to 1.6 MAC), significantly inhibited Ca2+ uptake (transport) by plasma membrane vesicles in a dose-related fashion. Xenon, at partial pressures ranging from 0.5 to 1.5 atm (equivalent to 0.5 to 1.6 MAC), similarly inhibited PMCA pumping activity. Additive effects on suppression of PMCA pump activity were observed when C6 cell plasma membrane vesicles were exposed to increasing partial pressures of xenon in the presence of halothane (1 vol%). Halothane also inhibited PMCA pumping in cells from two other lines of neural origin, B104 (rat neuroblastoma) and PC12 (rat pheochromocytoma). Studies described in this report support the thesis that PMCA in cells of neural origin is inhibited by quite different inhalational anesthetics at clinically relevant concentrations.

Animals↗
PubMed1989

A benzodiazepine receptor antagonist improves emergence of mice from halothane anaesthesia.

The benzodiazepine receptor antagonist, flumazenil, at a dose of 10 mg/kg given intraperitoneally to mice, had no effect on the minimum air concentration (MAC-50) of halothane causing anesthesia in 50% of the animals and which was 1.0% by volume of the inhaled air. Diazepam, 10 mg/kg, potentiated the effect of halothane. When the mice had been pretreated with diazepam and flumazenil, 10 mg/kg or 20 mg/kg, partial but not complete reversal of the potentiating effect of diazepam was observed, minimum air concentration values being 0.6% after diazepam alone and 0.8% after diazepam and flumazenil. However, mice pretreated intraperitoneally with flumazenil, in the concentration range 1-10 mg/kg, delivered as a solution in polyethylene glycol-Intralipid vehicle or as a suspension in saline, recovered control levels of spontaneous motor activity much faster than in the absence of flumazenil, on emergence from halothane-induced anaesthesia. In this range, the effect was not dose-dependent. These findings suggest that some of the effects of halothane are mediated at the level of the benzodiazepine receptor.

Anesthesia↗