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PubMed1995

Trifluoroacetylation potentiates the humoral immune response to halothane in the guinea pig.

Halothane hepatitis appears to result from an inappropriate immune response to the products of halothane metabolism. Attempts to produce an animal model for halothane hepatitis have been largely unsuccessful. Although guinea pigs produce neoantigens following treatment with halothane, the subsequent antibody response is weak, possibly accounting for the failure to produce halothane hepatitis in these animals. In order to increase the antibody response to halothane neoantigens, three methods for trifluoroacetylating proteins were used. Guinea pigs were either treated with S-ethylthiotrifluoroacetate, autologous lymphocytes trifluoroacetylated ex vivo, or immunized with trifluoroacetylated mycobacterial protein, followed by exposure to halothane, and examined for anti-halothane metabolite antibodies (anti-TFA antibodies). Animals treated with S-ethylthiotrifluoroacetate developed anti-TFA antibodies, and following exposure to halothane exhibited an enhanced antibody response. Treatment with trifluoroacetylated lymphocytes also resulted in an enhanced anti-TFA antibody response following halothane exposure. Immunization with trifluoroacetylated mycobacterial proteins resulted in very high anti-TFA antibody titers. However, subsequent exposure to halothane had no observable effect on specific antibody titers. Exposure to halothane, regardless of treatment, resulted in the production of anti-microsomal protein antibodies. Signs of halothane hepatitis were not observed, indicating that enhancement of the humoral immune response does not appear to be sufficient for production of halothane hepatitis.

Alanine Transaminase↗
PubMed1993

Halothane regulates G-protein-dependent phospholipase C activity in turkey erythrocyte membranes.

The ability of halothane to stimulate phospholipase C (PLC) was examined in turkey erythrocyte membranes prepared from [3H]inositol-labeled turkey erythrocytes by measuring [3H]inositol phosphate formation ([3H]InsP) in the presence and absence of G-protein activation. In the presence of guanosine 5'-3-O-(thio)triphosphate) (GTP gamma S), halothane (0.5-10 mM) caused a dose-dependent activation of PLC. The EC50 value for halothane-induced PLC activation was 2.8 +/- 0.3 mM. Halothane (0.1-30 mM) had no effect on PLC activity in the absence of G-protein activation and did not affect Ca(2+)-dependent PLC activity. The activation of PLC by GTP gamma S occurred after an initial lag period of 60 s which was followed by a linear increase in [3H]InsP. Halothane dose-dependently decreased the lag period for GTP gamma S-induced PLC activation (minimal value 15 s) and increased the rate of [3H]InsP formation at all time points following this lag. As a result, halothane shifted the EC50 value for GTP gamma S-induced PLC activation to the left (4-fold) and increased its maximal response. Halothane also caused a dose-dependent activation of PLC in the presence of AlF4-. Half-maximal stimulation of AlF4(-)-activated PLC occurred with an EC50 value of 2.9 +/- 0.4 mM halothane, which is similar to the halothane dose giving half-maximal stimulation of PLC in the presence of GTP gamma S. At low doses (0.1-0.3 mM) halothane inhibited both isoproterenol- and adenosine 5'-O-(2-thiodiphosphate) (ADP beta S)-induced [3H]InsP formation, whereas at higher concentrations it stimulated PLC independent of the presence of these agonists. At concentrations chosen to reflect their different membrane/buffer partition coefficients, both hexanol (5 mM) and benzyl alcohol (20 mM) fluidized turkey erythrocyte membranes to the same degree as halothane (5 mM). However, these agents had no effect on GTP gamma S- or AlF(4-)-induced PLC activity, indicating that halothane-induced PLC activation was not secondary to changes in bulk lipid fluidity properties. Halothane also stimulated [3H]inositol bisphosphate and [3H]inositol trisphosphate formation in intact erythrocytes. These data demonstrate that the anesthetic halothane can stimulate G-protein-dependent PLC activity and modify the responsiveness of this signaling system to activation by receptor-linked agonists.

Aluminum↗
PubMed1997

Cytochrome P450 2E1 is the principal catalyst of human oxidative halothane metabolism in vitro.

The volatile anesthetic halothane undergoes substantial biotransformation generating metabolites that mediate hepatotoxicity. Aerobically, halothane undergoes cytochrome P450-catalyzed oxidation to trifluoroacetic acid (TFA), bromide and a reactive intermediate that can acetylate liver proteins. These protein neo-antigens stimulate an immune reaction that mediates severe hepatic necrosis ("halothane hepatitis"). This investigation identified the human P450 isoform(s) that catalyze oxidative halothane metabolism. Halothane oxidation by human liver microsomes was assessed by TFA and bromide formation. Eadie-Hofstee plots of TFA and bromide formation were both nonlinear, suggesting the participation of multiple P450s. Microsomal TFA and bromide formation were inhibited 45 to 66% and 21 to 26%, respectively, by the P450 2A6 inhibitors 8-methoxypsoralen and coumarin, 84 to 90% by the P450 2E1 inhibitor 4-methylpyrazole and 55% by diethyldithiocarbamate, an inhibitor of both P450 2A6 and 2E1. Selective inhibitors of P450s 1A, 2B6, 2C9/10, 2D6 and 3A4 did not affect halothane oxidation. At saturating halothane concentrations (2.4 vol%) only cDNA-expressed P450 2A6 and 2B6 catalyzed significant rates of TFA and bromide formation, and P450 2E1 catalyzed comparatively minimal oxidation. Conversely, at subsaturating halothane concentrations (0.30 vol%), metabolism by P450 2E1 exceeded that by P450 2A6. Among a panel of human liver microsomes, there were significant linear correlations between halothane oxidation and P450 2A6 activity and protein content at saturating halothane concentrations (2.4 vol%), and a significant correlation between metabolite formation and P450 2E1 activity (but not P450 2A6 activity) at subsaturating concentrations (0.12 vol%). These experiments suggested P450 2A6 and 2E1 as the predominant catalysts at saturating and subsaturating halothane concentrations, respectively. Further kinetic analysis using cDNA-expressed P450 and liver microsomes clearly demonstrated that P450 2E1 is the high affinity/low capacity isoform (Km = 0.030-0.053 vol%) and P450 2A6 is the low affinity/high capacity isoform (Km = 0.77-1.2 vol%). Evidence was also obtained for substrate inhibition of P450 2E1. The in vitro clearance estimates (Vmax/Km) for microsomal P450 2E1 (4.3-5.7 ml/min/g) were substantially greater than those for microsomal P450 2A6 (0.12-0.21). These clearances, as well as rates of apparent halothane oxidation predicted from kinetic parameters in conjunction with plasma halothane concentrations measured during clinical anesthesia in humans, demonstrated that both P450 2E1 and P450 2A6 participate in human halothane metabolism, and that P450 2E1 is the predominant catalytic isoform.

Anesthetics, Inhalation↗
PubMed1996

Rat to human extrapolation of HCFC-123 kinetics deduced from halothane kinetics: a corollary approach to physiologically based pharmacokinetic modeling.

The goal of this study was to develop a human physiologically based pharmacokinetic (PBPK) model for the chemical HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) and its major metabolite, trifluoroacetic acid (TFA). No human kinetic data for HCFC-123 are available, thus a corollary approach was developed. HCFC-123 is a structural analog of the common anesthetic agent halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) and follows a common pathway of oxidative biotransformation, resulting in the formation of the same metabolite, TFA. In this study, halothane models for rats and humans were developed and validated. Then the corollary approach was used to develop a human HCFC-123 model from a rat HCFC-123 model. This strategy was implemented by using a previously validated PBPK model for HCFC-123/TFA in the Fisher 344 rat as a template model for halothane in rats. Model predictions were then compared to, and were in good agreement with, measured values for the concentration of halothane in rat blood and fat tissue. A human PBPK model for halothane was developed. The identical mode structure (with the exception of the description for the fat compartment) that was used to describe halothane and TFA in the rat was used for describing halothane and TFA in the human. Human physiological parameters for tissue volumes and flows were taken from the literature, and human tissue partition coefficients for halothane were measured in the laboratory. Based on reported similarity in metabolism of halothane by humans and rats, metabolic constants for halothane in the rat were used in the human model, and specific parameters describing the kinetics of TFA were estimated by optimization. The model was validated against human exposure data for halothane from six published studies (expired breath concentrations of halothane and serum/urine data for TFA). A similar approach was then used to derive a human HCFC-123 model for humans from the HCFC-123 rat model. The corollary approach described here illustrates the innovative use of template model structures to aid in the development and validation of models for structural analogs with similar metabolism and activity in biologic systems. Furthermore, given that the PBPK model adequately describes the kinetics of halothane in rats and humans and of HCFC-123 in rats, use of the human PBPK model is proposed for deriving dose-response estimates of human health risks in the absence of human kinetic data.

Animals↗
PubMed1986

Increased toxicity of the antitumor drug cyclophosphamide in mice in the presence of the volatile anesthetic agent halothane.

Exposure of mice to 0.5% halothane in air, which is close to a maintenance concentration in man, after an IP dose of cyclophosphamide produced an increase in the lethality of cyclophosphamide. The LD50 (30 day) for cyclophosphamide without halothane was 251 mg/kg; with 2 h subsequent exposure to halothane it was 152 mg/kg; and with 20 h subsequent exposure to halothane it was 158 mg/kg. The median survival time of mice receiving cyclophosphamide at doses between 137 and 240 mg/kg was more than 30 days in the absence of halothane, 12 days with 2 h halothane, and 10.5 days with 20 h halothane exposure. Survival of mice was decreased irrespective of whether 2 h halothane exposure preceded or followed cyclophosphamide administration. Separation of cyclophosphamide administration and preexposure to halothane by breathing air for 1 h abolished the decrease in survival. Halothane exposure for 2 h after cyclophosphamide had no effect on the antitumor activity of cyclophosphamide. Total-body clearance of cyclophosphamide in mice exposed to halothane was 60 ml/min/kg, as against 188 ml/min/kg in nonexposed mice. No change was produced by halothane in the area under the plasma concentration-time curve over 2 h for 4-hydroxycyclophosphamide following cyclophosphamide administration. The reason for the increased lethality of cyclophosphamide in the presence of halothane could not be determined. There was no increase in leukopenia caused by cyclophosphamide and no increase in bladder toxicity, in liver toxicity, in renal toxicity, or in the penetration of cyclophosphamide into the brain. The study, together with reports of increased toxicity in patients receiving cancer chemotherapy in close proximity to general anesthesia, should alert physicians and others to the possibility of an interaction between volatile anesthetic agents and chemotherapeutic drugs.

Animals↗
PubMed1989

Effects of halothane on arrhythmias induced by myocardial ischaemia.

The effect of halothane on arrhythmias induced by ischaemia was investigated in rats, isolated perfused rat hearts, and pigs. Responses to the occlusion of the left anterior descending coronary artery were determined in groups (n = 9) of chronically prepared rats treated with no halothane, 0.5, or 1.0 per cent halothane immediately after occlusion; in isolated rat hearts (n = 10) treated with no halothane, 0.5, 1.0, 2.0, or 4.0 per cent halothane for 15 min before and after occlusion; and 20-25 kg pigs (n = 11) anaesthetised with halothane or pentobarbital. The ECG, arrhythmias, blood pressure (BP), heart rate (HR) and extent of infarction were determined in each model. In pigs, left ventricular pressure, dp/dtmax and cardiac output were also measured. In chronically prepared rats, halothane anaesthesia started after occlusion was antiarrhythmic and decreased the incidence of ventricular fibrillation and resulting mortality. In isolated rat hearts, 0.5 or 1.0 per cent halothane had little effect on occlusion-induced arrhythmias. The highest concentration of halothane increased the incidence of ventricular fibrillation both before and after occlusion. Halothane decreased developed ventricular pressure in a dose-dependent manner. In acutely prepared pigs, halothane pre-treatment had no appreciable effect upon occlusion-induced arrhythmias when compared with pentobarbital anaesthesia. Thus, halothane is antiarrhythmic when treatment is initiated after occlusion in the rat but this action is not seen in isolated hearts or intact pigs. The antiarrhythmic action of halothane is, therefore, species and model dependent.

Animals↗
PubMed1991

Cerebrovascular responses to carbon dioxide in children anaesthetized with halothane and isoflurane.

To determine the effects of isoflurane and halothane on cerebrovascular reactivity to CO2, 30 children aged one to six years were anaesthetized with isoflurane or halothane in an air and oxygen mixture with an FIO2 of 0.3. The end-tidal concentrations (0.5 minimum alveolar concentration (MAC) or 1.0 MAC) of isoflurane or halothane were age-adjusted. After achieving a steady-state at both 0.5 MAC and 1.0 MAC isoflurane and halothane, the end-tidal carbon dioxide tension (PETCO2) was randomly adjusted to 20, 40, or 60 mmHg. Cerebral blood flow velocity (CBFV) and the cerebrovascular resistance index (RI+) in the middle cerebral artery (MCA) were measured by a transcranial Doppler monitor. Three measurements of CBFV and RI+ were obtained at each PETCO2 and isoflurane or halothane concentration. Any rise in the PETCO2 caused an increase in CBFV during both 0.5 MAC (r2 = 0.99 and 0.99) and 1.0 MAC (r2 = 0.96 and 0.95) isoflurane and halothane anaesthesia, respectively (P less than 0.05). The CBFV for isoflurane increased as PETCO2 increased from 20 to 60 mmHg for both 0.5 MAC and 1.0 MAC (P less than 0.05). The CBFV for halothane increased as PETCO2 increased from 20 to 40 mmHg for both 0.5 MAC and 1.0 MAC halothane (P less than 0.05), but did not change as PETCO2 increased from 40 to 60 mmHg for both 0.5 MAC and 1.0 MAC halothane. The RI+ showed an inverse relationship with CBFV at each PETCO2 for 0.5 MAC (r2 = 0.98 and 0.99) and 1.0 MAC (r2 = 0.76 and 0.53) isoflurane and halothane, respectively (P less than 0.05). The CBFV did not differ significantly between 0.5 and 1.0 MAC isoflurane and halothane at corresponding PETCO2 values. The cerebrovascular response to CO2 at 20 mmHg between 0.5 MAC and 1.0 MAC halothane was not significantly different. These data strongly suggest that isoflurane and halothane in doses up to 1.0 MAC do not affect the cerebrovascular reactivity of the MCA to CO2 in anaesthetized, healthy children.

Anesthesia, Inhalation↗
PubMedDate not supplied

Human halothane metabolism, lipid peroxidation, and cytochromes P(450)2A6 and P(450)3A4.

OBJECTIVE: Halothane undergoes both oxidative and reductive metabolism by cytochrome P450 (CYP), respectively causing rare immune-mediated hepatic necrosis and common, mild subclinical hepatic toxicity. Halothane also causes lipid peroxidation in rodents in vitro and in vivo, but in vivo effects in humans are unknown. In vitro investigations have identified a role for human CYPs 2E1 and 2A6 in oxidation and CYPs 2A6 and 3A4 in reduction. The mechanism-based CYP2E1 inhibitor disulfiram diminished human halothane oxidation in vivo. This investigation tested the hypotheses that halothane causes lipid peroxidation in humans in vivo, and that CYP2A6 or CYP3A4 inhibition can diminish halothane metabolism. METHODS: Patients (n = 9 each group) received single doses of the mechanism-based inhibitors troleandomycin (CYP3A4), methoxsalen (CYP2A6) or nothing (controls) before a standard halothane anaesthetic. Reductive halothane metabolites chlorotrifluoroethane and chlorodifluoroethylene in exhaled breath, fluoride in urine, and oxidative metabolites trifluoroacetic acid and bromide in urine were measured for 48 h postoperatively. Lipid peroxidation was assessed by plasma F2-isoprostane concentrations. RESULTS: The halothane dose was similar in all groups. Methoxsalen decreased 0- to 8-h trifluoroacetic acid (23 +/- 20 micromol vs 116 +/- 78 micromol) and bromide (17 +/- 11 micromol vs 53 +/- 49 micromol) excretion (P < 0.05), but not thereafter. Plasma F2-isoprostanes in controls were increased from 8.5 +/- 4.5 pg/ml to 12.5 +/- 5.0 pg/ml postoperatively (P < 0.05). Neither methoxsalen nor troleandomycin diminished reductive halothane metabolite or F2-isoprostane concentrations. CONCLUSIONS: These results provide the first evidence for halothane-dependent lipid peroxidation in humans. Methoxsalen effects on halothane oxidation confirm in vitro results and suggest limited CYP2A6 participation in vivo. CYP2A6-mediated, like CYP2E1-mediated human halothane oxidation, can be inhibited in vivo by mechanism-based CYP inhibitors. In contrast, clinical halothane reduction and lipid peroxidation were not amenable to suppression by CYP inhibitors.

Adult↗
PubMed1987

Halothane selectively attenuates alpha 2-adrenoceptor mediated vasoconstriction, in vivo and in vitro.

The mechanism by which halothane interferes with catecholamine-induced vasoconstriction was examined, utilizing specific agonists at postjunctional alpha 1- and alpha 2-adrenoceptors on vascular smooth muscle. Stimulation of either adrenoceptor subtype normally produces vasoconstriction. Two experimental models of drug-induced vasoconstriction were used: in vivo blood pressure response in pithed rats, and in vitro isometric tension development in canine saphenous vein rings. These models were then utilized to examine the anti-vasoconstriction properties of halothane. In vivo, halothane (1 MAC) produced a significant depression in the vascular response to azepexole (an alpha 2-adrenoceptor agonist), but halothane did not alter vasoconstriction by phenylephrine (an alpha 1-adrenoceptor agonist). Halothane caused a 24% reduction of maximal response (P less than 0.0001) to azepexole in pithed rats, and a 3.2-fold rightward shift of the log dose-response curve (P less than 0.0001). Similarly, in vitro, halothane significantly attenuated alpha 2- but not alpha 1-adrenoceptor responsiveness. Halothane (4%) depressed maximal vein contraction to azepexole by 26% (P less than 0.0001), and shifted the log concentration-response curve 2.4-fold to the right (P less than 0.0001). The observed selective interference with alpha 2-mediated vasoconstriction by halothane is unlikely to represent drug antagonism at the receptor level. Our observations may suggest, indirectly, that halothane interferes with Ca+2 entry into vascular smooth muscle. The phenomenon of selective anti-vasoconstriction at alpha 2-adrenoceptors by halothane may explain why alpha 1-adrenergic agonists often appear to retain their vasopressor activity during halothane anesthesia. The mechanism of halothane-induced vasodilation thus includes attenuation of alpha 2- but not alpha 1-adrenergic vasoconstriction; this further demonstrates the multifactorial nature of halothane-induced vasodilation.

Adrenergic alpha-Agonists↗
PubMed1989

The opiate antagonist naloxone counteracts the inhibition of sympathetic nerve activity caused by halothane anesthesia in rats.

The study was undertaken to examine if endogenous opioid systems mediate the response of the sympathetic nervous system to halothane anesthesia. Steady state values of renal sympathetic nerve activity (rSNA), mean arterial pressure (MAP), and heart rate (HR) were continuously recorded in the conscious state and at three depths of halothane anesthesia (0.6%, 1.2%, and 2.4%) in rats. Halothane caused an inhibition of rSNA and hypotension and a decrease in HR at the three halothane concentrations. Repeated bolus doses of the opiate antagonist (-)naloxone given iv during 1.2% halothane anesthesia did not significantly increase any of the variables. However, pretreatment with (-)naloxone (2 or 15 mg.kg-1) induced an increase in rSNA at 0.6% halothane, and subsequently the rSNA inhibition was less pronounced at the two higher halothane concentrations compared with control. HR showed a similar pattern, whereas the hypotension was essentially unaffected. Pretreatment with the pharmacologically inactive compound (+)naloxone had no effect on the halothane-induced depression of rSNA. The ED50 halothane concentration concerning nociceptive aversive behavior was not significantly changed with (-)naloxone pretreatment (2 mg.kg-1). In order to determine if sympathoinhibitory bulbospinal serotonin pathways are activated during halothane anesthesia, rSNA, MAP, and HR were recorded in rats pretreated with the serotonin synthesis inhibitor parachlorophenylalanine (PCPA). However, PCPA pretreatment did not affect the rSNA response to halothane compared with control. These findings indicate that the halothane-induced inhibition of rSNA might partially result from a stereospecific activation of opioid receptors, whereas halothane analgesia does not seem to be mediated by opioid mechanisms.

Anesthesia, Inhalation↗
PubMed1995

Halothane modulates thermosensitive hypothalamic neurons in rat brain slices.

BACKGROUND: In vivo, halothane alters spontaneous firing in and thermosensitivity of neurons in the preoptic region of the anterior hypothalamus. To better understand the mechanisms by which halothane specifically disrupts normal thermoregulation, this investigation examined the effects of halothane on thermosensitive preoptic region neurons in isolated hypothalamic tissue slices. METHODS: Brain slices were obtained and prepared from Sprague-Dawley rats. Preoptic region neurons were characterized by extracellular recording of spontaneous firing rates and thermosensitivity to localized heating and cooling, before, during, and after halothane equilibrated in the perfusate and carrier gas. RESULTS: One hundred sixteen neurons were characterized by their thermosensitivity as: 29% warm-sensitive (> 0.8 spikes.s-1.degrees C-1); 14% cold-sensitive (< 0.6 spikes.s-1.degrees C-1); and 57% temperature-insensitive. Halothane significantly reduced the spontaneous firing rates to 64% of control and the thermosensitivity to 55% of control for warm-sensitive neurons at 1% halothane. Halothane significantly reduced the spontaneous firing rate of cold-sensitive neurons to 24 and 40% of control, and the thermosensitivity to 61 and 36% of control at 0.5, and 1% halothane, respectively. Spontaneous firing rates and thermosensitivity returned toward control values in warm-sensitive neurons (92 and 122% of control, respectively) after discontinuation of halothane, which did not occur in cold-sensitive neurons (49 and 36% of control, respectively). Halothane did not alter the thermosensitive temperature range or the set point temperature at which neurons became most thermosensitive. Halothane also did not affect the firing rates of temperature-insensitive neurons. CONCLUSIONS: Halothane alters the firing rate and thermosensitivity of individual temperature-sensitive neurons in in vitro slices of the preoptic region of the anterior hypothalamus in the absence of afferent modulation. This disruption may result in an imprecision of thermoregulatory responses locally within the preoptic region, to thermal challenges and represents a potential mechanism by which halothane widens the thermoregulatory threshold range.

Action Potentials↗
PubMed1996

Effects of halothane and isoflurane on bradykinin-evoked Ca2+ influx inbovine aortic endothelial cells.

BACKGROUND: Volatile anesthetics, such as halothane and isoflurane, have been reported to affect the endothelium mediated relaxation of vascular smooth muscle cells. Because the activity of the constitutive nitric oxide synthase in endothelial cells depends on the availability of intracellular Ca2+, there is a definite possibility that the observed inhibitory effect of volatile anesthetics involves an action on the agonist-evoked internal Ca2+ mobilization and/or Ca2+ influx in these cells. Therefore, a study was undertaken to determine how halothane and isoflurane affect the Ca2+ signalling process in vascular endothelial cells. METHODS: The effect of halothane and isoflurane on the Ca2+ response to bradykinin of bovine aortic endothelial (BAE) cells was investigated using the fluorescent Ca2+ indicator fura-2. Halothane or isoflurane was applied either to resting cells or after bradykinin stimulation. The agonist-evoked Ca2+ influx in BAE cells was estimated by measuring either the rate of fura-2 quenching induced by Mn2+ or the increase in cytosolic Ca2+ concentration initiated after readmission of external Ca2+ after a brief exposure of the cells to a Ca(2+)-free external medium. The effects of halothane on cell potential and intracellular Ca2+ concentration were measured in cell-attached patch-clamp experiments in which a calcium-activated K+ channel and an inward rectifying Ca(2+)-independent K+ channel were used as probes to simultaneously monitor the intracellular Ca2+ concentration and the cell transmembrane potential. In addition, combined fura-2 and patch-clamp cell-attached recordings were carried out, to correlate the variations in internal Ca2+ caused by halothane and the activity of the Ca(2+)-dependent K+ channels, which are known in BAE cells to regulate intracellular potential. Finally, a direct action of halothane and isoflurane on the gating properties of the Ca(2+)-activated K+ channel present in these cells was investigated in patch-excised inside-out experiments. RESULTS: The results of the current study indicate that the initial Ca2+ increase in response to bradykinin stimulation is not affected by halothane, but that pulse applications of halothane (0.4-2 mM) or isoflurane (0.5-1 mM) reversibly reduce the sustained cytosolic Ca2+ increase initiated either by bradykinin or by the Ca2+ pump inhibitor thapsigargin. In addition, halothane appeared to dose-dependently inhibit the Ca2+ influx evoked by bradykinin, and to cause, concomitant to a decrease in cytosolic Ca2+ concentration, a depolarization of the cell potential. Halothane failed, however, to affect internal Ca2+ concentration in thapsigargin-treated endothelial cells, which were depolarized using a high K+ external solution. Finally, halothane and isoflurane decreased the open probability of the Ca(2+)-dependent K+ channel present in these cells. CONCLUSIONS: These observations suggest that the effects of halothane and isoflurane on Ca2+ homeostasis in BAE cells reflect, for the most part, a reduction of the thapsigargin- or bradykinin-evoked Ca2+ influx, which would be consequent to a cellular depolarization caused by an inhibition of the Ca(2+)-dependent K+ channel activity initiated after cell stimulation.

Anesthetics, Inhalation↗
PubMed1990

Halothane hepatitis in children.

Halothane hepatitis is now a well-recognized distinct entity in adults, but there prevails an often-taught "axiom" that halothane hepatitis "does not occur" in children. We describe 2 children who developed cholestatic hepatitis following halothane anesthesia. The first patient had no antecedent liver disease, and presented with anorexia, abdominal pain and delayed onset of jaundice after multiple halothane exposures. Halothane-specific antibodies were positive, and liver tests resolved completely. The second patient had antecedent liver disease and presented with delayed onset of unexplained high fevers for 10 days following a single halothane exposure. Gradually increasing cholestasis ensued in the absence of other causes of liver disease. Halothane antibodies were negative. These cases illustrate different clinical presentations of halothane hepatitis, such as delayed onset of jaundice or fever following halothane exposure. The difficulties in making a definitive diagnosis and the need to exclude other causes of liver disease are detailed. Risk factors and other presentations are discussed. While halothane hepatitis appears to be an uncommon entity in children, it does occur, and may present with manifestations less than fulminant hepatic failure. A high index of suspicion and a detailed history of the time sequence of events are necessary as the diagnosis is primarily clinical. Halothane-specific antibodies are helpful if positive. In any child developing unexplained jaundice or high fevers following halothane anesthesia, further exposures should be avoided and halothane-specific antibodies obtained.

Chemical and Drug Induced Liver Injury↗
PubMed1969

Effects of monoamine oxidase inhibitors on the hypothermia produced in cats by halothane.

1. In cats, the effects of intraperitoneal injections of four monoamine oxidase (MAO) inhibitors, tranylcypromine, pheniprazine, pargyline, and nialamide, were examined on rectal temperature and on the hypothermia during anaesthesia produced by a 2 hr period of halothane inhalation.2. A 2 hr period of halothane inhalation produced a steady fall in temperature amounting to between 2 degrees and 3.5 degrees C. After discontinuation of halothane inhalation, temperature quickly returned to the pre-anaesthetic level but no pyrexia developed. A peculiar stiffness of the leg muscles occurred in several experiments either at the beginning of the inhalation or after its discontinuation.3. An injection of tranylcypromine (5 mg/kg) caused a rise in rectal temperature and prevented the hypothermia of halothane anaesthesia. This effect lasted for at least 4 hr; 20 hr after the injection, halothane again caused hypothermia.4. An injection of pheniprazine (10 mg/kg) usually caused a small rise in temperature which was not sustained. Pheniprazine not only prevented the hypothermia of halothane anaesthesia during the subsequent 20 hr, but during the first few hours after the injection halothane inhalation actually produced a steep rise in temperature.5. An injection of pargyline (50 mg/kg) had no effect on temperature but the hypothermia due to halothane inhalation was prevented 1 hr after the injection and attenuated after 20 hr. Injection of 200 mg/kg caused a steady rise in temperature which was accelerated when halothane was administered 1 hr later.6. An injection of nialamide (10, 25 or 50 mg/kg) had no immediate effect on temperature, but pyrexia developed overnight after the two larger doses. The effect on the hypothermia due to halothane inhalation was greater 20 hr after the injection than it was after 1 to 2 hr. Twenty hours after injection of the two larger doses, halothane no longer produced hypothermia but caused a lethal rise in temperature either during or after its inhalation.7. In rabbits, the effect on temperature of halothane inhalation varied. Either temperature rose slightly or it fell, but not as much as in cats. In one rabbit in which the inhalation had produced a transient rise, pyrexia developed 40 min after discontinuation of halothane.

Anesthesia, Inhalation↗
PubMedDate not supplied

[Levels of "waste" halothane in operating rooms at gynecologic and obstetrical clinics--preliminary results].

INTRODUCTION: Medical staff working in surgical wards of hospitals, people that work on transport or storaging of gases and liquids, employees working on gas tanks and gas installations, mechanics for anesthetic devices and employees in the process of production of these substances are professionally exposed to anesthetic gases or and fumes that are released in their working environment. It has been confirmed that there were some deviations of indicators of the liver function after a long term exposure of the medical staff (surgeons, anesthesiologists, instrument nurses and anesthetists) to halothane and it has been notified that the level of wasted-halothane in the indoor air of the surgical theaters should be measured in order to get a correct and complete evaluation of the professional risk. The term "wasted-halothane" in this research means fumes of halothane that leave a closed circle: anesthetic device--respiratory organs (patient)--indoor air of the workplace (operating room). MATERIALS AND METHODS: Tests were done in the theaters of the surgical wards of the Department of Gynecology and Obstetrics of Novi Sad. During the testing period no ventilation system was used in any of the theaters. Tested groups included anesthesiologists, instrument nurses and anesthetists who were the members of the surgical team. Tests have not been done on same individuals, but the same workplace. Samples were taken using the "individual sample" method from the breathing zone of the tested person using a rubber pipe fixed on the shoulder. Pumps (personal samplers--"Casella") were set to absorb 0.2 liters of air per minute. Laboratory analyses of these samples were done using a method of desorption of the halothane fumes from the active coal with benzyl-alcohol, and their evaluation on gaschromatograph (Electron-Capture-Detector). The threshold Limit Value (TLV) of halothane fumes at the workplace is 40 mg/m3. RESULTS: During three days of sampling 32 samples of indoor air were taken from the surgical wards of the Department. 30 samples were taken in the surgical theaters, one in the hall between surgical theaters, and one in the room for rest of the staff. Concentration of halothane fumes in the theatre No 1 was between 6.9 mg/m3 and 27.31 mg/m3 in anesthetists, between 33.08 mg/m3 and 37.62 mg/m3 in anesthesiologists and between 6.9 mg/m3 and 27.31 mg/m3 in instrument nurses. At the theatre No 2 concentration of halothane fumes was between 31.27 mg/m3 and 37.9 mg/m3 in anesthetists, between 3.56 mg/m3 and 91.7 mg/m3 in anesthesiologists and up to 95.5 mg/m3 in instrumenting nurses. Concentration of halothane fumes in the theatre No 3 were between 4.19 mg/m3 and 17.18 mg/m3 in anesthetics, between 6.23 mg/m3 and 37.62 mg/m3 in anesthesiologists and between 8.27 mg/m3 and 12.33 mg/m3 in instrument nurses. In the hall between these surgical theaters the concentration was 3.02 mg/m3 and 0.28 mg/m3 in the room for rest. DISCUSSION: Halothane fumes were present in the atmosphere of the working environment in significant quantities at all tested places Especially indicative were the results that showed that the concentration of halothane fumes in the theatre No 1, at the end of surgical operational program, was much higher than at the beginning, and what is even more important it was much higher than those in TLV in anesthesiologists and instrument nurses (more than twice higher). The differences of concentrations between specific occupations within the surgical team were also significant. Our results show that the most exposed were anesthesiologists and instrument nurses, who spent most time nearby the operation table. The anesthetists were much less exposed, due to the fact that they are assistants that often leave the surgical theater during the surgical interventions. Indicators illustrate that the increase of the concentration of halothane fumes depends on the length the surgical theaters were used. It shows an increase of halothane fumes co

Air Pollutants↗
PubMed1991

The action of halothane on stimulus-secretion coupling in clonal (GH3) pituitary cells.

The effect of halothane on the physiological response to excitatory stimuli was assessed in clonal (GH3) pituitary cells. Halothane, at concentrations used to produce general anesthesia in animals (0.25-0.76 mM), inhibited thyrotropin-releasing hormone (TRH)-induced prolactin (PRL) secretion. The sustained (extracellular calcium-dependent) phase of PRL secretion was 70 +/- 7% inhibited by the highest concentration of halothane tested (0.76 mM); 50% inhibition was produced by approximately 0.4 mM halothane. The early (largely inositol trisphosphate-mediated) phase of secretion was less sensitive to halothane; 0.76 mM halothane produced 18 +/- 2% inhibition of the early phase of secretion. Consistent with these observations, halothane inhibited (IC50 approximately 0.45 mM) the sustained phase of the TRH-induced rise in intracellular calcium ([Ca2+]i) to a greater extent than the initial [Ca2+]i peak. The sustained phase of the [Ca2+]i elevation was inhibited by 75 +/- 7% at the highest concentration of halothane tested (0.76 mM), whereas the peak [Ca2+]i was only inhibited by 14 +/- 5%, consistent with the observation that halothane did not inhibit TRH-stimulated inositide hydrolysis in these cells. Halothane (0.5 mM) did not inhibit phorbol ester- or ionomycin-induced PRL secretion, indicating that halothane has inconsequential effects on the secretory apparatus. Halothane (0.5 mM) also inhibited KCl-induced PRL secretion by 50-80% and the corresponding KCl-induced rise in [Ca2+]i by 68 +/- 6%. These data indicate that halothane inhibits secretagogue-stimulated PRL secretion by reducing the elevation of [Ca2+]i produced by calcium (Ca2+) influx.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium↗
PubMed1991

[Effect of halothane, fentanyl and ketamine on the threshold for the passage of venous air embolism through lungs in dogs].

Effect of halothane, fentanyl and ketamine on the passage of air injected bolus across the pulmonary circulation was studied in dogs using transesophageal M-mode echocardiography. Dogs in Group 1 (N = 5) were anesthetized with halothane and then halothane with fentanyl. At least 3 weeks later the dogs were anesthetized with fentanyl and then fentanyl with halothane. The same procedure was utilized in group 2 (N = 4) using halothane and ketamine. The doses of halothane, fentanyl and ketamine were 1% inspired concentration, 100 micrograms.kg-1 followed by 1 microgram.kg-1.min-1 iv, and 10 mg.kg-1 followed by 0.1 mg.kg-1.min-1 iv, respectively. The threshold for bolus air detection during halothane, fentanyl and ketamine alone were 0.05, 0.5 and 0.2 ml.kg-1, respectively. The threshold during fentanyl administration, but not during ketamine administration, was significantly higher than that during halothane. The addition of halothane to fentanyl or ketamine lowered the threshold to the same level as with halothane alone, and the addition of either fentanyl or ketamine to halothane made no difference. Although there was no difference in baseline shunt fraction resistance index [PVRI/(Qs/Qt)] during administration of each anesthetic, every air injection decreased shunt fraction resistance index during halothane without fentanyl or during halothane with or without ketamine, and increased it during fentanyl administration.

Animals↗
PubMed1976

Inhibition of catecholamine release from the adrenal medulla by halothane. Site and mechanism of action.

In isolated bovine adrenals perfused with Locke solution in a retrograde fashion we investigated the effects of halothane on the catecholamine release evoked by various secretagogues. 1. The catecholamine release induced by activation of the nicotinic receptors on the chromaffin cells with 1,1-dimethyl-4-phenylpiperazinium was almost completely inhibited (by about 90%) by 1.4 X 10(-3) M halothane. 2. It was shown by means of cumulative concentration-response curves of acetylcholine for its stimulating effect on catecholamine release (pD2 = 4.04) that halothane was a non-competitive antagonist (pD'2 = 3.17). 3. Halothane (1.4 X 10(-3) and 4.3 X 10(-3) M) did not decrease the catecholamine secretion in response to pilocarpine or histamine. 4. The 5-hydroxytryptamine-induced catecholamine release was not impaired by 1.4 X 10(-3) M halothane, but was significantly inhibited (by 44%) by 4.3 X 10(-3) M halothane. 5. At 1.4 X 10(-3) M halothane the catecholamine release induced by gamma-aminobutyric acid (GABA) was inhibited by 40%. 4.3 X 10(-3) M halothane completely blocked the secretion induced by GABA. 6. The catecholamine secretion in response to 56 mM KCl or to introduction of CaCl2 after perfusion with Locke solution deficient in CaCl2 was not reduced by halothane (1.4 X 10(-3) and 1.4 X 10(-2) M). 7. Halothane (1.4 X 10(-3) M) did not inhibit the catecholamine release evoked by acetaldehyde or tyramine from glands perfused with Ca2+ -free Locke solution throughout the experiments. It is concluded that the site of action of halothane is the cell membrane of the chromaffin cell. The anaesthetic does not impair the permeability of the membrane to calcium ions. Halothane may cause a conformational change of membrane proteins, particularly of the nicotinic receptor (and at higher concentrations of GABA and 5-hydroxytryptamine receptors); thus, stimulation may be prevented by an inhibition of agonist-receptor interaction.

Acetaldehyde↗