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PubMed1995

Effects of halothane on the immature lamb heart.

The choice of anesthesia during pregnancy and fetal operations is controversial. Halothane frequently is used, but its direct effects on fetal cardiac performance are unknown. The effects of halothane on fetal cardiac mechanics were studied in 8 fetal lamb hearts (135 days' gestation) using a modified Langendorff model connected to a membrane oxygenator. The perfusate consisted of oxygenated maternal blood at a constant flow temperature, hematocrit value, and glucose level. Coronary blood flow, left ventricular systolic pressure, left ventricular end-diastolic pressure, and the developed left ventricular pressure at a fixed volume were evaluated at baseline and after the addition of incremental concentrations of halothane to the perfusate through the oxygenator. Perfusate halothane levels were maintained in a clinical range. Systolic and diastolic cardiac function were adversely affected by the administration of even low doses of halothane, despite a concomitant increase in coronary blood flow. Because of the immaturity of their calcium transport system, fetal hearts may be particularly sensitive to the known calcium channel-blocking properties of halothane.

Animals↗
PubMed1983

Characterization of hyperthyroidism enhancement of halothane-induced hepatotoxicity.

Administration of anesthetic doses of halothane to hyperthyroid male rats results in the development of hepatic necrosis. The severity of the hepatic lesion was dependent on the dose of triiodothyronine (T3) and the length of time it was administered. Pretreatment of rats with iodinated metabolites of thyroxin which do not induce hyperthyroidism did not result in any signs of hepatotoxicity after halothane exposure. The administration of halothane to hyperthyroid female rats or mice of either sex did not result in the development of any overt hepatotoxicity. Likewise, hyperthyroidism did not enhance the hepatotoxicity of another hepatotoxin bromobenzene. The in vitro enzymatic activities associated with cytochrome P-450-dependent metabolism and glutathione S-transferase conjugation activity were markedly altered in hyperthyroid rats. Cytochrome P-450 levels, aminopyrine N-demethylase activity, glutathione levels and glutathione S-transferase activity were all significantly lower in hyperthyroid rats. However, other enzyme activities were stimulated by T3 pretreatment; aniline hydroxylase activity was increased by 45% and cytochrome c reductase activity was increased by 54% in hyperthyroid rats. Glutathione levels were also reduced significantly in hyperthyroid male rats. Maximal changes in both the cytochrome P-450 system and in the glutathione detoxification system were required before halothane demonstrated its hepatotoxic effects. Thus, a new balance between cytochrome P-450-dependent bioactivation and glutathione conjugation of halothane may be necessary for the exaggerated hepatotoxicity of halothane seen in hyperthyroid male rats.

Alanine Transaminase↗
PubMed1987

Changes in rat hepatic microsomal mixed function oxidase activity following exposure to halothane under various oxygen concentrations.

This study demonstrates that the exposure of phenobarbitone-treated rats to halothane at an oxygen concentration of either 10% or 14% results in marked decreases in cytochrome P-450 content and aminopyrine demethylase activity in animals sacrificed from 1 to 48 hr post-exposure. The alterations observed in the hepatic mixed function oxidase system were accompanied by increases in serum alanine aminotransferase (ALT), ornithine carbamyl transferase (OCT) and changes in liver pathology. However, the minor changes in cytochrome P-450 content and aminopyrine demethylase activity observed following exposure of enzyme-induced rats to halothane under normoxic conditions (i.e. 21% oxygen) were not of a sufficient magnitude to lead to hepatic cell necrosis. Halothane administration in the absence of phenobarbitone pretreatment (i.e. 21% oxygen) or during hypoxia alone (i.e. either 10% or 14% oxygen) did not result in any systematic changes in the parameters assayed. The results suggest that cytochrome P-450 may catalyse its own inactivation by virtue of greater free radical production under conditions which favour the non-oxygen dependent metabolism of halothane. The impairment in microsomal function as evidenced by decreases in cytochrome P-450 and aminopyrine demethylase activity are considered to occur as a primary consequence of the reductive metabolism of halothane. Data are presented which support the concept of the initiation of hepatic damage occurring during the period of anaesthesia with halothane.

Alanine Transaminase↗
PubMed1988

Halothane attenuation of muscarinic inhibition of adenylate cyclase in rat heart.

Halothane stimulated basal adenylate cyclase activity in rat cardiac membranes. Maximal stimulation (54%) was obtained after equilibrating the membranes with 2% halothane. Halothane did not affect the fractional stimulation of adenylate cyclase activity produced by either forskolin or isoproterenol. However, halothane decreased carbamylcholine inhibition of adenylate cyclase activity stimulated by both forskolin and isoproterenol. Maximal depression of carbamylcholine inhibition of stimulated cyclase activity was obtained after equilibration with 1% halothane. These results are consistent with evidence from ligand binding studies and indicate that halothane disrupts muscarinic receptor-G-protein interactions.

Adenylyl Cyclase Inhibitors↗
PubMed1989

Suppressive effects of halothane on reactive synaptogenesis in the dentate gyrus of rats.

Reactive synaptogenesis was studied in the dentate gyrus of rats exposed to 100 parts per million of halothane for 15 days starting on the day after unilateral entorhinal lesioning. Halothane exposure markedly affected the replacement of synapses. Only 17% of the lost synapses were restored by day 15 postlesion in rats exposed to halothane, while 73% of the lost synapses were recovered in rats not exposed to halothane. However, this suppression in initial reactive synaptogenesis did not result in permanent deficits in synaptic population. After halothane exposure was stopped, reactive synaptogenesis resumed, and by day 30 after the lesion, the synaptic population of the experimental group caught up to the control level. This suppressive action of halothane suggests its utility as a research tool for delaying synaptogenesis during selected developmental epochs to study the relationship between synaptic and behavioral recovery.

Animals↗
PubMed1988

Effects of halothane dose and stimulus rate on canine spinal, far-field and near-field somatosensory evoked potentials.

Evidence that canine spinal, far-field and near-field somatosensory evoked potentials resemble those recorded in humans and other species has been presented, and the vulnerability of each component to varying depths of halothane anesthesia is reported. Lumbar spinal peak latencies are not affected by halothane dose, but the negative peak is significantly prolonged by rapid rates of stimulation. Elevated stimulus rates and halothane doses reduce lumbar spinal cord potential amplitudes. Early far-field cephalic components are refractory to halothane. Late far-field components and near-field cortical potentials are substantially altered by increments in halothane dose. Both near-field and far-field responses are more readily identified in vertex-neck than vertex-brow derivations. Early far-field somatosensory evoked potentials recorded from vertex to neck, together with lumbar spinal cord potentials, may be the preferred monitoring technique when the use of halothane anesthesia is desired. Rapid rates of stimulation may facilitate earlier recognition of cord dysfunction, but supplement rather than replace baseline recordings at slow stimulus rates.

Animals↗
PubMed1978

Halothane-induced sleeping time in the mouse: its modification by benzodiazepines.

The conditions under which prolongation of halothane-induced sleeping time in the mouse may be used as a test for centrally acting drugs are described. The test can be recommended for its practical advantages over methods using barbiturates to induce hypnosis; due cognizance must be taken of a diurnal variation in the response of mice to halothane. To assess the usefulness of the test the effects of amphetamine, chlorpromazine, histamine, morphine, nikethamide, pentobarbitone and SKF 525A have been investigated. The interaction between 5 benzodiazepines and halothane has been studied in particular. Results from sleeping time experiments, measurements of body temperature and of brain halothane concentrations suggest that the halothane-benzodiazepine interaction is due to additive CNS depressant effects. It was found that nitrazepam and diazepam were clearly more potent than chlorodiazepoxide, medazepam and oxazepam in respect of their interactions with halothane.

Animals↗
PubMed1991

Halothane markedly reduces mesenteric blood flow but does not impair gut mucosal oxygenation in pigs.

We investigated the effect of halothane on in mesenteric blood flow and gut mucosal oxygenation. Pittman-Moore mini-pigs (n = 6) were chronically instrumented with aortic, pulmonary arterial (Swan-Ganz), and mesenteric venous catheters and an intestinal tonometer. Blood flow in the superior mesenteric artery was measured with an ultrasonic flow probe. On the day of the experiment, data were obtained before and during halothane administration (1.5% end-tidal). Halothane caused a marked decrease in mesenteric blood flow, associated with an increase in mesenteric vascular resistance. Likewise mesenteric oxygen delivery and consumption were significantly decreased under halothane, while the oxygen extraction rate of the intestine was not significantly changed. There was no significant change in intramucosal gut pH after halothane administration, which indicates that an adequate mucosal tissue oxygenation was maintained. We conclude that the marked halothane-induced reduction in mesenteric blood flow did not seem to impair the oxygenation of the gut mucosa in our experimental model.

Animals↗
PubMed1988

Halothane, an inhalation anesthetic, activates protein kinase C and superoxide generation by neutrophils.

The rate of superoxide generation of guinea pig intraperitoneal neutrophils by a chemotactic peptide or 12-O-tetradecanoylphorbol-13-acetate (TPA) was increased by 2-bromo-2-chloro-1,1,1,-trifluoroethane (halothane), an inhalation anesthetic. This increase was inhibited by 1-(5-isoquinolinesulfonyl)methylpiperazine dihydrochloride (H-7), a specific inhibitor of Ca2+- and phospholipid-dependent protein kinase C (PKC). Halothane was found to significantly activate partially purified PKC. The activation required phosphatidylserine (PS) and Ca2+. Dioleoylglycerol- or TPA-activated PKC activity was further increased by halothane. The cytoplasmic proteins of guinea pig neutrophils phosphorylated by halothane-activated PKC were similar to those phosphorylated by PMA-activated PKC. The phosphorylation of a 48 kDa protein, a phosphorylated protein required for NADPH oxidase activation, was also increased by halothane. These data suggest that the increase of superoxide production by halothane is correlated with its activation of PKC.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Fatty acids markedly lower the threshold for halothane-induced calcium release from the terminal cisternae in human and porcine normal and malignant hyperthermia susceptible skeletal muscle.

Malignant hyperthermia is caused by an abnormal increase in Ca2+ levels in skeletal muscle in response to anesthetics, including halothane. Since fatty acid production is elevated in skeletal muscle from individuals with malignant hyperthermia, the effects of fatty acids on the threshold of halothane-induced Ca2+ release were examined. In the absence of fatty acids halothane caused Ca2+ release from porcine and human heavy sarcoplasmic reticulum fractions, but only at concentrations above the clinically relevant range. Oleic acid (20 microM), an unsaturated fatty acid, reduced the threshold at which halothane induced Ca2+ release to concentrations used for anesthesia. Stearic acid, a saturated fatty acid had considerably less effect on the threshold of halothane action. The greater sensitivity of malignant hyperthermia muscle to halothane can be explained by elevated fatty acid production.

Animals↗
PubMed1995

Interactions between NMDA and AMPA glutamate receptor antagonists during halothane anesthesia in the rat.

There is increasing evidence that pharmacologic antagonism of glutamatergic neurotransmission can potentiate the anesthetic effects of drugs such as halothane. The purpose of this study was to examine the anesthetic interaction between glutamate receptor antagonists. A competitive NMDA receptor antagonist (CGS 19755) and an AMPA receptor antagonist (NBQX) were administered either alone or in combination prior to determination of the minimum alveolar concentration (MAC) for halothane in the rat. CGS 19755 caused a dose-dependent maximum reduction in halothane MAC of approximately 80%. Doses of NBQX, which were low enough to cause no change in MAC when administered alone, substantially reduced MAC when administered with subanesthetic doses of CGS 19755. This effect decreased as the dose of CGS 19755 was increased. Finally, halothane MAC was reduced to zero when NBQX, in a dose sufficient to reduce halothane MAC by approximately 35% if given alone, was added to a pharmacodynamically similar dose of CGS 19755. Although MAC is believed to predominantly reflect nocioception at the spinal cord level, the results suggests that pharmacologic blockade of glutamatergic neurotransmission is sufficient to result in deep levels of anesthesia. Further, the effect of combinations of NMDA and AMPA receptor antagonists on halothane MAC is consistent with an in vivo physiologic interaction between the NMDA and AMPA receptors.

Anesthesia↗
PubMed1993

Effects of halothane, enflurane, and isoflurane on laryngeal receptors in dogs.

The effects of halothane, enflurane, and isoflurane on laryngeal receptors were investigated in 6 anesthetized dogs breathing spontaneously through a tracheostomy. Single unit action potentials were recorded from the peripheral cut end of the superior laryngeal nerve (SLN) while different concentrations of volatile anesthetics (1.25, 2.5, 5.0%) were administered in the expiratory direction at a constant air-flow (6 l/min) for 1 min through the functionally isolated upper airway. A total of 21 respiratory-modulated mechanoreceptors, 18 "irritant" receptors, and 7 cold receptors were studied. The overall results obtained from the 16 respiratory-modulated mechanoreceptors challenged with the 3 anesthetic gases disclosed a prevalent inhibitory effect and halothane proved to be the most effective of the 3 gases. The activity during both the inspiratory and expiratory phase was significantly reduced only by halothane (inspiratory phase, P < 0.01; expiratory phase, P < 0.05), while neither isoflurane nor enflurane caused significant changes in receptor activity. Of the 18 irritant receptors, 14 receptors increased their activity in a dose-related manner in response to one or more of the anesthetics although the effect of halothane was more pronounced than those of enflurane and isoflurane. All of the 7 cold receptors consistently increased their activity in a dose-related manner in response to halothane whereas 3 of 7 receptors were insensitive to enflurane and 4 of 7 receptors were insensitive to isoflurane. Our results indicate that, while all three commonly used anesthetics can have an effect on different types of laryngeal receptors, the effects of halothane are more pronounced than those of the other two gases in terms of changes in receptor activity.

Action Potentials↗
PubMed1983

Halothane hepatotoxicity in hyperthyroid rats as compared to the phenobarbital-hypoxia model.

Halothane hepatotoxicity was observed after exposing hyperthyroid rats to 0.625% halothane for 4 hr under hypoxic conditions (10% O2). In this model, increases in serum enzyme activities of the alanine aminotransferase (GPT) and the sorbitol dehydrogenase (SDH) were evident immediately following exposure and were six-fold higher than in the phenobarbital-hypoxic model. Plasma free-fluoride levels estimated immediately after exposure to halothane were increased twofold in halothane-exposed hyperthyroid rats under hypoxic conditions as were increased twofold in halothane-exposed hyperthyroid rats under hypoxic conditions as compared to a sixfold increase in the phenobarbital-hypoxic model. The concentration of glutathione in liver was more markedly decreased in hyperthyroid rats than in phenobarbital-induced rats. The fact that no clear-cut correlation was found between defluorination and hepatotoxicity in both models may favor the hypothesis that a non-defluorinated metabolite of halothane, e.g., 2-chloro-1,1,1-trifluoroethyl radical, is the reactive intermediate responsible for the liver lesions. On the other hand, intracellular hypoxia due to hypermetabolism during the hyperthyroid state may be the reason for the higher sensitivity of hyperthyroid rats.

Animals↗
PubMed1991

Generation and detection of neoantigens in guinea pig liver slices incubated with halothane.

The volatile anesthetic halothane can be biotransformed by the hepatic cytochrome P-450 system to produce a reactive intermediate, trifluoroacetyl chloride, capable of covalently binding to liver proteins. The product of this reaction, the trifluoroacetyl lysinyl moiety, can act as an epitope to alter protein antigenicity. An in vitro system has been developed to produce halothane induced neoantigens and to study conditions for formation in the liver. Liver slices, capable of halothane biotransformation, provide a viable means for mechanistic studies. Liver slices (1 cm diameter, 300 microns thick) from male Hartley guinea pigs (600-800 g) were exposed to either 1.0 or 1.7 mM halothane (media concentration) in 95% O2/5% CO2 for 12 h. Covalent binding was determined using 14C-halothane. Neoantigens were detected by Western immunoblot analysis using rabbit anti-trifluoroacetylated albumin antiserum. Covalent binding was detected by 1 h of incubation and increased linearly through 12 h (20.7-48.5 nmole equiv/mg protein). Covalent binding preceded and correlated with the appearance of neoantigens. By 12 h of incubation, five neoantigens were seen with molecular weights ranging from 51 to 97 kD. These neoantigens have molecular weights similar to those seen in vivo. Liver slices exposed to deuterated halothane, which is oxidatively metabolized to a lower extent, did not develop neoantigens. This in vitro model system can be used to examine the mechanism for covalent binding and neoantigen production in the hepatocyte.

Animals↗
PubMed1984

Paradoxical effects of perturbation of intracellular levels of glutathione on halothane-induced hepatotoxicity in hyperthyroid rats.

Exposure of hyperthyroid rats to halothane results in a centrilobular necrosis of the liver and an 11-fold increase in serum glutamate-pyruvate transaminase (SGPT) levels. These effects are not seen in euthyroid animals. Paradoxically, administration of diethylmaleate to hyperthyroid rats significantly decreased the levels of hepatic glutathione and blocked the halothane-induced hepatic necrosis as well as decreased the elevation of SGPT. In contrast, pretreatment of animals with N-acetylcysteine, an intracellular sulfhydryl repletor , significantly increased the severity of the halothane-induced hepatic necrosis and increased the elevation of SGPT. Similarly, cysteamine, another intracellular sulfhydryl repletor , also exacerbated halothane-induced liver injury. Halothane-induced hepatotoxicity is at least in part apparently regulated by cellular glutathione levels. Paradoxically, glutathione seems to be involved in the bioactivation rather than the detoxification of halothane.

Acetylcysteine↗
PubMed1994

Glutathione-S-transferase is a target for covalent modification by a halothane reactive intermediate in the guinea pig liver.

The anesthetic halothane is bioactivated by the liver cytochrome P450 system to the reactive intermediate, trifluoroacetyl chloride, which can acylate liver protein. Cytosolic glutathione-S-transferase (GST) was identified as a major target for protein adduct formation in guinea pig liver slices exposed to halothane. To determine if GST is also a target in vivo, male Hartley guinea pigs were exposed to 1% halothane in 40% O2 for 4 h. At 10 h post exposure, livers were removed and microsomal and cytosolic fractions prepared. Past studies have shown these conditions resulted in maximal covalent binding of halothane intermediates to hepatic protein. Protein was isolated by ethanol precipitation and washed with trichloroacetic acid to remove unbound metabolites. Cytosolic GST was isolated by gel filtration and S-hexyl-glutathione affinity chromatography to electrophoretic purity. Protein adducts were quantified using a covalently bound fluorine assay. Covalent binding of a halothane intermediate to cytosolic and microsomal protein was determined as 2.0 +/- 0.4 and 13.2 +/- 2.3 nmol F/mg protein, respectively. Liver glutathione depletion by buthionine sulfoximine pretreatment produced an increase in covalent binding only to cytosolic proteins (3.3 +/- 0.4 nmol F/mg protein). Adduct formation to cytosolic GST was determined to be 4.7 +/- 1.6 nmol F/mg protein. Glutathione-S-transferase is a target for covalent modification in the liver following an inhalation exposure to halothane.

Administration, Inhalation↗
PubMed1987

Spin-echo fluorine magnetic resonance imaging at 2 T: in vivo spatial distribution of halothane in the rabbit head.

Spin-echo 19F magnetic resonance imaging was performed at 2.0 T to explore the in vivo spatial distribution of halothane in the rabbit head. Because the halothane concentration is low in vivo, and because the measured relaxation times of the 19F resonance peak for halothane were T1 approximately equal to 1.0 sec and T2 approximately equal to 3.5-65 msec, 1-3-h imaging times were required (TR = 1 sec, TE = 9 msec) in order to obtain adequate images with a 64 X 256 raw data matrix and a 20-mm slice thickness. With this technique, halothane was primarily detected in lipophilic regions of the rabbit head, but little or no halothane was observed in brain tissue. Because T2 was shorter in brain tissue than in surrounding fat, a shorter TE than we could obtain is needed for optimal spin-echo imaging of brain halothane.

Animals↗
PubMed1988

Comparison of the hemodynamic and echocardiographic effects of sufentanil, fentanyl, isoflurane, and halothane for pediatric cardiovascular surgery.

Sufentanil, fentanyl, halothane, and isoflurane were compared as sole anesthetic agents in 48 infants and children aged 6 months to 9 years, undergoing repair of congenital heart defects. Patients were randomly assigned to receive sufentanil, 20 microg/kg, fentanyl, 100 microg/kg, isoflurane, 1.6%, or halothane, 0.9%, along with pancuronium, 0.08 mg/kg, for induction and maintenance of anesthesia. Cardiovascular function was measured by echocardiography prior to induction, postinduction, and postintubation. Systemic arterial pressure and heart rate were also recorded. Left ventricular ejection fraction (LVEF) decreased following induction with each agent: sufentanil 9%, fentanyl 9%, isoflurane 4%, and halothane 8%. Following intubation LVEF increased in the sufentanil, fentanyl, and isoflurane groups, but LVEF remained 13% below baseline values in the halothane group. Five of the 12 patients in the halothane group had a LVEF less than 55%. Arterial pressure immediately prior to bypass was significantly less than baseline in each group; however, arterial pressure was higher in the narcotic groups during isolation and cannulation of the great vessels. It is concluded that halothane, 0.9%, used as an induction agent in infants and children undergoing cardiac surgery causes a clinically significant decrease in LVEF. Based on the echocardiographic data, sufentanil, fentanyl, and isoflurane as used in the present study do not have a clinically significant effect on cardiac function and may offer an advantage to infants and children with marginal cardiovascular reserve.

Anesthetics, Inhalation↗