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PubMed1996

Cardiac and regional hemodynamic interactions between halothane and nitric oxide synthase activity in dogs.

BACKGROUND: In vitro, halothane appears to affect the role played by nitric oxide in the regulation of vascular tone and cardiac function. In vivo, the results of the interactions between halothane and the nitric oxide pathway remain controversial. The authors investigated the effects of halothane on the cardiac and regional hemodynamic properties of N-methyl-L-arginine (NMA), a specific nitric oxide synthase inhibitor, in dogs. METHODS: Twenty-five dogs were chronically instrumented. Aortic pressure, the first derivative of left ventricular pressure, cardiac output, heart rate, and carotid, coronary, mesenteric, hepatic, portal and renal blood flows were continuously recorded. N-methyl-L-arginine was infused intravenously at 20 mg/kg over 1 min in awake dogs (n = 11) and in 1.2% halothane-anesthetized dogs (n = 10). As a control group, the remaining four dogs were studied awake and during 1.2% halothane for 2 h in the absence of NMA. RESULTS: In awake dogs, NMA produced a sustained pressor response (34%) and systemic vasoconstriction (40%) associated with a decrease in cardiac output (16%). Regional circulation changes included an immediate and transient increase in carotid (43%) and coronary (237%) blood flows and a subsequent decrease in carotid blood flow (25%). Hepatic and mesenteric blood flows also decreased, by 43% and 16%, respectively. Except for the coronary circulation, regional vascular resistance increased significantly. Halothane did not affect the pressor response to NMA but did blunt the cardiac output changes. Consequently, the systemic vasoconstriction after nitric oxide synthase inhibition was of shorter duration and of lesser magnitude during halothane anesthesia. Halothane also blunted the carotid, mesenteric, and renal vasoconstriction induced by NMA. Finally, in 1.2% halothane-anesthetized dogs, NMA induced a coronary vasoconstriction. CONCLUSIONS: Halothane minimally interferes with the systemic and regional hemodynamic consequences of nitric oxide synthase blockade. The nature and magnitude of the interaction depend on the territory in which they occur.

Anesthetics, Inhalation↗

PubMed1997

Interaction of halothane with alpha- and beta-adrenoceptor stimulations in rat myocardium.

BACKGROUND: Halothane induces negative inotropic and lusitropic effects in myocardium. It has been suggested that halothane potentiates beta-adrenoceptor stimulation. However, its effects on the inotropic response to alpha-adrenoceptor stimulation and its effects on the lusitropic effects of alpha- and beta-adrenoceptor stimulation are unknown. METHODS: The effects of halothane (0.5 and 1 minimum alveolar concentration [MAC]) on the inotropic responses induced by phenylephrine (10(-8) to 10(-4) M) and isoproterenol (10(-8) to 10(-4) M) were studied in rat left ventricular papillary muscles in vitro (in Krebs-Henseleit solution at 29 degrees C, pH 7.40, with 0.5 mM calcium and stimulation frequency at 12 pulses/min). The lusitropic effects were studied in isotonic (R1) and isometric (R2) conditions. RESULTS: One MAC halothane induced a negative inotropic effect (54 +/- 3%, P < 0.05), increased R1 (109 +/- 3%, P < 0.05), and decreased R2 (88 +/- 2%, P < 0.05). In control groups, phenylephrine (137 +/- 7%, P > 0.05) and isoproterenol (162 +/- 6%, P < 0.05) induced a positive inotropic effect. Halothane did not significantly modify the positive inotropic effect of calcium, suggesting that it did not modify the inotropic reserve of papillary muscles. In contrast, 1 MAC halothane enhanced the positive inotropic effects of phenylephrine (237 +/- 19%, P < 0.05) and isoproterenol (205 +/- 11%, P < 0.05). Halothane did not modify the lusitropic effect of phenylephrine under high or low load. In contrast, 1 MAC halothane impaired the positive lusitropic effect of isoproterenol under low load (P < 0.05), whereas it did not modify the positive lusitropic effect of isoproterenol under high load. CONCLUSIONS: At clinically relevant concentrations, halothane potentiated the positive inotropic effects of both alpha- and beta-adrenoceptor stimulation. Furthermore, halothane alters the positive lusitropic-effect of beta-adrenoceptor stimulation under low load.

Anesthetics, Inhalation↗

PubMed1997

Halothane interactions with nicotinic acetylcholine receptor membranes. Steady-state and kinetic studies of intrinsic fluorescence quenching.

BACKGROUND: Although it has been suggested that anesthetics alter protein conformational states by binding to nonpolar sites within the interior regions of proteins, the rate and extent to which anesthetics penetrate membrane proteins has not been characterized. The authors report the use of steady-state and stopped-flow spectroscopy to characterize the interactions of halothane with receptor membranes. METHODS: Steady-state and stopped-flow fluorescence spectroscopy was used to characterize halothane quenching of nicotinic acetylcholine receptor (nAcChoR)-rich membrane intrinsic fluorescence and the rate of isoflurane-induced nAcChoR desensitization. RESULTS: At equilibrium, halothane quenched only 54 +/- 1.4% of all tryptophan fluorescence. Diethyl ether failed to reduce fluorescence quenching by halothane, suggesting that it does not bind to the same protein sites as halothane. Stopped-flow fluorescence traces defined two kinetic components of quenching: a fast component that occurred in less than 1 ms followed by a slower biphasic fluorescence decay. Protein unfolding with sodium dodecyl sulfate reduced halothane's Stern-Volmer quenching constant, eliminated the biphasic decay, and rendered fluorescence accessible to quenching by halothane within 1 ms. Functional studies indicate that anesthetic-induced desensitization of nAcChoR occurs in less than 2 ms. CONCLUSIONS: Unquenchable fluorescence arises from tryptophan residues that are buried within the protein and protected from halothane. Sodium dodecyl sulfate unfolds membrane proteins and allows previously buried fluorescence protein residues to be rapidly and homogeneously quenched by halothane. Halothane quenches protein components of nAcChoR membranes over the same concentration range and time scale that it exerts its functional effects, a finding that is generally consistent with a protein site of action.

Anesthetics, Inhalation↗

PubMed1997

Conformational state-dependent effects of halothane on cardiac Na+ current.

BACKGROUND: The Na+ channel is voltage gated and characterized by three distinct states: closed, open, and inactivated. To identify the effects of halothane on the cardiac Na+ current (I(Na)) at various membrane potentials, the effects of 1.2 mM halothane at different holding potentials (V(H)) on I(Na) were examined in single, enzymatically isolated guinea pig ventricular myocytes. METHODS: The I(Na) was recorded using the whole-cell configuration of the patch-clamp technique. Currents were generated from resting V(H)s of -110, -80, or -65 mV. State-dependent block was characterized by monitoring frequency dependence, tonic block, and removal of inactivation by veratridine. RESULTS: Halothane produced significant (P < 0.05) V(H)-dependent depressions of peak I(Na) (mean +/- SEM): 24.4 +/- 4.1% (V(H) = -110 mV), 42.1 +/- 3.4% (V(H) = -80 mV), and 75.2 +/- 1.5% (V(H) = -65 mV). Recovery from inactivation was significantly increased when cells were held at -80 mV (control, tau = 6.0 +/- 0.3 ms; halothane, tau = 7.1 +/- 0.4 ms), but not at -110 mV. When using a V(H) of -80 mV, halothane exhibited a use-dependent block, with block of I(Na) increasing from 8.6 +/- 1.4% to 30.7 +/- 3.5% at test pulse rates of 2 and 11 Hz, respectively. Use-dependent inhibition was not apparent at V(H) of -110 mV. When inactivation of I(Na) was removed by exposure to 100 microM veratridine, no significant difference was observed in the depressant effect of halothane at both V(H)s: 26.6 +/- 4.5% (V(H) = -80 mV) and 26.4 +/- 5.6% (V(H) = -110 mV). CONCLUSIONS: The present findings indicate that the depressant action of halothane on cardiac I(Na) depends on the conformational state of the channel. As more channels are in the inactivated state, the more potent is the effect of halothane. Removal of channel inactivation by veratridine abolished the dependence of the halothane effect on V(H), but depression of the current was still evident. These results indicate a complex interaction between halothane and the various conformational states of the Na+ channel.

Anesthetics, Inhalation↗

PubMed1998

Effects of halothane on the sarcoplasmic reticulum Ca2+ stores and contractile proteins in rabbit pulmonary arteries.

BACKGROUND: The authors' purpose of this study was to elucidate the mechanisms of direct effects of halothane on the contractile proteins and Ca2+ release from the sarcoplasmic reticulum Ca2+ stores using isolated skinned strips (sarcolemma permealized with saponin) from rabbit pulmonary arteries. METHODS: The sarcoplasmic reticular Ca2+ stores were examined by immersing the skinned strips sequentially in solutions to load Ca2+ into and release Ca2+ from the sarcoplasmic reticulum using caffeine, inositol 1,4,5-trisphosphate, or halothane. The contractile proteins were assessed by activating the strips with Ca2+ followed by administration of halothane (with or without protein kinase C inhibitors). Tension, fura-2 fluorescence activated by Ca2+ release, and phosphorylation of myosin light chains were measured. RESULTS: Halothane (0.07-3.00%) increased Ca2+, tension, and phosphorylation of myosin light chains in a dose-dependent manner. Halothane decreased accumulation of Ca2+ in the sarcoplasmic reticulum and enhanced the caffeine-induced tension transients. In strips pretreated with caffeine or inositol 1,4,5-trisphosphate, halothane-induced tension transients were reduced but Ca2+ was not. In strips activated by 1 microM Ca2+, halothane (0.5-3.0%) decreased 20-45% of the activated force at 15 min. Halothane (3%) transiently increased the force (20%) associated with increases in Ca2+ and phosphorylation of myosin light chains. The increased force was abolished and the subsequent relaxation was enhanced by the protein kinase C inhibitor bisindolylmaleimide but not by indolocarbazole Gö-6976. CONCLUSIONS: In skinned pulmonary arterial strips, halothane, at clinical concentrations, inhibits uptake of Ca2+ by and induces release of Ca2+ from intracellular stores possibly shared by caffeine and inositol 1,4,5-trisphosphate, which are regulated by phosphorylation of myosin light chains. The time-dependent inhibition of the contractile proteins by halothane may be mediated by Ca2+-independent protein kinase C.

Anesthetics, Inhalation↗

PubMed2000

Lack of whole-body pharmacokinetic differences of halothane enantiomers in the rat.

BACKGROUND: Halothane is made and used as a racemate (an equimolar mixture of R- and S- enantiomers). This study was initiated to determine whether there were demonstrable enantiomeric differences in the whole-body pharmacokinetics of halothane that might have significance for studies in which racemate is used. METHODS: Adult male Wistar rats were exposed to halothane vaporized in the atmosphere of a closed constant volume chamber supplied with O2 commensurate with CO2 production. Concentrations of halothane enantiomers were measured by a specific gas chromatography-mass spectrometry method. Experiments were performed at four initial concentrations of halothane (0.1%, 0.5%, 1.0%, and 1.5% vol/vol). Enantiomeric differences in whole-body pharmacokinetics were assessed indirectly from the relative chamber atmosphere concentrations of halothane enantiomers. RESULTS: Concentrations of halothane decreased biphasically. The initial more rapid decrease was interpreted as incorporating absorption, distribution, and clearance; the slower decrease was interpreted as principally incorporating metabolic clearance. The ratio of concentrations of the two halothane enantiomers and of the ratios of the respective areas under the concentration-time curves remained constant without differing from unity at any time at any concentration of halothane. The dose-normalized areas under the concentration-time curves for the concentrations 0.1%, 0.5%, and 1.0% did not differ; that for 1.5% was significantly greater, suggesting nonlinear clearance, but the values did not differ significantly between enantiomers at any concentration. CONCLUSIONS: As there were no significant differences in concentrations of the two enantiomers in the chamber atmosphere, enantioselectivity was not demonstrated in the whole-body pharmacokinetics of halothane.

Anesthetics, Inhalation↗

PubMed2001

Halothane but not isoflurane attenuates interleukin 1beta-induced nitric oxide synthase in vascular smooth muscle.

BACKGROUND: Inducible nitric oxide synthase (iNOS) is induced by endotoxin or cytokines, such as interleukin (IL)-1, through a protein synthesis pathway. Halothane reportedly inhibits protein synthesis in various tissues. The aim of the current study was to examine the effect of halothane on the IL-1beta-evoked induction of NOS in vascular smooth muscle. METHODS: After removal of the endothelium, arterial rings of rat aorta were mounted in an isometric force recording system. The effects of halothane (1.0-3.0%) or isoflurane (3.0%) on IL-1beta (20 ng/ml)-induced inhibition of the contractile responses to KCl (30 mM) and phenylephrine (10(-9)-10(-5) M) were studied. The cyclic guanosine monophosphate and cyclic adenosine monophosphate contents were determined by radioimmunoassay. Expression of iNOS and iNOS mRNA were measured by Western or Northern blot analysis, respectively. RESULTS: Halothane (1.0-3.0%) but not isoflurane (3%) significantly reduced the ML-1beta-induced inhibition of contraction in a concentration-dependent manner. The cyclic guanosine monophosphate content of the vascular smooth muscle increased significantly after a 5-h exposure to IL-1beta. Halothane at 3.0% significantly inhibited the increase in cyclic guanosine monophosphate content induced by IL-1beta. Halothane had no effect on cyclic adenosine monophosphate content. IL-1beta-induced expression of iNOS and iNOS mRNA in the rat aorta were inhibited significantly by halothane. CONCLUSION: The current study demonstrated that halothane but not isoflurane inhibits IL-1beta-stimulated hyporesponsiveness to vasoconstrictive agents in vascular smooth muscle and that this inhibitory effect of halothane involves the inhibition of iNOS mRNA expression. Thus, these findings suggest that halothane may have some sites to affect nitric oxide-signaling pathway.

Adenylyl Cyclases↗

PubMed2002

Does the immobilizing effect of thiopental in brain exceed that of halothane?

BACKGROUND: Recent studies suggest that anesthetics such as isoflurane act in the spinal cord to suppress movement that occurs during noxious stimulation. The authors examined the effect of halothane and thiopental on suppression of noxious-evoked movement using a model of differential anesthetic delivery. They hypothesized that halothane and thiopental, similar to isoflurane, would suppress movement primarily via an action in spinal cord. METHODS: Goats were anesthetized and prepared for differential anesthetic delivery. Anesthesia was maintained with halothane (n = 5) or thiopental (n = 5). Anesthetic requirements were determined (noxious clamp on a dewclaw for 1 min) during halothane or thiopental (via infusion) delivery to the whole body and delivery only to the head. RESULTS: Control (whole body) halothane requirement was 0.9 +/- 0.2%; halothane requirement in the head during differential delivery was 3.4 +/- 1% (P < 0.01). During selective halothane delivery, the electroencephalogram was greatly depressed or was isoelectric even though the animals moved during noxious stimulation. Control (whole body) plasma thiopental requirement was 20 +/- 10 microg/ml. When thiopental was selectively delivered to the head, the electroencephalogram was active in all five animals, and cranial thiopental requirement was 42 +/- 6 microg/ml (P < 0.01). CONCLUSION: These data suggest that halothane and thiopental, like isoflurane, act in spinal cord to suppress movement occurring with noxious stimulation. However, halothane appears to be less potent in the brain as evidenced by the electroencephalogram data, suggesting that action in spinal cord plays a more significant role for halothane than for thiopental.

Anesthetics, Inhalation↗

PubMed1996

Effect of halothane on phenylephrine-induced vascular smooth muscle contractions in endotoxin-exposed rat aortic rings.

OBJECTIVES: a) To determine the response of endotoxin-exposed vascular smooth muscle to exogenous vasoconstrictors during concomitant exposure to an inhaled anesthetic (halothane); and b) to determine if excess nitric oxide production is responsible for any altered response. DESIGN: In vitro, prospective, repeated-measures, dose-response study. SETTING: University/medical school experimental physiology laboratory. SUBJECTS: Adult male Sprague-Dawley rats, whose aortae were studied in an in vitro preparation. INTERVENTIONS: Thoracic aortae were excised from anesthetized animals and cut into 3-mm rings. After incubation in aerated organ baths containing a modified essential medium with or without Escherichia coli lipopolysaccharide (100 micrograms/mL) at 37 degrees C for 5 hrs, the rings were removed and suspended in separate baths for isometric tension recording. Phenylephrine dose-response data (10(-10) to 10(-5) M) were determined for lipopolysaccharide- and nonlipopolysaccharide-treated rings. After washout and equilibration, two vessels (one each lipopolysaccharide- and nonlipopolysaccharide-treated) were additionally exposed to 2% halothane and phenylephrine dose-response determinations were repeated for all vessels. This procedure was repeated for 1% halothane in a separate experiment. In some experiments, the nitric oxide synthase inhibitor, N omega-nitro-L-arginine (3 x 10(-4) M), was added to the bath after the washout from the second phenylephrine dose-response determination. Then, a third phenylephrine dose-response determination was performed, with and without 2% halothane. MEASUREMENTS AND MAIN RESULTS: Dose-response curves were evaluated using a logistic regression analysis. In addition, absolute and percentage changes in tension were compared between the first and second contractions. Exposure to lipopolysaccharide resulted in a decrease in the maximum tension from 2.07 +/- 0.03 (controls) to 1.24 +/- 0.04 g/mg of vessel dry weight and an increase in the dose at which the contraction is 50% of maximum (ED50) from 3.78 x 10(-8) to 2.05 x 10(-7) M (p < .05). Exposure to 2% halothane produced significant reductions in the maximum tensions in both groups. The lipopolysaccharide-treated vessels showed not only a proportionately larger decrease (-51 +/- 5% vs. -18 +/- 2% in the control plus halothane group), but also a significantly greater absolute decrease (0.59 +/- 0.09 vs. 0.34 +/- 0.04 g/mg in the control plus halothane group). The addition of 1% halothane produced less pronounced decreases in tension, with only an additive effect in the lipopolysaccharide-treated vessels. The addition of N omega-nitro-L-arginine resulted in a reversal of the lipopolysaccharide-induced decrease in tension. However, 2% halothane still had a significantly greater effect on the lipopolysaccharide-exposed rings. CONCLUSIONS: Exposure of rat aortic rings to lipopolysaccharide in vitro decreased the contractile response to phenylephrine. The addition of 2% halothane resulted in a more than additive decrease in tension in the lipopolysaccharide-treated vessels. Patients in septic or endotoxic shock are sensitive to most anesthetic regimens, and some of this sensitivity may be due to an altered vasoconstrictive response induced by lipopolysaccharide exposure. The inability of nitric oxide synthase inhibition to reverse this response completely suggests that induction of nitric oxide synthase and increased production of nitric oxide are not solely responsible for this finding.

Anesthetics, Inhalation↗

PubMed1987

Respiratory depression in children at different end tidal halothane concentrations.

Respiratory motor function and timing were investigated at end tidal halothane concentrations of 1.5%, 1.0% and 0.5% before and during 4% carbon dioxide stimulation in 10 spontaneously breathing children who weighed between 10.2 and 25.2 kg, during hypospadias repair under halothane anaesthesia. Their tracheas were intubated and all received a caudal block to eliminate surgical stimulation. Pneumotachography and capnography were used and in three cases movements of ribcage and abdomen were also studied by magnetometers. Respiratory drive was evaluated by occlusion tests. Ventilation was depressed at an end tidal halothane concentration of 1.5%, with smaller tidal volumes, higher respiratory rates, higher end tidal carbon dioxide tensions and a weaker respiratory drive compared with 1.0% and 0.5% halothane. Paradoxical breathing was noted at 1.5% as well as at 1.0% but not at 0.5% halothane anaesthesia; the ribcage moved inwards during inspiration. Respiratory compensation during periods of 4% carbon dioxide stimulation was inadequate at 1.5% halothane, as indicated by higher end tidal carbon dioxide tensions, less negative occlusion pressures and movements of ribcage and abdomen that were unresponsive to 4% carbon dioxide, when compared with 1.0% and 0.5% halothane. Respiratory rates were higher and duration of inspiration longer at 1.5% than at 1.0% and 0.5% halothane. Respiratory timing was unaltered by carbon dioxide stimulation. It is concluded that the ventilatory motor response to carbon dioxide is dose dependent and improves at more superficial anaesthetic levels, while respiratory timing is unresponsive to carbon dioxide stimulation irrespective of the halothane concentration used. Paradoxical breathing existed at end tidal halothane concentrations higher than 1%.

Abdomen↗

PubMed1995

Detection of autoantibodies directed against human hepatic endoplasmic reticulum in sera from patients with halothane-associated hepatitis.

1. Previous studies have demonstrated the presence of antibodies to trifluoroacetylated hepatic proteins (TFA-proteins) in sera from patients with the severe form of halothane-associated hepatitis (halothane hepatitis). The TFA-proteins are produced via cytochrome P450-mediated metabolism of halothane to the reactive species TFA-chloride. 2. To investigate the presence of autoantibodies (which recognize various non-TFA-modified human hepatic polypeptides) in patients with halothane hepatitis immunoblotting experiments were performed using microsomal fractions prepared freshly from livers of five different (halothane-free) tissue donors. Blots were developed using 15 well-characterised sera from patients with halothane hepatitis. 3. Autoantibodies to human hepatic polypeptides were detected in most, but not all, of the patients' sera. The pattern of antibody reactivity varied markedly between sera. Although no common pattern of antibody recognition was observed, polypeptides of molecular mass between 60 and 80 kDa were the predominant targets. A similar protein recognition pattern was seen when each positive serum was tested against the five individual human liver samples. 4. Such autoantibodies were not detected in sera from 16 normal human blood donors, but were detected in three of six sera from patients exposed to halothane without developing hepatitis. 5. The autoantibodies are thought to arise in patients exposed to halothane as a consequence of a halothane-induced immune response to chemically-modified proteins. Such antibodies could contribute to the complex pathological processes involved in halothane hepatitis.

Adult↗

PubMed1984

Comparison of halothane and enflurane anaesthesia for tonsillectomy in adults.

Halothane and enflurane in combination with N2O/O2 were compared in 103 adults undergoing tonsillectomy. Anaesthesia was induced with thiopental, and intubation was facilitated with suxamethonium. During halothane anaesthesia the mean heart rate ranged from 91 to 106 beats/min and the mean systolic arterial pressure from 111 to 127 mmHg. The values did not differ significantly from the corresponding values during enflurane anaesthesia. Electrocardiographic changes occurred in 56% and 31% of the patients anaesthetized with halothane or enflurane, respectively. the incidence of junctional rhythm, the most common ECG change, was 46% in the halothane group and 29% in the enflurane group. 19% of the patients in the halothane group and 31% in the enflurane group responded to surgical stimulus by swallowing or coughing. The responses were mostly short-lasting and did not much disturb the surgeon. The incidence of laryngospasm was 6% after halothane and 2% after enflurane anaesthesia. The mean total recovery score (0-10) was 6.1 after halothane and 6.3 after enflurane at arrival in the recovery room and 9.8 in both groups 30 min later. After halothane, nausea and vomiting occurred in 8 and 12% of the patients, respectively. The corresponding figures after enflurane were 2 and 8%. It is concluded that both halothane and enflurane are suitable anaesthetics for tonsillectomy in adults. The most striking difference between the anaesthetics was the significantly more common occurrence of ECG changes during halothane than enflurane anaesthesia.

Adult↗

PubMed1992

Halothane metabolism. Impairment of hepatic omega-oxidation of leukotrienes in vivo and in vitro.

Omega-oxidation of leukotrienes is the initial step of hepatic degradation and thus inactivation of these proinflammatory mediators. Omega-oxidation is followed by beta-oxidation of leukotrienes from the omega-end. After exposure of rats to a single dose of the anesthetic agent halothane, a transient decrease in leukotriene omega-oxidation was induced both in vivo and in vitro. In untreated rats, 44.1 +/- 6.0% of N-[3H]acetylleukotriene E4 injected intravenously was recovered unchanged in bile collected for 60 min in vivo; 46.5 +/- 3.0% was recovered as omega-/beta-oxidation products, of which 24.7 +/- 4.5% were associated with beta-oxidation products only (mean +/- SEM; n = 5). In rats receiving a single dose of halothane 18 h before the experiment, recovery of unchanged N-[3H]acetylleukotriene E4 was significantly increased to 79.8 +/- 4.8%, while the fraction of omega-/beta-oxidation products decreased to 9.0 +/- 1.7% (n = 5); 90 h after exposure to halothane, N-[3H]acetylleukotriene E4 recovery decreased to 30.0 +/- 3.0% and omega-/beta-oxidation products amounted to 49.1 +/- 3.8%; the fraction of beta-oxidation products was significantly increased to 43.1 +/- 3.4% (n = 5). Ten days after exposure of rats to halothane, the recoveries of N-[3H]acetylleukotriene E4, of omega-/beta-oxidation products, and of beta-oxidation products alone, returned to almost normal values. Microsomal fractions obtained from rat hepatocytes catalyzed the NADPH- and O2-dependent leukotriene omega-oxidation in vitro. The formation of omega-hydroxy-metabolites of leukotriene B4, leukotriene E4, and N-acetylleukotriene E4 was decreased by 50% in microsomal fractions obtained from rats 18 h and 90 h after halothane treatment, and returned back to control levels in microsomal fractions obtained 10 days after halothane treatment. The Km value of leukotriene B4 omega-oxidation revealed no significant change in enzyme affinity towards leukotriene B4; in contrast, as reflected by the reduction of the Vmax value by 65%, a decrease in the amount of the active enzyme in microsomes obtained from rats 18 h after halothane treatment was observed. Halothane-metabolism-dependent trifluoroacetylation of hepatic proteins may mediate this process. Thus, the time course of the density on immunoblots of trifluoroacetylated protein adducts paralleled that of the transient decrease in leukotriene omega-oxidation. In contrast to its omega-oxidation, leukotriene B4 synthesis from 5-hydroperoxyeicosatetraenoate was not inhibited in hepatocyte homogenates obtained from rats pretreated with halothane. The data suggest that metabolism of halothane causes a transient derangement of hepatic leukotriene homeostasis in vivo.

Animals↗

PubMed1988

Extrahepatic sites of metabolism of halothane in the rat.

Rats were given 14C-halothane intravenously and whole-body autoradiography with freeze-dried sections, or with sections extracted in trichloroacetic acid, water, and organic solvents, was carried out to trace tissues accumulating halothane metabolites. In vitro incubations of tissue homogenates were performed to examine the capacity by the various organs to form tissue-bound 14C from the 14C-halothane. Autoradiography of isolated organs after incubation with 14C-halothane was performed to study the tissue localization of halothane metabolites formed under in vitro conditions. A localization of halothane metabolites was observed in several extrahepatic tissues in vivo, and the in vitro experiments showed a capacity by the same tissues to transform 14C-halothane to metabolites that bind strongly to tissue components. In addition to the liver, the other tissues shown to have a marked halothane-metabolizing capacity were the nasal mucosa, lateral nasal gland, mucosa of the tongue, cheek, soft palate (but not the hard palate), pharynx, larynx, oesophagus, and the tracheo-bronchial mucosa. The in vivo data obtained indicated a diffusion of the halothane over the walls of the large intestine and the caecum, followed by the formation of apparently reductive metabolites by intestinal microbes and a binding of the metabolites to the intestinal contents. The localization of halothane metabolites in the upper alimentary and respiratory pathways is correlated to the presence of cytochrome P-450 at these sites.

Animals↗

PubMed1990

The inhibitory effect of halothane on the emetic response in the ferret.

Emesis and nausea are often associated with anaesthesia and continue to be a common clinical problem. Past clinical studies have demonstrated that halothane produces a higher incidence of vomiting compared with other anaesthetics, but some investigators have described an antiemetic effect. The purpose of this study was to investigate the effects of various doses of halothane on the emetic response in the decerebrate ferret. Following a control emetic response, a maximum of six increasing cumulative concentrations of halothane were delivered. At the end of each delivery period, the supradiaphragmatic vagal communicating branch, which has been shown to reproducibly elicit vomiting, was electrically stimulated and the emetic response was monitored. An increase in halothane concentration produced a marked depression of tongue, abdominal muscle, and diaphragm EMG activity as well as a decrease in central venous pressure. Licking, a prodromal response comparable to nausea in the human, appeared to be most sensitive. An increase in latency of the emetic response occurred as the concentration of halothane was increased. All phases of the response were observed at concentrations below 0.6 vol% halothane. At 0.6 vol% halothane, 75% of the animals vomited. At higher concentrations, the emetic response was completely abolished. One hour post-halothane, all latencies had returned to near control values. The methods utilized in this study provided a model that was not complicated by a large number of variables usually present in clinical studies. These data demonstrate that halothane exerts an inhibitory, concentration-dependent, and reversible effect on the emetic response in the ferret and provide further support that halothane alone does not possess emetic properties at clinical properties at clinical concentrations.

Animals↗

PubMedDate not supplied

Antiarrhythmic anesthetic action I: the effect of halothane on canine intracardiac impulse conduction during sinus rhythm.

The effect of halothane on intracardiac impulse conduction was assessed in dogs before and after pharmacologic vagotomy. Impulse conduction was measured by anesthetic-related changes in the A-H and H-V intervals of the His bundle electrogram. Prior to vagotomy, both "light" and "deep" halothane prolonged the A-H interval significantly. Maximal A-H interval prolongations corresponded to the maximal decrease in heart rate with either dose of anesthetic. Following vagotomy, the A-H prolongation produced by light halothane was abolished and the prolongation produced by the deep level greatly reduced. Neither dose of halothane had a measurable effect on the H-V interval before or after vagotomy. In one animal in which the effects of increasing rates of atrial pacing were measured without the addition of halothane, the A-H interval lengthened with no measurable change in the H-V interval. In two dogs in which the heart rate was held near pre-halothane levels by atrial pacing, the A-H interval was slightly prolonged and the H-V interval unchanged during the administration of deep halothane. These studies indicate that during sinus rhythm: (1) halothane prolongs A-V impulse conduction, (2) that this effect is correlated with a concomitant decrease in heart rate, and (3) that these effects are largely dependent upon intact vagal innervation of the heart. During atrial pacing, A-V conduction is prolonged by increased heart rate or by deep halothane when the heart rate is held constant. Thus, in addition to the known effects of halothane on pacemaker automaticity, concomitant changes in conduction may contribute to the antiarrhythmic action of this anesthetic.

Anesthesia, Inhalation↗

PubMed1992

Halothane reduces dysrhythmias and improves contractile function after global hypoperfusion in isolated hearts.

We investigated the effects of halothane on changes in cardiac function during hypoperfusion and recovery of function after reperfusion in the isolated perfused guinea pig heart. Heart rate, atrioventricular (AV) conduction time, the incidence and severity of dysrhythmias, and isovolumetric left ventricular systolic pressure (LVSP) and its derivative were measured. Hearts (n = 85) were divided into three groups for 30 min of perfusion at 0% (no flow), 10%, and 25% of the control perfusion pressure (PP, 55 mm Hg). These groups were subdivided and exposed to 0%, 0.74% (0.23 +/- 0.01 mM), or 1.65% (0.51 +/- 0.01 mM) halothane 10 min before, during, and 10 min after hypoperfusion. Hypoperfusion was followed by 40 min of reperfusion at control PP. Exposure to 0.74% and 1.65% halothane before hypoperfusion produced a 9% and 13% decrease in heart rate, a 2% and 30% increase in AV conduction time, and a 25% and 51% decrease in LVSP and dLVP/dtmax, respectively. During the 30 min of hypoperfusion, heart rate decreased and AV conduction time increased; second- and third-degree AV block occurred in all hearts in the 0% and 10% PP groups, but only in some hearts in the 25% PP groups. Left ventricular systolic pressure rapidly decreased during hypoperfusion in all groups. During early reperfusion ventricular fibrillation and ventricular tachycardia occurred in the 0% and 10% PP groups but not in the 25% PP groups. During reperfusion 0.74% and 1.65% halothane greatly reduced the duration of ventricular fibrillation from 8.1 +/- 3.3 min to 1.5 +/- 0.8 and 1.9 +/- 1.2 min in the 0% and 10% PP groups, respectively. A concentration of 0.74% halothane increased the incidence of supraventricular tachycardia on reperfusion in the 10% group (from a control of 20% to 65%), and 1.65% halothane increased the duration (2.6 +/- 2.5 min) and incidence (38%) of supraventricular tachycardia on reperfusion in the 0% PP group. A concentration of 1.65% halothane facilitated recovery of LVSP after hypoperfusion in the 25% group but not in the 0% and 10% PP groups. These results indicate that halothane, in some instances, can have protective cardiac effects after graded hypoperfusion as assessed by improved contractility and by reduced severity of some dysrhythmias during reperfusion; however halothane may also increase the incidence of supraventricular tachycardia. The cardiac protection by halothane could be a result of reduced cardiac work before, during, and after hypoperfusion, or of some other direct protective cellular effects.

Animals↗

PubMed1993

Halothane reduces release of adenosine, inosine, and lactate with ischemia and reperfusion in isolated hearts.

We investigated the protective effects of halothane on cardiac function of isolated hearts during global hypoperfusion and reperfusion by examining halothane's effects on altering coronary flow, myocardial oxygen utilization (MVO2), and release of adenosine (ADE), inosine (INO), and lactate (LAC). Isolated perfused guinea pig hearts were divided into three groups of perfusion at 25% (14 mm Hg), 10% (5.5 mm Hg), and 0% (no perfusion) from control perfusion pressure (PP, 55 mm Hg). Each of these PP groups was subdivided into three subgroups and perfused without halothane (control), with 0.23 +/- 0.01 mM (0.74%) halothane, or with 0.51 +/- 0.01 mM (1.65%) halothane. Halothane was present 10 min before reducing PP, during reduced PP (30 min), and for 10 min after reducing PP. Hypoperfusion was followed by 40 min of reperfusion at the control (100%, 55 mm Hg) PP. An additional group of control hearts was followed for the same period without reducing PP or perfusing with halothane. Exposure to 0.74% and 1.65% halothane, before reducing PP, decreased MVO2 and percent oxygen extraction (% O2E), but produced no significant change in coronary flow or release of ADE, ISO, or LAC. During early hypoperfusion (10 min) at 25% PP, 1.65% halothane significantly reduced release of ADE, INO, and LAC. During late hypoperfusion (40 min) the differences in LAC release diminished, but release of ADE and INO remained lower in the 1.65% halothane group. With early reperfusion there was a large increase in release of these metabolites, that was dependent on the decrease in perfusion pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗