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PubMed1989

Erythrocyte osmotic fragility in porcine malignant hyperthermia and effects of halothane.

Malignant Hyperthermia (MH) has been shown to be due to an inherited disorder in cellular membrane systems, which also seem to be affected by halothane. With the erythrocyte osmotic fragility test we tried to find out if the erythrocyte membrane can serve as a diagnostic tool in malignant hyperthermia and as a model for halothane effects on membranes. We obtained MH susceptible and MH resistant pigs and their crossbreeds. The MH susceptible pigs showed the greatest degree of haemolysis in the erythrocyte osmotic fragility test. Furthermore, halothane increased haemolysis more in the erythrocytes of MH susceptible pigs. The MH resistant pigs were only slightly affected in both and the crossbreeds showed intermediate results. The variance occurring within one halothane group could be used to add a further distinguishing characteristic apart from the discrete halothane challenge test and so enable selection within a pure halothane group.

Animals↗
PubMed1996

A comparison of sevoflurance to halothane in paediatric surgical patients: results of a multicentre international study.

Induction, emergence and recovery characteristics were compared during sevoflurane or halothane anaesthetic in a large (428) multicentre, international study of children undergoing elective inpatient surgical procedures. Two hundred and fourteen children in each group underwent inhalation induction with nitrous oxide/oxygen and sevoflurane or halothane. Incremental doses of either study drug were added until loss of eyelash reflex was achieved. Steady state concentrations of anaesthesia were maintained until the end of surgery when anaesthetic agents were terminated simultaneously. Time variables were recorded for induction, emergence and the first need for analgesia in the recovery room. In addition, in 86 of the children in both groups, venous blood samples were drawn for plasma fluoride levels during and after surgery. There was a trend toward smoother induction (induction of anaesthesia without coughing, breath holding, excitement laryngospasm, bronchospasm, increased secretion, and vomiting) in the sevoflurane group with faster induction (2.1 min vs 2.9 min, P = 0.037) and rapid emergence times (10.3 min vs 13.9 min, P = 0.003). Among the children given sevoflurane, 2% developed bradycardia compared with 11% in the halothane group. Postoperatively, 46% of the children in the halothane group developed nausea and or vomiting versus 31% in the sevoflurane group (P = 0.002). Two children in the halothane group developed cardiac dysrhythmia and were dropped from the study. In addition, a child in the halothane group developed malignant hyperthermia, received dantrolene, and had an uneventful recovery. Mean maximum inorganic fluoride concentration was 18.3 microM.l-1. The fluoride concentrations peaked within one h of termination of sevoflurane anaesthetic and returned rapidly to baseline within 48 h. This study suggests that sevoflurane may be the drug of choice for the anaesthetic management of children.

Adolescent↗
PubMed1980

Brain cyclic nucleotide responses to anesthesia with halothane delivered in air or purified oxygen.

Inhalation of either 0.5% or 1.0% halothane in air caused a slight decrease in the cAMP concentration in rat cerebral cortex and cerebellum. During recovery, concentrations returned to normal in 3 h, or less. In contrast, cGMP decreased sixfold in cerebellum, but increased twofold in cortex. Recovery time for cerebellum was several hours. When oxygen was used as the carrier gas for halothane delivery, cAMP in the cortex doubled, in striking contrast to the case with halothane in air. Oxygen alone had no apparent effect. The cGMP effect of halothane delivered in oxygen appeared the same as for halothane in air. Thus, the cAMP effects of brain halothane are related to the enrichment of oxygen.

Anesthesia, Inhalation↗
PubMed1988

Influence of halothane on electrical coupling in cell pairs isolated from guinea-pig ventricle.

1. The actions of halothane on electrical coupling between cells were investigated in cell pairs isolated from guinea-pig ventricular muscle. 2. Under voltage-clamp conditions a step depolarization applied to one cell caused a similar change in potential in the second. Application of halothane led to the appearance of double peaks in inward current evoked by step depolarizations. These observations were interpreted in terms of uncoupling of the cells leading to escape of the second cell from the influence of the voltage-clamp in the first cell. 3. This suggestion that uncoupling in the presence of halothane led to differences in electrical activity in the two cells was confirmed in experiments in which independent electrodes were used to measure membrane potential in the two cells. 4. The voltage responses of both cells of the pair were recorded in response to constant current pulses. Administration of halothane led to abolition of the response recorded from the second cell while that of the first was enhanced. The actions are consistent with an action of halothane on gap junctions to block electrical coupling. 5. Qualitatively similar observations, consistent with electrical uncoupling, were observed with isoflurane. 6. These findings may be significant in relation to the arrhythmogenic actions of halothane.

Animals↗
PubMed1993

Halothane inhibits the pressor effect of diphenyleneiodonium.

1. We have recently found that diphenyleneiodonium (DPI), a novel inhibitor of nitric oxide (NO) synthase, causes pressor and tachycardic responses in pentobarbitone- but not halothane-anaesthetized rats. The present study investigated the mechanism by which halothane suppresses the pressor response of DPI. The effects of halothane on the pressor response of DPI were also compared with those of other anaesthetic agents. 2. In conscious rats, i.v. bolus injections of DPI (0.025- 1.6 mg kg-1) caused dose-dependent increases in mean arterial pressure (MAP), with ED90 of 0.07 +/- 0.01 mg kg-1 and maximal rise of MAP (Emax) of 59 +/- 2 mmHg. While ketamine potentiated Emax without altering the ED50 and pentobarbitone increased the ED50 without changing Emax of the pressor response to DPI, chloralose, urethane and ethanol displaced the curve to the right and potentiated Emax. In contrast, halothane (0.5-1.25%) dose-dependently and non-competitively reduced the pressor responses to DPI. 3. Intravenous bolus injection of a single dose of DPI (1.6 mg kg-1) caused immediate and large increases in plasma noradrenaline and adrenaline, as well as MAP in conscious rats. Halothane (1.25%) almost completely inhibited these increases. 4. The results suggest that DPI causes a pressor response in conscious rats by activating the sympathetic nervous system and halothane abolishes this pressor response by inhibiting activities of the sympathetic nervous system. The results also show that influences of anaesthetics must be taken into consideration when evaluating pressor response of vasoactive agents.

Anesthetics↗
PubMed1999

Halothane as a neuroprotectant during constant stimulation of the perforant path.

PURPOSE: To determine the neuroprotective effects of halothane during constant stimulation of the perforant path. METHODS: Male Sprague-Dawley rats had electrodes implanted into the perforant path and dentate granule cell layer under halothane anaesthesia (1-2% in oxygen). They were then divided into four groups. In group 1 (n = 9), the perforant path was stimulated at 20 Hz for 2 h under halothane anaesthesia (1-2%). In group 2 (n = 3), the animals were unstimulated but maintained under halothane anaesthesia (1-2%) for 2 h with the electrodes in place. Both groups 1 and 2 had the electrodes removed and were then allowed to recover fully from the anaesthetic. In groups 3 and 4, the electrodes were held in place with dental acrylic. Both of these groups were allowed to recover fully from anaesthesia. In group 3 (n = 3), 24-48 h after recovery from anaesthesia, the perforant path was stimulated at 20 Hz for 2 h. Group 4 (n = 3) received no stimulation. After 14-17 days, the rats were killed, and morphometry and cell counts were performed on the hippocampi from rats in groups 1 and 2. RESULTS: Cell densities were not significantly different between control (group 2), unstimulated rats, and animals stimulated under halothane anaesthesia (group 1). Stimulation in the unanaesthetised rats resulted in severe neuronal loss in hilus, CA1, and CA3. CONCLUSIONS: Halothane protects hippocampal neurons against damage induced by constant stimulation of the perforant path.

Anesthesia, Inhalation↗
PubMedDate not supplied

Minimal anesthetic concentration and cardiopulmonary dose-response of halothane in ducks.

The minimal anesthetic concentration (MAC) for halothane and cardiopulmonary dose-responses at several concentrations of halothane were determined during spontaneous ventilation in nine young adult Pekin ducks. The MAC for halothane was 1.04 +/- 0.11 (mean +/- SD). There were dose-dependent decreases in ventilation, significant reductions in inspiratory and expiratory times, and prolongation of expiratory pause times. The end-tidal halothane concentration at apnea in five ducks was less than 1.53% and anesthetic index was less than 1.51. Heart rate increased significantly as the concentration of halothane was increased, but arterial blood pressure did not change. Cardiac arrhythmias developed in five ducks at end-tidal halothane concentrations as low as 1.15%, and one duck died of cardiac arrest.

Anesthesia↗
PubMed2005

Binding of the volatile general anesthetics halothane and isoflurane to a mammalian beta-barrel protein.

A molecular understanding of volatile anesthetic mechanisms of action will require structural descriptions of anesthetic-protein complexes. Porcine odorant binding protein is a 157 residue member of the lipocalin family that features a large beta-barrel internal cavity (515 +/- 30 angstroms(3)) lined predominantly by aromatic and aliphatic residues. Halothane binding to the beta-barrel cavity was determined using fluorescence quenching of Trp16, and a competitive binding assay with 1-aminoanthracene. In addition, the binding of halothane and isoflurane were characterized thermodynamically using isothermal titration calorimetry. Hydrogen exchange was used to evaluate the effects of bound halothane and isoflurane on global protein dynamics. Halothane bound to the cavity in the beta-barrel of porcine odorant binding protein with dissociation constants of 0.46 +/- 0.10 mM and 0.43 +/- 0.12 mM determined using fluorescence quenching and competitive binding with 1-aminoanthracene, respectively. Isothermal titration calorimetry revealed that halothane and isoflurane bound with K(d) values of 80 +/- 10 microM and 100 +/- 10 microM, respectively. Halothane and isoflurane binding resulted in an overall stabilization of the folded conformation of the protein by -0.9 +/- 0.1 kcal.mol(-1). In addition to indicating specific binding to the native protein conformation, such stabilization may represent a fundamental mechanism whereby anesthetics reversibly alter protein function. Because porcine odorant binding protein has been successfully analyzed by X-ray diffraction to 2.25 angstroms resolution [1], this represents an attractive system for atomic-level structural studies in the presence of bound anesthetic. Such studies will provide much needed insight into how volatile anesthetics interact with biological macromolecules.

Anesthetics, Inhalation↗
PubMed1997

Effect of high volume epidural morphine, ketamine and butorphanol on halothane minimum alveolar concentration in ponies.

This study determined the effects of epidurally administered morphine, ketamine and butorphanol on halothane minimum alveolar concentration (MAC) in ponies. Seven ponies were anaesthetised with thiopentone and succinylcholine, intubated and anaesthesia maintained with halothane. Ventilation was controlled and blood pressure was maintained within normal limits. Following the determination of baseline halothane MAC for the pelvic and thoracic limbs the ponies were given morphine (0.1 mg/kg bwt), ketamine (0.8 or 1.2 mg/kg bwt), butorphanol (0.05 mg/kg bwt) or saline, epidurally, to a final volume of 0.15 ml/kg bwt. The halothane MAC for the pelvic and thoracic limbs was redetermined following each treatment. The baseline halothane MAC for the control group was mean +/- s.e. 0.85 +/- 0.02% and no significant change occurred after saline administration. Morphine significantly (P = 0.002) decreased MAC from, mean +/- s.e. 0.90 +/- 0.05% to 0.77 +/- 0.06% in the pelvic limb. Ketamine significantly decreased MAC in the pelvic limb from mean +/- s.e. 0.86 +/- 0.06% to 0.71 +/- 0.04%, and 0.82 +/- 0.03% to 0.71 +/- 0.02%, for the low (P = 0.008) and high dose (P = 0.001), respectively. No significant change in MAC occurred following butorphanol. No treatment reduced halothane MAC for the thoracic limb.

Analgesics↗
PubMed1998

Effect of intravenous lidocaine on halothane minimum alveolar concentration in ponies.

This study investigated the effect of lidocaine i.v. on halothane minimum alveolar concentration (MAC) in ponies. Six ponies were anaesthetised with thiopentone and succinylcholine, intubated and anaesthesia maintained with halothane. Ventilation was controlled and blood pressure maintained within clinically acceptable limits. Following a 2 h equilibration period, baseline halothane MAC was determined. The ponies were then given a loading dose of lidocaine (2.5 or 5 mg/kg bwt) or saline over 5 min, followed by a constant infusion of lidocaine (50 or 100 microg/kg/min, or saline, respectively). The halothane MAC was redetermined after a 60 min infusion of lidocaine or saline. The baseline halothane MAC for the control group was mean +/- s.d. 0.94 +/- 0.03%, and no significant decrease occurred following saline infusion. Lidocaine decreased halothane MAC in a dose-dependent fashion (r = 0.86; P < 0.0003). The results indicate that i.v. lidocaine may have a role in equine anaesthesia.

Anesthetics↗
PubMed1991

Actions of halothane on single-channel currents evoked by acetylcholine in rat myoballs.

The actions of halothane on single-channel currents evoked by acetylcholine in myoballs cultured from neonatal rat skeletal muscle have been investigated using the patch clamp technique. Halothane at concentrations of 0.5-4.0 mM was applied to inside-out cell-free membrane patches in the presence of 1.0 microM-acetylcholine. Halothane produced concentration-dependent decrease in the mean duration of the single-channel current events; 3.0 mM-halothane halved the slow time constant of channel closure. There was no effect on the amplitude of the single-channel currents, and no increase in the number of closing events per burst was observed. The distribution of closed times was complex but halothane did not markedly alter the frequency of channel opening events. Halothane therefore decreased the time-averaged acetylcholine-evoked membrane current, largely through an increase in the rate of channel closure.

Acetylcholine↗
PubMed2002

Halothane, isoflurane and sevoflurane inhibit NADH:ubiquinone oxidoreductase (complex I) of cardiac mitochondria.

We have investigated the effects of volatile anaesthetics on electron transport chain activity in the mammalian heart. Halothane, isoflurane and sevoflurane reversibly increased NADH fluorescence (autofluorescence) in intact ventricular myocytes of guinea-pig, suggesting that NADH oxidation was impaired. Using pig heart submitochondrial particles we found that the anaesthetics dose-dependently inhibited NADH oxidation in the order: halothane > isoflurane = sevoflurane. Succinate oxidation was unaffected by either isoflurane or sevoflurane, indicating that these agents selectively inhibit complex I (NADH:ubiquinone oxidoreductase). In addition to inhibiting NADH oxidation, halothane also inhibited succinate oxidation (and succinate dehydrogenase), albeit to a lesser extent. To test the hypothesis that complex I is a target of volatile anaesthetics, we examined the effects of these agents on NADH:ubiquinone oxidoreductase (EC 1.6.99.3) activity using the ubiquinone analogue DBQ (decylubiquinone) as substrate. Halothane, isoflurane and sevoflurane dose-dependently inhibited NADH:DBQ oxidoreductase activity. Unlike the classical inhibitor rotenone, none of the anaesthetics completely inhibited enzyme activity at high concentration, suggesting that these agents bind weakly to the 'hydrophobic inhibitory site' of complex I. In conclusion, halothane, isoflurane and sevoflurane inhibit complex I (NADH:ubiquinone oxidoreductase) of the electron transport chain. At concentrations of approximately 2 MAC (minimal alveolar concentration), the activity of NADH:ubiquinone oxidoreductase was reduced by about 20 % in the presence of halothane or isoflurane, and by about 10 % in the presence of sevoflurane. These inhibitory effects are unlikely to compromise cardiac performance at usual clinical concentrations, but may contribute to the mechanism by which volatile anaesthetics induce pharmacological preconditioning.

Anesthetics, Inhalation↗
PubMed2006

Halothane directly modifies Na+ and K+ channel activities in cultured human alveolar epithelial cells.

During inhalational anesthesia, halogenated gases are in direct contact with the alveolar epithelium, in which they may affect transepithelial ion and fluid transport. The effects of halogenated gases in vivo on epithelial Na+ and K+ channels, which participate in alveolar liquid clearance, remain unclear. In the present study, the effects of halothane (1, 2, and 4% atm) on ion-channel function in cultured human alveolar cells were investigated using the patch-clamp technique. After exposure to 4% halothane, amiloride-sensitive whole-cell inward currents increased by 84+/-22%, whereas tetraethylammonium-sensitive outward currents decreased by 63+/-7%. These effects, which occurred within 30 s, remained for 30-min periods of exposure to the gas, were concentration-dependent, and were reversible upon washout. Pretreatment with amiloride prevented 90+/-7% of the increase in inward currents without change in outward currents, consistent with an activation of amiloride-sensitive epithelial sodium channels. Tetraethylammonium obliterated 90+/-9% of the effect of halothane on outward currents, without change in inward currents, indicating inhibition of Ca2+-activated K+ channels. These channels were identified in excised patches to be small-conductance Ca2+-activated K+ channels. These effects of halothane were not modified after the inhibition of cytosolic phospholipase A2 by aristolochic acid. Exposure of the cells to either trypsin or to low Na+ completely prevented the increase in amiloride-sensitive currents induced by halothane, suggesting a release of Na+ channels self-inhibition. Thus, halothane modifies differentially and independently Na+ and K+ permeabilities in human alveolar cells.

Adenocarcinoma↗
PubMed1987

Genetic analysis of halothane sensitivity in Caenorhabditis elegans.

The nematode Caenorhabditis elegans appears to be a useful model for studying the action of volatile anesthetics. A mutant strain that is hypersensitive to the widely used anesthetic halothane was described earlier. The mutation is now shown to be an allele of unc-79. Other alleles of unc-79 are also associated with hypersensitivity to halothane. A strain with a mutation in a second gene, unc-80, is also hypersensitive to halothane. Nematodes bearing mutations in both unc-79 and unc-80 are slightly more sensitive to halothane than those bearing only one of these mutations. Mutations in a third gene, unc-9, suppress both unc-79 and unc-80. Nematodes bearing the suppressor mutations alone have normal sensitivity to halothane. These results show that sensitivity to halothane can be altered by mutations in several different genes.

Alleles↗
PubMed1980

Anesthetic action and virus replication: inhibition of measles virus replication in cells exposed to halothane.

Replication of measles virus in BSC cells was studied in the presence of halothane, a commonly used volatile anesthetic. At clinical concentrations of the anesthetic, appearance of progeny virus was decreased in a dose-related manner. This inhibition was reversible as the removal of halothane allowed virus replication to be resumed. Studies attempting to elucidate the mechanism of action of the anesthetic inhibition of virus replication revealed that halothane did not directly inactivate the virus particle or prevent viral adsorption to the cell. Infectious virus and nucleocapsid production were decreased or stopped, depending on the anesthetic dosage used. Direct immunofluorescent staining for measles virus antigen was negative in cells treated at the higher concentrations of halothane. Recovery of nucleocapsid production started within a few hours after removal of halothane. Furthermore, the combined inhibitory effects on viral ribonucleic acid synthesis of 5-azacytidine and halothane were additive. This evidence suggests that inhibition of measles virus replication occurs at or before ribonucleic acid synthesis.

Anesthesia↗
PubMed1986

Changes in cytoplasmic free calcium caused by halothane. Role of the plasma membrane and intracellular Ca2+ stores.

Malignant hyperthermia is a muscle disease characterized by an abnormal response to anaesthetics, stress, and exercise. It is typified by muscle contracture and a dramatic elevation in body temperature. A defect in the regulation of the concentration of cytoplasmic free calcium, [Ca2]i, is thought to underlie this disease, but the actual [Ca2+]i was not measurable until recently. We have shown that the anaesthetic halothane increases [Ca2+]i in isolated lymphocytes from malignant hyperthermia-susceptible humans and pigs but not in the normal counterparts. In this report we extend these observations to a larger number of cases and analyze the molecular mechanisms responsible for the increase. The halothane-mediated rise in [Ca2+]i required external Ca2+ and was prevented by nifedipine, an inhibitor of the voltage-sensitive Ca2+ channels of the cell membrane. In addition, the effect of halothane on the releasable Ca2+ from intracellular stores was determined by measuring the size of the releasable pool before and after addition of the anaesthetic. After addition of halothane, about 73% of this Ca2+ pool was still available for release by the Ca2+ ionophore ionomycin in cells from normal humans and pigs. In contrast, only about 45% of the free Ca2+ in intracellular stores was left after treatment with halothane in cells from malignant hyperthermia-susceptible humans and swine. These results indicate that halothane acts both at the cell membrane and at intracellular organelles, and that this action results in a net increase in [Ca2+]i in malignant hyperthermia, but not in normal cells. The action at the cell membrane appears to be on the voltage-sensitive Ca2+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoquinolines↗
PubMed1990

Potentiation of the halothane-cooling contractures of mammalian muscles by denervation.

Denervation potentiated the cooling-induced contractures and the halothane-cooling contractures of isolated extensor digitorum longus and soleus muscles of the mouse. These effects were more striking in extensor digitorum longus than in soleus muscles. Significant increases in the peak amplitudes of the halothane-cooling contractures of both muscles and of the cooling contractures of soleus muscle were observed within 2 and 7 days of denervation. The potentiation of the contractures persisted for 90 days, the period of this study. Denervation (greater than 2 days) endowed extensor digitorum longus with the ability to generate cooling contractures in the absence of halothane. The rate of tension development of cooling-induced contractures in the absence or presence of halothane was significantly greater in denervated (2-90 days) than in innervated muscles. Denervation also reduced the effectiveness of procaine in inhibiting the halothane-cooling contractures. It is proposed that the potentiation of cooling-induced contractures in denervated muscles results primarily from an increase in the rate of efflux and in the quantity of Ca2+ released from the sarcoplasmic reticulum, upon cooling and (or) when challenged with halothane.

Animals↗
PubMed1989

Effects of the halothane-sensitivity gene on sarcoplasmic reticulum function.

Pigs heterozygous for the halothane-sensitivity gene exhibit a distinct phenotype with regard to both in vivo and in vitro muscle responses to halothane (E. M. Gallant, J. R. Mickelson, B. D. Roggow, S. K. Donaldson, C. F. Louis, and W. E. Rempel. Am. J. Physiol. 257 (Cell Physiol. 26): C781-C786, 1989). In this paper heavy sarcoplasmic reticulum (SR) preparations were isolated from the muscles of pigs of all three genotypes. The rate of calcium release from SR of pigs homozygous for the halothane-sensitivity gene was approximately twice that of SR from pigs homozygous for the normal allele. Furthermore, in the presence of 6 microM Ca2+, the binding of [3H]ryanodine to SR isolated from the homozygous halothane-sensitive pigs was of a higher affinity than was the binding to SR isolated from the homozygous normal pigs (Kd = 70-90 vs. 265 nM, respectively). The SR from pigs heterozygous for the halothane-sensitivity gene, however, demonstrated intermediate values for the rate of calcium release and the affinity for [3H]ryanodine (Kd = 192 nM). Thus the alterations in heavy SR calcium release and [3H]ryanodine binding in the pigs containing one copy of the halothane-sensitivity gene demonstrate a distinct heterozygote phenotype. These data also suggest that the protein product of this gene is closely associated with, and perhaps identical to, the SR calcium release channel-ryanodine receptor protein.

Adenosine Triphosphate↗