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PubMed1992

Halothane-induced hyperpolarization and depression of postsynaptic potentials of guinea pig thalamic neurons in vitro.

Intralaminar thalamic nuclei have been considered to be a component of the non-specific sensory system which is involved in physiological functions related to consciousness and pain sensation. The effect of halothane on membrane potentials and synaptic properties of neurons of the parafascicular (Pf) nucleus in guinea pig brain slices was investigated using intracellular recording methods. Halothane at concentrations of 0.4-1.0 mM, which are in the range of clinical concentrations, produced hyperpolarizations of 2-8 mV in approximately 50% of the cells. The halothane-induced hyperpolarization was nullified at a membrane potential close to the K+ equilibrium potential. The amplitude of the hyperpolarization was dependent on the external K+ concentration, and was decreased by either Ba2+, or 4-aminopyridine, or intracellular injection of Cs+. All these results indicate that the hyperpolarization was due to an increase in K+ conductance. Halothane at clinical concentrations depressed both excitatory and inhibitory postsynaptic potentials in a concentration-dependent manner. On the other hand hyperpolarizing responses to exogenous gamma-aminobutyric acid (GABA) in the presence of bicuculline were suppressed by halothane, but depolarizing responses to L-glutamate were not altered. The results indicate that the depressant action of the anesthetic on the excitatory postsynaptic potential (EPSP) may occur presynaptically, whereas the blocking action on the inhibitory postsynaptic potential (IPSP) may occur postsynaptically.

Animals↗
PubMed1995

Halothane effects on low-threshold receptive field size of rat spinal dorsal horn neurons appear to be independent of supraspinal modulatory systems.

Recent evidence strongly supports the importance of spinal sites of action for the ability of general anesthetic agents to block response to noxious stimuli. This study was designed to examine possible spinal anesthetic effects on non-noxiously evoked activity. Three groups of rats were prepared for acute experiments in which the response of spinal dorsal horn neurons to low threshold receptive field (RF) stimulation was evaluated. In each animal in each group extracellular activity was recorded from a single spinal dorsal horn neuron. A low-threshold RF of each neuron and, at times, the sensitivity to low-threshold stimulation of multiple sites in the RF were determined under baseline conditions (light anesthesia or decerebrate). In Group 1, reversible cooling of the thoracic spinal cord in the presence of either 0.5% or 1% halothane anesthesia caused no change in RF size. However, an increase from 0.5% to 1% halothane caused a 53% decrease in RF size both in the presence and absence of a reversible cold block of the spinal cord. In Group 2, animals with spinal cords transected at the thoracic level had a similar change in low-threshold receptive field size (52%) when halothane concentrations were increased from 0.5% to 1%. Testing sensitivity within the RF areas indicated that the silenced areas at the fringe of the receptive field could still elicit activation of spinal dorsal horn neurons but at a higher threshold. In the final group of animals, decerebration and spinal cord transection allowed us to compare effects of 0.5% and 1% halothane with an anesthetic free baseline. Here, again, a dose-dependent reduction in RF area was observed although the baseline RFs were significantly smaller than those in Groups 1 and 2. These results demonstrate that the reduction in low-threshold receptive field size due to the administration of the inhalation anesthetic halothane occurs in the absence of descending modulation from supraspinal sites. This implicates the spinal dorsal horn as a potentially important site of action for general anesthetics. These results also support the spinal cord as an important tool to study the pharmacology responsible for anesthetic effects on sensory processing.

Animals↗
PubMed1989

Halothane inhibits hyperpolarization and potassium channels in human red blood cells.

The effect of halothane on the Ca2+-sensitive K+ channel in human erythrocytes has been investigated. The red cells were suspended in buffer-free salt solutions containing Ca2+ or 45Ca2+. The protonophore CCCP was added to bring about a rapid equilibration of protons across the plasma membrane. After addition of the divalent cation ionophore A23187, the cells took up Ca2+ and this caused the K+ channels to open. When the medium contained 1 mM K+, the addition of A23187 induced a transient hyperpolarization of the cells, as monitored by measurement of the pH of the medium. The cellular pH, being buffered by haemoglobin, was virtually constant. Halothane reversibly inhibited hyperpolarization and limited the release of cellular K+ in a dose-dependent way, but did not inhibit the Ca2+-transporting properties of A23187. No stimulatory effects of halothane were observed even at low halothane concentrations. In conclusion, halothane reversibly inhibits the Ca2+-sensitive K+ channel in human erythrocytes with an ED50 of about 0.5 mM.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1988

L-phenylisopropyladenosine (L-PIA) diminishes halothane anesthetic requirements and decreases noradrenergic neurotransmission in rats.

The effect of L-phenylisopropyladenosine (L-PIA), the A1 adenosine agonist, on the depth of anesthesia was investigated in halothane-anesthetized rats. L-PIA treatment reduced the minimum anesthetic concentration (MAC) of halothane that prevented 50% of animals from moving in response to a painful stimulus by 49%. MAC experiments performed with L-PIA given in conjunction with A1 adenosine receptor antagonists which either permeate the blood-brain barrier (8-phenyltheophylline [8-PT] or do not (8-sulphophenyltheophylline [8-So-PT]) indicate that central mechanisms are involved. Noradrenergic neurotransmission was diminished following L-PIA administration in halothane-anesthetized rats in all brain regions. These data suggest that acute L-PIA treatment decreases central noradrenergic neurotransmission and may represent the mechanism for the decrease in halothane dose to achieve an anesthetic endpoint anesthetic response to halothane.

Adenosine↗
PubMed1987

Effects of halothane on high affinity agonist binding and guanine nucleotide sensitivity of muscarinic acetylcholine receptors from brainstem of rat.

The influence of halothane on muscarinic receptors with a high affinity for agonists was studied using [3H]oxotremorine-M. [3H]Oxotremorine-M bound with high affinity (KD = 2.8 nM) to a subpopulation of muscarinic receptors in the brainstem of rat, representing 32% of the total receptor pool. Agonist affinity for binding sites for [3H]oxotremorine-M was not affected by a guanine nucleotide (5'-guanylylimidodidiphosphate; Gpp(NH)p), although the level of binding was decreased, presumably due to the conversion of receptors to lower affinity conformations. However, only 58% of 3 nM binding of [3H]oxotremorine-M was sensitive to Gpp(NH)p. Halothane had two effects on the binding of [3H]oxotremorine-M: halothane (1) decreased the level of binding of [3H]oxotremorine-M without affecting agonist affinity for the surviving sites, and (2) lowered the sensitivity of the binding of [3H]oxotremorine-M to Gpp(NH)p by a factor of 120. The decrease in binding of [3H]oxotremorine-M binding was nonselective with regard to the sensitivity of the receptors to the guanine nucleotide, insofar as Gpp(NH)p inhibited the binding of [3H]oxotremorine-M to the same extent in the presence and absence of halothane. These results suggest that halothane (1) converts both G protein-coupled and -uncoupled muscarinic receptors to states of lower agonist affinity and (2) lowers the affinity of receptor-G protein complexes for guanine nucleotides.

Animals↗
PubMed1990

Halothane inhibits 5-hydroxytryptamine uptake by synaptosomes from rat brain.

The activity of 5-hydroxytryptamine (serotonin; 5-HT) in the central nervous system modulates sleep, the perception of pain and other functions of the body which might possibly relate to mechanisms of general anesthetic action. While administration of anesthetics has inconsistent effects on the content of 5-HT in brain, in vivo, accumulated data suggest that anesthetic drugs alter 5-HT homeostasis in the central nervous system. In an effort to identify one possible site of anesthetic action, the effect of halothane on the uptake of 5-HT was studied in synaptosomes isolated from the brain of rat. Established techniques were used to prepare the synaptosomal fractions and measure high affinity transport of radiolabelled 5-HT. Halothane inhibited synaptosomal accumulation of 5HT in a concentration-dependent manner, but had little effect on the passive or spontaneous release of the accumulated 5-HT. Rates of uptake of 5HT were inhibited by 43% in the presence of 1 mM halothane and by 75% of control in the presence of 5 mM halothane; the apparent I50 for halothane was 1.0 +/- 0.1 mM and Lineweaver-Burk analysis indicated the inhibition to be competitive at concentrations around the I50.

Animals↗
PubMed1992

Effects of halothane on membrane potential and discharge activity in pairs of bulbar respiratory neurons of decerebrate cats.

In aiming to test the possibility of synaptic interactions, the effect of inhalation of halothane (2% for 90 sec) was studied on 45 out of 88 pairs of respiratory neurons, simultaneously recorded with intracellular and extracellular microelectrodes, in both sides of the ventral respiratory group of decerebrate cats. Halothane produced various effects on these respiratory neurons; namely, depolarization (n = 30) or hyperpolarization (n = 15) of intracellularly recorded neurons, an increase (n = 7) or decrease (n = 38) in the firing of extracellularly recorded neurons. However, with repeated application, the agent produced a consistent effect in a given cell. Spike-triggered averaging of synaptic noise, using spikes of non-antidromically-activated respiratory units, did not reveal any unitary postsynaptic potential but a symmetric synaptic wave of medium-frequency-oscillation (35-50 Hz) in 7 pairs. In addition, power spectral analysis of the membrane potential and spike-interval histogram of the paired neuron, displayed no correlated activity suggestive of synaptic interactions. For all the neuronal pairs examined, halothane produced random effects on their patterns of firing and synaptic waves. The present results suggest that halothane exerts a selective effect on each respiratory neuron and that the lack of a correlated response to application of halothane reflects the lack of synaptic interaction between pairs of bilaterally sampled neurons of the ventral respiratory group.

Action Potentials↗
PubMed1987

Influence of cimetidine and diethyldithiocarbamate on the metabolism of halothane and methoxyflurane in vitro.

The metabolism of halothane and methoxyflurane was measured in vitro by the vial equilibration method using the S-9-fraction from rat liver as source of enzymes. Kinetic values were measured for halothane: Vmax = 11.6 nmol/g.min, KM = 19.6 mumol/l and methoxyflurane: Vmax = 12.0 nmol/g.min, KM = 17.5 mumol/l. Dithiocarb showed strong inhibitory activity on halothane and methoxyflurane metabolism; inhibition constants were calculated as Ki = 0.051 mmol/l and Ki = 0.004 mmol/l, respectively. Cimetidine inhibited the metabolism of both anesthetics to a lesser extent. Inhibition constants were calculated as Ki = 16.2 mmol/l and Ki = 8.2 mmol/l for halothane and methoxyflurane, respectively. The observed inhibitory properties of dithiocarb and cimetidine on the metabolism of halothane and methoxyflurane may be of interest in connection with the problem of toxic liver and kidney injury after anesthesia with these agents.

Animals↗
PubMed1992

Halothane anesthesia causes state-dependent retrieval failure in mice.

Effects of exposure to halothane on memory processing was studied using single-trial inhibitory avoidance learning to measure retention. Mice were anesthetized with halothane either before training, immediately after training, or both before training and before testing. Results showed that memory was not impaired by posttraining halothane exposure, indicating that the anesthetic does not cause retrograde amnesia. Mice trained after recovery from halothane showed a robust memory loss 24 h later. This deficit could be alleviated by reexposure to the anesthetic before the retention test. Mice given multiple training trials following recovery from the anesthetic showed a normal rate of learning when compared with controls, but deficient retention. This indicates that the performance deficit was the result of impaired retention (anterograde amnesia) rather than disrupted acquisition. Anterograde amnesia occurred when training was delayed up to 2 h after recovery from anesthesia. These findings indicate that the memory impairment following halothane anesthesia is the result of a state-dependent retrieval failure.

Amnesia, Retrograde↗
PubMed1993

Autoantibodies to hepatic microsomal carboxylesterase in halothane hepatitis.

Halothane hepatitis can be life-threatening, and this severe adverse reaction may arise via an immune process. We have detected autoantibodies to purified human liver microsomal carboxylesterase in sera of 17 out of 20 patients with halothane hepatitis (85%) but not in 9 halothane-exposed controls and in only 2 (at low levels) of 33 patients with liver disease due to other causes. Immunohistochemical studies localised the carboxylesterase predominantly to the centrilobular region of liver sections, which is consistent with the area affected by halothane hepatitis. Human hepatic microsomal carboxylesterase is a target antigen in halothane hepatitis, and an immune response to this protein may be involved in the liver damage observed.

Adult↗
PubMed1991

Development of a near anesthetic-free isolated canine hindlimb model. The effects of halothane and atropine sulfate on vascular resistance.

A denervated, isolated canine hindlimb (HL) model was developed to minimize residual anesthetic contamination. To test the preparation, we determined the peripheral arterial vascular effects of atropine sulfate and the effect of the basal anesthetic on arterial resistance. In four dogs that were under halothane and oxygen anesthesia, the HL was prepared to allow either vascular isolation of the limb or continuity with the systemic circulation. During isolation the HL was perfused by roller pump at a preset flow rate through an infant oxygenator. Inspired gas fed to the oxygenator contained either 0%, 1.25%, or 2.5% halothane to determine that anesthetic's effect on HL arterial vascular resistance. No halothane (0%) was used in the oxygenator inflow during the atropine measurements. Vascular resistance was calculated from HL arterial pressure at constant flow. Halothane caused a significant stepwise fall in vascular resistance, with a decrease of 68% at 2.5% inspired concentration (p less than 0.01). Atropine produced a progressive attenuation of resistance that decreased by 18% after the 2.5 mg/kg dose (p less than 0.01). The model proved stable over time and demonstrated an apparent direct, dose-dependent vasodilating effect of both atropine and halothane in the canine HL muscle arterial bed.

Animals↗
PubMed1986

Effects of halothane on intraoperative scalp-recorded somatosensory evoked potentials to posterior tibial nerve stimulation in man.

Somatosensory evoked potentials (SEPs) were monitored in 116 patients receiving halothane anesthesia during spinal fusion surgery. Whereas it has been generally assumed that the use of halogenated inhalational anesthetics should be avoided with SEP monitoring because of their purported deleterious effects on scalp-recorded sensory responses, we found that reproducible SEPs were obtained throughout the surgical procedure in 91% of the cases we monitored while using halothane at concentrations of 0.25-2.0%. In those cases in which halothane was delivered continuously at 0.5%, reproducible evoked responses were recorded in 96% (75 of 78) of the patients. Our data demonstrated 3 major effects of halothane on the SEP: (a) a small but significant decrease in the average amplitude of the first two components (N25 and P30), (b) a significant increase in the average latency of the late positive component (P53) of the wave form, and (c) occasional obliteration of components N25, N40, P53, and N71, but never of P30. These effects did not, in most cases, interfere with our ability to obtain clinically useful recordings. Our results suggest that in many instances the use of halothane anesthesia can be combined successfully with the recording of intraoperative SEPs.

Electric Stimulation↗
PubMed1986

Cardiopulmonary effect of halothane concentration during pulmonary air embolism in dogs.

The purpose of this study was to determine the effect of different halothane concentrations on the hemodynamic consequences of pulmonary air embolism in dogs. The animals were studied in two groups. Group A (N = 11) at a halothane concentration of 0.5%, and Group B (N = 8) at a halothane concentration of 1.5%. Air was injected into a central vein in a bolus of 0.5 ml/kg, 1 ml/kg, and 2 ml/kg. With the lower halothane concentration, sudden loading to the right heart and pulmonary artery occurred with air embolism. Recovery in this group was faster in comparison to the higher concentration of halothane. Survival was not effected with air embolism to 2 ml/kg.

Animals↗
PubMed1984

Effect of morphine on the heart rate response to noxious stimulation: interaction with halothane and naloxone.

The effect of morphine on the heart rate increase, in response to noxious somatic stimulation, was studied in 125 rat experiments. It was found that halothane, in a subanesthetic concentration of 0.3 vol%, profoundly weakened the effect of morphine on the heart rate response. As a result, the morphine ED50 value for blockade of the heart rate response was increased from 5.9 to 46.1 mg/kg (P less than 0.001). Naloxone in a dose of 0.05 mg/kg increased the morphine ED50 value for blockade of the heart rate response 11-fold (morphine was administered without halothane). However, the same dose of naloxone did not change the morphine ED50 value obtained with combined administration of morphine and halothane. An increase in the naloxone dosage (up to 1 mg/kg) was necessary to demonstrate the naloxone antagonistic effect (8-fold increase in the morphine ED50 value) when morphine was given with halothane. It has been suggested that the effect of morphine on the heart rate response to noxious stimulation results primarily from the activation of inhibitory control mechanisms concerned with this response (indirect effect). Halothane depresses the inhibitory control mechanisms and, therefore, weakens the effect of morphine. A significant increase in doses of morphine is needed to provide the direct antinociceptive effect.

Animals↗
PubMed1992

On the mechanism of the interaction of ketamine and halothane in vitro.

1. Electrically induced contraction of guinea pig ileum myenteric plexus-longitudinal muscle was inhibited by ketamine and halothane with IC50s of 2.1 x 10(-4) M and 1.8 v/v% respectively. 2. The inhibitory action of ketamine was partially antagonized by naloxone and the selective kappa antagonist nor-binaltorphimine. 3. The actions of ketamine and halothane were synergistic at high levels of response (above 30% inhibition). 4. The actions of ketamine and halothane became antagonistic after treatment with pertussis toxin. 5. The interaction of ketamine and halothane was similar to the interaction of morphine and halothane.

Animals↗
PubMed1988

Myocardial recovery from the cardiac depressant effects of enflurane and halothane.

Recovery from the cardiac depressant effects of enflurane and halothane was examined in the dog heart-lung preparation (HLP) and in right ventricular muscle isolated from guinea pig hearts. In the HLP. recovery was studied under two conditions: (1) After a two-hour exposure to anesthetic concentrations increasing from 0.36 to 1.2 MAC, and (2) after a one-hour exposure to a single concentration that raised the left atrial pressure (LAP) to 9 to 10 mmHg. Under either condition, +dP/dtmax. was significantly less depressed with enflurane and returned to preanesthetic control levels, while recovery with halothane remained significantly below control. Following the longer exposure. recovery of the LAP and left ventricular function curves (LVFC) was significantly less with halothane; however, this difference was not observed after the shorter exposure period. In electrically paced, isometrically contracting right ventricular strips exposed for one hour to 2.25 vol% enflurane (a concentration that reduced contractility by 45%), force development returned within 60 minutes to values above preanesthetic control values. After an identical depression for one hour with halothane (0.80 vol%), force development recovered to values less than those observed following enflurane. These data indicate that the recovery from anesthetic-induced negative inotropic effects in isolated cardiac preparations is better with enflurane than halothane.

Anesthetics, Inhalation↗
PubMedDate not supplied

Uptake and biotransformation of sevoflurane in humans: a comparative study of sevoflurane with halothane, enflurane, and isoflurane.

STUDY OBJECTIVE: To compare the volatile anesthetic sevoflurane with halothane, enflurane, and isoflurane on the uptake and biotransformation in humans. DESIGN: Prospective pharmacokinetic study of sevoflurane administration in human subjects. SETTING: Inpatient surgery clinic at a university medical center. PATIENTS: Thirty-two Japanese patients, free of systemic diseases, undergoing minor elective surgery with endotracheal general anesthesia. INTERVENTIONS: The patients were assigned randomly to one of four groups: halothane, enflurane, isoflurane, or sevoflurane. One of the four volatile anesthetics being investigated [equivalent to 1.1 minimum alveolar concentration (MAC): halothane, 0.85%; enflurane, 1.85%; isoflurane, 1.27%; and sevoflurane, 1.88%; in inspired concentrations throughout the first hour of anesthesia] was administered for 60 minutes. MEASUREMENTS AND MAIN RESULTS: In all patients, serum and urinary fluoride concentrations were measured. The concentrations of all gases were measured separately with a mass spectrometer. The cumulative uptake of each anesthetic agent during a certain period was calculated as an integration of the uptake rate per minute. The results for one-hour inhalation of sevoflurane (1.1 MAC) showed an uptake (corrected for body surface area and MAC) of 490 ml/m2/MAC and estimated degradation rate of 3.3%. For purposes of comparison, similar studies of halothane (uptake, 653 ml/m2/MAC; degradation rate 15.7%), enflurane (1150 ml/m2/MAC; 1.3%), and isoflurane (439 ml/m2/MAC; 0.6%) were also conducted. Sevoflurane had a peak serum inorganic fluoride concentration of 19.3 mumol/L, and no abnormality in hepatic or renal functions was observed in any of the subjects during the two weeks postoperatively. CONCLUSIONS: Accurate determinations of uptake and degradation rate for sevoflurane and three other volatile anesthetics in Japanese patients were obtained. These findings have established that, despite its relatively large MAC (1.71%), sevoflurane has a small uptake due to its low solubility. However, the degradation rate was shown to be as high as 3.3%, resulting in a higher serum fluoride concentration than seen after administration of isoflurane, halothane, and (possibly) enflurane.

Adult↗
PubMed1995

A lower solubility recommends the use of desflurane more than isoflurane, halothane, and enflurane under low-flow conditions.

STUDY OBJECTIVE: To determine whether the lower solubility of desflurane, over that of isoflurane, enflurane, and halothane, favors its use in low-flow anesthesia. DESIGN: Prospective clinical study. SETTING: Technical University of Munich. PATIENTS: 40 elderly (> or = 65 yrs), ASA physical status II and III surgical patients. INTERVENTIONS: All patients were anesthetized and received delivered concentrations (FD) of 4% desflurane, 1.5% isoflurane, 1.8% enflurane, or 0.9% halothane (n = 10 patients for each anesthetic) in a fresh gas inflow of 3 L/min (high-flow), until end-tidal target concentrations (FA) of 2% desflurane, 0.5% isoflurane, 0.6% enflurane, and 0.3% halothane were obtained. After 30 minutes, the inflow was decreased to 1 L/min (low-flow), and the FD and the inspired concentration (FI) were adjusted to maintain the target concentration. MEASUREMENTS AND MAIN RESULTS: The concentrations of the halogenated anesthetics, as well as nitrous oxide, oxygen (O2), and carbon dioxide, were measured in delivered gas at the common gas outlet and at the endotracheal tube connector. Transcutaneous O2 saturation, noninvasive blood pressure, and heart rate were also measured. During the first 30 minutes of high-flow administration, the target concentration was attained sooner with desflurane than with isoflurane, enflurane, or halothane (median levels: 4 min vs. 6 min, 8 min, or 10 min; p < 0.01). After the reduction of inflow to 1 L/min, FD had to be materially increased to maintain F1 and FA for the more soluble anesthetics, but not for desflurane. CONCLUSIONS: At low flows, FD provides a reasonable surrogate of F1 and FA for desflurane, but not for isoflurane, enflurane, or halothane. The rapid and predictable titrability of desflurane favors its safe use in low-flow technique.

Aged↗