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PubMed1989

Halothane antagonizes ouabain toxicity in isolated canine Purkinje fibers.

Standard intracellular microelectrode techniques were used to study the effects of halothane on ouabain-induced delayed after depolarizations (DAD) in canine Purkinje fibers. Free running Purkinje fibers were superfused with 2 X 10(-7)M ouabain in Krebs-Henseleit buffer for 30-50 min until DAD appeared. Purkinje fibers were then paced for 20 beats at cycle lengths between 1,000 ms and 200 ms, and the amplitude of the DAD and coupling interval between the DAD and last paced beat were determined. Halothane (0.5, 1, and 2%) was then administered and measurements repeated. Halothane produced dose-related decreases in DAD amplitude without changing DAD coupling interval. The ability of calcium to antagonize the effects of halothane was evaluated by doubling buffer calcium concentration to 5 mM in the presence of halothane 2%. Doubling buffer calcium concentration to 5 mM antagonized the reduction of DAD amplitude caused by halothane. In several preparations, dysrhythmias occurred during ouabain superfusion. Halothane reversibly terminated these arrhythmias. Halothane antagonizes DAD and dysrhythmias induced in vitro by ouabain toxicity. This effect, in part, may account for the apparent effectiveness of halothane against ouabain-induced dysrhythmias in vivo.

Animals↗
PubMed1990

A comparison of the effects of halothane and tetrodotoxin on the regional repolarization characteristics of canine Purkinje fibers.

The effects of halothane, tetrodotoxin (TTX), veratridine (VTD), and alterations of extracellular calcium ion concentration [Ca++]0) on regional differences of canine Purkinje fiber action potential duration (APD50 and APD90) were investigated in vitro at a paced rate of 75 beats per min. Under control conditions (n = 15 hearts) APD90 of proximal (false tendon) fibers (289 +/- 6 ms) always exceeded (P less than or equal to 0.01) that of distal (apical) fibers (213 +/- 4 ms). Halothane (0.35-1.07 mM) reduced regional differences of APD90 by producing dose-dependent decreases of proximal APD90 without decreases of distal APD90. The regional actions of halothane were similar to those of low (0.33-1.0 microM) concentrations of the Na+ channel antagonist TTX, which also decreased proximal APD90 more than distal APD90. The actions of halothane in combination with TTX further decreased proximal APD90, whereas the Na+ channel agonist VTD, which increased proximal APD90 more than distal APD90, reversed the regional actions of halothane. Decreasing Ca++ influx by reducing [Ca++]0 from 1.8 to 0.6 mM increased proximal APD90 more than distal APD90 in a manner opposite to the regional actions of halothane. Although there was no difference between the values of APD90 obtained for each region in the presence of halothane at 0.6, 1.8, and 3.6 mM [Ca++]0, the action of halothane decreasing APD90 of proximal fibers was more prominent at 0.6 mM [Ca++]0 because of the increased APD90 of fibers under this condition. The findings are consistent with, but do not definitively prove, the hypothesis that halothane may decrease APD90 of proximal Purkinje fibers by a mechanism similar to that of TTX involving inhibition of plateau-phase inward Na+ current.

Action Potentials↗
PubMed1990

The inhibitory action of halothane on reflex constriction in mesenteric capacitance veins.

Potent inhalational anesthetics depress autonomic reflex responses at multiple sites. Most studies emphasize cardiac chronotropic changes and changes in systemic blood pressure. Recently, active reflex venoconstriction of 500-1,000 microns O.D. mesenteric veins has been demonstrated. In the current study, the effects of halothane on the reflex responses of similar mesenteric veins were measured. Mesenteric vein diameter and intravenous pressure were measured in 500-1,000 microns O.D. veins from the mesentery of segments of terminal ileum externalized in situ from 27 New Zealand white rabbits anesthetized with alpha-chloralose. Mean arterial pressure was measured with femoral arterial cannulation, and heart rate was determined from the arterial pressure signal. In a separate group of six animals, sympathetic efferent nerve activity was measured from a postganglionic splanchnic nerve. Reflex venoconstriction and increases in mean arterial pressure and mesenteric vein pressure in response to bilateral carotid occlusion were attenuated by 0.5% and 1% inhaled halothane but not by superfusate equilibrated with 3% halothane. Decreases in mesenteric vein diameter and increases in mesenteric vein pressure in response to celiac ganglion stimulation were unaffected by both 0.5% inhaled halothane and superfusate equilibrated with 5% halothane. The bilateral carotid occlusion reflex-mediated increase in sympathetic efferent nerve activity was depressed by both 0.5% and 1% inhaled halothane. The effect of inhaled halothane on prestimulation baseline vein diameter was inconsistent. Superfusate equilibrated with 5% but not 3% halothane caused baseline venodilation. These results suggest a mechanism whereby control of venous tone is inhibited by halothane proximal to the postganglionic neuron. This could involve central or ganglionic inhibition.

Animals↗
PubMed1990

Covalent binding of oxidative biotransformation intermediates is associated with halothane hepatotoxicity in guinea pigs.

In vivo covalent binding of halothane biotransformation-reactive intermediates to hepatic protein and lipid was examined in association with the subsequent development of hepatic necrosis in the guinea pig. Oxidative halothane biotransformation was inhibited by the use of deuterated halothane, whereas reductive metabolism was enhanced by low inspired oxygen concentrations. Male outbred Hartley guinea pigs (n = 8) were exposed to either 1% (v/v) halothane or deuterated halothane--with a fractional inspired O2 concentration (FIO2) of 0.40 or 0.10--for 4 h. Livers removed from half of the animals immediately after anesthesia were evaluated for organic fluorine bound to protein and lipid. The remaining animals were evaluated for a hepatotoxic response up to 96 h after exposure. Only guinea pigs that received 1% halothane at an FIO2 of 0.40 had centrilobular necrosis develop with significantly increased plasma alanine aminotransferase activities. All other treatment conditions significantly reduced oxidative halothane biotransformation, as indicated by decreased plasma trifluoroacetic acid concentrations. These reductions were associated with a significant decrease in organic fluorine bound to hepatic proteins. An FIO2 of 0.10 during halothane anesthesia significantly enhanced reductive biotransformation, as indicated by plasma fluoride ion concentrations. This was associated with a significant increase in organic fluoride bound to hepatic lipids. Centrilobular necrosis did not develop under these conditions. Thus, covalent binding to subcellular proteins by the trifluoroacetyl acid chloride intermediate generated by oxidative halothane biotransformation is implicated as a mechanism of centrilobular necrosis in guinea pigs. Binding to lipids by reductive pathway generated free radicals does not appear to be involved in production of the lesion.

Animals↗
PubMed1991

Bronchodilation by halothane is not modulated by airway epithelium.

Halothane relaxes airway smooth muscles. To test the hypothesis that this relaxation is modulated by airway epithelium, we studied the effects of halothane on isolated second- and third-order canine bronchial rings and second-order canine bronchial segments. Paired rings or segments were examined, with the epithelium removed from one ring or segment of each pair. The bronchial rings were suspended in organ chambers and contracted with 10(-8)-10(-3) M acetylcholine (ACh), 10(-8)-10(-5) M 5-hydroxytryptamine (5HT), or 0.5-16 Hz electrical field stimulation (EFS, 15 V, 0.5-ms pulse duration). The tissue was contracted in the absence of halothane and during exposure to 1 and 2 MAC halothane. The bronchial segments were perfused intraluminally with physiologic salt solution (PSS) and contracted with 10(-6) M carbachol added to the tissue-bath PSS. One or 2 MAC halothane was then added to the perfusate. In the absence of halothane, epithelium removal increased the sensitivity of the bronchial rings to ACh and 5HT but not to EFS. Addition of 1 or 2 MAC halothane to the bathing fluid of the rings with or without epithelium decreased the sensitivity of the rings to ACh and 5HT. One MAC halothane decreased the sensitivity of the rings with and without epithelium to EFS. The decrease in sensitivity caused by halothane was not significantly different in rings with or without epithelium for any method of stimulation. In the bronchial segments, relaxations evoked by 1 or 2 MAC were not different in segments with or without epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1992

Prediction of malignant hyperthermia susceptibility in low-risk subjects. An epidemiologic investigation of caffeine halothane contracture responses. The North American Malignant Hyperthermia Registry.

The most commonly used laboratory test for predicting malignant hyperthermia susceptibility is the caffeine halothane contracture test. However, the specificity and sensitivity of proposed North American diagnostic guidelines for this test have never been evaluated in a large, human study population. Therefore, the authors conducted a multiinstitutional, prospective study of skeletal muscle contracture responses in a subject population at low risk for malignant hyperthermia susceptibility to help determine the specificity of the proposed guidelines. Subjects were selected arbitrarily from a population of patients undergoing surgery unrelated to performance of a diagnostic muscle biopsy. Subjects were admitted to this study and were presumed nonsusceptible if there was no evidence of any of the following malignant hyperthermia risk factors: prior abnormal response to triggering anesthetic agents, myopathy, or family history of malignant hyperthermia susceptibility. The authors suggested rejection of the proposed diagnostic guidelines if an 85% specificity estimate among subjects could not be obtained. The authors analyzed the responses of 1,022 muscle fascicles, derived from 176 subjects, to the following: 1) separate administration of 3% halothane or incremental caffeine concentrations, or 2) the joint administration of 1% halothane and incremental caffeine concentrations. The following contracture results were obtained. First, for individual fascicles, 9.2% exceeded a greater than 0.7 g threshold for 3% halothane, 15.2% exceeded a greater than or equal to 0.2 g threshold for 2 mM caffeine, 32.4% exceeded a 1-g increase for less than 4 mM caffeine, 2.6% had a greater than 7% maximal increase in tension at 2 mM caffeine, and 63.5% had a "halothane caffeine-specific concentration" at less than or equal to 1 mM caffeine. Second, the percentages of subjects with 1 or more fascicles exceeding the proposed threshold were as follows: 45.8% for the four-component, 28.8% for the three-component, and 32.7% for the two-component contracture test. Third, the percentages of subjects with 1 or more fascicles exceeding the proposed threshold for both halothane and caffeine were as follows: 9.5% for 3% halothane and 2 mM caffeine, 2.0% for 3% halothane and 7% maximal increase in tension at 2 mM caffeine, and 11.0% for 1% halothane and 2 mM caffeine. Fourth, center-to-center differences were the major source of variation in the rate that subjects exceeded proposed thresholds. These data demonstrate that proposed diagnostic guidelines must be modified to improve specificity estimates before adoption by diagnostic centers.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1992

Halothane inhibition of ion transport of the tracheal epithelium. A possible mechanism for anesthetic-induced impairment of mucociliary clearance.

Significant depression of mucociliary function occurs during general anesthesia. One possible mechanism to account for this effect is a change in ion and water transport across airway epithelium. To determine if anesthetics alter epithelial cell function, we used electrophysiologic techniques to measure the effects of halothane on ion transport of in vitro canine tracheal epithelial. Epithelial tissues were mounted in an Ussing chamber and the short-circuit current (Isc) (a measure of active ion transport) and transepithelial resistance were determined in the absence and presence of halothane. Halothane induced a rapid and reversible decrease in Isc that was dose-dependent. Four percent halothane reversibly decreased Isc from 90 +/- 11 to 39 +/- 6 microA/cm2 (n = 12; P = 0.001) and increased transepithelial resistance. Isoproterenol is a well-known activator of chloride secretion that acts via beta-adrenergic receptors and cyclic adenosine monophosphate (cAMP). Pretreatment with isoproterenol or dibutyryl cAMP (a cell permeable analogue of cAMP) increased the percent inhibition of Isc by 4% halothane. These effects are consistent with preferential inhibition of chloride secretion by halothane but rule out a primary action of halothane on the beta-adrenergic system. In the presence of indomethacin, which eliminates the contribution of chloride secretion to Isc, 4% halothane induced a much smaller but still significant inhibition. This suggests that sodium absorption is also affected. We conclude that halothane significantly decreases ion and water transport in canine epithelia and that impaired fluid secretion may contribute to decreased mucous clearance in the perioperative period.

Animals↗
PubMed1992

Insufflated halothane increases venous admixture less than nitroprusside in canine atelectasis.

Although it generally is agreed that halothane is a pulmonary vasodilator, its effect on venous admixture and hypoxic pulmonary vasoconstriction are more controversial. The effects of 2.4% halothane on pulmonary vascular resistance and venous admixture were investigated in an isolated canine lobe made atelectatic. Halothane was administered by three different methods: insufflation, addition to the pulmonary artery blood through a bubble deoxygenator, or a combination of both techniques. Pulmonary vascular resistance was divided into arterial, venous, and middle segmental resistance by a vascular occlusion technique. Middle resistance increased with 3% O2 ventilation (0.0238 +/- 0.0092 cmH2O.ml-1.min-1) or after production of atelectasis (0.0225 +/- 0.0074 cmH2O.ml-1.min-1), compared to control ventilation in the nonatelectatic lung 0.01 +/- 0.0067 cmH2O.ml-1.min-1). Halothane by any delivery method variably decreased middle resistance, with increasing potency from addition of halothane through the bubble deoxygenator (0.0118 +/- 0.0047 cmH2O.ml-1.min-1) to halothane insufflation (0.0072 +/- 0.0058 cmH2O.ml-1.min-1), and finally to a combination of both techniques (0.0026 +/- 0.0041 cmH2O.ml-1.min-1). In contrast to vascular resistance, venous admixture in the atelectatic (8 +/- 5%) and nonatelectatic lobes (7 +/- 4%) was increased with halothane insufflation (11 +/- 4%), addition of halothane through the bubble deoxygenator (26 +/- 16%), and a combination of both techniques (22 +/- 13%). Compared to intravenous nitroprusside (26 +/- 12%), halothane insufflation was less potent in increasing venous admixture when total pulmonary vascular resistances were of similar magnitude (0.0526 +/- 0.0112 and 0.0484 +/- 0.0088 cmH2O.ml-1.min-1, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Role of guanylate cyclase-cGMP systems in halothane-induced vasodilation in canine cerebral arteries.

The cellular mechanisms through which halothane dilates blood vessels remain largely unknown. The present studies were designed to determine the effects of 0.59 and 0.9 mM halothane (equivalent to 2.0% and 3.0%, respectively) on tissue cyclic guanosine 3,5-monophosphate (cGMP) level and guanylate cyclase enzyme activity in canine middle cerebral arteries. Rings of cerebral arteries preconstricted with 5-hydroxytryptamine (0.2 microM) were exposed for 15 min to low or high concentrations of halothane or for 5 min to sodium nitroprusside (50 microM). The vessels were instantaneously frozen by immersing them in liquid N2; they then were homogenized, and the tissue cGMP levels were determined using radioimmunoassay. Halothane produced 2.23 +/- 0.44- and 4.47 +/- 0.87-fold increases in tissue cGMP levels over control at 0.59 and 0.9 mM, respectively. Sodium nitroprusside, a nitrovasodilator, also increased the tissue cGMP level 7.80 +/- 1.36-fold over the control value. To understand better the mechanisms of halothane-induced increase of tissue cGMP level, the effects of this anesthetic agent on guanylate cyclase enzyme activity were examined. Halothane, unlike sodium nitroprusside, did not modulate the activity of the soluble guanylate cyclase enzyme. However, halothane (1.0 mM), like atrial natriuretic factor (5 microM), stimulated the particulate guanylate cyclase enzyme activity. LY-83583 (6-anilino-5,8-quinolinedione, 10 microM), an agent that inhibits soluble guanylate cyclase activity, significantly reduced the response of the vessels to calcium ionophore (A23187, 0.4 microM), an endothelium-dependent vasodilator, without producing a significant effect on halothane-induced vasodilation. These results suggest that halothane-induced vasodilation of cerebral blood vessels is partly mediated by an increase in tissue cGMP levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoquinolines↗
PubMed1993

Halothane decreases the rate of production of cerebrospinal fluid. Possible role of vasopressin V1 receptors.

BACKGROUND: Circulating vasoactive hormones (e.g., vasopressin) play an important role in the regulation of blood flow to the choroid plexus and the rate of cerebrospinal fluid (CSF) production. We tested the hypothesis that halothane decreases CSF production through a vasopressin-related mechanism and examined the related changes in blood flow to the choroid plexus. METHODS: Using ventriculocisternal perfusion, CSF production was measured in chloralose anesthetized, normothermic rabbits whose lungs were mechanically ventilated. Rabbits received either 0.5 minimum alveolar concentration (MAC; end-tidal) of halothane (added to a preestablished chloralose anesthetic), 0.5 MAC of halothane in the presence of a vasopressin V1 antagonist (iv), or the V1 antagonist alone. In addition, we examined animals in which no intervention was made (time control) and animals subjected to a 25% decrease in mean blood pressure produced by hemorrhage, with and without the V1-antagonist. In a separate series of rabbits, regional and total blood flows to the brain and the choroid plexus were measured using radioactive microspheres. These studies were carried out under similar conditions, except that the effects of end-tidal 0.25, 0.5, and 1 MAC of halothane were examined in each rabbit (each added to a preestablished chloralose anesthetic). RESULTS: Under control conditions, blood flow to the choroid plexus averaged 351 +/- 198 ml.min-1.100 g-1 (mean +/- SD) and CSF production averaged 10.1 +/- 1.9 microliters.min.-1. Halothane (0.25, 0.5, and 1 MAC) did not alter choroid plexus blood flow but decreased CSF production by 28 +/- 6% at 0.5 MAC (P < .05). In contrast, 1 MAC of halothane increased total blood flow to the brain by 20 +/- 25% (P < .05). The V1 antagonist, which did not affect production of CSF when given alone, prevented the decrease in CSF production in response to halothane. Hemorrhage decreased blood flow to the choroid plexus but not to the brain, and the V1 antagonist attenuated the decrease in the rate of CSF production by hemorrhage (34 +/- 11% vs. 48 +/- 18%, P < .05). CONCLUSIONS: Halothane decreases CSF production with no net change in the blood flow to the choroid plexus. Decrease in CSF production appears to be mediated through a vasopressin-related mechanism and not to the blood pressure decrease seen during halothane anesthesia.

Animals↗
PubMed1993

Altered release and metabolism of norepinephrine in superfused canine saphenous veins in the presence of halothane and hypoxia.

BACKGROUND: Hypoxia and halothane are both known to have different effects on the release and disposition of norepinephrine at sympathetic nerve terminals during neurotransmission. In adverse clinical situations, both conditions may be present, but the effects of halothane and hypoxia together are not known. Therefore, studies were made of the effects of low partial pressures of oxygen and of halothane on the release, action, and metabolism of norepinephrine at sympathetic nerve endings in isolated segments of a blood vessel in which halothane is known to affect norepinephrine release and action profoundly. METHODS: Saphenous veins were removed from dogs, suspended for superfusion with Krebs-Ringer solution, and stimulated electrically. The veins were exposed to either 0%, 0.75%, or 1.5% halothane in the presence of 95% O2, 5% CO2, or 5% O2, 5% CO2, and 90% N2. Superfusates were collected under basal conditions, during and after electrical field stimulation, and poststimulation. Norepinephrine and its intraneuronal metabolite, 3,4-dihydroxyphenylglycol, were measured in superfusates and in the tissues after superfusion using high-performance liquid chromatography with electrochemical detection. RESULTS: Halothane decreased 1) evoked release of norepinephrine, 2) contractile response of the smooth muscle to nerve stimulation, 3) formation of 3,4-dihydroxyphenylglycol, and 4) tissue content of norepinephrine. However, hypoxia 1) increased evoked release of norepinephrine but decreased 2) contractile response during nerve stimulation, 3) formation of 3,4-dihydroxyphenylglycol, and 4) tissue content of norepinephrine. When halothane and hypoxia were present together, their effects on 3,4-dihydroxyphenylglycol formation, tissue content of norepinephrine, and the contractile responses appeared to be additive, but norepinephrine release was decreased compared with control concentrations. CONCLUSIONS: Although halothane and hypoxia had similar and additive effects on the intraneuronal metabolism of norepinephrine and on the postjunctional responses of smooth muscle to nerve stimulation, they had opposite effects on norepinephrine release from sympathetic nerve endings. The halothane-induced decrease in norepinephrine release overrode the increased release of norepinephrine caused by hypoxia.

Animals↗
PubMed1993

Sevoflurane and halothane reduce focal ischemic brain damage in the rat. Possible influence on thermoregulation.

BACKGROUND: There has been little systematic examination concerning the comparative effects of the anesthetized versus the awake state on outcome from cerebral ischemia. This experiment evaluated infarct volume and neurologic function in rats subjected to temporary focal ischemia while anesthetized with either sevoflurane or halothane. Outcome in these animals was compared to that observed in rats maintained unanesthetized during a similar ischemic insult. METHODS: All rats were anesthetized with halothane and surgically prepared for filament occlusion of the middle cerebral artery. After preparation, one group (Halothane) remained anesthetized with approximately 1.4 MAC halothane. In another group (Sevoflurane), halothane was discontinued and substituted with sevoflurane, which was administered until electroencephalographic burst suppression was evident (approximately 1.4 MAC). The final group (Awake) was allowed to awaken immediately after the onset of ischemia. Middle cerebral artery occlusion persisted for 90 min in all groups. The middle cerebral artery filament then was removed, and a 96-h survival interval was allowed. Neurologic function and infarct volume were determined. Recent evidence indicates that transient mild hyperthermia occurs in awake rats undergoing filament occlusion of the middle cerebral artery. To examine the potential role of mild hyperthermia in this experiment, a second experiment was performed in which rats anesthetized with halothane underwent 90-min focal ischemia, with pericranial temperatures held at either 38.0 degrees C or 39.2 degrees C. RESULTS: Intraischemic mean arterial pressure was 20-25 mmHg lower in the two anesthetized groups compared with awake animals. Despite this finding, cortical infarct volumes (mean +/- SD; Halothane, 17 +/- 32 mm3; Sevoflurane, 36 +/- 57 mm3; Awake, 115 +/- 104 mm3; Sevoflurane, 36 +/- 57 mm3; Awake, 115 +/- 104 mm3) and subcortical infarct volumes (mean +/- SD; Halothane, 39 +/- 57 mm3; Sevoflurane, 50 +/- 29 mm3; Awake, 88 +/- 46 mm3) were reduced in both groups of anesthetized rats. This reduction correlated with improved neurologic function. The rats in whom the pericranial temperature was maintained at 39.2 degrees C had a larger total infarct volume (218 +/- 81 mm3) and increased neurologic deficits when compared to those in whom the pericranial temperature was maintained at 38.0 degrees C (total infarct volume, 75 +/- 77 mm3). CONCLUSIONS: Both halothane and sevoflurane substantially reduced damage in this focal ischemia model when compared to outcome resulting from the same insult induced in awake rats. The reduction in intraischemic mean arterial pressure caused by the anesthetics did not seem contributory to outcome. Brain temperature differences among the groups were not defined. Because small differences in pericranial temperature were shown to have major effects on outcome, further work is required to determine if differences in brain temperature explain the observed protective effects of these anesthetics.

Anesthesia, Inhalation↗
PubMed1994

Halothane inhibits bradykinin-stimulated prostacyclin production in endothelial cells.

BACKGROUND: Halothane and isoflurane alter signal transduction and function in several cell types. Vascular responses to these anesthetics may be attributable to agent-specific effects on vasoactive mediator production. This study investigated the effects of halothane and isoflurane on basal and agonist-stimulated prostacyclin production by endothelial cells. METHODS: Prostacyclin production by cultured bovine aortic endothelial cells was monitored by radioimmunoassay of 6-keto-prostaglandin F1 alpha, the stable breakdown product of prostacyclin. RESULTS: Neither halothane nor isoflurane (0.3-1 mM), altered prostacyclin production. Bradykinin (1 microM), adenosine triphosphate (ATP) (10 microM), and melittin (1 microgram.ml-1) stimulated prostacyclin production. Isoflurane had no effect on responses to bradykinin, ATP, or melittin. Halothane inhibited the response to bradykinin but not the response to ATP or melittin. Pretreatment with pertussis toxin (100 ng.ml-1), to inhibit the function of the guanosine triphosphate-binding protein G alpha i, did not alter the response to bradykinin in the presence or absence of halothane. Pretreatment with phorbol 12-myristate 13-acetate (100 nM), to stimulate protein kinase C activity, did not alter bradykinin-stimulated prostacyclin production and prevented the inhibition of the response to bradykinin by halothane. CONCLUSIONS: Isoflurane had no effect on the increase in prostacyclin production stimulated by bradykinin. Halothane inhibited the bradykinin-stimulated prostacyclin production but not that stimulated by ATP or melittin. These results suggest that the halothane-mediated inhibition of bradykinin-stimulated prostacyclin production does not involve a pertussis toxin-sensitive G-protein and may result from an interaction of halothane at some other step in the signal transduction pathway, including the inhibition of protein kinase C.

Adenosine Triphosphate↗
PubMed1994

The effects of halothane on voltage-dependent calcium channels in isolated Langendorff-perfused rat heart.

BACKGROUND: Halothane has been previously shown in vitro to decrease both the inward calcium current in isolated cells and the density of calcium antagonist binding sites in cardiac sarcolemmal membranes prepared from several species, including humans, presumably contributing to the negative inotropic effects seen with volatile anesthetics. In this study we examined whether halothane produced similar changes in calcium channel antagonist binding characteristics ex vivo in an intact perfused heart by using isradipine, a dihydropyridine calcium channel blocker that binds specifically to the alpha 1 subunit of the L-type voltage-dependent calcium channel. METHODS: The rat hearts were perfused by the Langendorff method in the presence of halothane and unlabeled isradipine. After the hearts were homogenized and prepared into membranes, a radioligand binding assay was performed and binding curves obtained. Data were analyzed by nonlinear regression analysis of a one-site binding equation and were evaluated by a paired t test. RESULTS: Halothane protected or inhibited the binding of unlabeled isradipine to calcium channels in a dose-dependent manner such that as the halothane is removed during the membrane preparation process, previously obscured sites were then available for specific binding of the radioligand. The sites that were protected by halothane had a lower affinity for [3H]-isradipine than controls. CONCLUSIONS: In both isolated membranes and the intact heart, halothane changes the availability of calcium channel antagonist binding sites, indicating a change in conformation of the voltage-dependent calcium channel in the presence of anesthetic. This change may result from a direct effect on the protein or from an indirect effect mediated through the membrane lipid bilayer. It also is demonstrated that halothane "protected" channels are probably a modified class of channels compared to those in control tissues as exemplified by the much lower affinity that the protected channels have for [3H]-isradipine. We conclude that a major mechanism by which halothane depresses contractility is mediated through the voltage-dependent calcium channel, and this process results from a conformational change in the channel.

Animals↗
PubMed1995

Distribution of cerebral blood flow during anesthesia with isoflurane or halothane in humans.

BACKGROUND: Halothane and isoflurane have been shown to induce disparate effects on different brain structures in animals. In humans, various methods for measuring cerebral blood flow (CBF) have produced results compatible with a redistribution of CBF toward deep brain structures during isoflurane anesthesia in humans. This study was undertaken to examine the effects of halothane and isoflurance on the distribution of CBF. METHODS: Twenty ASA physical status patients (four groups, five in each) anesthetized with either isoflurane or halothane (1 MAC) during normo- or hypocapnia (PaCO2 5.6 or 4.2 kPa (42 or 32 mmHg)) were investigated with a two-dimensional CBF measurement (CBFxenon, intravenous 133xenon washout technique) and a three-dimensional method for measurement of the regional CBF (rCBF) distribution with single photon emission computer-aided tomography (SPECT; 99mTc-HMPAO). In the presentation of SPECT data, the mean CBF of the brain was defined as 100%, and all relative flow values are related to this value. RESULTS: The mean CBFxenon level was significantly influenced by the PaCO2 as well as by the anesthetic used. At normocapnia, patients anesthetized with halothane had a mean CBFxenon of 40 +/- 3 (SE) ISI units. With isoflurane, the flow was significantly (P < 0.01, 33 +/- 3 ISI units) less than with halothane. Hypocapnia decreased mean CBFxenon (P < 0.0001) during both anesthetics (halothane 24 +/- 3, isoflurane 13 +/- 2 ISI units). The effects on CBFxenon, between the anesthetics, differed significantly (P < 0.01) also during hypocapnia. There were significant differences in rCBF distribution measured between the two anesthetics (P < 0.05). During isoflurane anesthesia, there was a relative increase in flow values in subcortical regions (thalamus and basal ganglia) to 10-15%, and in pons to 7-10% above average. Halothane, in contrast, induced the highest relative flow levels in the occipital lobes, which increased by approximately 10% above average. The rCBF level was increased approximately 10% in cerebellum with both anesthetics. Changes in PaCO2 did not alter the rCBF distribution significantly. CONCLUSIONS: There is a difference in the human rCBF distribution between halothane and isoflurane with higher relative flows in subcortical regions during isoflurane anesthesia. However, despite this redistribution, isoflurane anesthesia resulted in a lower mean CBFxenon than did anesthesia with halothane.

Anesthesia↗
PubMed1995

Binding of halothane to serum albumin demonstrated using tryptophan fluorescence.

BACKGROUND: The site of action of general anesthesia remains controversial, but evidence in favor of specific protein target(s) is accumulating. Saturable binding of halothane to bovine serum albumin (BSA) has recently been reported using photoaffinity labeling and fluorine 19 nuclear magnetic resonance spectroscopy. We report a new approach to study anesthetic binding to soluble proteins, based on native tryptophan fluorescence. METHODS: Thymol-free halothane and fatty acid-free BSA were equilibrated in gas-tight Hamilton syringes and dispensed into stoppered quartz cuvettes at predetermined dilutions. Steady-state fluorescence spectroscopy was used to study their interaction. RESULTS: Halothane quenched the tryptophan fluorescence of BSA in a concentration-dependent, saturable manner with a dissociation constant = 1.8 +/- 0.2 mM and a Hill number = 1.0 +/- 0.1. The two optical isomers of halothane bound to BSA with equal affinity. The ability of halothane to quench BSA tryptophan fluorescence was markedly decreased at pH 3.0 (which causes full uncoiling of BSA), with loss of saturable binding. Diethyl ether displaced a portion of halothane from its binding sites. Circular dichroism spectroscopy revealed no significant effect of halothane or diethyl ether on the secondary structure of BSA. CONCLUSIONS: The results suggest that halothane binds in hydrophobic domains containing tryptophan in BSA. This approach may prove useful for studying the interaction of volatile anesthetics and proteins and has the advantage that the location of halothane in the protein is identified.

Fluorescence↗
PubMed1996

Antagonism of the antinocifensive action of halothane by intrathecal administration of GABAA receptor antagonists.

BACKGROUND: The hind brain and the spinal cord, regions that contain high concentrations of gamma-aminobutyric acid (GABA) and GABA receptors, have been implicated as sites of action of inhalational anesthetics. Previous studies have established that general anesthetics potentiate the effects of gamma-aminobutyric acid at the GABAA receptor. It was therefore hypothesized that the suppression of nocifensive movements during anesthesia is due to an enhancement of GABAA receptor-mediated transmission within the spinal cord. METHODS: Rats in which an intrathecal catheter had been implanted 1 week earlier were anesthetized with halothane. Core temperature was maintained at a steady level. After MAC determination, the concentration of halothane was adjusted to that at which the rats last moved in response to tail clamping. Saline, a GABAA, a GABAB, or glycine receptor antagonist was then injected intrathecally. The latency to move in response to application of the tail clamp was redetermined 5 min later, after which the halothane concentration was increased by 0.2%. Response latencies to application of the noxious stimulus were measured at 7-min intervals during the subsequent 35 min. To determine whether these antagonists altered baseline response latencies by themselves, another experiment was conducted in which the concentration of halothane was not increased after intrathecal administration of GABAA receptor antagonists. RESULTS: Intrathecal administration of the GABAA receptor antagonists bicuculline (0.3 micrograms) or picrotoxin (0.3, 1.0 micrograms) antagonized the suppression of nocifensive movement produced by the small increase in halothane concentration. In contrast, the antinocifensive effect of the increase in halothane concentration was not attenuated by the GABAB receptor antagonist CGP 35348 or the glycine receptor antagonist strychnine. By themselves, the GABAA receptor antagonists did not alter response latency in rats anesthetized with sub-MAC concentrations of halothane. CONCLUSIONS: Intrathecal administration of bicuculline or picrotoxin, at doses that do not change the latency to pinch-evoked movement when administered alone, antagonized the suppression of noxious-evoked movement produced by halothane concentrations equal to or greater than MAC. These results suggest that enhancement of GABAA receptor-mediated transmission within the spinal cord contributes to halothane's ability to suppress nocifensive movements.

Analgesics↗
PubMed1996

Effects of halothane and isoflurane on carbon monoxide-induced relaxations in the rat aorta.

BACKGROUND: Halothane and isoflurane previously were reported to attenuate endothelium-derived relaxing factor/nitric oxide-mediated vasodilation and cyclic guanosine monophosphate (cGMP) formation in isolated rat aortic rings. Carbon monoxide has many chemical and physiologic similarities to nitric oxide. This study was designed to investigate the effects of halothane and isoflurane on carbon monoxide-induced relaxations and cGMP formation in the isolated rat aorta. METHODS: Isometric tension was recorded continuously from endothelium denuded rat aortic rings suspended in Krebs-filled organ baths. Rings precontracted with submaximal concentrations of norepinephrine were exposed to cumulative concentrations of carbon monoxide (26-176 microM). This procedure was repeated three times, with anesthetics delivered 10 min before the second procedure. Carbon monoxide responses of rings contracted with the same concentration of norepinephrine (10(-6) M and 2 x 10(-6) M) used in the anesthetic-exposed preparations also were examined. The concentrations of cGMP were determined in denuded rings using radioimmunoassay. The rings were treated with carbon monoxide (176 microM, 30 s) alone, or carbon monoxide after a 10-min incubation with halothane (0.34 mM or 0.72 mM). To determine whether the sequence of anesthetic delivery influenced results, vascular rings pretreated with halothane were compared with nonpretreated rings. RESULTS: Carbon monoxide (26-176 microM) caused a dose-dependent reduction of norepinephrine-induced tension, with a maximal relaxation of 1.51 +/- 0.07 g (85 +/- 7% of norepinephrine-induced contraction). Halothane (0.34 mM and 0.72 mM) significantly attenuated the carbon monoxide-induced relaxations, but only the highest concentration of isoflurane (0.53 mM) significantly attenuated the carbon monoxide-induced relaxations. Carbon monoxide (176 microM) significantly increased cGMP content (+88.1 +/- 7.1%) and preincubation of the aortic rings with halothane (0.34 mM and 0.72 mM) inhibited this increase (-70.7 +/- 6.8% and -108.1 +/- 10.6%, respectively). When aortic rings and carbon monoxide were added simultaneously to Krebs solution equilibrated with halothane (0.72 mM), no inhibition of cGMP formation occurred. CONCLUSION: Carbon monoxide-induced endothelium-independent relaxations of rat aortic rings were decreased by clinically relevant concentrations of halothane and isoflurane. The carbon monoxide-induced elevations of cGMP were attenuated by halothane only when the anesthetic was incubated with aortic rings before carbon monoxide treatment. The possible clinical significance of the actions of the anesthetics on this endogenous vasodilator is yet to be determined.

Anesthetics, Inhalation↗