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PubMed1997

Impaired antioxidant defence in guinea pig heart tissues treated with halothane.

PURPOSE: To investigate the effects of halothane and halothane plus vitamin E treatment on myocardial free radical metabolism in guinea pigs. METHODS: Four groups of seven animals were studied: control, halothane, halothane plus vitamin E and vitamin E groups. In the halothane group, halothane 1.5% in oxygen was given for 90 min over three days. In the halothane plus vitamin E group, 300 mg.kg-1.day-1 vitamin E im was started three days before the first halothane treatment and continued for three days. Following sacrifice, the hearts were assayed for superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) and malondialdehyde (MDA) level was determined. Electron spin resonance (ESR) analysis and electron microscopy (EM) were also performed. RESULTS: In the halothane group, SOD activities and MDA concentrations were increased compared with control and GSH-Px and CAT activities were decreased. In the halothane plus vitamin E group, there were no differences in enzyme activity compared with halothane alone but the MDA level was decreased. In the vitamin E group, enzyme activities were increased compared with control. Mainly the CF3CHCl radical was identified by ESR analysis in heart tissues exposed to halothane and the concentration of this radical was reduced by vitamin E. Electron microscopy showed cytoplasmic vacuolisation and dilation in sarcoplasmic reticulum in the heart tissues exposed to halothane: both were prevented by vitamin E. CONCLUSION: Although halothane causes impairment in enzymatic antioxidant defence potential, due to lowered GSH-Px and CAT activity, and accelerates peroxidative reactions in the tissues affected, no subcellular damage occurred. Vitamin E may protect tissues against free radical attack by scavenging toxic free radicals formed in heart tissue during halothane anaesthesia.

Anesthetics, Inhalation↗
PubMed1997

Halothane reduces reperfusion injury after regional ischaemia in the rabbit heart in vivo.

In addition to having anti-ischaemic effects, halothane can protect isolated rat hearts and isolated cardiomyocytes against reperfusion injury of the "oxygen paradox" type. The aim of this study was to investigate if halothane can also protect against myocardial reperfusion injury in vivo. Twenty-two rabbits anaesthetized with alpha-chloralose underwent 30 min of occlusion of a major coronary artery and 2 h of subsequent reperfusion. Seven animals received 1 MAC of halothane for the first 15 min of reperfusion (halothane group), and eight animals served as untreated controls (controls group). In seven additional animals, the haemodynamic effects of halothane were antagonized by an i.v. infusion of noradrenaline (halothane-noradrenaline group). We measured cardiac output (CO) by an ultrasonic flow probe around the ascending aorta, left ventricular pressure (LVP) by a tip manometer and infarct size by triphenyltetrazolium staining. Baseline LVP was mean 92 (SEM 4) mm Hg and CO was 289 (16) ml min-1. During coronary occlusion, LVP was reduced to 86 (4)% of baseline and CO to 84 (4)% (similar in all groups). During halothane administration at reperfusion, LVP declined further to 55 (6)% of baseline and CO to 66 (9)% (P < 0.05 halothane group vs control group). Noradrenaline prevented the reduction in LVP (halothane-noradrenaline group 87 (5)% of baseline, control group 84 (6)% and reduction in CO (halothane-noradrenaline group 89 (5)%, control group 83 (6)%. Infarct size was 49 (6)% of the area at risk in controls and was reduced markedly by administration of halothane to 32 (3)% in the halothane group (P < 0.05) and to 30 (3)% in the halothane-noradrenaline group (P < 0.05). Treatment with halothane during the early reperfusion period after myocardial ischaemia protected the myocardium against infarction in vivo, independent of the haemodynamic effect of halothane.

Anesthetics, Inhalation↗
PubMed1991

Halothane and isoflurane increase pulmonary artery endothelial cell sensitivity to oxidant-mediated injury.

Volatile anesthetics inhibit phagocytic cell function, yet little is known about their effects on target tissues or on the target tissue response to stimulated phagocytes. Experiments were performed to determine how exposure to halothane and isoflurane changes rat pulmonary artery endothelial cell (RPAEC) viability in response to the toxic oxygen metabolites produced by stimulated phagocytic cells. RPAECs were grown in monolayer culture. The monolayers were treated with phorbol myristate acetate (PMA) -stimulated human neutrophils at an effector-to-target ratio of 20:1 after equilibration with 0.4% or 1.7% halothane or 0.7% or 2.8% isoflurane. As measured by percent-specific release of incorporated 51Cr label (mean +/- SE), cytotoxicity in the presence of 1.7% halothane (75.3 +/- 3.4%) was significantly greater (P less than 0.02) than cytotoxicity in 5% CO2 in air (44.7 +/- 3.3%) and in 0.4% halothane (57.3 +/- 4.7%). Also, cytotoxicity in 1.7% halothane was significantly greater than in 0.4% halothane (P less than 0.02). The authors found that RPAECs incubated in isoflurane exhibited significantly greater release of 51Cr than cells incubated in the MAC equivalent concentrations of halothane: 78.2 +/- 2.6% in 0.7% isoflurane (P = 0.0004) and 83.8 +/- 1% in 2.8% isoflurane (P = 0.005). Because early neutrophil cytotoxicity has been found to be mediated primarily by hydroxyl radical (HO.) and hydrogen peroxide (H2O2), the authors measured H2O2 production by similar numbers of PMA-stimulated neutrophils under similar exposure conditions. In carrier gas, PMA-stimulated neutrophils produced 20.5 +/- 1.3 nmol H2O2.10(6) cells-1.h-1. At the higher concentrations of halothane, H2O2 production actually was inhibited in comparison with carrier gas (15.4 +/- 1.4 nmol H2O2.10(6) cells-1.h-1 in 1.7% halothane and 16.8 +/- 0.8 in 2.8% halothane), but the degree of inhibition did not reach statistical significance. In isoflurane, however, H2O2 production was not different from that seen in carrier gas. In other experiments, the monolayers were treated with 0, 200, 500, and 1,000 microM H2O2 after equilibration with 0.4%, 1.7%, and 2.8% halothane or 0.7%, 2.8%, and 5% isoflurane in 5% CO2 in air. Efficiency of replating was used to measure degree of injury. Both halothane and isoflurane enhance the sensitivity of the RPAEC monolayers to injury by H2O2. The sensitizing effect of halothane was reversed by removing the anesthetic. Halothane and isoflurane thus enhance RPAEC sensitivity to injury by both H2O2 and PMA-stimulated neutrophils. In increasing RPAEC sensitivity to injury by oxygen metabolites, halothane and isoflurane may be inhibiting processes involved in intracellular antioxidant defenses.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2000

Neuronal nitric oxide synthase mediates halothane-induced cerebral microvascular dilation.

BACKGROUND: The causes of volatile anesthetic-induced cerebral vasodilation include direct effects on smooth muscle and indirect effects via changes in metabolic rate and release of mediators from vascular endothelium and brain parenchyma. The role of nitric oxide and the relative importance of neuronal and endothelial nitric oxide synthase (nNOS and eNOS, respectively) are unclear. METHODS: Rat brain slices were superfused with oxygenated artificial cerebrospinal fluid. Hippocampal arteriolar diameters were measured using computerized videomicrometry. Vessels were preconstricted with prostaglandin F2alpha (PGF2alpha; halothane group) or pretreated with 7-nitroindazole sodium (7-NINA, specific nNOS inhibitor, 7-NINA + halothane group) or N-nitro-L-arginine methylester (L-NAME; nonselective NOS inhibitor, L-NAME + halothane group) and subsequently given PGF2alpha to achieve the same total preconstriction as in the halothane group. Increasing concentrations of halothane were administered and vasodilation was calculated as a percentage of preconstriction. RESULTS: Halothane caused significant, dose-dependent dilation of hippocampal microvessels (halothane group). Inhibition of nNOS by 7-NINA or nNOS + eNOS by L-NAME similarly attenuated halothane-induced dilation at 0.6, 1.6, and 2.6% halothane. The dilation (mean +/- SEM) at 1.6% halothane was 104 +/- 10%, 65 +/- 6%, and 51 +/- 9% in the halothane, 7-NINA + halothane and L-NAME + halothane groups, respectively. The specificity of 7-NINA was confirmed by showing that acetylcholine-induced dilation was not inhibited by 7-NINA but was converted to constriction by L-NAME. CONCLUSIONS: At clinically relevant concentrations, halothane potently dilates intracerebral arterioles. This dilation is mediated, in part, by neuronally derived nitric oxide. Endothelial NOS does not play a major role in halothane-induced dilation of hippocampal microvessels.

Analysis of Variance↗
PubMed2002

Antioxidants prevent depression of the acute hypoxic ventilatory response by subanaesthetic halothane in men.

We studied the effect of the antioxidants (AOX) ascorbic acid (2 g, I.V.) and alpha-tocopherol (200 mg, P.O.) on the depressant effect of subanaesthetic doses of halothane (0.11 % end-tidal concentration) on the acute isocapnic hypoxic ventilatory response (AHR), i.e. the ventilatory response upon inhalation of a hypoxic gas mixture for 3 min (leading to a haemoglobin saturation of 82 +/- 1.8 %) in healthy male volunteers. In the first set of protocols, two groups of eight subjects each underwent a control hypoxic study, a halothane hypoxic study and finally a halothane hypoxic study after pretreatment with AOX (study 1) or placebo (study 2). Halothane reduced the AHR by more than 50 %, from 0.79 +/- 0.31 to 0.36 +/- 0.14 l min(-1) %(-1) in study 1 and from 0.79 +/- 0.40 to 0.36 +/- 0.19 l min(-1) %(-1) in study 2, P < 0.01 for both. Pretreatment with AOX prevented this depressant effect of halothane in the subjects of study 1 (AHR returning to 0.77 +/- 0.32 l min(-1) %(-1), n.s. from control), whereas placebo (study 2) had no effect (AHR remaining depressed at 0.36 +/- 0.27 l min(-1) %(-1), P < 0.01 from control). In a second set of protocols, two separate groups of eight subjects each underwent a control hypoxic study, a sham halothane hypoxic study and finally a sham halothane hypoxic study after pretreatment with AOX (study 3) or placebo (study 4). In studies 3 and 4, sham halothane did not modify the control hypoxic response, nor did AOX (study 3) or placebo (study 4). The 95 % confidence intervals for the ratio of hypoxic sensitivities, (AOX + halothane) : halothane in study 1 and (AOX - sham halothane) : sham halothane in study 3, were [1.7, 2.6] and [1.0, 1.2], respectively. Because the antioxidants prevented the reduction of the acute hypoxic response by halothane, we suggest that this depressant effect may be caused by reactive species produced by a reductive metabolism of halothane during hypoxia or that a change in redox state of carotid body cells by the antioxidants prevented or changed the binding of halothane to its effect site. Our findings may also suggest that reactive species have an inhibiting effect on the acute hypoxic ventilatory response.

Acute Disease↗
PubMed1994

Formation of trifluoroacetylated protein antigens in cultured rat hepatocytes exposed to halothane in vitro.

Immune responses to novel, halothane metabolite-modified protein antigens (tri-fluoroacetylated proteins; TFA-proteins) have been implicated in the pathogenesis of halothane hepatitis. The aim of the present study was to investigate and characterize expression of TFA-proteins in cultures of rat hepatocytes which were exposed to halothane in vitro. Following exposure to halothane, the hepatocytes were harvested, then subcellular fractions were prepared and were analysed by immunoblotting for expression of antigens recognized by a rabbit anti-TFA antiserum, and by antibodies in sera from two patients with halothane hepatitis. Hepatocytes exposed to halothane in vitro were shown to express novel microsomal protein antigens, which exhibited molecular masses that were identical to the molecular masses of the major TFA-protein antigens expressed in vivo, in livers of halothane-treated rats (100, 80 and 60 kDa). Experiments in which hepatocytes were exposed to halothane in the presence of SKF-525A, or were exposed to deuterated halothane in place of halothane, confirmed that these novel antigens were TFA-modified proteins whose generation required cytochrome P450-mediated metabolism of halothane. The maximal levels of TFA-antigens expressed in vitro were about 30% of the levels expressed in halothane-treated rats in vivo. Maximal expression of the TFA-antigens in vitro occurred when hepatocytes were exposed to halothane at doses which yielded concentrations of the drug in culture medium of about 13 microM. Expression of the antigens in vitro occurred slowly, with an apparent half-time of about 8 hr. Overall, these results demonstrate that the properties of the TFA-antigens expressed in cultured hepatocytes in vitro closely resemble the properties exhibited by the antigens expressed in vivo, in livers of halothane-treated rats.

Animals↗
PubMed1988

Effects of piperonyl butoxide on halothane hepatotoxicity and metabolism in the hyperthyroid rat.

A series of experiments were conducted to examine the potential role of phase I metabolism in halothane-induced liver injury in the hyperthyroid rat. The metabolism of halothane was determined in both hyperthyroid (triiodothyronine, 3 mg/kg per day, for 6 days) and euthyroid rats and in animals pre-treated with the cytochrome P-450 inhibitor piperonyl butoxide (75-100 mg/kg, i.p.). It was found that the hyperthyroid state, which is associated with a substantial increase in sensitivity to the hepatotoxic effects of halothane, decreases both oxidative and reductive routes of halothane metabolism in the rat. The production of trifluoroacetic acid (TFA), an oxidative metabolite, as well as that of chlorodifluoroethylene (CDF) and chlorotrifluoroethane (CTF), 2 reductive metabolites, was significantly reduced in hyperthyroid animals. Consistent with these findings serum and urinary bromide levels resulting from the formation of TFA, CDF or CTF were significantly reduced. The only route of halothane metabolism significantly increased by the hyperthyroid condition was the defluorination of halothane. Piperonyl butoxide administration did not render euthyroid animals sensitive to the halothane-induced hepatotoxicity and had no effect on the defluorination of halothane in euthyroid animals. However, piperonyl butoxide markedly increased the hepatotoxicity of halothane in hyperthyroid rats and, except for a modest increase in debromination reactions, decreased all measured indices of halothane metabolism including the defluorination of halothane. Thus, none of the observed changes in halothane metabolism produced by triiodothyronine or piperonyl butoxide treatment could be consistently correlated to the increases in hepatotoxicity linked to these 2 treatments. Based on these studies we suggest that the halothane hepatotoxicity induced in the hyperthyroid rat results from effects produced by either the parent compound or an as yet unidentified metabolite. In addition, these studies further demonstrate that considerable mechanistic differences exist for halothane-induced hepatotoxicity when comparing euthyroid and hyperthyroid animal models.

Administration, Inhalation↗
PubMed1998

Halothane attenuates nitric oxide relaxation of rat aortas by competition for the nitric oxide receptor site on soluble guanylyl cyclase.

Endothelial cells play an important role in the regulation of vascular activity through the release of endothelium derived relaxing factor (EDRF) now believed to be nitric oxide (NO). NO and the NO donor drug nitroglycerin relax vascular smooth muscle by stimulating soluble guanylyl cyclase leading to elevation of intracellular levels of cyclic guanosine 3',5'-monophosphate (cGMP). Halothane has been shown to inhibit the action of NO on blood vessels. This study was designed to further investigate the mechanisms by which halothane attenuates NO-induced vascular relaxations. This was done by examining the effects of halothane on nitroglycerin and NO-induced relaxations in the presence and absence of the inhibitors of soluble guanylyl cyclase, methylene blue and 6-anilino-5,8-quinolinedione (LY 83583). Thoracic aortas from anesthetized male Sprague-Dawley rats were excised and cut into rings and the endothelium was removed. The aortic rings were suspended in organ baths containing Krebs solution and equilibrated at their optimal passive tension. When a stable plateau of contraction was produced by EC60 concentrations of norepinephrine, increasing concentrations of nitroglycerin or NO were added to the baths to relax the rings. This contraction-relaxation procedure was repeated three or four times. In some baths halothane was administered by a calibrated vaporizer 10 min before beginning the second procedure. Either methylene blue or LY 83583 was added to the baths 20 min before the third procedure. The combination of halothane, methylene blue or LY 83583 was added before the fourth procedure. Halothane, methylene blue or LY 83583 significantly inhibited nitroglycerin-induced relaxation individually. Halothane and LY 83583 also significantly inhibited NO-induced relaxations (5 x 10(-9)-3 x 10(-8) M and 5 x 10(-9)-3 x 10(-5) M, respectively) individually. The combination of halothane and methylene blue or halothane and LY 83583 significantly inhibited nitroglycerin-induced relaxation, also, the combination of halothane and LY 83583 significantly inhibited NO-induced relaxations. Halothane, methylene blue and LY 83583 treatment led to rightward shift in the concentration-effect curves. Halothane, in combination with methylene blue or LY 83583, produced inhibition equivalent to the sum of their individual effects. The present study demonstrates that the halothane, methylene blue and LY 83583 attenuate nitroglycerin and NO-induced relaxations of endothelium-denuded rat aortic rings. This suggests that halothane, methylene blue and LY 83583 may act through competitive antagonism at a common site of action on soluble guanylyl cyclase in the EDRF/NO relaxation pathway.

Aminoquinolines↗
PubMed1981

Interactions among ventilation, the circulation, and the uptake and distribution of halothane--use of a hybrid computer multiple model: I. The basic model.

The authors describe an 18-compartment hybrid computer multiple model of the uptake and distribution of halothane. This model uses 88 equations and 124 parameter settings. Three submodels are incorporated into the basic model: 1) The mass transport of halothane is simulated on the digital portion of the hybrid computer. 2) A breath-by-breath pulmonary model with two compartments describes air pressure-flow relations in the airway system. 3) A beat-to-beat cardiovascular model with 15 compartments describes in detail blood pressure-flow relations. In addition, a baroreceptor-heart rate loop is included: an increase in arterial pressure causes a decrease in heart rate. The slope of the baroreceptor response is progressively decreased by halothane until at 2 per cent there is no response. The model of halothane uptake and distribution is separate from the blood and air pressure-flow models, but is, in effect, driven by them. Myocardial "contractility" (stroke volume) and certain regional vascular resistances can be affected by the concentration of halothane in one or any proportion of any combination of three compartments: arterial blood (arteriolar concentrations), cerebral gray matter, or myocardial. In turn, these factors significantly affect the uptake and distribution of halothane. The responses to three steady-state concentration, as well as to a step change in concentration from 0 to 2 per cent, were examined. Twenty-four outputs were recorded, including halothane concentrations in ten compartments; myocardial "contractility"; left and right ventricular and right atrial pressures; cardiac output; stroke volume, R-R interval; and blood flows in six regions. Two variables--alveolar concentration of halothane and arterial blood pressure--were recorded during a step change of 0 to 5 per cent. The model describes the appropriate steady-state and dynamic cardiovascular responses to halothane. It also demonstrates the complex interrelationships among caridac output, regional blood flow distribution, and the uptake and distribution of halothane. During step change in halothane concentration, most of the responses occur early, a phenomenon also seen in man and goats. Thus, the model is useful not only for representing organ and tissue halothane concentrations, but also for gaining new insights into cardiovascular alterations produced by rapidly changing concentrations of halothane and into the complex interactions between the circulation and the uptake and distribution of halothane.

Anesthesia, Inhalation↗
PubMed1981

Genetic differences in reductive metabolism and hepatotoxicity of halothane in three rat strains.

The relationship between the reductive metabolism of halothane and hepatotoxicity was examined in three rat strains (Fischer 344, Sprague-Dawley, and black hooded Wistar) to determine if there were genetic differences in 1) the reductive metabolism of halothane under identical exposure conditions, and 2) the susceptibility to the hepatotoxic effects of halothane. Halothane hepatotoxic was produced in all rat strains by exposing phenobarbital-pretreated rats to 1 per cent halothane under mild hypoxia (14 per cent oxygen, inspired) for 2 h. Generally the levels of both 2-chloro-1,1,1-trifluoroethane (CTF) and 2-chloro-1,1-difluoroethylene (CDF), two volatile metabolites of halothane, increased from the onset of anesthetic exposure and reached a plateau after approximately 60 min. The exception to this trend were phenobarbital-pretreated Wistar rats (exposed to 1 per cent halothane with 14 per cent oxygen) where the levels of either CDF or CTF were high initially (10-min sample) and decreased in subsequent samples to reach a plateau after 80 min. The plateau levels of both CDF (approximately 6 ppm) and CTF (approximately 20 ppm) were not significantly different among the three rat strains exposed to halothane (1 per cent) and hypoxia with prior enzyme induction. There were, however, significant differences in both biochemical and pathological changes among the three strains exposed under the above identical conditions when the rats were killed 24 h after anesthetic exposure. For example, serum alanine aminotransferase (ALT) was increased fourfold in the Fischer strain but only doubled for the other two strains. Moreover, while all three strains had various amounts of hepatocyte damage in the vicinity of the central veins when the rats were exposed to halothane, hypoxia, and enzyme induction, only the Fischer strain showed hepatocyte damage under the exposure conditions of halothane (1 per cent) and normoxia (21 per cent oxygen, inspired) with prior enzyme induction. The results support the role of reductive metabolism of halothane in the etiology of halothane hepatotoxicity. Furthermore, they suggest that genetic variations in the susceptibility of the liver to the reactive intermediates or metabolites formed during reductive metabolism of halothane may be a significant factor in halothane hepatotoxicity.

Alanine Transaminase↗
PubMed1988

Halothane decreases albumin and transferrin synthesis: studies in the isolated, perfused rat liver and in the intact rat.

Isolated perfused rat livers exposed to 1.5% halothane (equivalent to 1.35 MAC) in O2/CO2 or to O2/CO2 alone produced urea, as well as albumin and transferrin (both measured by immunodiffusion), at constant rates during a 4.25-h perfusion. Urea production did not differ in the two treatment groups, but halothane depressed albumin and transferrin synthesis 43% and 45%, respectively. Intact rats were also exposed to halothane, after which albumin synthesis was measured by the (14C)carbonate technique. The minimum halothane concentration required to insure sufficient relaxation for ventilation was selected and ranged from 1.0 to 1.5%. Measurements were made in control rats not exposed to halothane (group I) and in halothane exposed rats immediately after 1 h of anesthesia (group II), 24 h after the start of 1 h of anesthesia (group III), and immediately after 1/2 h of anesthesia preceded by a 1-h exposure 24 h earlier (group IV). Single exposures to halothane (groups II and III) resulted in a decrease in albumin synthesis immediately or 24 h later that did not differ significantly from controls (group I). However, halothane given twice to rats at 24-h intervals (group IV) reduced their mean albumin synthesis rate to half that of controls. The early onset and constancy of halothane depression of export protein synthesis by isolated, perfused livers may reflect a response to halothane itself, rather than an effect resulting from the accumulation of halothane metabolites. Similarly, reduction of albumin synthesis in intact rats immediately after a second halothane exposure may indicate a response to halothane, rather than to halothane metabolites.

Albumins↗
PubMed1994

Effects of halothane on surfactant biosynthesis by rat alveolar type II cells in primary culture.

BACKGROUND: Pulmonary surfactant, which is synthesized by alveolar type II cells (ATII cells) almost exclusively, plays a major role in maintaining alveolar homeostasis by reducing surface tension at the fluid-gas interface. Phosphatidylcholine (PC), the main surfactant lipid component, is largely responsible for this surface activity. The effects of halothane on the phospholipid metabolism of the pulmonary surfactant by ATII cells are unknown, even though these cells are exposed directly to volatile anesthetics during anesthesia and even though any alteration in surfactant biosynthesis by anesthetics may have deleterious effects on lung function and thereby facilitate postoperative pulmonary complications. In the current study, the effects of halothane exposure on surfactant synthesis by rat ATII cells in primary culture were investigated. METHODS: ATII cells were isolated from adult rat lungs and used for the experiments after 24 h in primary culture. The ability of ATII cells to synthesize surfactant was assessed by the incorporation of radioactive precursors in PC. Cytotoxicity was measured by the rate of lactate dehydrogenase release into the culture medium, and the lactate metabolism was taken as an index of glycolytic metabolism. All metabolic measurements were made after 24 h in primary culture. Effects of various halothane concentrations (1, 2, 4, and 8%) exposure for 4 h were studied, as were the effects of 2% halothane for various durations of exposure (2, 4, 8, and 12 h). The reversibility of halothane effects on PC synthesis was assessed after a 2% halothane exposure for 4 h. PC secretion and adenosine triphosphate cellular content were also measured for 4 h exposure at the various halothane concentrations. RESULTS: During a 4-h exposure, PC synthesis was reduced by 10, 24, 29 and 36% for 1, 2, 4, and 8% halothane respectively when compared with control values. At 2% halothane concentration, the observed decreases in PC synthesis were 12, 24, 31 and 34% for 2, 4, 8, and 12 h exposure, respectively. The inhibitory effect of halothane was completely reversed 2 h after the end of exposure. PC secretion was unaffected by increasing halothane concentrations during a 4-h exposure. Halothane did not produce cell damage except for the longest exposure durations (8 and 12 h) at 2% vapor concentration. Whatever the exposure conditions, lactate production by ATII cells exposed to halothane was greater than production by unexposed cells. CONCLUSIONS: These results indicate that halothane decreases the biosynthesis of pulmonary surfactant by ATII cells in primary culture and alters the high energy phosphate metabolism of these cells.

Adenosine Triphosphate↗
PubMed1995

Endothelium-independent vasoconstricting and vasodilating actions of halothane on rat mesenteric resistance blood vessels.

BACKGROUND: Whether volatile anesthetics produce changes in vascular resistance and blood flow because of direct effects on vascular tissue is unclear. Direct vasoconstricting and vasodilating actions have been demonstrated in isolated conductance arteries in vitro, but there is little information regarding direct effects on the small vessels that mediate resistance and flow changes in vivo. METHODS: We investigated the actions of halothane on 50-200 microM branches of the rat mesenteric artery that were cannulated and studied in vitro. The vessels were pressurized to 60 mmHg, and vascular dimensions were continuously monitored using a computer-based real-time image analysis system. The vessel bath was perfused with HCO3(-)-buffered saline (37 degrees C) equilibrated with 95% O2/5% CO2 (+/- halothane). The vascular endothelium was mechanically removed before cannulation in some vessels. RESULTS: In unstimulated vessels, halothane had a concentration-dependent vasoconstricting action (EC50 = 0.45 mM approximately 1.5 vol% at 37 degrees C) that was largely transient and was similar to that produced by caffeine. Both halothane and caffeine constrictions were unaffected by bath [Ca2+], nifedipine (1 microM) or Cd2+ (100 microM) and were abolished by ryanodine (10 microM). In addition, caffeine responses were attenuated by halothane in a concentration-dependent manner (EC50 = 1.6 mM). In vessels preconstricted with KCl (40 mM) or phenylephrine (10(-6) M), halothane produced transient constriction followed by concentration-dependent vasodilation. Ryanodine, which abolished halothane constrictions, had little effect on the amplitude of KCl- or phenylephrine-induced constrictions or the vasodilating action of halothane. Removal of the endothelium likewise had little effect on the vasoconstricting or the vasodilating actions of halothane in unstimulated, KCl- or phenylephrine-constricted vessels. Halothane completely relaxed KCl and phenylephrine constrictions with EC50 values of 0.36 mM (1.2% at 37 degrees C) and 0.75 mM (2.5%), respectively, in intact vessels before ryanodine; 0.25 mM (0.8%) and 0.59 mM (1.9%) in intact vessels after ryanodine; and 0.52 mM (1.7%) and 0.67 mM (2.2%) in endothelium-denuded vessels. CONCLUSIONS: Halothane has endothelium-independent vasoconstricting and vasodilating actions in isolated mesenteric resistance blood vessels. The vasoconstricting action appears to involve halothane-induced Ca2+ release from caffeine/ryanodine-sensitive intracellular store(s). The vasodilating action in phenylephrine- or KC1-constricted vessels is independent of the Ca(2+)-releasing action and most likely involves an effect(s) on sarcolemmal-dependent Ca2+ signaling (e.g., extracellular Ca2+ influx) and/or Ca2+ activation of contractile proteins. The magnitude of both the vasoconstricting and the vasodilating actions of halothane in these vessels at clinically relevant concentrations suggests these direct actions contribute to the overall cardiovascular effects of halothane in vivo.

Animals↗
PubMed1995

Interaction of halothane with inhibitory G-proteins in the human myocardium.

BACKGROUND: Halothane has been reported to possess a catecholamine-sensitizing effect in laboratory animals and in anesthetized patients and to enhance the positive inotropic effect of isoproterenol in human papillary muscle strips. The current study was designed to investigate further the underlying subcellular mechanisms on human myocardium, in particular the mechanism of action of halothane on G-proteins. METHODS: To investigate the effect of halothane on adenylyl cyclase activity, isoproterenol-, guanylylimidodiphosphate (Gpp(NH)p)-, and forskolin-activated enzyme activities were studied alone and in the presence of halothane in native and manganese-treated membranes. The mechanisms of halothane interaction with inhibitory G-proteins (G1) were studied in adenosine diphosphate-ribosylation studies with pertussis toxin and immunochemical techniques. RESULTS: Halothane (1%) augmented isoproterenol- and Gpp(NH)p-stimulated adenylyl cyclase activity but had no effect on forskolin-stimulated enzyme activity. Manganese ions inhibited the stimulating effect of isoproterenol and Gpp(NH)p on adenylyl cyclase activity, but the effect of forskolin remained unchanged in control and halothane-treated membranes. In the presence of pertussis toxin, the effect of isoproterenol and Gpp(NH)p on adenylyl cyclase activity was enhanced, but further stimulation by halothane was abolished. Halothane did not influence the attachment of Gi alpha to the membrane. No effect of halothane on adenosine diphosphate-ribosylation of Gi alpha by pertussis toxin was observed. CONCLUSIONS: Halothane stimulates adenylyl cyclase activity by inhibiting the function of the inhibitory G-proteins by interfering with the effects of the alpha subunits or beta gamma subunits with the effector. Decreased membrane attachment of Gi alpha in the presence of halothane does not occur. The interaction of alpha and beta gamma subunits is not affected by halothane. Halothane does not impair the binding of pertussis toxin to the Gi alpha-protein.

Adenosine Diphosphate Ribose↗
PubMed1995

One-day hypothermic preservation of isolated hearts with halothane improves cardiac function better than low calcium.

BACKGROUND: Halothane exerts a potent negative inotropic effect on the heart and mimics many of the cardiac effects of lowered extracellular CaCl2. Reduced slow inward Ca2+ current and sarcoplasmic reticular effects on intracellular Ca2+ are likely involved. The authors reported previously that halothane protects against hypoxic and ischemia reperfusion injury in isolated hearts. The aim of this isolated heart study was to compare protective effects of halothane and low CaCl2 (0.5 mM) administered during 1 day of hypothermic perfusion on return of normothermic perfusion. METHODS: Guinea pig hearts (n = 66) were isolated and perfused at 37 degrees C with a Krebs' solution, gassed with 96% O2, 4% CO2, and containing 2.5 mM Ca2+, and 4.5 mM K+. Heart rate, isovolumetric left ventricular pressure, coronary flow, %O2 extraction, O2 consumption rate, and relative cardiac efficiency (EFF = heart rate.left ventricular pressure/O2 consumption rate) were measured in five groups of hearts: time controls (no hypothermia); 1.5, and 3% halothane delivered by vaporizer; cold controls (hypothermia only); and 0.5 mM CaCl2. Halothane was administered, or CaCl2 was decreased 0.5 h before hypothermia at 3.8 +/- 0.1 degrees C, during hypothermia for 22 h, and for 0.5 h after rewarming to 37.0 +/- 0.1 degrees C. Hearts were perfused at 25% of initial coronary flow during hypothermia. RESULTS: All groups had similar ventricular function and vasodilator responses before hypothermia. During normothermic reperfusion after hypothermia, both concentrations of halothane protected better than low CaCl2. Values, expressed as a percent of initial values in the five groups (time control, 3% halothane, 1.5% halothane, cold control, and 0.5 mM CaCl2, were respectively: 90 +/- 6, 54 +/- 6*, 48 +/- 5*, 27 +/- 8, 27 +/- 4% for left ventricular pressure; 84 +/- 5, 61 +/- 4*, 62 +/- 6*, 40 +/- 5, 34 +/- 5% for EFF; and 102 +/- 3, 63 +/- 3*, 66 +/- 3*, 55 +/- 2, 42 +/- 2% for coronary flow (*P < 0.05 halothane vs. 0.5 mM CaCl2). The coronary flow response to endothelium-dependent (acetylcholine) and endothelium-independent (nitroprusside) vasodilators was also greater after halothane than after 0.5 mM CaCl2. CONCLUSIONS: Halothane administered during hypothermia restores left ventricular pressure, cardiac efficiency, basal coronary flow, and flow responses better than low CaCl2. Although halothane and low CaCl2 both reduce intracellular Ca2+, contractile force, and metabolic demand, the better protective effect of halothane is not likely simply due to a reduction in contractile function and metabolic rate before or initially after hypothermia because these were reduced much more by low CaCl2 than by halothane.

Anesthetics↗
PubMed1996

Dual actions of halothane on intracellular calcium stores of vascular smooth muscle.

BACKGROUND: Halothane has been reported to affect the integrity of intracellular Ca2+ stores in a number of tissues including vascular smooth muscle. However, the actions of halothane on intracellular Ca2+ stores are not yet fully understood. METHODS: Employing the isometric tension recording method, the action of halothane in isolated endothelium-denuded rat mesenteric arteries under either intact or beta-escinmembrane-permeabilized conditions was investigated. RESULTS: Halothane (0.125-5%) produced concentration-dependent contractions in Ca2+ free solution in both intact and membrane-permeabilized muscle strips. Ryanodine treatment or repetitive application of phenylephrine eliminated both caffeine-and halothane-induced contractions in the Ca2+ free solution. When either halothane and caffeine, caffeine and halothane, phenylephrine and halothane, or inositol 1,4,5-triphosphate and halothane were applied consecutively in the Ca2+ free solution in either intact or membrane-permeabilized muscle strips, the contraction induced by application of the second agent of the pair was inhibited compared to application of that agent alone. However, when procaine was applied before and during application of the first agent, the contraction induced by the first agent was inhibited and the contraction induced by the second agent was restored. Heparin inhibited the inositol 1,4,5-triphosphate-mediated contraction, but not contractions induced by halothane or caffeine. Halothane (0.125-5%), applied during Ca2+ loading, produced concentration-dependent inhibition of the caffeine contraction (used to estimate the amount of Ca2+ in the store) in both intact and membrane-permeabilized muscle strips. In contrast, halothane applied with procaine during Ca2+ loading produced concentration-dependent enhancement of the caffeine contraction. This enhancement was observed only in the intact but not in the membrane-permeabilized condition. CONCLUSIONS: Halothane has two distinct actions on the intracellular Ca2+ stores of vascular smooth muscle, a Ca2+ releasing action and a stimulating action on Ca2+ uptake. Halothane releases Ca2+ from the stores that are sensitive to both caffeine/ryanodine and phenylephrine/inositol 1,4,5-triphosphate through a procaine-sensitive mechanism. The observed inhibitory effect on Ca2+ uptake is probably caused by the Ca2+ uptake after blockade of Ca2+ release may be membrane-mediated.

Anesthetics, Inhalation↗
PubMed2004

Mg2+ dependence of halothane-induced Ca2+ release from the sarcoplasmic reticulum in skeletal muscle from humans susceptible to malignant hyperthermia.

BACKGROUND: Recent work suggests that impaired Mg(2+) regulation of the ryanodine receptor is a common feature of both pig and human malignant hyperthermia. Therefore, the influence of [Mg(2+)] on halothane-induced Ca(2+) release from the sarcoplasmic reticulum was studied in malignant hyperthermia-susceptible (MHS) or -nonsusceptible (MHN) muscle. METHODS: Vastus medialis fibers were mechanically skinned and perfused with solutions containing physiologic (1 mm) or reduced concentrations of free [Mg(2+)]. Sarcoplasmic reticulum Ca(2+) release was detected using fura-2 or fluo-3. RESULTS: In MHN fibers, 1 mm halothane consistently did not induce sarcoplasmic reticulum Ca(2+) release in the presence of 1 mm Mg(2+). It was necessary to increase the halothane concentration to 20 mm or greater before Ca release occurred. However, when [Mg(2+)] was reduced below 1 mm, halothane became an increasingly effective stimulus for Ca(2+) release; e.g., at 0.4 mm Mg(2+), 58% of MHN fibers responded to halothane. In MHS fibers, 1 mm halothane induced Ca(2+) release in 57% of MHS fibers at 1 mm Mg(2+). Reducing [Mg(2+)] increased the proportion of MHS fibers that responded to 1 mm halothane. Further experiments revealed differences in the characteristics of halothane-induced Ca(2+) release in MHS and MHN fibers: In MHN fibers, at 1 mm Mg(2+), halothane induced a diffuse increase in [Ca(2+)], which began at the periphery of the fiber and spread slowly inward. In MHS fibers, halothane induced a localized C(2+)a release, which then propagated along the fiber. However, propagated Ca(2+) release was observed in MHN fibers when halothane was applied at an Mg(2+) concentration of 0.4 mm or less. CONCLUSIONS: When Mg(2+) inhibition of the ryanodine receptor is reduced, the halothane sensitivity of MHN fibers and the characteristics of the Ca release process approach that of the MHS phenotype. In MHS fibers, reduced Mg(2+) inhibition of the ryanodine receptor would be expected to have a major influence on halothane sensitivity. The Mg dependence of the halothane response in MHN and MHS may have important clinical implications in circumstances where intracellular [Mg(2+)] deviates from normal physiologic concentrations.

Anesthetics, Inhalation↗
PubMed1987

Studies of the halothane-cooling contractures of skeletal muscle.

The characteristics of transient contractures elicited by rapid cooling of frog or mouse muscles perfused in vitro with solutions equilibrated with 0.5-2.0% halothane are reviewed. The data indicate that these halothane-cooling contractures are dose dependent and reproducible, and their amplitude is larger in muscles containing predominantly slow-twitch type fibers, such as the mouse soleus, than in muscles in which fast-twitch fibers predominate, such as the mouse extensor digitorum longus. The halothane-cooling contractures are potentiated in muscles exposed to succinylcholine. The effects of Ca2+-free solutions, of the local anesthetics procaine, procainamide, and lidocaine, and of the muscle relaxant dantrolene on the halothane-cooling contractures are consistent with the proposal that the halothane-cooling contractures result from synergistic effects of halothane and low temperature on Ca sequestration by the sarcoplasmic reticulum. Preliminary results from skinned rabbit muscle fibers support this proposal. The halothane concentrations required for the halothane-cooling contractures of isolated frog or mouse muscles are comparable with those observed in serum of patients during general anesthesia. Accordingly, fascicles dissected from muscle biopsies of patients under halothane anesthesia for programmed surgery develop large contractures when rapidly cooled. The amplitude of these halothane-cooling contractures declined with the time of perfusion of the muscle fascicles in vitro with halothane-free physiological solutions. It is suggested that the halothane-cooling contractures could be used as a simple experimental model for the investigation of the effects of halothane on Ca homeostasis and contractility in skeletal muscle and for study of drugs of potential use in the management of the contractures associated with the halothane-induced malignant hyperthermia syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics, Local↗