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PubMed1997

Dose-dependent effects of halothane on the phrenic nerve responses to acute hypoxia in vagotomized dogs.

BACKGROUND: Previous studies in dogs and humans suggest that the carotid body chemoreceptor response to hypoxia is selectively impaired by halothane. The present studies in an open-loop canine preparation were performed to better delineate the effects of anesthetic concentrations of halothane on the carotid body chemoreceptor-mediated phrenic nerve response to an acute hypoxic stimulus. METHODS: Three protocols were performed to study the effects of halothane anesthesia on the phrenic nerve response to 1 min of isocapnic hypoxia (partial pressure of oxygen [PaO2] at peak hypoxia, 35-38 mmHg) in unpremedicated, anesthetized, paralyzed, vagotomized dogs during constant mechanical ventilation. In protocol 1, the dose-dependent effects of halothane from 0.5-2.0 minimum alveolar concentration (MAC) on the hypoxic response during moderate hypercapnia (partial pressure of carbon dioxide [PaCO2], 60-65 mmHg) were studied in 10 animals. In protocol 2, the hypoxic responses at 1 MAC halothane near normocapnia (PaCO2, 40-45 mmHg) and during moderate hypercapnia were compared in an additional four animals. In protocol 3, the hypoxic response of 4 of 10 dogs from protocol 1 was also studied under sodium thiopental (STP) anesthesia after they completed protocol 1. RESULTS: Protocol 1: Peak phrenic nerve activity (PPA) increased significantly during the hypoxic runs compared with the isocapnic hyperoxic controls at all halothane doses. The phrenic nerve response to the hypoxic stimulus was present even at the 2 MAC dose. Protocol 2: The net hypoxic responses for the two carbon dioxide background levels at 1 MAC were not significantly different. Protocol 3: The net hypoxic response of PPA for the STP anesthetic was not significantly different from the 1 MAC halothane dose. Bilateral carotid sinus denervation abolished the PPA response to hypoxia. CONCLUSIONS: The phrenic nerve response to an acute, moderately severe isocapnic hypoxic stimulus is dose-dependently depressed but not abolished by surgical doses of halothane. This analysis does not suggest a selective depression of the carotid body chemoreceptor response by halothane. The observed hypoxic phrenic response was mediated by the carotid body chemoreceptors in vagotomized dogs because bilateral carotid sinus denervation abolished all increases in PPA.

Anesthetics, Inhalation↗
PubMed1998

Halothane decreases Na,K-ATPase, and Na channel activity in alveolar type II cells.

BACKGROUND: Halothane alters surfactant biosynthesis and metabolism of alveolar type II cells. In addition to synthesizing surfactant, alveolar type II cells actively transport sodium (Na) from the alveolar space to the interstitium. Na enters the cells through amiloride-sensitive Na channels or Na cotransporters and is extruded by a Na pump. The purpose of this study was to examine the effects of halothane on Na transport activities. METHODS: Epithelial type II cells from adult rat lungs were exposed to halothane concentrations of 1, 2, and 4% from 0.5-4 h. In some experiments, cells that were exposed to 1% halothane for 1 h were allowed to recover after replacement of the medium for 15 and 30 min. Na transport was then evaluated by direct measurement of radiolabeled ions uptake. In addition, the effects of halothane were assessed in the absence of extracellular calcium (Ca) with or without 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, an intracellular Ca chelating agent. RESULTS: Exposure of epithelial type II cells to halothane reduced the activity of sodium, potassium-adenosine triphosphatase, and amiloride-sensitive Na channels, whereas Na cotransporters were unchanged. The decrease in sodium, potassium-adenosine triphosphatase activity was maximal for 30 min of exposure and reached 50, 42, and 56% for halothane concentrations of 1, 2, and 4%, respectively, and did not change for longer exposure times. This effect was not prevented by either the absence of extracellular Ca or 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid pretreatment. Exposure for 45 min to 1% halothane also decreased Na channel activity by 46%. These effects were completely reversible after 30 min of recovery. CONCLUSIONS: Sodium, potassium-adenosine triphosphatase, and amiloride-sensitive Na channel activities are impaired by halothane in alveolar type II cells in vitro. This inhibition could reduce transepithelial Na transport.

Alanine↗
PubMed1998

Halothane attenuates calcium sensitization in airway smooth muscle by inhibiting G-proteins.

BACKGROUND: Halothane directly relaxes airway smooth muscle partly by decreasing the Ca2+ sensitivity. In smooth muscle, receptor stimulation is thought to increase Ca2+ sensitivity via a cascade of heterotrimeric and small monomeric guanine nucleotide-binding proteins (G-proteins). Whether this model is applicable in the airway and where halothane acts in this pathway were investigated. METHODS: A beta-escin-permeabilized canine tracheal smooth muscle preparation was used. Exoenzyme C3 of Clostridium botulinum, which inactivates Rho monomeric G-proteins, was used to evaluate the involvement of this protein in the Ca2+ sensitization pathway. The effects of halothane on different stimulants acting at different levels of signal transduction were compared: acetylcholine on the muscarinic receptor, aluminum fluoride (AIF4-) on heterotrimeric G-proteins, and guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) on all G-proteins. RESULTS: Exoenzyme C3 equally attenuated acetylcholine- and AIF4--induced Ca2+ sensitization, suggesting that these pathways are both mediated by Rho. Halothane applied before stimulation equally attenuated acetylcholine- and AIF4--induced Ca2+ sensitization. However, when added after Ca2+ sensitization was established, the effect of halothane was greater during Ca2+ sensitization induced by acetylcholine compared with AIF4-, which, along with the previous result, suggests that halothane may interfere with dissociation of heterotrimeric G-proteins. Halothane applied during GTPgammaS-induced Ca2+ sensitization had no significant effect on force, suggesting that halothane has no effect downstream from monomeric G-proteins. CONCLUSION: Halothane inhibits increases in Ca2+ sensitivity of canine tracheal smooth muscle primarily by interfering with the activation of heterotrimeric G-proteins, probably by inhibiting their dissociation.

ADP Ribose Transferases↗
PubMed2000

Effects of halothane and isoflurane on the intracellular Ca2+ transient in ferret cardiac muscle.

BACKGROUND: Halothane and isoflurane depress myocardial contractility by decreasing transsarcolemmal Ca2+ influx and Ca2+ release from the sarcoplasmic reticulum. Decreases in Ca2+ sensitivity of the contractile proteins have been shown in skinned cardiac fibers, but the relative importance of this effect in intact living myocardium is unknown. The aims of this study were to assess whether halothane and isoflurane decrease myofibrillar Ca2+ sensitivity in intact, living cardiac fibers and to quantify the relative importance of changes in myofibrillar Ca2+ sensitivity versus changes in myoplasmic Ca2+ availability caused by these anesthetics. METHODS: The effects of halothane and isoflurane (0-1.5 times the minimum alveolar concentration (MAC) in three equal increments) on isometric and isotonic variables of contractility and on the intracellular calcium transient were assessed in isolated ferret right ventricular papillary muscle microinjected with the Ca2+-regulated photoprotein aequorin. The intracellular calcium transient was analyzed in the context of a multicompartment model of intracellular Ca2+ buffers in mammalian ventricular myocardium. RESULTS: Halothane and isoflurane decreased contractility, time-to-peak force, time to half-isometric relaxation, and intracellular Ca2+ transient in a reversible, concentration-dependent manner. Halothane, but not isoflurane, slowed the increase and the decrease of the intracellular Ca2+ transient. Increasing extracellular Ca2+ in the presence of anesthetic to produce peak force equal to control values increased intracellular Ca2+ to values higher than control values. CONCLUSIONS: Halothane decreases myoplasmic Ca2+ availability more than isoflurane; halothane and isoflurane decrease myofibrillar Ca2+ sensitivity to the same extent; in halothane at 0.5 MAC and isoflurane at 1.0 MAC, the decrease in Ca2+ sensitivity is already fully apparent; halothane decreases intracellular Ca2+ availability more than myofibrillar Ca2+ sensitivity; and isoflurane decreases myoplasmic Ca2+ availability and Ca2+ sensitivity to the same extent, except at 1.5 times the MAC, which decreases Ca2+ availability more.

Aequorin↗
PubMed2001

Halothane inhibits contraction and action potential duration to a greater extent in subendocardial than subepicardial myocytes from the rat left ventricle.

BACKGROUND: Halothane inhibits the 4-aminopyridine-sensitive transient outward K(+) current (I(to)) which in many species, including humans, plays an important role in determining action potential duration. As I(to) is greater in the ventricular subepicardium than subendocardium, halothane may have differential effects on action potential duration and, therefore, contraction in cells isolated from these two regions. METHODS: Myocytes were isolated from the subendocardium and subepicardium of the rat left ventricle. Myocytes from each region were electrically stimulated at 1 Hz to measure contractions and action potentials and exposed to 0.6 mm halothane (approximately 2 x minimum alveolar concentration(50) for the rat) for 1 min. The time from the peak of the action potential to repolarization at 0 and -50 mV was measured to assess the effects of halothane on action potential duration. RESULTS: Halothane inhibited contraction to a significantly (P = 0.002) greater extent in subendocardial myocytes than in subepicardial myocytes: the amplitude of contraction during control conditions was 3.6 +/- 0.4 microm and 3.2 +/- 0.7 microm in subendocardial and subepicardial cells, respectively, and this was reduced to 1.1 +/- 0.2 microm (29 +/- 2% of control, P < 0.0001, n = 10) and 1.4 +/- 0.3 microm (46 +/- 3% of control, P = 0.007, n = 7), respectively, after a 1-min exposure to 0.6 mm halothane. Control action potential duration (at -50 mV) was 67 +/- 10 and 28 +/- 4 ms in subendocardial and subepicardial myocytes, respectively, and these values were reduced to 39 +/- 6 ms (58 +/- 3% of control, P < 0.001) and 20 +/- 3 ms (73 +/- 5% of control, P = 0.009) by halothane, respectively. CONCLUSIONS: Action potential duration was reduced to a greater extent in subendocardial than subepicardial myocytes, which would contribute to the greater negative inotropic effect of halothane in the subendocardium. Furthermore, the transmural difference in action potential duration was reduced by halothane, which could contribute to its arrhythmogenic properties.

Action Potentials↗
PubMed2006

Halothane does not inhibit the functional coupling between the beta2-adrenergic receptor and the Galphas heterotrimeric G protein.

BACKGROUND: This study investigated whether halothane affects the functional coupling between the beta2 adrenergic receptor and the alpha subunit of its cognate stimulatory heterotrimeric guanosine-5'-triphosphate (GTP)-binding protein (Galphas). The authors hypothesized that halothane does not affect isoproterenol-promoted guanosine nucleotide exchange at Galphas and hence would not affect isoproterenol-induced relaxation of airway smooth muscle. METHODS: Halothane effects on isoproterenol-induced inhibition of calcium sensitivity were measured in permeabilized porcine airway smooth muscle. Galphas nucleotide exchange was measured in crude membranes prepared from COS-7 cells transfected to transiently coexpress the human beta1 or beta2 receptor each with human short Galphas. A radioactive, nonhydrolyzable analog of GTP, [S]GTPgammaS, was used as the reporter for nucleotide exchange at Galphas. RESULTS: Halothane (0.75 mm, approximately 2.8 minimum alveolar concentration [MAC] in pigs) did not affect isoproterenol-induced inhibition of calcium sensitivity. Isoproterenol caused a time- and concentration-dependent increase in Galphas nucleotide exchange. Halothane, even at concentrations of 1.5 mm (approximately 5.6 MAC), had no effect on basal Galphas nucleotide exchange in the absence of isoproterenol, whereas halothane inhibited isoproterenol-promoted Galphas nucleotide exchange in both the beta1-Galphas and beta2-Galphas expressing membranes. However, the effect was significantly greater on beta1-Galphas coupling compared with beta2-Galphas coupling, with no effect on beta2-Galphas coupling at 2.8 MAC halothane. CONCLUSION: Halothane does not inhibit the biochemical coupling between the beta2 receptor and Galphas and hence does not affect the inhibition of calcium sensitivity induced by isoproterenol. Therefore, halothane should not affect the efficacy of beta2 agonists, as suggested by studies of in vivo animal models of asthma.

Anesthetics, Inhalation↗
PubMedDate not supplied

Comparative metabolic effects of halothane and enflurane in rat heart cell culture.

The effects of halothane and enflurane on the oxygen consumption rates and substrate utilization by beating and nonbeating rat heart myocytes in cell culture were compared. Halothane, on an equal dose and equal MAC (minimum alveolar concentration producing immobilization of 50% of subjects) basis, was significantly more effective than enflurane in reducing total myocyte oxygen consumption and contractile rate. The greater effect of halothane on oxygen consumption was not due entirely to its effect on myocyte contractile rate, since quiescent (nonbeating) cells and cells rendered nonbeating by large doses of halothane also showed greater reductions in oxygen consumption than with large doses of enflurane. Both halothane and enflurane reduced glucose and palmitic acid metabolism by myocytes when compared with controls. However, there were no significant differences between halothane or enflurane with regard to glucose metabolism. Halothane was significantly more effective than enflurane in reducing cellular palmitic acid metabolism. Although palmitic acid uptake by myocytes was reduced to the same extent by both anesthetics when compared with control uptake values, halothane reduced myocyte uptake of glucose to a greater degree than enflurane. The results of this study indicate that halothane is a more potent myocardial metabolic depressant than enflurane.

Animals↗
PubMed2002

Hepatobiliary scintigraphy for evaluating the hepatotoxic effect of halothane and the protective effect of catechin in comparison with histo-chemical analysis of liver tissue.

Halothane and its metabolites cause liver damage by decreasing liver blood flow and generating free-radical species. Catechin suppresses lipid peroxidation and increases enzyme activity, therefore it seems to be capable of protecting liver parenchyma against the direct toxic effect of halothane. The aim of this study was to investigate the role of hepatobiliary scintigraphy in detecting liver damage after halothane anaesthesia and the protective effect of catechin in comparison with histo-chemical analysis. Thirty rabbits, divided into three groups (A, controls; B, halothane; and C, catechin+halothane), were investigated. In group A no anaesthesia was administered. Group B only received halothane, while group C was pretreated with catechin and halothane anaesthesia was administered for 2 h. Dynamic scintigrams were taken for 60 min after injecting 99mTc-mebrofenin, and the time of peak uptake (TPU) and the time for half of the activity to clear from the liver (T(1/2)) were calculated. Rabbits were killed, and malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) levels were measured in hepatic tissue. The TPU and T(1/2) values of group A is significantly lower than in groups B and C (P<0.0002 and P<0.0002, respectively, for TPU; and P<0.0002 and P<0.0003, respectively, for T(1/2)). The TPU and T(1/2) values of group B were significantly higher than in group C (P<0.0003 and P<0.0003, respectively). The hepatic MDA level of group A was significantly lower than in groups B and C (P<0.0002 and P<0.0002, respectively). SOD, GSH-Px and CAT levels of group A were significantly higher than in groups B and C (P<0.0002, P<0.0001 and P<0.003, respectively, for group A vs group B; and P<0.0005, P<0.0002 and P<0.03, respectively, for group A vs group C). The MDA level of group B was significantly higher than that in group C (P<0.0002). SOD, GSH-Px and CAT levels of group B were significantly lower than in group C (P<0.0002, P<0.0002 and P<0.003, respectively). According to these results, we suggest that catechin protects liver parenchyma against the toxic effect of halothane and its metabolites, and that, compared to invasive histo-chemical analysis, hepatobiliary scintigraphy is a useful and alternative non-invasive method for detecting the protective effect of catechin on liver parenchyma after halothane anaesthesia.

Anesthesia↗
PubMed1999

Effects of postischemic halothane administration on outcome from transient focal cerebral ischemia in the rat.

This study examined the effect of prolonged postischemic halothane administration on outcome from transient focal cerebral ischemia in rats. Conscious normothermic rats were subjected to 75 minutes of filament middle cerebral artery occlusion (MCAO). Animals were then divided into two groups. The Awake group (n = 15) remained awake following ischemia. The Halothane group (n = 15) received 1.3-1.4% halothane for 5 hours after onset of recirculation. In both groups, brain temperature was maintained at 37.5 degrees C during ischemia and the first 22 hours of recovery. Seven days after ischemia, the severity of hemiparesis and cerebral infarct size were examined. Neurologic scores did not differ between groups (Awake = 1+/-2.75; Halothane = 2+/-2; p = 0.772, median +/- interquartile range). Neurologic scores and total infarct volumes were correlated (R = 0.653; p = 0.0004). Cortical (Awake = 76+/-57 mm3; Halothane = 90+/-57 mm3; p = 0.494, mean +/- standard deviation), subcortical (Awake = 71+/-33 mm3; Halothane = 80+/-35 mm3; p = 0.472), and total (Awake = 147+/-88 mm3; Halothane = 171+/-91 mm3; p = 0.477) infarct volumes were not significantly different between groups. The data indicate that postischemic halothane administration offers no benefit in ameliorating damage from focal cerebral ischemia. This suggests that the neuroprotective effect of halothane observed in other studies is consistent with influences on intra-ischemic pathophysiology only.

Anesthesia, Inhalation↗
PubMed1976

Halothane anaesthesia in caesarean section.

The safety and efficacy of halothane anaesthesia were investigated in 97 caesarean sections using 0.4-0.6% halothane added to a mixture of 61 N2O/3-4 1 O2. The administration of halothane was initiated before intubation and terminated immediately prior to delivery. Only one patient reported memories from the operation. The mean Apgar score 1 min after delivery (8.5) was significantly better than that (8.2) in 100 caesarean sections in which a mixture of 71 N2O/3 1 O2 was used. In 17 caesarean sections, the halothane concentrations were examined after 0.9% halothane had been given for exactly 1 min after intubation. It was found that halothane reached and passed the placenta after only 1 min. The levels in the maternal artery and umbilical vein were comparable. The levels in the maternal artery, maternal vein and umbilical vein were markedly higher than in the umbilical artery, which indicated an accumulation of halothane in the foetal tissues. However, due to the vigour of the newborn, halothane concentrations 10 min after birth were very low. The half-life of halothane in the maternal circulation was approximately 1 min with the described method of administration. Blood gas determinations, which were made in seven newborns, proved satisfactory.

Anesthesia, Inhalation↗
PubMed1995

Effects of halothane and isoflurane on antigen- and leukotriene-D4-induced constriction of guinea pig trachea.

We investigated the mechanism of the action of volatile anesthetics on the airway smooth muscle constricted by an antigen and leukotriene-D4 (LTD4). Excised tracheal rings from ovalbumin-sensitized guinea pigs were suspended in eight tissue baths. Halothane or isoflurane was aerated into four tissue baths, while the remaining four served as time controls. To assess the antispasmogenic activity of halothane and isoflurane, concentration-response curves for antigen and LTD, were constructed exposed to anesthetics and compared to controls. The spasmolytic activity of halothane and isoflurane was measured in the tracheal rings constricted by a single antigen challenge or by EC50 of LTD. Both halothane and isoflurane produced significant rightward shifts of ovalbumin and LTD, concentration-response curve with corresponding increases in the EC50 values. Halothane increased the EC50 value for LTD, from 5.38 +/- 0.43 x 10-9 M to 1.2 +/- 0.18 x 10-8 M, and for ovalbumin from 1.2 +/- 0.06 x 10-4 mg/ml to 3.03 +/- 0.28 x 10-4 mg/ml. Isoflurane increased the EC50 value for LTD, from 5.17 +/- 0.64 x 10-9 M to 8.98 +/- 1.01 x 10-9 M, and for ovalbumin from 1.21 +/- 0.09 x 10-4 mg/ml to 2.61 +/- 0.19 x 10-4 mg/ml. Furthermore, halothane and isoflurane significantly reduced the magnitude of the antigen-and LTD4-induced constriction. In 30 min intervals, 1% and 2% halothane reduced the magnitude of the ovalbumin-induced constriction by 32% and 50%, respectively, while isoflurane (2% and 4%) caused relaxation of 16% and 35%, respectively. The magnitude of LTD4-induced constriction was reduced by 17% and 24%, with 1% and 2% halothane, respectively. Isoflurane (2% and 4%) reduced this constriction by 25% and 25% respectively. In conclusion, halothane and isoflurane attenuate and prevent the constrictive response of airway smooth muscle to allergen and LTD. A direct, nonspecific dilating effect is suggested as the mechanism responsible for the observed effects.

Anesthetics, Inhalation↗
PubMed1997

Bupivacaine does not suppress cardiac sympathetic nerve activity during halothane anesthesia in the cat.

BACKGROUND: The finding that i.v. lidocaine suppresses cardiac sympathetic nerve activity during 1 MAC halothane, but not during 2 MAC or 3 MAC halothane, suggests that the neurally mediated circulatory effects of i.v. local anesthetics may vary with background autonomic activity. This study aimed to compare the effects of i.v. lidocaine and bupivacaine on cardiac sympathetic nerve activity (CSNA) during normal and high levels of CSNA. METHODS: Cats were anesthetized with halothane and allocated to three groups. In groups I-L and I-B, sympathetic hyperactivity was induced by electrical stimulation of the posterior hypothalamus. CSNA, heart rate and mean arterial pressure were then measured before and after administration of lidocaine 2 mg.kg BW-1 i.v. (Group I-L, n = 7) or bupivacaine 0.5 mg.kg BW-1 i.v. (Group I-B, n = 7) during 1% halothane anesthesia. In Group II (n = 7), following administration of bupivacaine 0.5 mg.kg BW-1 i.v., CSNA, sinus cycle length (SCL), and subintervals of atrioventricular conduction time (A-H, H-V, and H-S) at pacing were measured during 0.8%, 1.6% and 2.4% halothane anesthesia without sympathetic hyperactivity. RESULTS: Lidocaine suppressed CSNA hyperactivity and tachycardia significantly in Group I-L, but bupivacaine did not do so in Group I-B. In Group II, bupivacaine did not affect CSNA at any concentrations of halothane, but lengthened SCL, A-H, H-V and H-S intervals significantly at each concentration of halothane. CONCLUSIONS: We conclude that i.v. bupivacaine, unlike i.v. lidocaine, does not suppress CSNA during either normal or high CSNA under halothane anesthesia although i.v. bupivacaine has stronger depressive effects on cardiac conduction than does i.v. lidocaine during deep halothane anesthesia.

Anesthesia, General↗
PubMed1987

Equilibration of halothane with brain tissue in vitro: comparison to brain concentrations during anesthesia.

A method was devised for reproducing anesthetic concentrations of halothane in slice and membrane preparations of rat brain in vitro. Rats were anesthetized with varying concentrations of halothane, responsiveness was tested, and brain halothane content was determined by heptane extraction and gas chromatography. The inspired concentration of halothane at which half of all animals were unresponsive was 1.05%. At 1.25% halothane, all animals were unresponsive and brain halothane was determined to be 41 +/- 1.3 nmol/mg lipid. No significant differences in halothane concentration between whole brain and a variety of brain regions were detected. To obtain similar concentrations in vitro, membranes or slices of cerebral cortex were incubated in Krebs-Ringer bicarbonate buffer (KRB) that had been preequilibrated with anesthetic. Halothane equilibrated rapidly with the buffer and the tissues. The partition coefficient between gas and KRB was found to be 0.78, and between brain slices and KRB approximately 12. Slightly lower gas concentrations were necessary in vitro than in vivo to obtain the same tissue levels of anesthetic. Using this method, it was shown that there was no effect of anesthetic concentrations of halothane on the uptake of [3H]norepinephrine or [3H]choline into slices of rat cerebral cortex.

Anesthesia↗
PubMed1976

Determination of halothane-induced sleeping time in the rat: effect of prior administration of centrally active drugs.

A method is described for the determination of halothane-induced sleeping time in the rat. 2 The sleeping time exhibited a diurnal variation which was due, at least in part, to a change in the sensitivity of the central nervous system (CNS) to the anaesthetic. 3 Tolerance to halothane did not develop in rats repeatedly exposed to the anaesthetic over a period of over 48 hours. 4 Repeated sleeping time determinations have been used to follow changes in the sensitivity of the CNS to the anaesthetic occurring with time. 5 A tolerance to halothane was induced by pretreatment of rats with doses of amylobarbitone, pentobarbitone or meprobamate sufficient to keep animals anaesthetized for approximately 12 hours. This tolerance was followed by a period of halothane-hypersensitivity. 6 Halothane-tolerant animals awakened with higher brain halothane concentrations and were also tolerant to intracerebroventricularly administered pentobarbitone. 7 Halothane-hypertensive rats awakened with lower brain halothane concentrations and were also hypersensitivity to intracerebroventricularly administered pentobarbitone. 8 The possibility that the induction of cross-tolerance to halothane may be indicative of a drug's potential to produce dependence is discussed.

Animals↗
PubMed1973

On the mechanism of halothane anaesthesia.

1. The effects of halothane on the evoked potentials of in vitro preparations of guinea-pig olfactory cortex were studied.2. The evoked potentials recorded from the cortical surface comprised an initial diphasic wave - the lateral olfactory tract (l.o.t.) compound action potential - followed by a negative wave of 1-3 mV amplitude and about 10 msec duration. Superimposed on the negative wave was a number of positive peaks. The negative wave has been identified as an extracellularly recorded, monosynaptic, excitatory post-synaptic potential (e.p.s.p.) and the positive peaks have been shown to reflect the discharge of the cortical cell population in response to the evoked e.p.s.p. and are therefore termed ;population spikes'.3. When halothane (0.4-1.5%) was added to the gas stream that superfused the surface of the preparation the evoked e.p.s.p.s became smaller in amplitude and the size of the population spikes diminished. The l.o.t. compound action potential was unaffected by these levels of halothane. Higher levels of halothane (above 2%) further reduced the amplitude of the evoked e.p.s.p.s, abolished the population spikes, decreased the amplitude of the l.o.t. compound action potential and slowed its time course. The effects of halothane on the evoked potentials were dose-related and were independent (after the first 10 min of treatment) of the duration of the exposure to halothane.4. The decrease in the size of the population spike caused by the exposure to halothane implied that transmission through the cortical relay had been impaired. This was also shown by the decrease in the evoked activity of units in the prepiriform cortex. Of eleven units, eight were depressed by halothane (0.5-1.5%) two were unaffected and one showed a transient increase in the number of spikes generated in response to a l.o.t. volley.5. Halothane (up to 1.5%) had no effect on the threshold of the l.o.t. fibres to electrical stimulation or on that of the post-synaptic cells to synaptic excitation.6. Post-tetanic potentiation and frequency potentiation of the evoked e.p.s.p.s were enhanced in the presence of 1% halothane.7. It is concluded that halothane reduces excitatory synaptic transmission not by an increase in the electrical threshold of the post-synaptic cells to synaptic excitation but by interference with the process of chemical transmission either by reducing the output of transmitter from the pre-synaptic nerve terminal or by reducing the sensitivity of the post-synaptic membrane to the released transmitter substance.

Action Potentials↗
PubMed1993

Cerebrovasodilation elicited by fastigial stimulation is preserved under deep halothane anesthesia.

We studied the effect of halothane anesthesia on the increases in cerebral blood flow (CBF) and arterial pressure (AP) elicited by electrical stimulation of the cerebellar fastigial nucleus (FN). Rats were anesthetized (0.75-2% halothane), instrumented for continuous recording of AP, and ventilated. The FN was stimulated through stereotaxically implanted microelectrodes. In CBF experiments the elevations in AP resulting from FN stimulation were eliminated by spinal cord transection at C1. After cord transection AP was maintained by intravenous phenylephrine. CBF or cerebral glucose utilization (CGU) was measured by laser-Doppler flowmetry or the 2-deoxyglucose method, respectively. FN stimulation produced increases in CBF that were graded with the intensity (10-150 microA) or frequency (10-150 Hz) of stimulation. At 1% halothane, FN stimulation (100 microA; 75 Hz; n = 8) increased CBF by 123 +/- 16%. The elevations in CBF were attenuated by increasing levels of halothane anesthesia in a dose-dependent manner. At halothane concentrations of 1.5 and 2% the CBF response to FN stimulation (100 microA; 75 Hz) was reduced by 58 +/- 6 and 77 +/- 4%, respectively (p < 0.05 from 0.75% halothane; analysis of variance and Tukey's test). In contrast, the increases in CBF elicited by hypercapnia were not attenuated (P > 0.05 from 0.75% halothane). At 1% halothane, FN stimulation did not change CGU in neocortex (frontal cortex: unstimulated 48 +/- 6, mumol.100 g-1.min-1, FN stimulation: 47 +/- 11; P > 0.05; n = 5/group). In the group of rats in which the pressor response was studied (n = 7), halothane produced a dose-dependent attenuation of the elevations in AP. The degree of attenuation of the AP response was comparable to that of the CBF response (P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1988

Halothane hepatitis.

Hepatitis following halothane anaesthesia may take two forms: a mild self-limiting disease or a more severe hepatitis with a high mortality. Whether these two forms represent two distinct entities or ends of a spectrum is unclear. Severe hepatitis is commoner after multiple exposures and has many of the characteristics of an immune-mediated hypersensitivity reaction. The incidence is very low; the best, albeit unsatisfactory, estimate of the incidence is about 1 in 3,700 patients with multiple halothane exposures. The mechanism of liver damage is uncertain: in some circumstances halothane may be directly hepatotoxic, but it remains to be conclusively proved that immune mechanisms are responsible. Studies from our unit have suggested that halothane hepatitis can positively be diagnosed by demonstration of antibodies reacting with halothane-altered liver cell determinants. The incidence of the condition can be reduced by taking a full anaesthetic history and avoiding the use of halothane in the high-risk patients, namely those who have had recent previous halothane anaesthesia and those who have had jaundice or unexplained post-operative pyrexia following earlier halothane anaesthetics. When halothane hepatitis has occurred, treatment is purely supportive with the possibility of transplantation for those in grade IV encephalopathy.

Adult↗
PubMed2000

Halothane reduces the early lipopolysaccharide-induced lung inflammation in mechanically ventilated rats.

Several studies suggest that anesthetics modulate the immune response. The aim of this study was to investigate the effect of halothane and thiopental on the lung inflammatory response. Rats submitted or not to intratracheal (IT) instillation of lipopolysaccharides (LPS) were anesthetized with either halothane (0. 5, 1, or 1.5%) or thiopental (60 mg. kg(-1)) and mechanically ventilated for 4 h. Control rats were treated or not by LPS without anesthesia. Lung inflammation was assessed by total and differential cell counts in bronchoalveolar lavage fluids (BALF) and by cytokine measurements (tumor necrosis factor-alpha [TNF-alpha], interleukin-6 [IL-6], macrophage inflammatory protein-2 [MIP-2], and monocyte chemoattractant protein-1 [MCP-1]) in BALF and lung homogenates. In the absence of LPS treatment, neither halothane nor thiopental modified the moderate inflammatory response induced by tracheotomy or mechanical ventilation. Cell recruitment and cytokine concentrations were increased in all groups receiving IT LPS. However, in halothane-anesthetized rats (halothane > or = 1%), but not in thiopental-anesthetized rats, the LPS-induced lung inflammation was altered in a dose-dependent manner. Indeed, when using 1% halothane, polymorphonuclear leukocyte (PMN) recruitment was decreased by 55% (p < 0.001) and TNF-alpha, IL-6, and MIP-2 concentrations in BALF and lung homogenates were decreased by more than 60% (p < 0.001) whereas total protein and MCP-1 concentrations remained unchanged. The decrease of MIP-2 (observed at the protein and messenger RNA [mRNA] level) was strongly correlated to the decrease of PMN recruitment (r = 0.73, p < 0.05). This halothane-reduced lung inflammatory response was transient and was reversed 20 h after the end of the anesthesia. Our study shows that halothane > or = 1%, delivered during 4 h by mechanical ventilation, but not mechanical ventilation per se, alters the early LPS-induced lung inflammation in the rat, suggesting a specific effect of halothane on this response.

Anesthetics, Inhalation↗