Effects of saikosaponins on hepatic damage induced by halothane and hypoxia in phenobarbital-pretreated rats

The effects of saikosaponins-a.-b₁,-b₂,-c, and-d on hepatic damage induced by halothane and hypoxia were investigated in the rat. Inhalation of halothane under a hypoxic condition significantly increased serum glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) levels in rats pretreated with phenobarbital compared with rats pretreated without phenobarbital. Pretreatment with saikosaponin (especially-a and-d) and with phenobarbital suppressed the increase in serum GOT and GPT levels in comparison with the rats treated with phenobarbital, halothane, and hypoxia. Histological observation also confirmed that pretreatment with saikosaponin had a protective effect against liver cell damage caused by halothane and hypoxia. Saikosaponins-a and-d, the most effective saikosaponins against hepatic damage, inhibited the increases in cytochrome P450 and NADPH-cytochromec reductase activity which are induced by phenobarbital treatment. Therefore, it is suggested that the cytoprotective effect of saikosaponin against halothane-induced hepatitis under hypoxia is caused by inhibition of phenobarbital stimulation of the enzyme system for hepatic drug metabolism.     

Halothane-dependent lipid peroxidation in human liver microsomes is catalyzed by cytochrome P4502A6 (CYP2A6)

BACKGROUND: Halothane is extensively (approximately 50%) metabolized in humans and undergoes both oxidative and reductive cytochrome P450-catalyzed hepatic biotransformation. Halothane is reduced under low oxygen tensions by CYP2A6 and CYP3A4 in human liver microsome to an unstable free radical, and then to the volatile metabolites chlorodifluoroethene (CDE) and chlorotrifluoroethane (CTE). The free radical is also thought to initiate lipid peroxidation. Halothane-dependent lipid peroxidation has been shown in animals in vitro and in vivo but has not been evaluated in humans. This investigation tested the hypothesis that halothane causes lipid peroxidation in human liver microsomes, identified P450 isoforms responsible for halothane-dependent lipid peroxidation, and tested the hypothesis that lipid peroxidation is prevented by inhibiting halothane reduction. METHODS: Halothane metabolism was determined using human liver microsomes or cDNA-expressed P450. Lipid peroxidation was quantified by malondialdehyde (MDA) formation using high-pressure liquid chromatography-ultraviolet analysis of the thiobarbituric acid-MDA adduct. CTE and CDE were determined by gas chromatography-mass spectrometry. RESULTS: Halothane caused MDA formation in human liver microsomes at rates much lower than in rat liver microsomes. Human liver microsomal MDA production exhibited biphasic enzyme kinetics, similar to CDE and CTE production. MDA production was inhibited by the CYP2A6 inhibitor methoxsalen but not by the CYP3A4 inhibitor troleandomycin. Halothane-dependent MDA production was catalyzed by cDNA-expressed CYP2A6 but not CYP3A4 or P450 reductase alone. CYP2A6-catalyzed MDA production was inhibited by methoxsalen or anti-CYP2A6 antibody. CONCLUSIONS: Halothane causes lipid peroxidation in human liver microsomes, which is catalyzed by CYP2A6, and inhibition of halothane reduction prevents halothane-dependent lipid peroxidation in vitro.     

Halothane hepatotoxicity and fluoride production in mice and rats.

Other investigators have demonstrated halothane-induced hepatic injury in rats anesthetized in hypoxic environments. The authors examined this phenomenon in mice and investigated plasma fluoride levels in mice and rats anesthetized with halothane in 40, 21 and 7 per cent oxygen with or without pretreatment with phenobarbital or carbon tetrachloride. They found no hepatic necrosis in mice. Mice produced less fluoride than rats. This difference in halothane metabolism between Sprague-Dawley rats and Swiss-Webster mice may explain the failure to observe hepatic necrosis in mice.     

The opiate antagonist naloxone counteracts the inhibition of sympathetic nerve activity caused by halothane anesthesia in rats

The study was undertaken to examine if endogenous opioid systems mediate the response of the sympathetic nervous system to halothane anesthesia. Steady state values of renal sympathetic nerve activity (rSNA), mean arterial pressure (MAP), and heart rate (HR) were continuously recorded in the conscious state and at three depths of halothane anesthesia (0.6%, 1.2%, and 2.4%) in rats. Halothane caused an inhibition of rSNA and hypotension and a decrease in HR at the three halothane concentrations. Repeated bolus doses of the opiate antagonist (-)naloxone given iv during 1.2% halothane anesthesia did not significantly increase any of the variables. However, pretreatment with (-)naloxone (2 or 15 mg.kg-1) induced an increase in rSNA at 0.6% halothane, and subsequently the rSNA inhibition was less pronounced at the two higher halothane concentrations compared with control. HR showed a similar pattern, whereas the hypotension was essentially unaffected. Pretreatment with the pharmacologically inactive compound (+)naloxone had no effect on the halothane-induced depression of rSNA. The ED50 halothane concentration concerning nociceptive aversive behavior was not significantly changed with (-)naloxone pretreatment (2 mg.kg-1). In order to determine if sympathoinhibitory bulbospinal serotonin pathways are activated during halothane anesthesia, rSNA, MAP, and HR were recorded in rats pretreated with the serotonin synthesis inhibitor parachlorophenylalanine (PCPA). However, PCPA pretreatment did not affect the rSNA response to halothane compared with control. These findings indicate that the halothane-induced inhibition of rSNA might partially result from a stereospecific activation of opioid receptors, whereas halothane analgesia does not seem to be mediated by opioid mechanisms.     

Halothane-dependent Lipid Peroxidation in Human Liver Microsomes Is Catalyzed by Cytochrome P4502A6 (CYP2A6)

Background: Halothane is extensively (approximately 50%) metabolized in humans and undergoes both oxidative and reductive cytochrome P450-catalyzed hepatic biotransformation. Halothane is reduced under low oxygen tensions by CYP2A6 and CYP3A4 in human liver microsome to an unstable free radical, and then to the volatile metabolites chlorodifluoroethene (CDE) and chlorotrifluoroethane (CTE). The free radical is also thought to initiate lipid peroxidation. Halothane-dependent lipid peroxidation has been shown in animals in vitro and in vivo but has not been evaluated in humans. This investigation tested the hypothesis that halothane causes lipid peroxidation in human liver microsomes, identified P450 isoforms responsible for halothane-dependent lipid peroxidation, and tested the hypothesis that lipid peroxidation is prevented by inhibiting halothane reduction.

Methods: Halothane metabolism was determined using human liver microsomes or cDNA-expressed P450. Lipid peroxidation was quantified by malondialdehyde (MDA) formation using high-pressure liquid chromatography-ultraviolet analysis of the thiobarbituric acid-MDA adduct. CTE and CDE were determined by gas chromatography-mass spectrometry.

Results: Halothane caused MDA formation in human liver microsomes at rates much lower than in rat liver microsomes. Human liver microsomal MDA production exhibited biphasic enzyme kinetics, similar to CDE and CTE production. MDA production was inhibited by the CYP2A6 inhibitor methoxsalen but not by the CYP3A4 inhibitor troleandomycin. Halothane-dependent MDA production was catalyzed by cDNA-expressed CYP2A6 but not CYP3A4 or P450 reductase alone. CYP2A6-catalyzed MDA production was inhibited by methoxsalen or anti-CYP2A6 antibody.     

Effects of volatile anesthetics or fentanyl on hepatic function in cirrhotic rats

Halothane, enflurane, isoflurane, and fentanyl were examined for their potential to exacerbate liver dysfunction in rats with preexisting cirrhosis. Male Wistar rats given sodium phenobarbital for 2 weeks are assigned randomly to two groups. One group (cirrhotic) was exposed by inhalation to carbon tetrachloride (CCl4) in air at weekly intervals for 12 weeks to induce cirrhosis. The other group (noncirrhotic) was handled similarly but received air only. Five weeks after the last exposure to CCl4, cirrhotic and noncirrhotic rats were given three hours of 1 MAC halothane, enflurane, or isoflurane in 50% oxygen, or 350 micrograms fentanyl per kg of body weight and 50% oxygen, or 50% oxygen only. Blood gas tensions and blood glucose levels were measured before, during, and at the end of exposure. Forty-eight hours after exposure, serum chemistries were measured in each rat for comparison with preexposure values. Rats were then killed by CO2 overdose, and liver, kidney, and testis were prepared for microscopic examination. Enflurane, isoflurane, and halothane, but not fentanyl, produced mild respiratory acidosis and no change in serum glucose levels. All anesthetics resulted in a mild but similar degree of acute liver dysfunction as indicated by small increases in SGOT or SGPT in both cirrhotic and noncirrhotic rats. Liver histology revealed mild to moderate portal cirrhosis with fibrosis and well-developed micronodules in rats exposed to CCl4, but no superimposed acute hepatocellular damage was noted. It is concluded that all the anesthetics used in this study were associated with the same minimal degree of postanesthetic hepatic dysfunction and that the dysfunction was similar in both cirrhotic and noncirrhotic rats.     

Changes in mucociliary activity may be used to investigate the airway- irritating potency of volatile anaesthetics

We have examined the short-term effects of three volatile anaesthetics, halothane, isoflurane and desflurane, on mucociliary activity in the rabbit maxillary sinus in vivo. Mucociliary activity was recorded photoelectrically and the signal processed by fast Fourier transformation. Administration of 1.0 MAC of halothane, isoflurane or desflurane caused a temporary increase in mucociliary activity, with mean peak responses of 47.8 (SEM 13.0)%, 44.0 (9.6)% and 45.1 (23.7)% (n = 6), respectively. The response to all three compounds was biphasic; an initial peak was observed within 2 min and a second peak at 3-8 min. The second response was not significant for halothane. In contrast, desflurane produced a significant second peak while the first was small and failed to reach significance. Halothane displayed an initial peak within 2 min which was blocked by atropine but not by the neurokinin 1 (NK1) receptor antagonist CP-99. The second peak at 3-5 min was less pronounced for halothane than for isoflurane or desflurane. The second peak was not affected by atropine pretreatment, but was blocked by pretreatment with CP-99. A combination of atropine and CP-99 pretreatment abolished the mucociliary response to halothane. Atropine pretreatment did not affect, whereas CP-99 significantly reduced, the response to desflurane. We conclude that the NK1-mediated response was most pronounced for desflurane which is considered the most airway irritating compound of the three. It is likely that the size of the NK1-mediated response reflects the airway-irritating properties of the volatile anaesthetic used.      

Celiac plexus block does not alter hepatic injury in rats

We previously demonstrated that upper abdominal surgery on rats pretreated with phenobarbital and anesthetized with halothane caused centrilobular necrosis of the liver, which may be secondary to hepatic hypoxia induced by vasoconstriction. This study examined the possibility that celiac plexus blockade might decrease the degree of injury seen in the surgical model. Rats, pretreated with phenobarbital, were anesthetized with halothane, enflurane, isoflurane, or fentanyl with 100% oxygen. At the start of the hepatic artery dissection, the celiac plexus was blocked by injection of bupivacaine. Subsequently, the rat livers were evaluated for presence and degree of centrilobular necrosis. Animals anesthetized with halothane or fentanyl had a significantly greater incidence of centrilobular necrosis than controls (rats pretreated with phenobarbital who received no anesthesia or surgery). Hepatic injury in rats anesthetized with isoflurane or enflurane did not differ from that in controls. We conclude that celiac plexus blockade with bupivacaine provides no protection against hepatic necrosis in this model.     

Effect of oxygen concentration, hyperthermia, and choice of vendor on anesthetic-induced hepatic injury in rats

Although hypoxic rats exposed to anesthetics may develop hepatic injury, divergent results have been obtained. These discrepancies might be due to different levels of hypoxia, hypothermia, or choice of vendor. Male Sprague-Dawley rats purchased from Zivic-Miller were pretreated with phenobarbital for 4 days. After 24 h without phenobarbital, they were exposed to 2 h of hypoxia and halothane, enflurane, isoflurane, thiopental, or fentanyl. Rectal temperature was kept between 36.5 degrees C and 38.5 degrees C. All agents given in 10% oxygen produced more hepatic injury than did control conditions (exposure to 10% oxygen alone) (P less than 0.01). Only halothane given in 12% and 14% oxygen produced hepatic injury. No agent given in 20% or 100% oxygen demonstrated hepatotoxicity. In a separate study, rectal temperatures were kept between 32 degrees C and 34 degrees C during 2 h of exposure to 0.3 MAC halothane, enflurane, or isoflurane in 10% oxygen. Hypothermia prevented hepatotoxicity by enflurane and isoflurane, but not by halothane. Finally, although livers of rats obtained from Zivic-Miller were injured, specific pathogen-free rats from Charles River were not injured or were less injured by enflurane, thiopental, or fentanyl. Apparently, minor changes in experimental conditions can substantially affect results; hepatic hypoxia per se, anesthetic metabolism (especially that of halothane), and perhaps anesthesia itself may produce hepatic injury.     

Volatile anaesthetics and the atmosphere: atmospheric lifetimes and atmospheric effects of halothane, enflurane, isoflurane, desflurane and sevoflurane

The atmospheric lifetimes of the halogenated anaesthetics halothane, enflurane, isoflurane, desflurane and sevoflurane with respect to reaction with the hydroxyl radical (OH.) and UV photolysis have been determined from observations of OH. reaction kinetics and UV absorption spectra. Rate coefficients for the reaction with OH radicals for all halogenated anaesthetics investigated ranged from 0.44 to 2.7 x 10(-14) cm3 molec-1 s-1. Halothane, enflurane and isoflurane showed distinct UV absorption in the range 200-350 nm. In contrast, no absorption in this wavelength range was detected for desflurane or sevoflurane. The total atmospheric lifetimes, as derived from both OH. reactivity and photolysis, were 4.0-21.4 yr. It has been calculated that up to 20% of anaesthetics enter the stratosphere. As a result of chlorine and bromine content, the ozone depletion potential (ODP) relative to chlorofluorocarbon CFC-11 varies between 0 and 1.56, leading to a contribution to the total ozone depletion in the stratosphere of approximately 1% for halothane and 0.02% for enflurane and isoflurane. Estimates of the greenhouse warming potential (GWP) relative to CFC-12 yield values of 0.02-0.14, resulting in a relative contribution to global warming of all volatile anaesthetics of approximately 0.03%. The stratospheric impact of halothane, isoflurane and enflurane and their influence on ozone depletion is of increasing importance because of decreasing chlorofluorocarbons globally. However, the influence of volatile anaesthetics on greenhouse warming is small.      

Repeat anaesthesia: hepatic injury

Hepatic injury following repeat anaesthesia is a very rare but potentially fatal complication. The halogenated anaesthetic agents have been implicated in hepatic injury. Predisposing factors include repeat exposure to halogenated anaesthetics, genetic factors, middle age, female gender and liver enzyme induction. Halothane is a well-known cause of halothane hepatitis, but isoflurane, enflurane and desflurane have also been implicated with this clinical syndrome. A cross-sensitivity has been shown that is potentiated by the use of nitrous oxide. Although sevoflurane is metabolized differently, cases of hepatic injury following sevoflurane anaesthesia have been reported. The diagnosis of halothane hepatitis can be made only once other causes have been eliminated. Halogenated anaesthetics should be avoided for patients who have survived halothane hepatitis. Total intravenous anaesthetics and or regional techniques may be used instead.     

Hypoxia and halothane metabolism in vivo: release of inorganic fluoride and halothane metabolite binding to cellular constituents.

Fluoride release and covalent binding of halothane metabolites were studied in rats pretreated with phenobarbital and anesthestized with halothane in the presence of high (40 per cent) and low (7 per cent) oxygen tensions. The purpose of producing hypoxia was to promote the reductive pathways involved in the metabolism of halothane. Halothane anesthesia under hypoxic conditions caused a significant elevation in the plasma fluoride concentration. There was also a greater than three-fold increase in covalent binding of 14C-halothane metabolites to microsomal lipids in hypoxic rats. The lipid/protein binding ratio in control animals averaged 0.76, while hypoxic animals had a binding ratio of 3.24. The findings demonstrate that defluorination of halothane does occur during hypoxic conditions. It is hypothesized that the products produced by this reductive metabolic pathway are also potentially more hepatotoxic than the oxidative metabolites, based upon the increased covalent binding of halothane metabolites under hypoxic conditions.     

Comparison of the requirements for hepatic injury with halothane and enflurane in rats

A rat model of enflurane-associated hepatotoxicity was compared with the halothane-hypoxia (HH) model (adult male rats, phenobarbital induction, 1% halothane, 14% O2, for 2 hr). The enflurane-hypoxia heating (EHH) model involved exposing phenobarbital-pretreated male adult rats to 1.5-1.8% enflurane at 10% O2 for 2 hr with external heating to help maintain body temperature. Exposure to either anesthetic without temperature support led to a decrease in body temperature of 7-9 degrees C, while heating the animals during anesthesia resulted in only a 0.5-2 degree decrease. Reducing the oxygen tension to 10% O2 combined with heating the animals during exposure produced significant decreases in the oxidative metabolism of both halothane and enflurane as compared to exposures of 14% O2. The same conditions also caused a significant increase in the reductive metabolism of halothane, indicating that a severe hepatic hypoxia or anoxia occurs during anesthesia at 10% O2 with external heating. The time course of lesion development in the HH model paralleled results obtained with an oral dose of CCl4: gradual progression of necrosis up to 24 hr. EHH resulted in a classic hypoxic/anoxic injury with elevated serum glutamate pyruvate transaminase values and a watery vacuolization of centrilobular hepatocytes immediately after exposure. The HH model required phenobarbital pretreatment of the rats for expression of hepatic injury; EHH did not. Heating of the animals during anesthesia exposure was necessary for enflurane-induced hepatoxicity but had little effect on the HH model. Exposure to 5% O2 without anesthetic mimicked EHH in both requirements for and type of hepatic injury.     

DRUG METABOLIZING ENZYMES IN THE RAT AFTER INHALATION OF HALOTHANE AND ENFLURANE: Different pattern of response in liver, kidney and lung and possible implications for toxicity

Male Sprague-Dawley rats were exposed in inhalation chambersto halothane and enflurane in concentrations from 50 to 1000p.p.m. (0.0025 MAC-0.05MAC) 6 h a day for 3–11 days. Nosigns of general toxicity were found. There was a normal increasein weight, and normal food consumption, organ to body weightratios and normal histological findings in liver, kidney andlung. Exposure to 500 p.p.m. (0.05 MAC) of halothane inducedthe activity of NADPH-cytochrome-c-reductase in the liver, decreasedthe concentration of cytochrome P-450 in the kidney and decreasedall the enzyme concentrations measured in lung microsomes. Exposureto halothane 50 p.p.m. (0.005 MAC) and enflurane produced onlyminor changes. It is concluded that the inhalation of halothane,in contrast to enflurane, may affect drug metabolism and therebydrug kinetics and toxicity. Halothane may increase its own toxicityby increasing the activity of NADPH-cytochrome-c-reductase inliver. An organ differentiation in enzymatic response was observed.     

氟烷、安氟醚、七氟醚肝毒性与TXB_2、6－keto－PGF（1α）含量变化（氟烷性肝炎的研究Ⅲ）

雄性ＳＤ大鼠饮用含苯巴比妥钠（１ｍｇ／ｍｌ）的饮水１周后，随机分为四组，每组８例，分别吸入：Ｃ，１４％Ｏ＿２／８６％Ｎ＿２；Ｅ，１４％Ｏ＿２／８６％Ｎ＿２／１．２ＭＡＣ安氟醚；Ｓ，１４％Ｏ＿２／８６％Ｎ＿２／１．２ＭＡＣ七氟醚；Ｈ，１４％Ｏ＿２／８６％Ｎ＿２／１．２ＭＡＣ氟烷１ｈ。２４ｈ后发现Ｈ组血浆ＡＬＴ活性显著高于其它各组，并有明显的小叶中心性肝细胞坏死及汇管区炎细胞浸润，血窦重度充血。Ｅ组可见部分肝小叶内有小叶中心性坏死及空泡变性。Ｈ组肝匀浆及血浆中ＴＸＢ＿２含量显著高于其它各组。６－ｋｅｔｏ－ＰＧＦ１ａ各组间均无显著差异。提示氟烷性肝炎与ＴＸＡ＿２／ＰＧＩ＿２平衡失调有一定的关系。     

Halothane-induced lipid peroxidation and glucose-6-phosphatase inactivation in microsomes under hypoxic conditions

Halothane-induced lipid peroxidation was studied in microsomes from phenobarbital-pretreated male rats at defined steady state oxygen partial pressures (PO2). At PO2 less than 10 mmHg on addition of halothane to NADPH-reduced microsomes, significant increases in malondialdehyde (MDA) formation, oxygen uptake, and conjugated dienes were measured. At the maximum, near a PO2 of 1 mmHg, halothane induced the formation of about 0.75 nmol MDA X mg microsomal protein-1 X min-1; it also stimulated microsomal oxygen uptake twofold to threefold, and caused an almost threefold increase in conjugated diene absorption. Moreover, at this PO2 microsomal glucose-6-phosphatase lost about 70% of its activity. At PO2 greater than 10 mmHg, no significant effects of halothane on MDA formation, oxygen uptake, conjugated diene absorption, and glucose-6-phosphatase activity were observed; likewise under anaerobic conditions there was only a slight increase in conjugated dienes. The findings demonstrate that halothane induces microsomal lipid peroxidation at low PO2 and in the presence of particular cytochrome P-450 isoenzymes, and that the halothane-induced lipid peroxidation leads to severe microsomal lesions, as indicated by the loss of glucose-6-phosphatase activity.     

Behavioural effects of chronic exposure to sub-anesthetic concentrations of halothane, sevoflurane and desflurane in rats

BACKGROUND: A double-blind, randomized trial was conducted to determine the behavioural effects of chronic exposure to subanesthetic concentrations of halothane, sevoflurane and desflurane in rats. METHODS: Halothane, sevoflurane and desflurane group rats received 0.1%, 0.3%, and 0.6% concentrations in a flow rate of 3 L.min(-1) O(2) respectively. Control animals also received 3 L.min(-1) O(2) in another investigation room, which had the same properties as the study group rooms. Rats breathed inhaled agents or oxygen between 09:00-13:00 hr every day for 30 days. After 30 days of inhalation of subanesthetic doses of inhaled agents or oxygen, behavioural tests were applied. RESULTS: Tests of exploratory activity and curiosity (hole-board test), anxiety (elevated plus maze test) and learning and memory functions (multiple T maze test), demonstrated that chronic exposure to subanesthetic concentrations of all three anesthetics alters behavioural functions in rats. However, impairment of learning (P<0.05) and memory function (P<0.05) were greater in association with desflurane, in comparison to halothane and sevoflurane-treated rats. CONCLUSION: Chronic exposure to subanesthetic concentrations of halothane, sevoflurane and desflurane is associated with behavioural change in rats. Of the three drugs, desflurane was associated with the lowest learning and memory function test scores.     

Hepatic oxygen supply and consumption in rats exposed to thiopental, halothane, enflurane, and isoflurane in the presence of hypoxia

Hepatic oxygen supply and uptake were assessed in phenobarbital-pretreated male Sprague-Dawley rats receiving subanesthetic doses of thiopental, halothane, enflurane, or isoflurane combined with hypoxia (approximately 0.5 MAC and 12% oxygen) for the purpose of evaluating the role of these combinations in hepatic blood flow alterations and the concomitant hepatic oxygen supply and uptake. Hepatic blood flow was measured using microspheres; hepatic oxygen supply and consumption was calculated from measured hepatic blood flow and oxygen content in hepatic arterial, portal venous, and hepatic venous blood. In all anesthetic groups, total hepatic blood flow did not change from the control value. Oxygen supply to the liver was decreased from air control values in all anesthetic groups, but there were no significant differences among anesthetic groups. Hepatic oxygen consumption was significantly lower in animals exposed to halothane and isoflurane versus air controls, whereas it was not significantly decreased in animals receiving thiopental or enflurane. The hepatic oxygen supply/consumption ratio was higher in the air control and the isoflurane groups than in other groups; however, no significant differences in this ratio were observed among the thiopental, halothane, and enflurane groups. Oxygen content in hepatic venous blood correlated well with hepatic oxygen supply/consumption ratio in all five groups. These results show that, during exposure to mild hypoxia, a sub-MAC dose of isoflurane maintains the relationship of hepatic oxygen supply to uptake better than thiopental, halothane, or enflurane. However, a subanesthetic dose of halothane did not aggravate liver hypoxia specifically, compared with thiopental or enflurane.     

Effects of halothane, isoflurane, enflurane, thiopental, and fentanyl on blood gas values in rats exposed to hypoxia

In rats pretreated with phenobarbital breathing 10% oxygen, subanesthetic doses of halothane, isoflurane, enflurane, thiopental, and fentanyl caused hepatic injury. Because hypoxia per se can produce such injury, we hypothesized that the anesthetic-induced injury resulted from increased hypoxemia secondary to respiratory depression. Male Sprague-Dawley rats were pretreated with phenobarbital; half of the rats were fed and the other half were deprived of food for the 24 h before study. Isoflurane anesthesia was given for the placement of a catheter into the femoral artery. After 1 h of recovery, the rats were exposed to 10% oxygen. Control samples were obtained and halothane, isoflurane, enflurane, thiopental, or fentanyl was administered. Rats given food had higher PaCO2 and lower pH values than starved rats. Also, arterial oxygen saturation (SaO2) tended to be lower in rats given food. At concentrations of 0.15-0.2 MAC or higher, halothane, isoflurane, and enflurane slightly increased PaCO2 values relative to values for a control group exposed only to hypoxia. However, SaO2 and PaO2 did not show significant drug-induced changes. Fentanyl transiently decreased PaO2 and SaO2. Thiopental caused no changes. Thus, we conclude that subanesthetic doses of anesthetics may depress the ventilatory response to hypoxia but that this depression is inconsistent and appears to be too small to cause hepatic damage.     

Effect of halothane on rat liver adenylate cyclase: role of cytosol components

Halothane, in a number of tissues, alters the activity of adenylate cyclase, the enzyme that catalyzes the formation of cyclic 3',5'-adenosine monophosphate, an important intracellular regulator. The present studies demonstrate that in rat liver whole homogenates, basal and glucagon-stimulated adenylate cyclase activity is increased by halothane. In isolated rat liver membranes, halothane does not increase basal activity and it decreases activity stimulated by glucagon. Suspension of membranes in the cytosol fraction restores the halothane-induced increase of basal and glucagon-stimulated activity. When cytosol denatured by trypsin or heat was used, the halothane-induced increase in glucagon-stimulated activity was lost, but the increase of basal activity was still observed. Suspension of membranes in albumin solution restored the effect of halothane on basal activity only. These results suggest that presence of heat-labile proteins in the cytosol fraction that modulate the halothane interaction with rat liver adenylate cyclase.