Halogenated anesthetics reduce interleukin-1beta-induced cytokine secretion by rat alveolar type II cells in primary culture

BACKGROUND: Alveolar epithelial type II (AT II ) cells participate in the intraalveolar cytokine network by secreting cytokines and are widely exposed to volatile anesthetics during general anesthesia. The aim of the current study was to evaluate the effects of halothane, enflurane, and isoflurane on rat AT II cell cytokine secretions in AT II primary cell cultures. METHODS: Alveolar epithelial type II primary cell cultures were obtained from adult rat lungs. AT II cells were stimulated by recombinant murine interleukin-1beta (rmIL-1beta) to mimic an inflammatory response, and immediately exposed for various duration to different concentration of halothane, enflurane, or isoflurane. Interleukin-6, macrophage inflammatory protein-2 (MIP-2), and monocyte chemoattractant protein-1 (MCP-1) protein concentrations were then measured in cell culture supernatants. Recombinant mIL-1beta-stimulated AT II cells exposed to air served as control. RESULTS: Halothane, isoflurane, and enflurane (1 minimum alveolar concentration [MAC], 4 h) decreased rmIL-1beta-stimulated AT II cell secretions of interleukin-6, MIP-2, and MCP-1, but did not modify total protein secretion. Halothane exposure decreased rmIL-1beta-stimulated AT II cell secretions of interleukin-6, MIP-2, and MCP-1 in a dose- and time-dependent manner. Total protein concentrations remained unchanged except AT II 1.5 MAC of halothane, and no cytotoxic effect could be evidenced by lactate dehydrogenase release. These effects were transient as rmIL-1beta-stimulated AT II cell secretions of interleukin-6 and MIP-2 progressively reached control values between 4 and 24 h after the end of halothane exposure. However, MCP-1 inhibition persisted until 24 h. rmIL-1beta-induced MIP-2 and tumor necrosis factor-alpha mRNA expression were decreased by 36 and 24%, respectively, after halothane exposure. CONCLUSIONS: The current study shows that exposure of rmIL-1beta-stimulated AT II cells to volatile anesthetics reversibly alters their cytokine secretion. Therefore, volatile anesthesia, by modulating pulmonary epithelial cell secretion of inflammatory cytokines, might affect the lung inflammatory response.     

Subanesthetic concentrations of volatile anesthetics may enhance acquired avoidance training in ddN mice

The effects of halothane, enflurane, and isoflurane on avoidance training were assessed in male ddN mice. Animals were trained to escape an aversive unconditioned stimulus (electric foot shock) within 3 s after being exposed to a conditioned stimulus (light and buzzer). Immediately after training (first session), the animals were exposed to halothane, enflurane, or isoflurane for 120 min and were then tested again on the avoidance task (second session) 30 min after cessation of the exposure. The performance ratios [B/A] (i.e., A is the score in the first session, and B the score in the second) were compared between the anesthetic groups and their respective control groups. Performance ratios in the control animals ([B/A]c) did not reach 100% except for those corresponding to the 0.5 and 1.0 MAC (minimal alveolar anesthetic concentration) halothane groups. Four of the nine performance ratios in the anesthetic groups ([B/A]a) exceeded 1.0. [B/A]a exceeded [B/A]c by 18.7% in the 0.25 MAC halothane group (P less than 0.05), by 13.5% in the 0.31 MAC enflurane group (i.e., not significant), and by 17.3% in the 0.29 MAC isoflurane group (P less than 0.01). [B/A]a/[B/A]c decreased dose-dependently for each anesthetic group. These results suggest that low concentrations of halothane, enflurane, and isoflurane may enhance the performance of ddN mice in acquired avoidance training performed 30 min after anesthetic exposure.     

Suppression of ventricular arrhythmias by volatile anesthetics in a canine model of chronic myocardial infarction

Ventricular tachycardia likely secondary to a reentrant mechanism may be reliably induced by programmed electrical stimulation in dogs 4-6 days after creating a 2-h experimental, occlusion-reperfusion myocardial infarction. The effects of 1.1 and 1.8 MAC halothane, isoflurane, and enflurane on pacing-induced arrhythmias were studied in this model. The ease of initiation of ventricular tachycardia was measured in both awake and anesthetized dogs (n = 18). Excitation thresholds, conduction times, and refractory periods in both normal and infarcted myocardium were also determined to understand changes in the ease of induction of the arrhythmias secondary to anesthetic exposure. Halothane and enflurane administration suppressed the induction of ventricular tachycardia compared with the unanesthetized control (P less than 0.01 for both). During isoflurane anesthesia, there was a trend that was not statistically significant for pacing-induced ventricular tachycardia to be less frequent than during the conscious state (P = 0.11). Halothane and enflurane prolonged refractory periods in both normal and infarcted myocardium, whereas isoflurane had that effect only in normal myocardium. In addition, halothane and enflurane tended to increase refractory periods more than isoflurane in both regions. Conduction times and excitation thresholds were not altered by anesthetic administration. It is concluded that halothane and enflurane suppress inducible ventricular arrhythmias secondary to a prior myocardial infarction. In addition, the increased efficacy of halothane and enflurane as antiarrhythmic agents compared with isoflurane in this model may be related to their greater prolongation of refractory periods.     

吸入麻醉药对人血浆和血小板血栓素B2生成与血小板聚集的影响

目的：探讨吸入麻醉剂氟烷、安氟醚和异氟醚对人血浆血栓素Ｂ２（ＴＸＢ２），血小板ＴＸＢ２生成与血小板聚集的影响。方法：血浆ＴＸＢ２和血小板ＴＸＢ２的生成量用放免分析法测量，血小板聚集率用比浊法测量。结果：吸入１ＭＡＣ氟烷３０分钟后，血浆ＴＸＢ２浓度、二磷酸腺苷（ＡＤＰ）和肾上腺素（Ｅ）诱导的血小板ＴＸＢ２生成量与血小板聚集率显著下降，吸入１ＭＡＣ安氟醚３０分钟后，血浆ＴＸＢ２浓度和血小板ＴＸＢ２生成量与血小板聚集率亦显著下降，其降低的程度比氟烷轻。吸入１ＭＡＣ异氟醚对上述指标无明显影响。血小板ＴＸＢ２生成的减少与血小板聚集率的下降呈显著正相关。结论：氟烷显著抑制血小板聚集，安氟醚次之，异氟醚对血小板聚集无明显影响。其机制可能与氟烷和安氟醚通过抑制血小板上血栓素Ａ２受体的亲和力，降低ＡＤＰ和Ｅ诱导的血小板ＴＸＢ２的生成有关。     

Volatile anesthetics excite mammalian nociceptor afferents recorded in vitro

The present study investigated the actions of halothane, isoflurane, and enflurane on spontaneous discharge and evoked action potential activity in mammalian A-delta and C fiber nociceptors from the in vitro rabbit cornea. At 1 MAC halothane, isoflurane, and enflurane significantly (P less than 0.001) increased spontaneous discharge frequency of C fibers to 410%, 388%, and 569% of control, respectively. The anesthetics produced burst discharge activity over the concentration range of 0.25-1.5 MAC and depressed discharge activity at higher concentrations (greater than 3.0 MAC). Similar excitatory effects were produced by the potassium channel blocker 4-aminopyridine (250-500 microM). Variable effects on evoked discharge activity of A-delta fibers were observed. Halothane reduced action potential amplitude (77.3 +/- 4.5% of control +/- SD; n = 6 at 1 MAC) and increased spike latency (0.42 +/- 0.075 ms). In contrast, the ethers decreased both spike latency (isoflurane by 0.31 +/- 0.064 ms and enflurane by 0.35 +/- 0.058 ms) and action potential amplitude. Halothane and the ether anesthetics produced a common excitatory action on C fibers; however, the differential depressant effects on A-delta fibers suggest that different membrane mechanisms of action are involved.     

Halothane, enflurane, and isoflurane attenuate both receptor- and non-receptor-mediated EDRF production in rat thoracic aorta.

EDRF (endothelium-derived relaxing factor) is a cellular and intercellular messenger that activates soluble guanylate cyclase. In blood vessels it is released from the endothelium and causes relaxation of vascular smooth muscle. Halothane previously has been shown to attenuate EDRF-induced vasodilation elicited by the receptor-mediated vasodilators acetylcholine and bradykinin and to alter muscarinic receptor activity. We examined and compared the effects of the inhaled anesthetics halothane, enflurane, and isoflurane on endothelium-dependent vasodilation and tested the hypothesis that these agents inhibit EDRF-mediated vasodilation solely through inhibition of endothelial cell receptor-mediated EDRF release. Isolated rat thoracic aortic rings were mounted for isometric tension recording and preconstricted with phenylephrine. Cumulative dose-response curves were obtained to methacholine, a receptor-mediated endothelium-dependent dilator; to A23187, a nonreceptor-mediated endothelium-dependent dilator; and to sodium nitroprusside, a direct-acting endothelium-independent dilator before, during, and after inhalational anesthetic exposure. Both receptor-mediated and non-receptor-mediated endothelium-dependent relaxation by methacholine and A23187, respectively, were significantly (P less than 0.01 to P less than 0.05) and reversibly attenuated by halothane, enflurane, and isoflurane at 2 MAC and by isoflurane at 1 MAC. Endothelium-independent relaxation by sodium nitroprusside, an agent that acts directly on the vascular smooth muscle cell to activate guanylate cyclase, was unaffected by any of the anesthetics at any concentration tested. Indomethacin had no significant effect on the inhibition of endothelium-dependent vasodilation by these inhalational anesthetics. We conclude that halothane, enflurane, and isoflurane inhibit endothelium-dependent vasodilation; that isoflurane is more potent than halothane and enflurane in this regard.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of sevoflurane, halothane, enflurane, and isoflurane on hepatic blood flow and oxygenation in chronically instrumented greyhound dogs.

Inhalational anesthetics produce differential effects on hepatic blood flow and oxygenation that may impact hepatocellular function and drug clearance. In this investigation, the effects of sevoflurane on hepatic blood flow and oxygenation were compared with those of enflurane, halothane, and isoflurane in ten chronically instrumented greyhound dogs. Each dog randomly received enflurane, halothane, isoflurane, and sevoflurane, each at 1.0, 1.5, and 2.0 MAC concentrations. Mean arterial blood pressure and cardiac output decreased in a dose-dependent fashion during all four anesthetics studied. Heart rate increased compared to control during enflurane, isoflurane, and sevoflurane anesthesia and did not change during halothane anesthesia. Hepatic arterial blood flow and portal venous blood flow were measured by chronically implanted electromagnetic flow probes. Hepatic O2 delivery and consumption were calculated after hepatic arterial, portal venous, and hepatic venous blood gas analysis. Hepatic arterial blood flow was maintained with sevoflurane and isoflurane. Halothane and enflurane reduced hepatic arterial blood flow during all anesthetic levels compared to control (P less than 0.05), with marked reductions occurring with 1.5 and 2.0 MAC halothane concomitant with an increase in hepatic arterial vascular resistance. Portal venous blood flow was reduced with isoflurane and sevoflurane at 1.5 and 2.0 MAC. A somewhat greater reduction in portal venous blood flow occurred during 2.0 MAC sevoflurane (P less than 0.05 compared to control and 1.0 MAC values for sevoflurane). Enflurane reduced portal venous blood flow at 1.0, 1.5, and 2.0 MAC compared to control. Halothane produced the greatest reduction in portal venous blood flow (P less than 0.05 compared to sevoflurane).(ABSTRACT TRUNCATED AT 250 WORDS)     

Interaction of Volatile Anesthetics with Human Kv Channels in Relation to Clinical Concentrations

Background: Recent evidence shows that inhibition of human Kv3 channels by intravenous anesthetics occurs at clinical concentrations. The effects of volatile anesthetics on these human ion channels are unknown. This study was designed to establish whether minimum alveolar concentrations (MAC) of halothane, enflurane, isoflurane, and desflurane exhibit effects on Kv3 channels. To obtain an indication whether these findings may be specific to Kv3 channels, the effects of enflurane and isoflurane on human Kv1.1 channels were also investigated.

Methods: Kv3 channels natively expressed in SH-SY5Y cells and Kv1.1 channels expressed in HEK293 cells were measured with the whole cell patch clamp technique by standard protocols. Concentrations of volatile anesthetics were determined by gas chromatography.

Results: Halothane, enflurane, isoflurane, and desflurane reversibly inhibited Kv3 channels in a concentration-dependent manner. Concentrations at half-maximal effect (IC50 values) ranged between 1,800 and 4,600 [mu]m. Hill coefficients were between 1.7 and 2.5. IC50 values for inhibition of Kv1.1 channels were 2,800 and 5,200 [mu]m, and Hill coefficients were 3.9 and 5.6 for enflurane and isoflurane, respectively.     

Effect of Halothane and Isoflurane on Binding of ADP- and TRAP-6- activated Platelets to Leukocytes in Whole Blood

Background: Adhesion of activated platelets to neutrophils and monocytes has an important role in the regulation of inflammatory processes. This study investigates whether halothane and isoflurane affect binding of activated platelets to leukocytes in human whole blood.

Methods: Citrated whole blood was incubated for 60 min with either 1 or 2 minimum alveolar concentration (MAC) halothane or isoflurane. After stimulation with adenosine-5-diphosphate (ADP) or the thrombin receptor agonist protein TRAP-6, platelet-leukocyte adhesion and surface expression of CD62P on platelets were evaluated by flow cytometry.

Results: Halothane led to an inhibition of agonist-induced adhesion of activated platelets to neutrophils and monocytes. One MAC halothane reduced the formation of TRAP-6-induced platelet-monocyte conjugates. After exposure to 2 MAC halothane, agonist-induced platelet-monocyte and platelet-neutrophil adhesion were inhibited. Surface expression of CD62P on ADP- and TRAP-6-stimulated platelets were significantly reduced after 1 and 2 MAC halothane. After 2 MAC isoflurane, the authors observed an increase of the percentage of lymphocytes with bound platelets after activation with ADP. The percentage of neutrophils with bound platelets after activation with ADP or TRAP-6 was also increased in this group. Two MAC isoflurane led to an increase of the percentage of platelets expressing CD62P in the unstimulated and TRAP-6 stimulated samples, and of the amount of CD62P epitopes on the surface of platelets in the ADP-stimulated samples.     

Effect of Isoflurane and Other Potent Inhaled Anesthetics on Minimum Alveolar Concentration, Learning, and the Righting Reflex in Mice Engineered to Express α1 γ-Aminobutyric Acid Type A Receptors Unresponsive to Isoflurane

Background: Enhancement of the function of [gamma]-aminobutyric acid type A receptors containing the [alpha]1 subunit may underlie a portion of inhaled anesthetic action. To test this, the authors created gene knock-in mice harboring mutations that render the receptors insensitive to isoflurane while preserving sensitivity to halothane.

Methods: The authors recorded miniature inhibitory synaptic currents in hippocampal neurons from hippocampal slices from knock-in and wild-type mice. They also determined the minimum alveolar concentration (MAC), and the concentration at which 50% of animals lost their righting reflexes and which suppressed pavlovian fear conditioning to tone and context in both genotypes.

Results: Miniature inhibitory postsynaptic currents decayed more rapidly in interneurons and CA1 pyramidal cells from the knock-in mice compared with wild-type animals. Isoflurane (0.5-1 MAC) prolonged the decay phase of miniature inhibitory postsynaptic currents in neurons of the wild-type mice, but this effect was significantly reduced in neurons from knock-in mice. Halothane (1 MAC) slowed the decay of miniature inhibitory postsynaptic current in both genotypes. The homozygous knock-in mice were more resistant than wild-type controls to loss of righting reflexes induced by isoflurane and enflurane, but not to halothane. The MAC for isoflurane, desflurane, and halothane did not differ between knock-in and wild-type mice. The knock-in mice and wild-type mice did not differ in their sensitivity to isoflurane for fear conditioning.     

Minimum alveolar concentrations (MAC) of halothane, enflurane, and isoflurane in ferrets

The minimum alveolar concentrations (MAC) of isoflurane, enflurane, and halothane were determined in adult male ferrets during controlled ventilation at normothermia (37 degrees C). Mean (+/- SD) MAC values for isoflurane (n = 8), enflurane (n = 8), and halothane (n = 8) at 37 degrees C were 1.52 +/- 0.10%, 1.99 +/- 0.18%, and 1.01 +/- 0.10%, respectively. Halothane MAC was reduced by 26% in the presence of 70% N2O. At 29.9 +/- 0.2 degrees C, the mean MAC value of halothane (0.85 +/- 0.11%) was 16% less than MAC at 37 degrees C. The relative potencies of the halogenated anesthetics are of the same order as those reported for large animals and for humans.     

Norepinephrine-induced Apoptosis Is Inhibited in Adult Rat Ventricular Myocytes Exposed to Volatile Anesthetics

Background: Volatile anesthetics are used to provide anesthesia to patients with heart disease under heightened adrenergic drive. The purpose of this study was to test whether volatile anesthetics can inhibit norepinephrine (NE)-induced apoptosis in cardiomyocytes.

Methods: Rat ventricular cardiomyocytes were exposed to NE (10 [mu]m) alone or in the presence of increasing concentrations of isoflurane and halothane.

Results: Isoflurane at 1.6 minimum alveolar concentration (MAC) (4 +/- 2% [SD]) and halothane at 1.2 MAC (3 +/- 2%) abolished the percentage of cardiomyocytes undergoing NE-induced apoptosis (34 +/- 8%), as assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) (P < 0.0001). Lower concentrations of isoflurane and halothane markedly decreased the number of TUNEL-positive cells. Similarly, isoflurane at 1.6 MAC (5 +/- 3%) and halothane at 1.2 MAC (6 +/- 3%) prevented the increase in annexinV-staining cardiomyocytes (38 +/- 7%;P < 0.0001). These findings were corroborated with a decreased quantity of NE-induced DNA laddering by volatile anesthetics. Halothane at 1.2 MAC abolished the increase in TUNEL-positive cardiomyocytes exposed to the dihydropyridine Ca2+-channel agonist BAY K-8644 (1 [mu]m) (BAY K-8644 + halothane: 3 +/- 2%vs BAY K-8644: 34 +/- 6%;P < 0.0001) and the Ca2+-ionophore 4-bromo-A23187 (1 [mu]m) (4-bromo-A23187 + halothane: 2 +/- 2%vs 4-bromo-A23187: 13 +/- 4%;P = 0.03). NE treatment increased caspase-9 activity to 197 +/- 62% over control myocytes (P < 0.0001), whereas no caspase-8 activation was detectable. This increase in caspase-9 activity was blocked by isoflurane at 1.6 MAC and halothane at 1.2 MAC.     

Pulmonary ventilation and gas exchange in children anaesthetized with halothane, enflurane and isoflurane

The effects of similar anaesthetic levels of halothane (1.3 MAC), enflurane (1.2 MAC) and isoflurane (1.1 MAC) on pulmonary ventilation and gas exchange were investigated in 24 children subjected to minor and intermediate paediatric surgical procedures. Eight children were anaesthetized with each agent, pneumotachography and capnography were used, and airway as well as oesophageal pressures were measured. Minute ventilation (VE) was lower with enflurane than with halothane (P less than 0.001) and isoflurane (ns). Tidal volumes were, however, similar and variations in VE were thus caused by lower respiratory rates with enflurane than with the two other agents. Alveolar ventilation (VABohr) and carbon dioxide elimination (VCO2) were smaller and end-tidal CO2 tension higher with enflurane. Ventilatory efficiency was, however, somewhat better with enflurane as indicated by lower VDBohr/VT (ns) and VE/VCO2 (P less than 0.05) ratios compared with the two other agents. The effects of all three agents on dynamic compliance were similar, while total pulmonary resistance was less with isoflurane than with halothane and enflurane. It is concluded that although minute ventilation was smaller with enflurane than with halothane and isoflurane, ventilatory efficiency was similar due to a smaller dead space ventilation as a result of the lower respiratory rates in children anaesthetized with enflurane.     

The effect of halothane, enflurane and isoflurane on the circulation

This study, in open-chested dogs, sought to explore the relationship between whole-body oxygen delivery and oxygen consumption during anaesthesia, using increasing concentrations of halothane, enflurane and isoflurane. Results indicate that the cardiac index and oxygen delivery became critical at less than 1 MAC (minimal alveolar concentration of anaesthetic) for the three commonly used vapours. Halothane caused the least depression of contractility, but the stroke volume was reduced by the well-maintained afterload at 1 MAC. Enflurane and isoflurane were associated with more depression of contractility, but the cardiac output was maintained by an increase in heart rate in the case of isoflurane and reduced mean arterial pressure during the use of enflurane.     

Halothane Does Not Inhibit the Functional Coupling between the β2-Adrenergic Receptor and the Gαs Heterotrimeric G Protein

Background: This study investigated whether halothane affects the functional coupling between the [beta]2 adrenergic receptor and the [alpha] subunit of its cognate stimulatory heterotrimeric guanosine-5'-triphosphate (GTP)-binding protein (G[alpha]s). The authors hypothesized that halothane does not affect isoproterenol-promoted guanosine nucleotide exchange at G[alpha]s 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. G[alpha]s nucleotide exchange was measured in crude membranes prepared from COS-7 cells transfected to transiently coexpress the human [beta]1 or [beta]2 receptor each with human short G[alpha]s. A radioactive, nonhydrolyzable analog of GTP, [35S]GTP[gamma]S, was used as the reporter for nucleotide exchange at G[alpha]s.

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 G[alpha]s nucleotide exchange. Halothane, even at concentrations of 1.5 mm (approximately 5.6 MAC), had no effect on basal G[alpha]s nucleotide exchange in the absence of isoproterenol, whereas halothane inhibited isoproterenol-promoted G[alpha]s nucleotide exchange in both the [beta]1-G[alpha]s and [beta]2-G[alpha]s expressing membranes. However, the effect was significantly greater on [beta]1-G[alpha]s coupling compared with [beta]2-G[alpha]s coupling, with no effect on [beta]2-G[alpha]s coupling at 2.8 MAC halothane.     

Volatile agent use: perception and practice A survey of agent use over a 3-year period

We calculated the quantity, as MAC hours and MAC hours anaesthetic, of halothane, enflurane and isoflurane, used in this Health District over a 3-year period. Halothane accounted for 77% of anaesthesia in the first year and for 57% in the final year. Overall usage of volatile agents decreased. Fifteen consultants and 19 senior registrars perceived, in a survey of practice, only a change in relative use of volatile anaesthetic agents with a large swing from halothane to both enflurane and isoflurane. Half the anaesthetists stated that the medicolegal consideration was the prime reason for their change. The perceived total demise of halothane does not appear to have been realised, despite individual anaesthetist's perceptions.     

Halogenated anesthetics increase oxygen consumption in isolated hepatocytes from phenobarbital-treated rats

Using suspensions of hepatocytes isolated from phenobarbital-treated and untreated rats (+PB cells and -PB cells, respectively), the authors examined the effects of halothane, enflurane, and isoflurane on O2 consumption (VO2) and on extracellular PO2 and energy status at steady states of O2 and energy metabolism. In +PB cells, all three agents produced increases in VO2 which were largest at 1 MAC and progressively smaller at 2 and 3 MAC. At all three doses, VO2 increases were largest with enflurane (48% at 1 MAC), intermediate with halothane (24%), and smallest with isoflurane (11%). These anesthetic-induced VO2 increases were abolished by prior addition of a cytochrome P450 inhibitor (metyrapone) to the incubations. In -PB cells, all three agents produced slight and comparable decreases in VO2 at 1 MAC, with further decreases at 2 and 3 MAC. In +PB cell suspensions at steady states of O2 and energy metabolism, 1 MAC enflurane or halothane, but not isoflurane, produced significant declines in steady state PO2 (from initial values of 24 mmHg to values less than 10 mmHg) and reductions in adenosine triphosphate/adenosine diphosphate ratio (ATP/ADP). These changes were absent in -PB cells exposed to the same conditions or in +PB cells not exposed to anesthetic. The authors conclude that clinical doses of enflurane and, to a lesser extent, halothane produce statistically significant increases in O2 consumption, reflecting enhanced cytochrome P450 activity, in liver cells isolated from phenobarbital-treated rats. Such increases in O2 demand represent a mechanism by which anesthetic metabolism could contribute to intrahepatic hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of halothane and isoflurane on binding of ADP- and TRAP-6- activated platelets to leukocytes in Whole blood.

BACKGROUND: Adhesion of activated platelets to neutrophils and monocytes has an important role in the regulation of inflammatory processes. This study investigates whether halothane and isoflurane affect binding of activated platelets to leukocytes in human whole blood. METHODS: Citrated whole blood was incubated for 60 min with either 1 or 2 minimum alveolar concentration (MAC) halothane or isoflurane. After stimulation with adenosine-5-diphosphate (ADP) or the thrombin receptor agonist protein TRAP-6, platelet-leukocyte adhesion and surface expression of CD62P on platelets were evaluated by flow cytometry. RESULTS: Halothane led to an inhibition of agonist-induced adhesion of activated platelets to neutrophils and monocytes. One MAC halothane reduced the formation of TRAP-6-induced platelet-monocyte conjugates. After exposure to 2 MAC halothane, agonist-induced platelet-monocyte and platelet-neutrophil adhesion were inhibited. Surface expression of CD62P on ADP- and TRAP-6-stimulated platelets were significantly reduced after 1 and 2 MAC halothane. After 2 MAC isoflurane, the authors observed an increase of the percentage of lymphocytes with bound platelets after activation with ADP. The percentage of neutrophils with bound platelets after activation with ADP or TRAP-6 was also increased in this group. Two MAC isoflurane led to an increase of the percentage of platelets expressing CD62P in the unstimulated and TRAP-6 stimulated samples, and of the amount of CD62P epitopes on the surface of platelets in the ADP-stimulated samples. CONCLUSION: This study indicates that halothane inhibits, whereas isoflurane enhances, adhesion of agonist-activated platelets to leukocytes. Interaction of both anesthetics with the expression of CD62P on platelets contribute to theses effects.     

Halothane but Not Isoflurane Attenuates Interleukin 1β- induced Nitric Oxide Synthase in Vascular Smooth Muscle

Background: Inducible nitric oxide synthase (iNOS) is induced by endotoxin or cytokines, such as interleukin (IL)-1, through a protein synthesis pathway. Halothane reportedly inhibits protein synthesis in various tissues. The aim of the current study was to examine the effect of halothane on the IL-1[beta]-evoked induction of NOS in vascular smooth muscle.

Methods: After removal of the endothelium, arterial rings of rat aorta were mounted in an isometric force recording system. The effects of halothane (1.0-3.0%) or isoflurane (3.0%) on IL-1[beta] (20 ng/ml)-induced inhibition of the contractile responses to KCl (30 mm) and phenylephrine (10-9~10-5 m) were studied. The cyclic guanosine monophosphate and cyclic adenosine monophosphate contents were determined by radioimmunoassay. Expression of iNOS and iNOS mRNA were measured by Western or Northern blot analysis, respectively.

Results: Halothane (1.0-3.0%) but not isoflurane (3%) significantly reduced the IL-1[beta]-induced inhibition of contraction in a concentration-dependent manner. The cyclic guanosine monophosphate content of the vascular smooth muscle increased significantly after a 5-h exposure to IL-1[beta]. Halothane at 3.0% significantly inhibited the increase in cyclic guanosine monophosphate content induced by IL-1[beta]. Halothane had no effect on cyclic adenosine monophosphate content. IL-1[beta]-induced expression of iNOS and iNOS mRNA in the rat aorta were inhibited significantly by halothane.     

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.