Determinants of the sensitivity of AMPA receptors to xenon

BACKGROUND: There is substantial and growing literature on the actions of general anesthetics on a variety of neurotransmitter-gated ion channels, with the greatest attention being focused on inhibitory gamma-amino butyric acid type A receptors. In contrast, glutamate receptors, the most important class of fast excitatory neurotransmitter-gated receptor channels, have received much less attention, and their role in the production of the anesthetic state remains controversial. METHODS: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors formed from a variety of different subunits were expressed in Xenopus oocytes and HEK-293 cells, and their sensitivities to the inhalational general anesthetics xenon, isoflurane, and halothane were determined using two-electrode voltage clamp and patch clamp techniques. The effects of desensitization on anesthetic sensitivity were investigated using cyclothiazide and site-directed mutagenesis. An ultrarapid application system was also used to mimic rapid high-concentration glutamate release at synapses. RESULTS: The authors show that xenon can potently inhibit AMPA receptors when assayed using bath application of kainate. However, when the natural neurotransmitter l-glutamate is used under conditions in which the receptor desensitization is blocked and the peak of the glutamate-activated response can be accurately measured, the pattern of inhibition changes markedly. When desensitization is abolished by a single-point mutation (L497Y in GluR1 and the equivalent mutation L505Y in GluR4), the xenon inhibition is eliminated. When AMPA receptors are activated by glutamate using an ultrarapid application system that mimics synaptic conditions, sensitivity to xenon, halothane, and isoflurane is negligible. CONCLUSIONS: AMPA receptors, when assayed in heterologous expression systems, showed a sensitivity to inhalational anesthetics that was minimal when glutamate was applied rapidly at high concentrations. Because these are the conditions that are most relevant to synaptic transmission, the authors conclude that AMPA receptors are unlikely to play a major role in the production of the anesthetic state by inhalational agents.     

Blockade of Glutamate Receptors and Barbiturate Anesthesia: Increased Sensitivity to Pentobarbital-induced Anesthesia Despite Reduced Inhibition of AMPA Receptors in GluR2 Null Mutant Mice

Background: Barbiturates enhance [gamma]-aminobutyric acid type A (GABAA) receptor function and also inhibit the [alpha]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of glutamate receptor. The relative contribution of these actions to the behavioral properties of barbiturates is not certain. Because AMPA receptor complexes that lack the GluR2 subunit are relatively insensitive to pentobarbital inhibition, GluR2 null mutant mice provide a novel tool to investigate the importance of AMPA receptor inhibition to the anesthetic effects of barbiturates.

Methods: GluR2 null allele (-/-), heterozygous (+/-), and wild-type (+/+) mice were injected with pentobarbital (30 and 35 mg/kg intraperitoneally). Sensitivity to anesthetics was assessed by measuring the latency to loss of righting reflex, sleep time, and the loss of corneal, pineal, and toe-pinch withdrawal reflexes. In addition, patch-clamp recordings of acutely dissociated CA1 hippocampal pyramidal neurons from (-/-) and (+/+) mice were undertaken to investigate the effects of barbiturates on kainate-activated AMPA receptors and GABA-activated GABAA receptors.

Results: Behavioral tests indicate that sensitivity to pentobarbital was increased in (-/-) mice. In contrast, AMPA receptors from (-/-) neurons were less sensitive to inhibition by pentobarbital (concentrations that produced 50% of the maximal inhibition [IC50], 301 vs. 51 [mu]M), thiopental (IC50, 153 vs. 34 [mu]M), and phenobarbital (IC50, 930 vs. 205 [mu]M) compared with wild-type controls, respectively. In addition, the potency of kainate was greater in (-/-) neurons, whereas no differences were observed for the potentiation of GABAA receptors by pentobarbital.     

Xenon: no stranger to anaesthesia

Br J Anaesth 2003; 91: 709–17     

Xenon anesthesia: from myth to reality

OBJECTIVE: To analyze the current knowledge concerning xenon anaesthesia. DATA SOURCES: References were obtained from computerized bibliographic research (Medline), recent review articles, the library of the service and personal files. STUDY SELECTION: All categories of articles on this topic have been selected. DATA EXTRACTION: Articles have been analysed for history, biophysics, pharmacology, toxicity and environmental effects and using prospect. DATA SYNTHESIS: The noble gas xenon has anaesthetic properties that have been recognized 50 years ago. Xenon is receiving renewed interest because it has many characteristics of an ideal anaesthetic. In addition to its lack of effects on cardiovascular system, xenon has a low solubility enabling faster induction of and emergence from anaesthesia than with other inhalational agents. Nevertheless, at present, the cost and arety of xenon limit its widespread use in clinical practice. The developement of closed rebreathing system that allowed recycling of xenon and therefore reducing its waste has led to a recent interest in this gas. Reducing its cost will help xenon to find its place among anaesthetic agents. An European multicentric clinical trial under submission will contribute to the discussion of the opportunity for xenon introduction in anaesthesia.     

Xenon and the inflammatory response to cardiopulmonary bypass in the rat

OBJECTIVE: The purpose of this study was to investigate the effect of xenon on the inflammatory response to cardiopulmonary bypass. DESIGN: Prospective, randomized experimental study. SETTING: University research laboratory. PARTICIPANTS: Sprague-Dawley rats. INTERVENTIONS: After surgical preparation, rats were randomly divided into 4 groups: (1) SHAM rats were cannulated but did not undergo cardiopulmonary bypass; (2) cardiopulmonary bypass rats were subjected to 60 minutes of cardiopulmonary bypass using an oxygenator receiving a 30% O(2), 65% N(2), and 5% CO(2) gas mixture; (3) MK801 rats received MK801 (0.15 mg/kg intravenous) 15 minutes before 60 minutes of cardiopulmonary bypass with the same gas mixture; and (4) xenon rats underwent 60 minutes of cardiopulmonary bypass receiving a 30% O(2), 60% xenon, 5% N(2), and 5% CO(2) gas mixture. MEASUREMENTS AND MAIN RESULTS: All bypass groups showed elevations in both cytokines compared with the SHAM-operated group. However, the inflammatory response to cardiopulmonary bypass in the group receiving xenon was no different from the other bypass groups. CONCLUSIONS: Xenon appears to have no effect on the inflammatory response to cardiopulmonary bypass, making its previously described neuroprotective effect during cardiopulmonary bypass likely independent of any inflammation modulation.     

Xenon suppresses the hypnotic arousal in response to surgical stimulation.

STUDY OBJECTIVE: To evaluate the suppressive effects of xenon (Xe) on hypnotic arousal at skin incision. DESIGN: Prospective, randomized study. SETTING: Operating rooms at a university hospital. PATIENTS: 35 ASA physical status I and II patients presenting for elective lower abdominal surgery. INTERVENTIONS: Patients were randomly assigned to receive one of the following regimens: 1.3 minimum alveolar concentration (MAC) isoflurane, 1.3 MAC sevoflurane, 0.7 MAC Xe with 0.6 MAC sevoflurane, 1 MAC Xe with 0.3 MAC sevoflurane, or 0.7 MAC nitrous oxide (N2O) with 0.6 MAC sevoflurane (n = 7 each group). MEASUREMENTS AND MAIN RESULTS: The bispectral index (BIS) was measured at baseline, during anesthesia, and after skin incision. BIS increased significantly at skin incision from the values noted during anesthesia in the sevoflurane and N2O groups, whereas it remained stable at incision in the other three groups (mean change in BIS: 0 +/- 9 for isoflurane, 15 +/- 8 for sevoflurane, 5 +/- 6 for 0.7 MAC Xe, 4 +/- 11 for 1 MAC Xe, and 9 +/- 5 for N2O). CONCLUSIONS: Unlike N2O, Xe was able to suppress hypnotic arousal in response to surgical stimulation when administered with sevoflurane.     

Effects of Xenon on Hemodynamic Responses to Skin Incision in Humans

Background: The authors evaluated the hemodynamic suppressive effects of xenon in combination with sevoflurane at skin incision in patients undergoing surgery.

Methods: Forty patients were assigned randomly to receive one of the following four anesthetics: 1.3 minimum alveolar concentration (MAC) sevoflurane, 0.7 MAC xenon with 0.6 MAC sevoflurane, 1 MAC xenon with 0.3 MAC sevoflurane, or 0.7 MAC nitrous oxide with 0.6 MAC sevoflurane (n = 10 each group). Systolic blood pressure and heart rate were measured before anesthesia, before incision, and approximately 1 min after incision.

Results: The changes in hemodynamic variables in response to incision were less with sevoflurane in combination with xenon and nitrous oxide than with sevoflurane alone. Changes in heart rate (in beats/min) were 19 +/- 11 (+/- SD) for sevoflurane alone, 11 +/- 6 for 0.7 MAC xenon-sevoflurane, 4 +/- 4 for 1 MAC xenon-sevoflurane, and 8 +/- 7 for nitrous oxide-sevoflurane. Changes in systolic blood pressure were 35 +/- 18 mmHg for sevoflurane alone, 18 +/- 8 mmHg for 0.7 MAC xenon-sevoflurane, 16 +/- 7 mmHg for 1 MAC xenon-sevoflurane, and 14 +/- 10 mmHg for nitrous oxide-sevoflurane.     

Sensitivity to propofol in the elderly

Two studies were carried out on 609 fit, unpremedicated patients to assess the influence of patient age on the response to the rapidly-acting hindered phenol, propofol, which is being evaluated for induction of anaesthesia. In the first study, 1.25 mg/kg was injected over 20 seconds followed by 10-mg increments every 15 seconds until loss of verbal contact. This showed a great individual variation in response to the drug. A reduction in the 'induction' dose was found in elderly patients, which became marked around 60 years. In the second (340), doses ranging from 1.5-3.0 mg/kg in patients under 60 years and 1.25-2.25 mg/kg in those over 60 years were injected as a bolus over 20 seconds. Doses of 2.25-2.5 mg/kg were required to induce anaesthesia in patients under 60 years, whilst 1.5-1.75 mg/kg was adequate in those over 60 years. Side effects were more marked with the rapid injection and doses in excess of 1.75 mg/kg caused significant hypotension and apnoea in the elderly. These studies reveal marked sensitivity to propofol in the elderly with respect to both induction dose and acute toxicity.     

Diffusion of Xenon and Nitrous Oxide into the Bowel

Background: Nitrous oxide diffuses easily from blood into air filled spaces. Xenon is also a relatively insoluble gas, like nitrous oxide. Therefore, the authors measured xenon diffusion into obstructed bowel segments during xenon anesthesia and compared this with nitrous oxide and nitrogen diffusion.

Methods: Twenty-one pentobarbital-anesthetized pigs were randomly assigned to three groups to receive either xenon-oxygen, nitrous oxide-oxygen, or nitrogen-oxygen (75%-25%), respectively. In each animal, four bowel segments of 15-cm length were isolated. A pressure-measuring catheter was inserted into the lumen, and 30 ml of room air was injected into the segments. Anesthesia with the selected gas mixture was performed for 4 h. Pressure in the segments was measured continuously. The volume of gaseous bowel content was measured on completion of the study.

Results: The median volume of bowel gas in animals breathing nitrous oxide was 88.0 ml as compared with 39.0 ml with xenon anesthesia and 21.5 ml in the nitrogen-oxygen group. After 4 h of anesthesia, the intraluminal pressures in the nitrous oxide group were found to be significantly greater than in the control group and in the xenon group.     

Plasma Concentration of Fentanyl with Xenon to Block Somatic and Hemodynamic Responses to Surgical Incision

Background: Although anesthesia with xenon has been supplemented with fentanyl, its requirement has not been established. This study was conducted to determine the plasma concentrations of fentanyl necessary to suppress somatic and hemodynamic responses to surgical incision in 50% patients in the presence of 0.7 minimum alveolar concentration (MAC) xenon.

Methods: Twenty-five patients were allocated randomly to predetermined fentanyl concentration between 0.5 and 4.0 ng/ml during 0.7 MAC xenon anesthesia. Fentanyl was administered using a pharmacokinetic model-driven computer-assisted continuous infusion device. At surgical incision each patient was monitored for somatic and hemodynamic responses. A somatic response was defined as any purposeful bodily movement. A positive hemodynamic response was defined as a more than 15% increase in heart rate or mean arterial pressure more than the preincision value. The concentrations of fentanyl to prevent somatic and hemodynamic responses in 50% of patients were calculated using logistic regression.

Results: The concentration of fentanyl to prevent a somatic response to skin incision in 50% of patients in the presence of 0.7 MAC xenon was 0.72 +/- 0.07 ng/ml and to prevent a hemodynamic response was 0.94 +/- 0.06 ng/ml.     

Effects of Xenon on the Performance of Various Respiratory Flowmeters

Background: The anesthetic gas xenon has distinctly different physical properties compared with air, nitrous oxide, or oxygen. This led us to predict that xenon would affect the performance of commercially available flowmeters.

Methods: Flow was generated by an anesthesia ventilator connected to a lung simulator via a semiclosed breathing circuit. With the system filled with air or with various concentrations of xenon or nitrous oxide in a balance of oxygen, the tidal volume was measured with two rotating vanes, a Pitot tube, a variable-orifice flowmeter, and two constant-temperature hot-wire flowmeters.

Results: Although xenon minimally affected both rotating vane flowmeters, it caused the Pitot tube and the variable-orifice flowmeters to overread in proportion to the square root of the density of the gas mixture used (xenon is 4.6 times more dense than air). In contrast, the hot-wire anemometers underread with xenon; for example, their readings in the presence of 45% and 70% xenon were less than 10% of those displayed when air was used. Nitrous oxide minimally affected all the flowmeters except the variable-orifice device. The Pitot flowmeter was also affected, but only when its gas analyzer port was open to the ambient air so that it no longer corrected its readings for changes in gas composition. In these cases, nitrous oxide produced overreadings in the same manner as did xenon.