Local Xenon-Protein Interaction Produces Global Conformational Change and Allosteric Inhibition in Lysozyme.

Noble gases have well-established biological effects, yet their molecular mechanisms remain poorly understood. Here, we investigated, both experimentally and computationally, the molecular modes of xenon (Xe) action in bacteriophage T4 lysozyme (T4L). By combining indirect gassing methods with a colorimetric lysozyme activity assay, a reversible, Xe-specific (20 ± 3)% inhibition effect was observed. Accelerated molecular dynamic simulations revealed that Xe exerts allosteric inhibition on the protein by expanding a C-terminal hydrophobic cavity. Xe-induced cavity expansion results in global conformational changes, with long-range transduction distorting the active site where peptidoglycan binds. Interestingly, the peptide substrate binding site that enables lysozyme specificity does not change conformation. Two T4L mutants designed to reshape the C-terminal Xe cavity established a correlation between cavity expansion and enzyme inhibition. This work also highlights the use of Xe flooding simulations to identify new cryptic binding pockets. These results enrich our understanding of Xe-protein interactions at the molecular level and inspire further biochemical investigations with noble gases.

Identifying medically relevant xenon protein targets by in silico screening of the structural proteome.

In a previous study, in silico screening of the binding of almost all proteins in the Protein Data Bank to each of the five noble gases xenon, krypton, argon, neon, and helium was reported. This massive and rich data set requires analysis to identify the gas-protein interactions that have the best binding strengths, those where the binding of the noble gas occurs at a site that can modulate the function of the protein, and where this modulation might generate clinically relevant effects. Here, we report a preliminary analysis of this data set using a rational, heuristic score based on binding strength and location. We report a partial prioritized list of xenon protein targets and describe how these data can be analyzed, using arginase and carbonic anhydrase as examples. Our aim is to make the scientific community aware of this massive, rich data set and how it can be analyzed to accelerate future discoveries of xenon-induced biological activity and, ultimately, the development of new "atomic" drugs.

Method for the Identification of Potentially Bioactive Argon Binding Sites in Protein Families.

Argon belongs to the group of chemically inert noble gases, which display a remarkable spectrum of clinically useful biological properties. In an attempt to better understand noble gases, notably argon's mechanism of action, we mined a massive noble gas modeling database which lists all possible noble gas binding sites in the proteins from the Protein Data Bank. We developed a method of analysis to identify among all predicted noble gas binding sites the potentially relevant ones within protein families which are likely to be modulated by Ar. Our method consists in determining within structurally aligned proteins the conserved binding sites whose shape, localization, hydrophobicity, and binding energies are to be further examined. This method was applied to the analysis of two protein families where crystallographic noble gas binding sites have been experimentally determined. Our findings indicate that among the most conserved binding sites, either the most hydrophobic one and/or the site which has the best binding energy corresponds to the crystallographic noble gas binding sites with the best occupancies, therefore the best affinity for the gas. This method will allow us to predict relevant noble gas binding sites that have potential pharmacological interest and thus potential Ar targets that will be prioritized for further studies including in vitro validation.

Massive in Silico Study of Noble Gas Binding to the Structural Proteome.

Noble gases are chemically inert, and it was therefore thought they would have little effect on biology. Paradoxically, it was found that they do exhibit a wide range of biological effects, many of which are target-specific and potentially useful and some of which have been demonstrated in vivo. The underlying mechanisms by which useful pharmacology, such as tissue and neuroprotection, anti-addiction effects, and analgesia, is elicited are relatively unexplored. Experiments to probe the interactions of noble gases with specific proteins are more difficult with gases than those with other chemicals. It is clearly impractical to conduct the large number of gas-protein experiments required to gain a complete picture of noble gas biology. Given the simplicity of atoms as ligands, in silico methods provide an opportunity to gain insight into which noble gas-protein interactions are worthy of further experimental or advanced computational investigation. Our previous validation studies showed that in silico methods can accurately predict experimentally determined noble gas binding sites in X-ray structures of proteins. Here, we summarize the largest reported in silico reverse docking study involving 127 854 protein structures and the five nonradioactive noble gases. We describe how these computational screening methods are implemented, summarize the main types of interactions that occur between noble gases and target proteins, describe how the massive data set that this study generated can be analyzed (freely available at group18.csiro.au), and provide the NDMA receptor as an example of how these data can be used to understand the molecular pharmacology underlying the biology of the noble gases. We encourage chemical biologists to access the data and use them to expand the knowledge base of noble gas pharmacology, and to use this information, together with more efficient delivery systems, to develop "atomic drugs" that can fully exploit their considerable and relatively unexplored potential in medicine.

Precapillary pulmonary gas exchange is similar for oxygen and inert gases.

KEY POINTS: Precapillary gas exchange for oxygen has been documented in both humans and animals. It has been suggested that, if precapillary gas exchange occurs to a greater extent for inert gases than for oxygen, shunt and its effects on arterial oxygenation may be underestimated by the multiple inert gas elimination technique (MIGET). We evaluated fractional precapillary gas exchange in canines for O2 and two inert gases, sulphur hexafluoride and ethane, by measuring these gases in the proximal pulmonary artery, distal pulmonary artery (1 cm proximal to the wedge position) and systemic artery. Some 12-19% of pulmonary gas exchange occurred within small (1.7 mm in diameter or larger) pulmonary arteries and this was quantitatively similar for oxygen, sulphur hexafluoride and ethane. Under these experimental conditions, this suggests only minor effects of precapillary gas exchange on the magnitude of calculated shunt and the associated effect on pulmonary gas exchange estimated by MIGET. ABSTRACT: Some pulmonary gas exchange is known to occur proximal to the pulmonary capillary, although the magnitude of this gas exchange is uncertain, and it is unclear whether oxygen and inert gases are similarly affected. This has implications for measuring shunt and associated gas exchange consequences. By measuring respiratory and inert gas levels in the proximal pulmonary artery (P), a distal pulmonary artery 1 cm proximal to the wedge position (using a 5-F catheter) (D) and a systemic artery (A), we evaluated precapillary gas exchange in 27 paired samples from seven anaesthetized, ventilated canines. Fractional precapillary gas exchange (F) was quantified for each gas as F = (P - D)/(P - A). The lowest solubility inert gases, sulphur hexafluoride (SF6 ) and ethane were used because, with higher solubility gases, the P-A difference is sufficiently small that experimental error prevents accurate assessment of F. Distal samples (n = 12) with oxygen (O2 ) saturation values that were (within experimental error) equal to or above systemic arterial values, suggestive of retrograde capillary blood aspiration, were discarded, leaving 15 for analysis. D was significantly lower than P for SF6 (D/P = 88.6 ± 18.1%; P = 0.03) and ethane (D/P = 90.6 ± 16.0%; P = 0.04), indicating partial excretion of inert gas across small pulmonary arteries. Distal pulmonary arterial O2 saturation was significantly higher than proximal (74.1 ± 6.8% vs. 69.0 ± 4.9%; P = 0.03). Fractional precapillary gas exchange was similar for SF6 , ethane and O2 (0.12 ± 0.19, 0.12 ± 0.20 and 0.19 ± 0.26, respectively; P = 0.54). Under these experimental conditions, 12-19% of pulmonary gas exchange occurs within the small pulmonary arteries and the extent is similar between oxygen and inert gases.

Modelling the effect of gravity on inert-gas washout outputs.

Multiple-breath washout (MBW) is a pulmonary function test (PFT) that is used to infer lung function through measurement of ventilation heterogeneity (VH). However, the body position that a test is taken in may also influence VH, due to the "Slinky" effect of gravity on the lungs. In healthy subjects this has minimal effect, but in unhealthy groups, PFT outputs have been seen to change drastically with body position. In this study, we used a combined computational and clinical approach to better understand the response of outputs from the MBW to body position. A patient-specific model of the MBW was developed, then validated against clinically measured washout data, as well as broader results in the literature. This model was then used to compare changes in MBW outputs with respect to body position, showing that output changes sensitively predict regional airway size differences between lobes. We then highlight cases in which body position effects may bias MBW outputs, leading to elevated or masked responses to bronchoconstriction. We close by placing this result in context with broader clinical practice, and showing how it can help improve interpretation of test outputs.

An in vitro lung model to assess true shunt fraction by multiple inert gas elimination.

The Multiple Inert Gas Elimination Technique, based on Micropore Membrane Inlet Mass Spectrometry, (MMIMS-MIGET) has been designed as a rapid and direct method to assess the full range of ventilation-to-perfusion (V/Q) ratios. MMIMS-MIGET distributions have not been assessed in an experimental setup with predefined V/Q-distributions. We aimed (I) to construct a novel in vitro lung model (IVLM) for the simulation of predefined V/Q distributions with five gas exchange compartments and (II) to correlate shunt fractions derived from MMIMS-MIGET with preset reference shunt values of the IVLM. Five hollow-fiber membrane oxygenators switched in parallel within a closed extracorporeal oxygenation circuit were ventilated with sweep gas (V) and perfused with human red cell suspension or saline (Q). Inert gas solution was infused into the perfusion circuit of the gas exchange assembly. Sweep gas flow (V) was kept constant and reference shunt fractions (IVLM-S) were established by bypassing one or more oxygenators with perfusate flow (Q). The derived shunt fractions (MM-S) were determined using MIGET by MMIMS from the retention data. Shunt derived by MMIMS-MIGET correlated well with preset reference shunt fractions. The in vitro lung model is a convenient system for the setup of predefined true shunt fractions in validation of MMIMS-MIGET.

Ventilation heterogeneity measured by multiple breath inert gas testing is not affected by inspired oxygen concentration in healthy humans.

Multiple breath washout (MBW) and oxygen-enhanced MRI techniques use acute exposure to 100% oxygen to measure ventilation heterogeneity. Implicit is the assumption that breathing 100% oxygen does not induce changes in ventilation heterogeneity; however, this is untested. We hypothesized that ventilation heterogeneity decreases with increasing inspired oxygen concentration in healthy subjects. We performed MBW in 8 healthy subjects (4 women, 4 men; age = 43 ± 15 yr) with normal pulmonary function (FEV1 = 98 ± 6% predicted) using 10% argon as a tracer gas and oxygen concentrations of 12.5%, 21%, or 90%. MBW was performed in accordance with ERS-ATS guidelines. Subjects initially inspired air followed by a wash-in of test gas. Tests were performed in balanced order in triplicate. Gas concentrations were measured at the mouth, and argon signals rescaled to mimic a N2 washout, and analyzed to determine the distribution of specific ventilation (SV). Heterogeneity was characterized by the width of a log-Gaussian fit of the SV distribution and from Sacin and Scond indexes derived from the phase III slope. There were no significant differences in the ventilation heterogeneity due to altered inspired oxygen: histogram width (hypoxia 0.57 ± 0.11, normoxia 0.60 ± 0.08, hyperoxia 0.59 ± 0.09, P = 0.51), Scond (hypoxia 0.014 ± 0.011, normoxia 0.012 ± 0.015, hyperoxia 0.010 ± 0.011, P = 0.34), or Sacin (hypoxia 0.11 ± 0.04, normoxia 0.10 ± 0.03, hyperoxia 0.12 ± 0.03, P = 0.23). Functional residual capacity was increased in hypoxia (P = 0.04) and dead space increased in hyperoxia (P = 0.0001) compared with the other conditions. The acute use of 100% oxygen in MBW or MRI is unlikely to affect ventilation heterogeneity.NEW & NOTEWORTHY Hyperoxia is used to measure the distribution of ventilation in imaging and MBW but may alter the underlying ventilation distribution. We used MBW to evaluate the effect of inspired oxygen concentration on the ventilation distribution using 10% argon as a tracer. Short-duration exposure to hypoxia (12.5% oxygen) and hyperoxia (90% oxygen) during MBW had no significant effect on ventilation heterogeneity, suggesting that hyperoxia can be used to assess the ventilation distribution.

Modelling responses of the inert-gas washout and MRI to bronchoconstriction.

Many lung diseases lead to an increase in ventilation heterogeneity (VH). Two clinical practices for the measurement of patient VH are in vivo imaging, and the inert gas multiple breath washout (MBW). In this study computational modelling was used to compare the responses of MBW indices LCI and scond and MRI measured global and local ventilation indices, σr and σlocal, to constriction of airways in the conducting zone of the lungs. The simulations show that scond, LCI and σr behave quite similarly to each other, all being sensitive to increases in the severity of constriction, while exhibiting little sensitivity to the depth at which constriction occurs. In contrast, the local MRI index σlocal shows strong sensitivity to depth of constriction, but lowered sensitivity to constriction severity. We finish with an analysis of the sensitivity of MRI indices to grid sizes, showing that results should be interpreted with reference to the image resolution. Overall we conclude that the application of both local and global VH measures may help to classify different types of bronchoconstriction.

Physiological phenotyping of pediatric chronic obstructive airway diseases.

Inert tracer gas washout (IGW) measurements detect increased ventilation inhomogeneity (VI) in chronic lung diseases. Their suitability for different diseases, such as cystic fibrosis (CF) and primary ciliary dyskinesia (PCD), has already been shown. However, it is still unclear if physiological phenotypes based on different IGW variables can be defined independently of underlying disease. Eighty school-age children, 20 with CF, 20 with PCD, 20 former preterm children, and 20 healthy children, performed nitrogen multiple-breath washout, double-tracer gas (DTG) single-breath washout, and spirometry. Our primary outcome was the definition of physiological phenotypes based on IGW variables. We applied principal component analysis, hierarchical Ward's clustering, and enrichment analysis to compare clinical characteristics between the clusters. IGW variables used for clustering were lung clearance index (LCI) and convection-dependent [conductive ventilation heterogeneity index (Scond)] and diffusion-convection-dependent variables [acinar ventilation heterogeneity index (Sacin) and carbon dioxide and DTG phase III slopes]. Three main phenotypes were identified. Phenotype I (n = 38) showed normal values in all IGW outcome variables. Phenotype II (n = 21) was characterized by pronounced global and convection-dependent VI while diffusion-dependent VI was normal. Phenotype III (n = 21) was characterized by increased global and diffusion- and convection-dependent VI. Enrichment analysis revealed an overrepresentation of healthy children and former preterm children in phenotype I and of CF and PCD in phenotypes II and III. Patients in phenotype III showed the highest proportion and frequency of exacerbations and hospitalization in the year prior to the measurement. IGW techniques allow identification of clinically meaningful, disease-independent physiological clusters. Their predictive value of future disease outcomes remains to be determined.

Exploring the Effects on Lipid Bilayer Induced by Noble Gases via Molecular Dynamics Simulations.

Noble gases seem to have no significant effect on the anesthetic targets due to their simple, spherical shape. However, xenon has strong narcotic efficacy and can be used clinically, while other noble gases cannot. The mechanism remains unclear. Here, we performed molecular dynamics simulations on phospholipid bilayers with four kinds of noble gases to elucidate the difference of their effects on the membrane. Our results showed that the sequence of effects on membrane exerted by noble gases from weak to strong was Ne, Ar, Kr and Xe, the same order as their relative narcotic potencies as well as their lipid/water partition percentages. Compared with the other three kinds of noble gases, more xenon molecules were distributed between the lipid tails and headgroups, resulting in membrane's lateral expansion and lipid tail disorder. It may contribute to xenon's strong anesthetic potency. The results are well consistent with the membrane mediated mechanism of general anesthesia.

Influence of bag volume on reproducibility of inert gas rebreathing pulmonary blood flow measurements in patients with pulmonary diseases.

PURPOSE: Non-invasive inert gas rebreathing (IGR) has shown promising results in the determination of pulmonary blood flow. The volume of the rebreathing bag (V bag) is proposed by the system. However, elderly patients or those with severe pulmonary disease may be unable to rebreathe this volume entirely. We evaluated the effect of adapting V bag on the reproducibility of IGR. METHODS: A total of 270 valid measurements were obtained from 45 patients with obstruction (group A), restriction (group B), and in healthy controls (group C). Two measurements for each of three different V bag of 1,200, 1,700, and 2,200 ml were conducted in the supine position. RESULTS: We found no statistically significant difference of the repeated measurements neither between the different V bag in groups A to C nor between the three groups for identical V bag. There was a weak yet significantly worse coefficient of variation between a V bag of 2,200 ml in group A compared with group C with 2,200 and 1,200 ml, respectively. Intraclass correlation coefficient and repeatability coefficient yielded significantly worse values in group A for a V bag of 2,200 ml compared with healthy controls and lower bag volumes. No difference could be found intraclass nor interclass in groups B and C. CONCLUSIONS: V bag can be altered between 1,200 and 2,200 ml in most situations without affecting the reproducibility. Attention has to be paid to extreme volumes in obstructive patients. Nevertheless, V bag should be chosen as large as possible and therefore has to be carefully adapted, particularly in patients with obstruction or restriction.

Relating indices of inert gas washout to localised bronchoconstriction.

Asthma is typically characterised by increased ventilation heterogeneity. This can be directly inferred from the visualisation of ventilation defects in imaging studies, or indirectly inferred from indices derived from the multiple-breath nitrogen washout (MBNW). The basis for the understanding of the MBNW indices and their implication for changes in structure and function at the largest and smallest scales in the lung has been facilitated by mathematical models for inert gas transport. A new model is presented that couples airway resistance and regional tissue compliance, for simulation of the effect of 'patchy' bronchoconstriction - as inferred from imaging studies - on the Scond index of ventilation heterogeneity. Patches of reduced washin gas concentration can emerge by constricting only the terminal bronchioles within localised regions, however this pattern of constriction is insufficient to affect Scond; Scond from this model is only sensitive to constriction that occurs within entire contiguous regions. Furthermore the model illustrates the possibility that the MBNW may not detect gas trapped in ventilation defects.

Inert gas clearance from tissue by co-currently and counter-currently arranged microvessels.

To elucidate the clearance of dissolved inert gas from tissues, we have developed numerical models of gas transport in a cylindrical block of tissue supplied by one or two capillaries. With two capillaries, attention is given to the effects of co-current and counter-current flow on tissue gas clearance. Clearance by counter-current flow is compared with clearance by a single capillary or by two co-currently arranged capillaries. Effects of the blood velocity, solubility, and diffusivity of the gas in the tissue are investigated using parameters with physiological values. It is found that under the conditions investigated, almost identical clearances are achieved by a single capillary as by a co-current pair when the total flow per tissue volume in each unit is the same (i.e., flow velocity in the single capillary is twice that in each co-current vessel). For both co-current and counter-current arrangements, approximate linear relations exist between the tissue gas clearance rate and tissue blood perfusion rate. However, the counter-current arrangement of capillaries results in less-efficient clearance of the inert gas from tissues. Furthermore, this difference in efficiency increases at higher blood flow rates. At a given blood flow, the simple conduction-capacitance model, which has been used to estimate tissue blood perfusion rate from inert gas clearance, underestimates gas clearance rates predicted by the numerical models for single vessel or for two vessels with co-current flow. This difference is accounted for in discussion, which also considers the choice of parameters and possible effects of microvascular architecture on the interpretation of tissue inert gas clearance.

A new biophysical decompression model for estimating the risk of articular bends during and after decompression.

The biophysical models that intend to predict the risk of decompression sickness after a change of pressure are not numerous. Few approaches focus in particular on joints as target tissues, with the aim to describe properly the mechanisms inducing pain. Nevertheless, for this type of decompression incidents, called articular bends, no model proved to fit the empirical results for a broad range of exposures and decompression procedures. We present here an original biophysical decompression model for describing the occurrence of articular bends. A target joint is broken down into two parts that exchange inert gases with the blood by perfusion and with each other by diffusion over distances of a few millimetres. This diffusion pathway allows the slow amplification of microbubbles growing during and after decompression, consistent with the possible delayed occurrence of bends. The diffusion coefficients introduced into this model are larger than those introduced into most modern decompression models. Their value remains physical (#10(-9)m(2)/s). Inert gas exchanges and the formation, amplification and resorption of microbubbles during and after decompression were simulated. We used a critical gas volume criterion for predicting the occurrence of bends. A risk database extracted from COMEX experience and other published studies were used for the correlation of model parameters not known a priori. We considered a large range of exposure, and the commonly used inert gases nitrogen and helium. This correlation phase identified the worst biophysical conformations most likely to lead to the formation, in tissues such as tendons, of a large number of microbubbles recruited from pre-existing gas nuclei during decompression. The risk of bends occurrence was found to be linked to the total separated gas volume generated during and after decompression. A clamping phenomenon occurs soon after the start of decompression, greatly slowing the gas exchanges controlled especially by the oxygen window. This model, which reproduces many empirical findings, may be considered both descriptive and predictive.

Dynamic profiles of volatile organic compounds in exhaled breath as determined by a coupled PTR-MS/GC-MS study.

In this phenomenological study we focus on dynamic measurements of volatile organic compounds (VOCs) in exhaled breath under exercise conditions. An experimental setup efficiently combining breath-by-breath analyses using proton transfer reaction mass spectrometry (PTR-MS) with data reflecting the behaviour of major hemodynamic and respiratory parameters is presented. Furthermore, a methodology for complementing continuous VOC profiles obtained by PTR-MS with simultaneous SPME/GC-MS measurements is outlined. These investigations aim at evaluating the impact of breathing patterns, cardiac output or blood pressure on the observed breath concentration and allow for the detection and identification of several VOCs revealing characteristic rest-to-work transitions in response to variations in ventilation or perfusion. Examples of such compounds include isoprene, methyl acetate, butane, DMS and 2-pentanone. In particular, both isoprene and methyl acetate exhibit a drastic rise in concentration shortly after the onset of exercise, usually by a factor of about 3-5 within approximately 1 min of pedalling. These specific VOCs might also be interpreted as potentially sensitive indicators for fluctuations of blood or respiratory flow and can therefore be viewed as candidate compounds for future assessments of hemodynamics, pulmonary function and gas exchange patterns via observed VOC behaviour.

Inert gas rebreathing: the effect of haemoglobin based pulmonary shunt flow correction on the accuracy of cardiac output measurements in clinical practice.

BACKGROUND: Cardiac output (CO) is an important cardiac parameter, however its determination is difficult in clinical routine. Non-invasive inert gas rebreathing (IGR) measurements yielded promising results in recent studies. It directly measures pulmonary blood flow (PBF) which equals CO in absence of significant pulmonary shunt flow (Q(S)). A reliable shunt correction requiring the haemoglobin concentration (c(Hb)) as only value to be entered manually has been implemented. Therefore, the aim of the study was to evaluate the effect of various approaches to Q(S) correction on the accuracy of IGR. METHODS: Cardiac output determined by cardiac magnetic resonance imaging (CMR) served as reference values. The data was analysed in four groups: PBF without correcting for Q(S) (group A), shunt correction using the patients' individual c(Hb) values (group B), a fixed standard c(Hb) of 14.0 g dl(-1) (group C) and a gender-adapted standard c(Hb) for male (15.0 g dl(-1)) and female (13.5 g dl(-1)) probands each (group D). RESULTS: 147 patients were analysed. Mean CO(CMR) was 5.2 +/- 1.4 l min(-1), mean CO(IGR) was 4.8 +/- 1.3 l min(-1) in group A, 5.1 +/- 1.3 in group B, 5.1 +/- 1.3 l min(-1) in group C and 5.1 +/- 1.4 l min(-1) in group D. The accuracy in group A (mean bias 0.5 +/- 1.1 l min(-1)) was significantly lower as compared to groups B, C and D (0.1 +/- 1.1 l min(-1); P<0.01). CONCLUSION: IGR allows a reliable non-invasive determination of CO. Since PBF significantly increased the measurement bias, shunt correction should always be applied. A fixed c(Hb) of 14.0 g dl(-1) can be used for both genders if the exact c(Hb) value is not known. Nevertheless, the individual value should be used if any possible.

Noble gas binding to human serum albumin using docking simulation: nonimmobilizers and anesthetics bind to different sites.

BACKGROUND: Nonimmobilizers are structurally similar to anesthetics, but do not produce anesthesia at clinically relevant concentrations. Xenon, krypton, and argon are anesthetics, whereas neon and helium are nonimmobilizers. The structures of noble gases with anesthetics or nonimmobilizers are similar and their interactions are simple. Whether the binding site of anesthetics differs from that of nonimmobilizers has long been a question in molecular anesthesiology. METHODS: We investigated the binding sites and energies of anesthetic and nonimmobilizer noble gases in human serum albumin (HSA) because the 3D structure of HSA is well known and it has an anesthetic binding site. The computational docking simulation we used searches for binding sites and calculates the binding energy for small molecules and a template molecule. RESULTS: Xenon, krypton, and argon were found to bind to the enflurane binding site of HSA, whereas neon and helium were found to bind to sites different from the xenon binding site. Rare gas anesthetic binding was dominated by van der Waals energy, while nonimmobilizer binding was dominated by solvent-effect energy. Binding site preference was determined by the ratios of local binding energy (van der Waals energy) and nonspecific binding energy (solvent-effect energy) to the total binding energy. van der Waals energy dominance is necessary for anesthetic binding. CONCLUSIONS: This analysis of binding energy components provides a rationale for the binding site difference of anesthetics and nonimmobilizers, reveals the differences between the binding interactions of anesthetics and nonimmobilizers, may explain pharmacological differences between anesthetics and nonimmobilizers, and provide an understanding of anesthetic action at the atomic level.

Confirming the existence of five peaks in 129Xe rat head spectra.

A series of experiments were performed to investigate why two peaks (D and E) of the five dissolved phase peaks in hyperpolarized (129)Xe rat head spectra appeared inconsistently in previous work. Specifically, spectra were acquired under conditions of various shim states, anaesthetics, and arterial ligation. The shimming experiments showed that slice-shimming can be used to improve resolution of the dissolved phase peaks, but even so, subtle changes in the shim state that may dramatically alter the shape of peak E remain poorly understood. Also, the inability to shim gas spaces and tissue simultaneously may explain why inconsistent chemical shift values have been reported in the literature. A possible solution for this problem is suggested. The results of pre- and postligation spectra from the same animal indicated that two peaks (A and E) originate from brain. Changing the anaesthetic was found to have no effect on the number of dissolved peaks in xenon spectra.