Pressure Reversal Of Anesthesia Research Articles

Hydration structure, thermodynamics, and functions of protein studied by the 3D-RISM theory

The three-dimensional reference interaction site model (3D-RISM) theory is a molecular theory of solvation, which has been developed recently. Unlike the conventional statistical-mechanical theories of liquids, the applications of which are limited to rather simple systems, the new theory has been demonstrating great success in predicting the hydration structure and thermodynamic quantities of protein. Here, we review the recent applications of the 3D-RISM theory to some subjects concerning protein hydration: detecting water molecules in protein cavities, the pressure effects on protein conformation in terms of the partial molar volume, and the pressure reversal of anesthesia. These results demonstrate the outstanding capability of the theory for investigating various issues in biochemistry and biophysics.

Myristate, a 14-carbon fatty acid, effectively reverses anesthesia.

THE pressure reversal of anesthesia was discovered in the light intensity of bacterial luciferase. 1 This in vitro study implies that the partial molar volume of the luciferase is greater during anesthesia than during the awake state. 1 This observation was confirmed in vivo in tadpoles, 2 newts, 3 and rats. 4 We found that the light intensity of firefly luciferase (FFL) also responds to high pressure. 5 We also measured the effects of anesthetics and myristate (a 14-carbon fatty acid, neutralized by NaOH) on the volume of FFL. 6 Halothane 0.5 mM increased the FFL volume by 3.93 cm 3 mol -1 whereas myristate 2.5 μM decreased it by 7.66 cm 3 mol -1 . We hypothesized that if the molar volume of FFL determines depth of anesthesia, myristate may antagonize anesthesia. As expected, our preliminary study showed that myristate antagonized anesthesia in goldfish. 7 Contrary to the general belief that fatty acids are toxic to mammals, the intravenous hyperalimentation fluids, Intralipid (Baxter, Deerfield, IL), and others are composed of a variety of long-chain fatty acids: linoleic, oleic, palmitic, linolenic, stearic acids, and so on. These fatty acids are neutralized by triglycerides. They are called essential fatty acids (EFA), and are well tolerated by debilitated patients. The generally held idea among anesthesiologists that fatty acids do not cross the blood-brain barrier is contradicted by oleamide (18-carbon fatty acid, oleic acid, neutralized by NH 4 OH) which crosses the blood-brain barrier and induces sleep. 8,9 .

Volumetric study on the protein–anesthetic binding

Thermodynamic equations describing the volume behavior of protein–ligand mixtures in water were derived. In order to estimate the volume and binding parameters, the equations were combined with a Langmuir-type binding isotherm. Densities of aqueous solutions of mixtures of bovine serum albumin (BSA) and octanol (C8OH) were measured as a function of total BSA molality, m M T , at constant total C8OH molalities, m X T . The data were analyzed by the equations. The partial molar volumes at infinite dilution of BSA and C8OH, V M T,0 and V X T,0 , respectively, were estimated. It was seen that V M T,0 decreases by the addition of C8OH to the solution and that V X T,0 decreases gradually with increasing m M T and approaches asymptotically to a certain value at high m M T . From the concentration dependence of V M T,0 and V X T,0 , the values of the association constant K=392 kg mol −1, the maximum binding number b max=1.9, and the volume change Δ V=−109 cm 3 mol −1 were obtained for BSA–C8OH interaction in water. The negative value of Δ V indicates that the hydrophobic interaction reduces the protein volume and elevation of pressure promotes BSA–C8OH binding. These results is inconsistent with the pressure reversal of anesthesia.

Minimum Alveolar Concentrations of Noble Gases, Nitrogen, and Sulfur Hexafluoride in Rats

We assessed the anesthetic properties of helium and neon at hyperbaric pressures by testing their capacity to decrease anesthetic requirement for desflurane using electrical stimulation of the tail as the anesthetic endpoint (i.e., the minimum alveolar anesthetic concentration [MAC]) in rats. Partial pressures of helium or neon near those predicted to produce anesthesia by the Meyer-Overton hypothesis (approximately 80-90 atm), tended to increase desflurane MAC, and these partial pressures of helium and neon produced convulsions when administered alone. In contrast, the noble gases argon, krypton, and xenon were anesthetic with mean MAC values of (+/- SD) of 27.0 +/- 2.6, 7.31 +/- 0.54, and 1.61 +/- 0.17 atm, respectively. Because the lethal partial pressures of nitrogen and sulfur hexafluoride overlapped their anesthetic partial pressures, MAC values were determined for these gases by additivity studies with desflurane. Nitrogen and sulfur hexafluoride MAC values were estimated to be 110 and 14.6 atm, respectively. Of the gases with anesthetic properties, nitrogen deviated the most from the Meyer-Overton hypothesis. Implications: It has been thought that the high pressures of helium and neon that might be needed to produce anesthesia antagonize their anesthetic properties (pressure reversal of anesthesia). We propose an alternative explanation: like other compounds with a low affinity to water, helium and neon are intrinsically without anesthetic effect. (Anesth Analg 1998;87:419-24)

Minimum alveolar concentrations of noble gases, nitrogen, and sulfur hexafluoride in rats: helium and neon as nonimmobilizers (nonanesthetics)

We assessed the anesthetic properties of helium and neon at hyperbaric pressures by testing their capacity to decrease anesthetic requirement for desflurane using electrical stimulation of the tail as the anesthetic endpoint (i.e., the minimum alveolar anesthetic concentration [MAC]) in rats. Partial pressures of helium or neon near those predicted to produce anesthesia by the Meyer-Overton hypothesis (approximately 80-90 atm), tended to increase desflurane MAC, and these partial pressures of helium and neon produced convulsions when administered alone. In contrast, the noble gases argon, krypton, and xenon were anesthetic with mean MAC values of (+/- SD) of 27.0 +/- 2.6, 7.31 +/- 0.54, and 1.61 +/- 0.17 atm, respectively. Because the lethal partial pressures of nitrogen and sulfur hexafluoride overlapped their anesthetic partial pressures, MAC values were determined for these gases by additivity studies with desflurane. Nitrogen and sulfur hexafluoride MAC values were estimated to be 110 and 14.6 atm, respectively. Of the gases with anesthetic properties, nitrogen deviated the most from the Meyer-Overton hypothesis. It has been thought that the high pressures of helium and neon that might be needed to produce anesthesia antagonize their anesthetic properties (pressure reversal of anesthesia). We propose an alternative explanation: like other compounds with a low affinity to water, helium and neon are intrinsically without anesthetic effect.

The Anesthetic Effect of Dexmedetomidine Does Not Adhere to the Meyer-Overton Rule but Is Reversed by Hydrostatic Pressure

To test the hypothesis that the anesthetic action of dexmedetomidine is similar to that of other anesthetics, dexmedetomidine was studied using two classical descriptors of anesthesia, the Meyer-Overton correlation and the pressure reversal of anesthesia. The anesthetic potency of dexmedetomidine and its isomer, levomedetomidine, were determined in Xenopus laevis tadpoles. Anesthesia was defined as loss of righting reflex. Octanol/water partition coefficients were determined using ultraviolet absorbance spectrophotometry. Pressure experiments were performed at pressures ranging from 1 to 91 atmospheres absolute (ata). A concentration-response curve was obtained with a half-maximum effective concentration (EC50) of dexmedetomidine of 7.1 +/- 1.1 micro M (mean +/- SEM), whereas levomedetomidine showed an EC50 of 59.3 +/- 5.5 micro M. The octanol/water partition coefficient was 206 +/- 49. With increasing pressure, the EC50 of dexmedetomidine increased linearly up to a value of 23.9 +/- 3.2 micro M at 91 ata. Correlation of lipid solubility and anesthetic potency demonstrates that dexmedetomidine does not adhere to the Meyer-Overton rule. However, the anesthetic action of dexmedetomidine is diminished by increased pressures, thus demonstrating a similar effect compared with other general anesthetics. (Anesth Analg 1997;84:618-22)

The anesthetic effect of dexmedetomidine does not adhere to the Meyer-Overton rule but is reversed by hydrostatic pressure.

To test the hypothesis that the anesthetic action of dexmedetomidine is similar to that of other anesthetics, dexmedetomidine was studied using two classical descriptors of anesthesia, the Meyer-Overton correlation and the pressure reversal of anesthesia. The anesthetic potency of dexmedetomidine and its isomer, levomedetomidine, were determined in Xenopus laevis tadpoles. Anesthesia was defined as loss of righting reflex. Octanol/water partition coefficients were determined using ultraviolet absorbance spectrophotometry. Pressure experiments were performed at pressures ranging from 1 to 91 atmospheres absolute (ata). A concentration-response curve was obtained with a half-maximum effective concentration (EC50) of dexmedetomidine of 7.1 +/- 1.1 microM (mean +/- SEM), whereas levomedetomidine showed an EC50 of 59.3 +/- 5.5 microM. The octanol/water partition coefficient was 206 +/- 49. With increasing pressure, the EC50 of dexmedetomidine increased linearly up to a value of 23.9 +/- 3.2 microM at 91 ata. Correlation of lipid solubility and anesthetic potency demonstrates that dexmedetomidine does not adhere to the Meyer-Overton rule. However, the anesthetic action of dexmedetomidine is diminished by increased pressures, thus demonstrating a similar effect compared with other general anesthetics.

Keith W. Miller

Keith W. Miller

PRESSURE REVERSAL OF ANAESTHESIA: A SYNAPTIC MECHANISM

Hyperbaric pressure induces seizures and increases anaesthetic requirements ("pressure reversal of anaesthesia"), but both pressure and anaesthetic agents depress excitatory synaptic transmission. The present study has attempted to resolve this paradox. The interaction between helium pressure to 10.1 MPa and anaesthetic agents (pentobarbitone, halothane, methoxyflurane) was investigated at a crustacean glutaminergic excitatory neuromuscular junction which can be modulated by GABA inhibition. Both pressure and the anaesthetics depressed the singly evoked excitatory junctional potential (EJP). During repetitive stimulation, both pressure and pentobarbitone antagonized their own depressant effects by enhancing tetanic potentiation. The additive enhancement at 10.1 MPa was sufficient to increase the pentobarbitone-depressed response above the corresponding normobaric level. No significant antagonism between pressure and any of the anaesthetics was observed on the properties of EJP amplitude and time course, facilitation, potentiation or inhibition. Additivity rather than antagonism is the basis for pressure reversal of anaesthetic depression at this model synapse. The functional antagonism is therefore indirect, and probably involves multiple sites of action for both pressure and anaesthetics.

Effects of prolonged simultaneous exposure of CD-1 mice to high pressures and inert gas narcosis

Addition of N2 to the heliox used in pressure conditioning exposures reduces or suppresses the increase in convulsion threshold pressure (Pc) as well as the change in compression rate effect resulting from pressure exposures in the absence of N2; 18 atm N2 neutralizes the effect of 80 ATA total pressure so that Pc remains at a constant level throughout the conditioning period. Since N2 habituation is much slower than pressure conditioning (t1/2 6 days vs. 12 h), this precludes mere addition of pressure and N2 effects in this situation. In contrast to Pc, anesthesia tolerance of mice exposed to 80 ATA in the presence of 18 atm N2 increases even more (25%) than at the same PN2 but at a total pressure of only 18 ATA, indicating that pressure reversal of anesthesia does not extend to the habituation events. The implications of the striking asymmetry between the effects of protracted high pressure and inert gas narcotic exposures for an understanding of the nature of the supposed IG/HP antagonism are discussed.

Thermodynamics of pressure—anesthetic antagonism on the phase transition of lipid membranes: Displacement of anesthetic molecules

From the depression of the phase-transition temperature of dipalmitoylphosphatidylcholine vesicle membranes by inhalation anesthetics (halothane, methoxyflurane, enflurane, and chloroform), the apparent partition coefficient, K app, of these drugs between the lipid membrane and water was estimated and the effect of hydrostatic pressure upon the partition was examined. By assuming nonzero partition of anesthetics into the solid-gel membrane, K app is defined as (1 - k) K, where K is the partition coefficient between the liquid-crystalline membrane and water, and k is the partition coefficient between the liquid-crystalline membrane and the solid-gel membrane. The value of K app was little affected by the change of temperature but was significantly decreased by the high pressure. The high pressure squeezed out the anesthetic molecules from the liquid-crystalline membrane, as evidenced by the decrease of the partition coefficient. The decrement of the number of the anesthetic molecules from that adsorbed at ambient pressure was halothane 10.4 × 10 −2, chloroform 6.42 × 10 −2, enflurane 9.58 × 10 −2, and methoxyflurane 8.45 × 10 −2% per 1 bar. The volume change due to the transfer of anesthetics from the aqueous phase to the lipid membrane, calculated from the pressure dependence of the apparent partition coefficient, was found to show a large positive value of about 15% of their molal volume. The magnitude of the volume increase is rather large and is difficult to ascribe to the breakage of anesthetic-water contact alone. The volume increase may be caused by the following factors: the structural change of the membrane, the change of the interaction forces between membrane and water due to anesthetic adsorption, the change of interaction between the anesthetics and water, etc. The positive sign indicates that anesthetics must be translocated from the lipid membrane into the aqueous phase by high pressure. Although pressure reversal of anesthesia may be caused mainly by restoration of order in the membrane and by enhancement of the cooperativity of the phase transition, displacement of anesthetics from the binding sites may also contribute to the phenomenon.

Nonlinear antagonism of anesthesia in mice by pressure.

Previous studies have shown a rectilinear antagonism by pressure of nitrous oxide or isoflurane anesthesia in mice (pressure reversal). Since a rectilinear pressure reversal is predicted by the critical volume hypothesis for anesthesia, we examined this phenomenon with two other gases. We measured the doses of argon or nitrogen which abolished the righting reflex in 50% of animals (ED50) at various high pressures produced by the addition of helium. The ED50 values of argon and nitrogen alone are 16.7 +/- 1.37 and 38.3 +/- 1.62 atmospheres absolute (ATA). Fifty-five percent more argon and 27% more nitrogen is needed to produce anesthesia at 100 ATA. However the increasing anesthetic requirements with pressure were curvilinearly related to pressure, rising most steeply at pressures near the ED50 without helium. This suggests that the pressure reversal of anesthesia is not simply a reciprocal anesthetic expansion-pressure compression phenomenon as predicted by the critical volume hypothesis. It suggests that anesthetics and pressure act at different sites.

Interaction of central nervous system effects of high pressures with barbiturates.

The interactions of phenobarbital, barbital, and pentobarbital with high pressures of heliox were explored. Principal features of the complex results include: double peaks in the time course of convulsion thresholds (Pc); an early peak and a shoulder in the time course of pressures reversing anesthesia (Pa); far steeper dose-response curves for Pa than for Pc; selectively greater anticonvulsant effect for phenobarbital than for the other barbiturates; and enhancement of Pa with simultaneous depression of Pc by reserpine in phenobarbital-pretreated mice. The data indicate the existence of at least two discrete sites of interaction between barbiturates and high pressure, reflected by Pc and Pa. The implications of the data for the development of biophysical theories of pressure reversal of anesthesia and anti-high-pressure neurological syndrome action of anesthetics are discussed, together with implications for the experimental study of convulsant and anticonvulsant agents, and their applications to underwater physiology.

Anesthetics and pressure reversal of anesthesia: expansion and recompression of membrane proteins, lipids, and water.

Anesthetics and pressure reversal of anesthesia: expansion and recompression of membrane proteins, lipids, and water.

Pressure reversal of anesthesia: the extent of small-molecule exclusion from spin-labeled phospholipid model membranes.

Pressure reversal of anesthesia: the extent of small-molecule exclusion from spin-labeled phospholipid model membranes.