The solubility of anesthetic gases in lipid bilayers

We have measured the lipid/gas partition coefficients at various temperatures of eight anesthetic agents in two sonicated lipid bilayers containing either 96% egg phosphatidylcholine/4% phosphatidic acid or 64% egg phosphatidylcholine/3% phosphatidic acid/33% cholesterol. The Bunsen lipid/gas partition coefficients in the pure phospholipid bilayer at 25 degrees C were: methoxyflurane 820 (interpolated), halothane 150, isoflurane 140, fluroxene 52, xenon 1.4, sulfur hexafluoride 0.24, carbon tetrafluoride 0.056 and hexafluoroethane 0.34. These partition coefficients were close to those in a bulk hydrophobic solvent (olive oil) but were reduced by about 20% in the cholesterol-containing bilayer preparation. In biomembranes the partition coefficient for halothane was lower than in lipid bilayers by about half an order of magnitude. As in olive oil, the partition coefficients mostly increased with decreasing temperature. The enthalpy, entropy and free energy associated with transfer of 1 mol of these agents from the gas phase at 1 atmosphere partial pressure and 25 degrees C into the lipid bilayers under the same conditions were calculated from the temperature variation of the partition coefficients. All of these compounds, with the exception of methoxyflurane, fit the Barclay Butler relationship between entropy and enthalpy of partitioning. The Bunsen partition coefficients were correlated with the anesthetic potencies of seven of these agents in mice and in dogs. Comparisons were made between the different bilayers and olive oil and between hypotheses of anesthesia based on concentration of anesthetic at the active site (Meyer-Overton) and based on the product of concentration and molar volume of anesthetic at the active site (Mullins). Excellent correlations between anesthetic potency and lipid bilayer partition were obtained in all cases. The most consistent fits to the predicted slopes were achieved when both molar volume and partitioning of the anesthetic into the cholesterol-containing bilayer were taken into account, but the differences between the models were small.