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

Abstract

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.