Simulations of general anaesthetics in membranes at raised pressures: the search for mechanisms for pressure reversal of general anaesthetics

Experiments have shown that general anaesthetics lose their efficacy at pressures of around 20 MPa, but their efficacy is recovered at pressures of around 40 MPa. Molecular dynamics simulations of the general anaesthetic halothane in DMPC or POPC bilayers show that halothane aggregates inside the membrane at 20 MPa, but not at atmospheric pressure, nor at 40 MPa. The parallelism in effects suggests that aggregation could conceivably be the mechanism for pressure reversal. Further molecular dynamics simulations of another general anaesthetic, isoflurane, in POPC show that isoflurane does not aggregate at 20 MPa. This and other quantitative considerations show that general anaesthetic aggregation inside the membrane could not be the mechanism for pressure reversal.