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

ABSTRACT

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.

KEYWORDS:

• Molecular dynamics simulations
• halothane
• isoflurane
• DMPC
• POPC
• general anaesthetics
• pressure reversal

Acknowledgments

I thank Ruth Lynden-Bell, Paul Hoang, Matubayasi Nobuyuki, Nikolay Todorov and Nick Brooks for scientific discussions, Bill Smith and Ilian Todorov for help with use of DL_POLY in molecular dynamics simulations, and Stuart Rankin, Michael Rutter, Leung Hin-Tak and the High-Resolution Electron Microscopy Group of the Department of Materials Science and Metallurgy, University of Cambridge, for computational support. Some of the simulations in this work were carried out on the Darwin Supercomputer of the University of Cambridge High Performance Computing Service using Strategic Research Infrastructure Funding from the Higher Education Funding Council for England. I thank Liang Kuo-Kan for visiting fellowships during my numerous visits to Academia Sinica, Taipei, and Mike Payne for accepting me as a visiting scientist in the Theory of Condensed Matter Group, Cavendish Laboratory, University of Cambridge, during which time part of this work was carried out.

Disclosure statement

No potential conflict of interest was reported by the author.

Additional information

Funding

This work was supported by the Institut Pasteur, Paris and the Higher Education Funding Council for England.