A combined X-ray scattering and simulation study of halothane in membranes at raised pressures

N.L.C Mccarthy,N.J Brooks,A.I.I Tyler,Mohammad Elgamacy,P.R.L Welche,M.C Payne,P.-L Chau

doi:10.1016/j.cplett.2016.12.041

Abstract

Using a combination of high pressure wide angle X-ray scattering experiments and molecular dynamics simulations, we probe the effect of the archetypal general anaesthetic halothane on the lipid hydrocarbon chain packing and ordering in model bilayers and the variation in these parameters with pressure. Incorporation of halothane into the membrane causes an expansion of the lipid hydrocarbon chain packing at all pressures. The effect of halothane incorporation on the hydrocarbon chain order parameter is significantly reduced at elevated pressure.

Highlights

General anaesthetics (GAs) have been used for over 170 years, and millions of surgical procedures have been performed using these drugs, but their site and mechanism of action are still not entirely clear
Cantor [42] suggested that drugs could induce lateral pressure change in the lipid membrane; these changes would shift the conformational equilibrium of membrane proteins and cause anaesthesia [43]
Scientists have certainly observed the effect of membrane on ion channel gating [44], but there still is a debate about the relative contributions of the membrane and the protein to general anaesthetic effects [45]

Summary

Introduction

General anaesthetics (GAs) have been used for over 170 years, and millions of surgical procedures have been performed using these drugs, but their site and mechanism of action are still not entirely clear. In the beginning of the 20th century, Meyer [1] and Overton [2] attempted to rationalise the experimental findings, and proposed what is known as the Meyer-Overton rule. It stated that the logarithm of the efficacy of an anaesthetic was proportional to the logarithm of its lipophilicity. Johnson and Flagler [3,4] discovered the phenomenon of pressure reversal They found that, by increasing ambient pressure to between 14 MPa and 21 MPa (140 and 210 bar), general anaesthesia by ethanol could be reversed in tadpoles.

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Conclusion