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High-affinity block of voltage-operated rat IIA neuronal sodium channels by 2,6 di-tert-butylphenol, a propofol analogue

Published online by Cambridge University Press:  02 June 2005

G. Haeseler  and
M. Leuwer
G. Haeseler
Affiliation:
Hannover Medical School, Department of Anesthesiology, Hannover, Germany
M. Leuwer
Affiliation:
University of Liverpool, University Department of Anaesthesia, Liverpool, UK
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Extract

Summary

Background and objective: Propofol is a phenol derivative (2,6 di-isopropylphenol) with a unique effect profile including activating effects on GABAA and blocking effects on voltage-operated sodium channels. If the substituents in the 2- and the 6-positions are replaced by tert-butyl groups, the resulting phenol derivative, 2,6 di-tert-butylphenol, despite being a close structural propofol analogue, completely lacks GABAA receptor effects. The aim of this in vitro study was to investigate the effects of 2,6 di-tert-butylphenol on voltage-operated neuronal sodium channels in order to determine whether and, if so, how these structural changes alter the sodium channel-blocking effect seen with propofol.

Methods: Whole-cell sodium inward currents through heterologously expressed rat type IIA sodium channels were recorded in the absence and presence of definite concentrations of 2,6 di-tert-butylphenol and propofol.

Results: When applied at concentrations ≥30 μmol, 2,6 di-tert-butylphenol completely and irreversibly blocked sodium inward currents. The blockade equilibrium time was about 2 min. A partial washout was possible only if the application was stopped before the equilibrium of the blockade was achieved.

Conclusions: 2,6 Di-tert-butylphenol exerts a high-affinity block of neuronal sodium channels. Apparently, the slight structural differences of 2,6 di-tert-butylphenol in comparison with propofol – which account for the lack of GABAA receptor effects – enhance its voltage-operated sodium channel-blocking effects. As 2,6 di-tert-butylphenol is much more potent than most sodium channel blockers in clinical use, it might be of interest in the development of local anaesthetics.

Keywords

ANAESTHETICS, INTRAVENOUS, propofolBIOCHEMICAL PHENOMENA, binding sitesMEMBRANE TRANSPORT PROTEINS, ion channels, sodium channelsPHENOLS, 2,6 di-tert-butylphenol
Type
Original Article
Information
European Journal of Anaesthesiology , Volume 20 , Issue 3 , March 2003 , pp. 220 - 224
Copyright
© 2003 European Society of Anaesthesiology

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