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Block of voltage‐operated sodium channels by 2,6‐dimethylphenol, a structural analogue of lidocaine's aromatic tail
Author(s) -
Haeseler Gertrud,
Bufler Johannes,
Merken Sarah,
Dengler Reinhard,
Aronson Jeffrey,
Leuwer Martin
Publication year - 2002
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704854
Subject(s) - sodium channel , lidocaine , chemistry , potency , skeletal muscle , sodium , sodium channel blocker , biophysics , dissociation constant , pharmacology , gene isoform , patch clamp , voltage clamp , blockade , stereochemistry , biochemistry , membrane potential , endocrinology , anesthesia , in vitro , medicine , receptor , biology , organic chemistry , gene
The structural features that determine the state‐dependent interaction of local anaesthetics with voltage‐operated sodium channels are still a matter of debate. We have studied the blockade of sodium channels by 2,6‐dimethylphenol, a phenol derivative which resembles the aromatic tail of lidocaine, etidocaine, and bupivacaine. The effects of 2,6‐dimethylphenol were studied on heterologously (HEK 293) expressed rat neuronal (rat brain IIA) and human skeletal muscle (hSkM1) sodium channels using whole‐cell voltage‐clamp experiments. 2,6‐Dimethylphenol was effective in blocking whole‐cell sodium inward currents. Its potency was comparable to the potency of lidocaine previously obtained with similar protocols by others. The IC 50 at −70 mV holding potential was 150 and 187 μ M for the skeletal muscle and the neuronal isoform, respectively. In both isoforms, the blocking potency increased with the fraction of inactivated channels at depolarized holding potentials. However, the block achieved at −70 mV with respect to −150 mV holding potential was significantly higher only in the skeletal muscle isoform. The estimated dissociation constant K d from the inactivated state was 25 μ M and 28 μ M in the skeletal muscle and the neuronal isoform, respectively. The kinetics of drug equilibration between resting and inactivated channel states were about 10 fold faster compared with lidocaine. Our results show that the blockade induced by 2,6‐dimethylphenol retains voltage‐dependency, a typical feature of lidocaine‐like local anaesthetics. This is consistent with the hypothesis that the ‘aromatic tail’ determines the state‐dependent interaction of local anaesthetics with the sodium channel.British Journal of Pharmacology (2002) 137 , 285–293. doi: 10.1038/sj.bjp.0704854