NA+- and K+-channels as molecular targets of the alkaloid ajmaline in skeletal muscle fibres

Friedrich, O., v Wegner, F., Wink, M. and Fink, R. H. A. (2007) NA+- and K+-channels as molecular targets of the alkaloid ajmaline in skeletal muscle fibres. British Journal of Pharmacology, 151 1: 82-93. doi:10.1038/sj.bjp.0707194


Author Friedrich, O.
v Wegner, F.
Wink, M.
Fink, R. H. A.
Title NA+- and K+-channels as molecular targets of the alkaloid ajmaline in skeletal muscle fibres
Formatted title
NA+- and K+-channels as molecular targets of the alkaloid ajmaline in skeletal muscle fibres
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 0007-1188
1476-5381
1359-5075
Publication date 2007-05-01
Sub-type Article (original research)
DOI 10.1038/sj.bjp.0707194
Volume 151
Issue 1
Start page 82
End page 93
Total pages 12
Editor J. C. McGrath
Place of publication London, U.K.
Publisher Macmillan
Language eng
Subject 1115 Pharmacology and Pharmaceutical Sciences
Formatted abstract
Background and purpose:  Ajmaline is a widely used antiarrhythmic drug. Its action on voltage-gated ion channels in skeletal muscle is not well documented and we have here elucidated its effects on Na+ and K+ channels.
Experimental approach: Sodium (INa) and potassium (IK) currents in amphibian skeletal muscle fibres were recorded using 'loose-patch' and two-microelectrode voltage clamp techniques (2-MVC). Action potentials were generated using current clamp.
Key results: Under 'loose patch' clamp conditions, the IC50 for INa was 23.2 μM with Hill-coefficient h=1.21. For IK, IC50 was 9.2 μM, h=0.87. Clinically relevant ajmaline concentrations (1-3 μM) reduced peak INa by approximately 5% but outward IK values were reduced by approximately 20%. Na+ channel steady-state activation and fast inactivation were concentration-dependently shifted towards hyperpolarized potentials ( approximately 10 mV at 25 μM). Inactivation curves were markedly flattened by ajmaline. Peak-IK under maintained depolarisation was reduced to approximately 30% of control values by 100 μM ajmaline. Ik activation time constants were increased at least two-fold. Lower concentrations (10 or 25 μM) reduced steady-state-Ik slightly but peak-Ik significantly. Action potential generation threshold was increased by 10 μM ajmaline and repolarisation prolonged.
Conclusions and implications: Ajmaline acts differentially on Na+ and K+channels in skeletal muscle. This suggests at least multiple sites of action including the S4 subunit. Our data may provide a first insight into specific mechanisms of ajmaline-ion channel interaction in tissues other than cardiac muscle and could suggest possible side-effects that need to be further evaluated.
©2007 Nature Publishing Group All rights reserved

Keyword Skeletal muscle
Ajmaline
Loose-patch
Sodium channel
Potassium channel
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Biomedical Sciences Publications
 
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