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


METHODS
Sodium (I(Na)) and potassium (I(K)) 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.


RESULTS
Under 'loose patch' clamp conditions, the IC(50) for I(Na) was 23.2 microM with Hill-coefficient h=1.21. For I(K), IC(50) was 9.2 microM, h=0.87. Clinically relevant ajmaline concentrations (1-3 microM) reduced peak I(Na) by approximately 5% but outward I(K) 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 microM). Inactivation curves were markedly flattened by ajmaline. Peak-I(K) under maintained depolarisation was reduced to approximately 30% of control values by 100 microM ajmaline. I(K) activation time constants were increased at least two-fold. Lower concentrations (10 or 25 microM) reduced steady-state-I(K) slightly but peak-I(K) significantly. Action potential generation threshold was increased by 10 microM ajmaline and repolarisation prolonged.


CONCLUSIONS
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.
Friedrich
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O
Medical Biophysics, Institute of Physiology and Pathophysiology, University Heidelberg, Heidelberg, Germany. oliver.friedrich@physiologie.uni-heidelberg.de
V Wegner
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Wink
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D000200:Action Potentials / Q000187:drug effects; D000404:Ajmaline / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology; D014982:Xenopus laevis
D000889:Anti-Arrhythmia Agents; D015221:Potassium Channels; D015222:Sodium Channels; D000404:Ajmaline