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

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 (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. Key results: Under ‘loose patch’ clamp conditions, the IC 50 for I Na was 23.2 μM with Hill‐coefficient h =1.21. For I K , IC 50 was 9.2 μM, h =0.87. Clinically relevant ajmaline concentrations (1‐3 μM) reduced peak I Na by ∼5% but outward I K values were reduced by ∼20%. Na + channel steady‐state activation and fast inactivation were concentration‐dependently shifted towards hyperpolarized potentials (∼10 mV at 25 μM). Inactivation curves were markedly flattened by ajmaline. Peak‐I K under maintained depolarisation was reduced to ∼30% of control values by 100 μM ajmaline. I K activation time constants were increased at least two‐fold. Lower concentrations (10 or 25 μM) reduced steady‐state‐I K slightly but peak‐I K 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. British Journal of Pharmacology (2007) 151 , 63–74. doi: 10.1038/sj.bjp.0707194