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Bertosamil blocks HERG potassium channels in their open and inactivated states.
Zitron E, Karle CA, Wendt-Nordahl G, Kathöfer S, Zhang W, Thomas D, Weretka S, Kiehn J.
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1. Bertosamil is chemically related to the class-III anti-arrhythmic drug tedisamil and has been developed as a bradycardic, anti-ischemic and anti-arrhythmic drug. Its anti-arrhythmic properties might in part be attributed to its block of voltage-dependent potassium channels Kv(1.2), Kv(1.4). and Kv(1.5). However, HERG-potassium channel block as an important target for class-III drugs has not yet been investigated. 2. We investigated the effect of bertosamil on the HERG potassium channel heterologously expressed in Xenopus oocytes with the two-electrode voltage-clamp technique. 3. Bertosamil (70 microM) inhibited HERGtail currrent after a test pulse to 30 mV by 49.3+/-8.4% (n=5) and the IC(50) was 62.7 microM. Onset of block was fast, i.e. 90% of inhibition developed within 180+/-8.22 s (n=5), and block was totally reversible upon washout within 294+/-38.7 s (n=5). 4. Bertosamil-induced block of HERG potassium channels was state-dependent with block mainly to open- and inactivated channels. Half-maximal activation voltage was slightly shifted towards more negative potentials. 5. Steady-state inactivation of HERG was not influenced by bertosamil. Bertosamil block elicited voltage-but no frequency-dependent effects. 6. In summary, bertosamil blocked the HERG potassium channel. These blocking properties may contribute to the anti-arrhythmic effects of bertosamil in the treatment of atrial and particular ventricular arrhythmias.
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