Bertosamil blocks HERG potassium channels in their open and inactivated states

Abstract

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 μM) inhibited HERG tail currrent after a test pulse to 30 mV by 49.3±8.4% (n = 5) and the IC 50 was 62.7 μM. 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.