Bertosamil blocks HERG potassium channels in their open and inactivated states.
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 HERG tail 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.
3rd Department of Internal Medicine (Cardiology), University of Heidelberg Medical School, Heidelberg, Germany.
Edgar
E
Zitron
Christoph A
CA
Karle
Gunnar
G
Wendt-Nordahl
Sven
S
Kathöfer
Wei
W
Zhang
Dierk
D
Thomas
Slawomir
S
Weretka
Johann
J
Kiehn
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D027682:Cation Transport Proteins; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins / Q000187:drug effects; D014981:Xenopus
D019086:Bridged Bicyclo Compounds, Heterocyclic; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011994:Recombinant Proteins; C103329:bertosamil