Tedisamil blocks BK-type Ca(2+)-dependent K(+) channels and modulates action potentials in rat hippocampal neurons.
Tedisamil, a bradycardic compound in heart, also acts on K(+) channels in neurons. We determined the actions of tedisamil on action potentials in CA1 pyramidal neurons in hippocampal slices and on BK-type Ca(2+)-activated K(+) channel activity in inside-out patches excised from hippocampal neurons. In slices, tedisamil (5 microM) attenuated the fast afterhyperpolarization (AHP) and prolonged the repolarization phase of the action potential. Additionally, the compound induced burst-firing activity and enhanced the slow AHP that follows a train of action potentials. The single channel data showed tedisamil actions to be consistent with open channel blockade of the BK-type of K(+) channel. Together, the results are consistent with the possibility that prolongation of the action potential by tedisamil is mediated by a tetraethylammonium-like effect of the agent to block BK-type Ca(2+)-activated K(+) channels. The study also points to a number of effects that may contribute to the known nervous system toxicity induced by tedisamil.
Church
John
J
Department of Anatomy, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
McLarnon
James G
JG
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D003521:Cyclopropanes / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000889:Anti-Arrhythmia Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003521:Cyclopropanes; D051036:Large-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; C059921:tedisamil; D002118:Calcium