Actions of cardiac drugs on a calcium-dependent potassium channel in hippocampal neurons.
The patch-clamp method has been used to determine the actions of three newly synthesized cardiac drugs on a calcium-dependent potassium channel, K(Ca), in CA1 hippocampal neurons. Activation of a 65-pS channel was evident in excised inside-out patches with the internal side of the membrane exposed to Ca2+ (0.2 mM); cessation of channel activity was immediate upon perfusion with ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid-containing solution. In the presence of low concentrations (0.1-10 microM) of the drugs UK-68798, KC-8857 (tedisamil), or WY-48986 (risotilide), channel openings evinced rapid flickering behavior from open to nonconducting levels; current amplitude was not affected by the drugs. The actions of the drugs were consistent with a voltage-independent block of open K(Ca) channels. In addition, the three drugs, at concentrations similar to those applied to inside-out patches, also blocked K(Ca) when they were applied to the bath solution for outside-out patches. The potencies for channel block of the drugs acting either externally or internally were in the order UK-68798 greater than tedisamil greater than risotilide, with UK-68798 reducing the mean open time of K(Ca) by one-half at a concentration near 0.4 microM.
McLarnon
J G
JG
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
Wang
X P
XP
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003521:Cyclopropanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D010627:Phenethylamines / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D013424:Sulfanilamides; D013449:Sulfonamides / Q000494:pharmacology*; D000096926:Benzenesulfonamides
D000889:Anti-Arrhythmia Agents; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002118:Calcium; D002316:Cardiotonic Agents; D003521:Cyclopropanes; D010627:Phenethylamines; D011188:Potassium; D015221:Potassium Channels; D013424:Sulfanilamides; D013449:Sulfonamides; C063978:risotilide; D000096926:Benzenesulfonamides; C059921:tedisamil; C063533:dofetilide