Block of heart potassium channels by clofilium and its tertiary analogs: relationship between drug structure and type of channel blocked.
The whole-cell arrangement of the patch clamp was used to study delayed rectifier and inward rectifier K channels in isolated guinea pig ventricular cells. Block of these channels by an externally applied quaternary nitrogen compound, clofilium, and two of its tertiary nitrogen structural analogs (LY97241 and LY97119) were investigated. Clofilium reduced delayed rectifier current but had little effect on inward rectifier currents in concentrations as high as 100 microM. The block of delayed rectifier did not reverse upon washout. In contrast, lower concentrations of the tertiary analogs blocked both delayed rectifier and inward rectifier K currents. Onset of block of delayed rectifier was fast and block was reversible. The onset of block of inward rectifier by the tertiary compounds was slower than for delayed rectifier current and more difficult to reverse. We conclude from this work that tertiary, but not quaternary, clofilium blocks inward as well as delayed rectifier channels in these cells. Block of inward rectifier current is presumably caused by access to a receptor for the molecule that is gained by the tertiary, but not the quaternary, forms of the drug.
Arena
J P
JP
Department of Physiology, University of Rochester School of Medicine and Dentistry, New York 14642.
Kass
R S
RS
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D007473:Ion Channels / Q000187:drug effects*; D008297:Male; D011188:Potassium / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D007473:Ion Channels; D000644:Quaternary Ammonium Compounds; C056527:LY 97119; C056528:LY 97241; C022799:clofilium; D011188:Potassium