Inhibition of ATP-sensitive potassium channels of adult rat heart cells by antiarrhythmic drugs.
We have investigated the effect of antiarrhythmic drugs on the increased potassium conductance induced in isolated adult rat heart cells by ATP depletion. The rate of 86Rb uptake in the presence of ouabain was used as a measure of potassium conductance. Treatment of cells with rotenone plus p-trifluoromethoxyphenylhydrazone (FCCP) rapidly depleted ATP levels and strongly stimulated the rate of 86Rb uptake. The stimulated uptake and the ATP depletion were inhibited by oligomycin; thus, the uptake was not induced by rotenone plus FCCP directly. The stimulated uptake, but not the ATP depletion, was inhibited potently by glyburide (IC50, 38.3 nM), quinidine (IC50, 2.7 microM), verapamil (IC50, 4.5 microM), and amiodarone (IC50, 19.1 microM). The stimulated uptake was also inhibited by tetraethylammonium ion and by 4-aminopyridine but not by tetrodotoxin or manganese. We conclude that 1) the stimulated 86Rb uptake is measuring ATP-sensitive potassium channel activity, 2) the ATP-sensitive potassium channel is strongly inhibited by quinidine, verapamil, and amiodarone, and 3) this inhibition may contribute to the antiarrhythmic action of these drugs.
Haworth
R A
RA
Department of Surgery, University of Wisconsin Clinical Science Center, Madison.
Goknur
A B
AB
Berkoff
H A
HA
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D006168:Guinea Pigs; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010042:Ouabain / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D012413:Rubidium / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D015221:Potassium Channels; D012402:Rotenone; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D010042:Ouabain; D000255:Adenosine Triphosphate; D012413:Rubidium