Blockade of the ATP-sensitive K+ channel by 5-hydroxydecanoate in guinea pig ventricular myocytes.
Effects of a novel antiarrhythmic agent, 5-hydroxydecanoate (5-HD), were investigated on the electrical activity of the guinea pig ventricular myocytes. The shortening of action potential duration induced by applying iodoacetate (IAA) for 5 to 10 min was reversed completely by 5-HD (100 microM) in the papillary muscle. The single channel current recording in the cell-attached configuration revealed both activation of the ATP-sensitive K+ channel during the treatment with IAA and after depression of the channel by the additional application of 100 microM 5-HD. The quick rundown of the ATP-sensitive K+ channel activity interfered the analysis of the drug effect in the usual inside-out patch configuration. The channel activity in the isolated patch was partially recovered and stabilized by applying a tissue extract, which was prepared from guinea pig ventricle. Under this condition relationship between the 5-HD concentration and the K+ channel open probability was characterized with a K1/2 of 0.16 microM and a Hill coefficient of 0.88. The open- and close-time analysis revealed a decrease of the mean duration of the bursting channel opening and an increase of the interburst time under the effect of 5-HD. The inward-rectifier K+ channel, responsible for the resting K+ conductance, was not affected by 5-HD. It was concluded that the curative effect of 5-HD on the shortened action potential in the IAA-treated myocytes is mediated by the depression of the ATP-sensitive K+ channel.
Notsu
T
T
Fuji Central Research Laboratory, Mochida Pharmaceutical Co., Ltd., Shizuoka, Japan.
Tanaka
I
I
Takano
M
M
Noma
A
A
D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D003652:Decanoic Acids / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D006880:Hydroxy Acids / Q000494:pharmacology*; D066298:In Vitro Techniques; D007461:Iodoacetates / Q000494:pharmacology; D019807:Iodoacetic Acid; D007700:Kinetics; D015221:Potassium Channels / Q000187:drug effects*
D000889:Anti-Arrhythmia Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D007461:Iodoacetates; D015221:Potassium Channels; C052853:5-hydroxydecanoic acid; D000255:Adenosine Triphosphate; D005905:Glyburide; D019807:Iodoacetic Acid