Intracellular [Mg++] determines specificity of K+ channel block by a class III antiarrhythmic drug.
E-4031 and related methanesulfonanilide class III antiarrhythmic drugs block I(Kr), a cardiac delayed rectifier K+ current. The current-voltage relationship of I(Kr) exhibits rectification; currents progressively decline in magnitude at test potentials >0 mV. Whole-cell voltage-clamp techniques were used to determine whether rectification results from block of channels by intracellular Mg++. The properties of E-4031-sensitive current were compared in guinea pig ventricular myocytes internally perfused with either a nominally Mg++ -free solution or with a solution containing 1mM Mg++. Based on an envelope of tails test, we conclude that inward rectification of guinea pig I(Kr) is due to a voltage-dependent gating mechanism and does not result from block of the channel by intracellular Mg++. Under normal physiologic conditions, E-4031 is a specific blocker of I(Kr). However, in the absence of intracellular Mg++, E-4031 also partially blocks I(Ks). Block of I(Ks) is prevented by prior treatment of cells with isoproterenol, which suggests that E-4031 only blocks unphosphorylated I(Ks) channels in the absence of intracellular Mg++.
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Merck Research Laboratories, Department of Pharmacology, West Point, Pennsylvania, USA.
Sanguinetti
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D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D008274:Magnesium / Q000494:pharmacology*; D008297:Male; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D010880:Piperidines; D015221:Potassium Channels; D011725:Pyridines; C063968:E 4031; D008274:Magnesium