Extracellular potassium modulation of drug block of IKr. Implications for torsade de pointes and reverse use-dependence.
BACKGROUND
Torsade de pointes often occurs with underlying hypokalemia and bradycardia. A common effect of many drugs producing torsade de pointes is block of the rapidly activating component of the cardiac delayed rectifier (IKr). In this study, we evaluated the effect of changing extracellular potassium ([K+]o) on IKr block by the nonspecific agent quinidine and by the specific IKr blocker dofetilide.


RESULTS
IKr was measured in AT-1 cells, where contaminating outward currents are absent. The drug concentration producing 50% inhibition of IKr tails (IC50) was strikingly [K+]o-dependent. Elevating [K+]o from 1 to 8 mmol/L increased the IC50 for dofetilide block from 2.7 +/- 0.9 to 79 +/- 32 nmol/L and for quinidine block from 0.4 +/- 0.1 to 3.8 +/- 1.2 mumol/L.


CONCLUSIONS
(1) The increase in drug block with low [K+]o provides a mechanism to explain the link between hypokalemia and torsade de pointes. (2) Elevations in [K+]o occur with myocardial ischemia and with rapid pacing. Possible consequences of blunted drug block with high [K+]o include loss of drug efficacy with ischemia and with rapid pacing; the latter may contribute to "reverse use-dependent" action potential prolongation. Extracellular potassium is a critical determinant of drug block of IKr, with substantial clinical implications.
Yang
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Vanderbilt University School of Medicine, Department of Medicine, Nashville, Tenn 37232-6602, USA.
Roden
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DM
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004594:Electrophysiology; D005110:Extracellular Space / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D051379:Mice; D009206:Myocardium / Q000166:cytology; D010627:Phenethylamines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism / Q000502:physiology*; D011802:Quinidine / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D016171:Torsades de Pointes / Q000209:etiology*
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; D011802:Quinidine; C063533:dofetilide; D011188:Potassium