Extracellular potassium modulation of drug block of I-Kr - 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 (I-Kr). In this study, we evaluated the effect of changing extracellular potassium ([K+](0)) on I-Kt block by the nonspecific agent quinidine and by the specific I-Kr blocker dofetilide. Methods and Results I-Kr was measured in AT-1 cells, where contaminating outward currents are absent. The drug concentration producing 50% inhibition of I-Kr tails (IC50) was strikingly [K+](0)-dependent. Elevating [K+](0) 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 mu mol/L. Conclusions (1) The increase in drug block with low [K+](0) provides a mechanism to explain the link between hypokalemia and torsade de pointes. (2) Elevations in [K+](0) occur with myocardial ischemia and with rapid pacing. Possible consequences of blunted drug block with high [K+](0) 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 I-Kr, with substantial clinical implications.