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Am J Physiol Heart Circ Physiol 283: H664-H670, 2002. First published May 2, 2002; doi:10.1152/ajpheart.00076.2002
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Vol. 283, Issue 2, H664-H670, August 2002

Increasing IKs corrects abnormal repolarization in rabbit models of acquired LQT2 and ventricular hypertrophy

Xiaoping Xu1, Joseph J. Salata2, Jixin Wang2, Ying Wu1, Gan-Xin Yan1, Tengxian Liu1, Roger A. Marinchak1,3, and Peter R. Kowey1,3

1 Main Line Health Heart Center, Wynnewood 19096; 2 Department of Pharmacology, Merck Research Laboratories, West Point 19486; and 3 Jefferson Medical College, Philadelphia, Pennsylvania 19107

Excessive action potential (AP) prolongation and early afterdepolarizations (EAD) are triggers of malignant ventricular arrhythmias. A slowly activating delayed rectifier K+ current (IKs) is important for repolarization of ventricular AP. We examined the effects of IKs activation by a new benzodiazepine (L3) on the AP of control, dofetilide-treated, and hypertrophied rabbit ventricular myocytes. In both control and hypertrophied myocytes, L3 activated IKs via a negative shift in the voltage dependence of activation and a slowing of deactivation. L3 had no effect on L-type Ca2+ current or other cardiac K+ currents tested. L3 shortened AP of control, dofetilide-treated, and hypertrophied myocytes more at 0.5 than 2 Hz. Selective activation of IKs by L3 attenuates prolonged AP and eliminated EAD induced by rapidly activating delayed rectifier K+ current inhibition in control myocytes at 0.5 Hz and spontaneous EAD in hypertrophied myocytes at 0.2 Hz. Pharmacological activation of IKs is a promising new strategy to suppress arrhythmias resulting from excessive AP prolongation in patients with certain forms of long QT syndrome or cardiac hypertrophy and failure.

action potential; ion channel; early afterdepolarization; arrhythmia


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