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Am J Physiol Heart Circ Physiol (May 2, 2002). doi:10.1152/ajpheart.00076.2002
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Articles in PresS, published online ahead of print May 2, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00076.2002
Submitted on January 30, 2002
Accepted on April 24, 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. Marinchak3, and Peter R. Kowey3

1 Basic Cardiovascular Research Laboratory, Main Line Health Heart Center, Wynnewood, PA, USA
2 Pharmacology, Merck Research Laboratories, West Point, PA, USA
3 Basic Cardiovascular Research Laboratory, Main Line Health Heart Center, Wynnewood, PA, USA; Jeferson Medical College, Philadelphia, PA, USA

* To whom correspondence should be addressed. E-mail: XXUJWANG{at}AOL.COM.

Excessive action potential (AP) prolongation and early after-depolarizations (EAD) are triggers of malignant ventricular arrhythmias. Slowly activating delayed rectifier K+ current (IKs) is important for repolarization of ventricular AP. We examined the effects of IKs activation by a novel benzodiazepine (L3), on 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 Hz than 2 Hz. Selective activation of IKs by L3 attenuates prolonged AP and eliminated EAD induced by IKr 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.




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