Increasing I(Ks) corrects abnormal repolarization in rabbit models of acquired LQT2 and ventricular hypertrophy.
Excessive action potential (AP) prolongation and early afterdepolarizations (EAD) are triggers of malignant ventricular arrhythmias. A slowly activating delayed rectifier K+ current (I(Ks)) is important for repolarization of ventricular AP. We examined the effects of I(Ks) 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 I(Ks) via a negative shift in the voltage dependence of activation and a slowing of deactivation. L3 had no effect on L-type Ca(2+) 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 I(Ks) 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 I(Ks) 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.
Main Line Health Heart Center, Suite 558, Medical Office Building East, 100 Lancaster Avenue, Wynnewood, PA 19096, USA. xxujwang@aol.com
Xiaoping
X
Xu
Joseph J
JJ
Salata
Jixin
J
Wang
Ying
Y
Wu
Gan-Xin
GX
Yan
Tengxian
T
Liu
Roger A
RA
Marinchak
Peter R
PR
Kowey
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D051668:Delayed Rectifier Potassium Channels; D004594:Electrophysiology; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology*; D008133:Long QT Syndrome / Q000145:classification / Q000503:physiopathology*; D008297:Male; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011817:Rabbits; D011930:Reaction Time / Q000187:drug effects
D051668:Delayed Rectifier Potassium Channels; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D001569:Benzodiazepines