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.
Xu
Xiaoping
X
Main Line Health Heart Center, Suite 558, Medical Office Building East, 100 Lancaster Avenue, Wynnewood, PA 19096, USA. xxujwang@aol.com
Salata
Joseph J
JJ
Wang
Jixin
J
Wu
Ying
Y
Yan
Gan-Xin
GX
Liu
Tengxian
T
Marinchak
Roger A
RA
Kowey
Peter R
PR
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