I(Ks) block by HMR 1556 lowers ventricular defibrillation threshold and reverses the repolarization shortening by isoproterenol without rate-dependence in rabbits.
BACKGROUND
The slow delayed rectifier K+ current (I(Ks)) contributes little to ventricular repolarization at rest. It is unclear whether I(Ks) plays a role during ventricular fibrillation (VF) or ventricular repolarization at rapid rates during beta-adrenergic stimulation.


RESULTS
In an in vivo rabbit model, we evaluated the effects of HMR 1556 (1 mg Kg(-1) + 1 mg kg(-1) hr(-1) i.v.), a selective I(Ks) blocker, on monophasic action potential duration at 90% repolarization (MAPD90), ventricular effective refractory period (VERP), and defibrillation threshold (DFT). In perfused rabbit hearts, the effects of HMR 1556 (10 and 100 nM) in the presence of isoproterenol (5 nM) on MAPD90 and VERP were studied at cycle lengths (CLs) 200-500 msec. In vivo, HMR 1556 prolonged MAPD90 by 6 +/- 1 msec at CL 200 msec (P < 0.01, n = 6), lowered DFT from 558 +/- 46 V to 417 +/- 31 V (P < 0.01), and decreased the coefficient of variation in the VF inter-beat deflection intervals from 8.9 +/- 0.6% to 6.5 +/- 0.4% (P < 0.05) compared with control. In perfused rabbit hearts, isoproterenol shortened MAPD90 by 5 +/- 1 msec at CL 200 msec and 11 +/- 4 msec at CL 500 msec (P < 0.05, n = 7). This shortening was reversed by HMR 1556 (P < 0.05), and both effects were rate-independent.


CONCLUSIONS
I(Ks) block increases VF temporal organization and lowers DFT, and I(Ks) that is activated following beta-adrenergic stimulation contributes to ventricular repolarization without rate dependence.
So
Petsy Pui-Sze
PP
Division of Cardiology, St. Michael's Hospital, Toronto, Ontario, Canada.
Backx
Peter H
PH
Hu
Xu-Dong
XD
Dorian
Paul
P
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D002839:Chromans / Q000494:pharmacology* / Q000627:therapeutic use; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D004554:Electric Countershock / Q000379:methods*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D014693:Ventricular Fibrillation / Q000188:drug therapy / Q000503:physiopathology
D002839:Chromans; D051668:Delayed Rectifier Potassium Channels; C420023:HMR 1556; D013449:Sulfonamides; D007545:Isoproterenol