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Vol. 54, Issue 1, 220-230, July 1998
Department of Pharmacology, Merck Research Laboratories,
West Point, Pennsylvania 19486, (J.J.S., N.K.J., J.W., B.E.E.) and
Department of Medicine, Division of Cardiology and Eccles Program in
Human Molecular Biology and Genetics, University of Utah, Salt Lake
City, Utah 84112 (H.T.O., M.C.S.)
The slowly activating delayed rectifier K+ current,
IKs, is an important modulator of cardiac action potential
repolarization. Here, we describe a novel benzodiazepine,
[L-364,373
[(3-R)-1,3-dihydro-5-(2-fluorophenyl)-3-(1H-indol-3-ylmethyl)-1-methyl-2H-1,4-benzodiazepin-2-one] (R-L3), that activates IKs and shortens action potentials
in guinea pig cardiac myocytes. These effects were additive to
isoproterenol, indicating that channel activation by R-L3 was
independent of 
-adrenergic receptor stimulation. The increase of
IKs by R-L3 was stereospecific; the
S-enantiomer, S-L3, blocked IKs at all concentrations examined. The increase in IKs by R-L3 was
greatest at voltages near the threshold for normal channel activation, caused by a shift in the voltage dependence of IKs
activation. R-L3 slowed the rate of IKs deactivation and
shifted the half-point of the isochronal (7.5 sec) activation curve for
IKs by 
16 mV at 0.1 µM and 24 mV at 1 µM. R-L3 had similar effects on cloned KvLQT1 channels
expressed in Xenopus laevis oocytes but did not affect
channels formed by coassembly of KvLQT1 and hminK subunits. These
findings indicate that the association of minK with KvLQT1 interferes
with the binding of R-L3 or prevents its action once bound to KvLQT1
subunits.
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