The slowly activating delayed rectifier K+ current, I-Ks, is an import
ant modulator of cardiac action potential repolarization. Here, we des
cribe a novel benzodiazepine, [L-364,373 l-3-ylmethyl)-1-methyl-2H-1,4
-benzodiazepin-2-one] (R-L3), that activates I-Ks and shortens action
potentials in guinea pig cardiac myocytes. These effects were additive
to isoproterenol, indicating that channel activation by R-L3 was inde
pendent of beta-adrenergic receptor stimulation. The increase of I-Ks
by R-L3 was stereospecific; the S-enantiomer, S-L3, blocked I-Ks at al
l concentrations examined. The increase in I-Ks by R-L3 was greatest a
t voltages near the threshold for normal channel activation, caused by
a shift in the voltage dependence of I-Ks activation. R-L3 slowed the
rate of I-Ks deactivation and shifted the half-point of the isochrona
l (7.5 sec) activation curve for I-Ks by -16 mV at 0.1 mu M and -24 mV
at 1 mu M. R-L3 had similar effects on cloned KvLQT1 channels express
ed in Xenopus laevis oocytes but did not affect channels formed by coa
ssembly of KvLQT1 and hminK subunits. These findings indicate that the
association of minK with KvLQT1 interferes with the binding of R-L3 o
r prevents its action once bound to KvLQT1 subunits.