Abstract

The slowly activating delayed rectifier K⁺ current, I_Ks, 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 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 independent of β-adrenergic receptor stimulation. The increase of I_Ks by R-L3 was stereospecific; theS-enantiomer, S-L3, blocked I_Ks at all concentrations examined. The increase in I_Ks by R-L3 was greatest at voltages near the threshold for normal channel activation, caused by a shift in the voltage dependence of I_Ksactivation. R-L3 slowed the rate of I_Ks deactivation and shifted the half-point of the isochronal (7.5 sec) activation curve for I_Ks 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.