Abstract
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 β-adrenergic receptor stimulation. The increase of IKs by R-L3 was stereospecific; theS-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 IKsactivation. 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.
Footnotes
- Received July 10, 1997.
- Accepted January 29, 1998.
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Send reprint requests to: Dr. Joseph J. Salata, Department of Pharmacology, Merck Research Laboratories, Sumneytown Pike, P.O. Box 4, WP46–300, West Point, PA 19486. E-mail:joseph—salata{at}merck.com
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This study was supported in part by U.S. Public Health Service Grant RO1-HL55236 (M.C.S.).
- The American Society for Pharmacology and Experimental Therapeutics
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