A Novel Benzodiazepine that Activates Cardiac Slow Delayed Rectifier K+ Currents

  1. Joseph J. Salata1,
  2. Nancy K. Jurkiewicz1,
  3. Jixin Wang1,
  4. Ben E. Evans1,
  5. Heidi T. Orme2 and
  6. Michael C. Sanguinetti2
  1. 1Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, (J.J.S., N.K.J., J.W., B.E.E.) and2Department 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.)

    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

    • 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

    • This study was supported in part by U.S. Public Health Service Grant RO1-HL55236 (M.C.S.).

    • Abbreviations:
      AP
      action potential
      APA50ms
      action potential amplitude measured at 50 msec after the upstroke
      APD90
      action potential duration at 90% repolarization
      APD50
      action potential duration at 50% repolarization
      HEPES
      4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
      HBS
      HEPES-buffered saline
      Ica
      L-type Ca2+ current
      IK
      delayed rectifier K+ current
      Ikr
      rapidly activating component of delayed rectifier K+ current
      IKs slowly activating component of delayed rectifier K+ current
      IK1, inward rectifier K+ current
      Iktail
      IKtail current
      Iktail-max
      maximum amplitude IKtail current
      Iso
      isoproterenol
      I-V
      current-voltage
      [K+]o
      extracellular K+concentration
      LQT
      long QT syndrome
      R-L3
      (3-R)-1,3-dihydro-5-(2-fluorophenyl)-3-(1H-indol-3-ylmethyl)-1-methyl-2H-1,4-benzodiazepin-2-one
      Vh
      holding potential
      Vt
      test potential
      • Received July 10, 1997.
      • Accepted January 29, 1998.
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    1. Molecular Pharmacology July 1, 1998 vol. 54 no. 1 220-230
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