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

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 beta-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 microM and -24 mV at 1 microM. 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.

Desensitization of Chemical Activation by Auxiliary Subunits

“…This behavior bares some resemblance to that by KCNE1. A similar effect was also reported for L-364,373 ((3-R)-1, 3-dihydro-5-(2-fluorophenyl)-3-(1H-indol-3-ylmethyl)-1-methyl-2H-1,4-benzodiazepine-2) (also known as R-L3), a benzodiazepine-like compound with lower potency compared with that of ZnPy (41). Indeed, the slowing of deactivation is in agreement with the overall current potentiation.…”

“…Complete desensitization of an agonistic ligand for voltage-gated ion channels is rare, perhaps in part due to few openers that are available. For KCNQ channels, a known case so far is differential potentiation by R-L3 for KCNQ1 and KCNQ1-KCNE1, in which case there is a noticeable reduction of R-L3 effects for the heteromultimeric channels when titrated with amounts of the injected cRNA in the Xenopus oocyte expression system (41). This is intriguing especially in light of a recent paper arguing for KCNQ1-KCNE1 with 4:2 stoichiometry (59) and the evidence that one KCNQ1 channel complex may recruit more than one type of KCNE subunits (60).…”

Counting membrane-embedded KCNE β-subunits in functioning K + channel complexes

“…Goldstein and coworkers (6) have strongly argued that Q1 channels average two KCNE peptides per complex; however, they could not definitively rule out K ϩ channel complexes containing a solitary KCNE peptide. Another complicating factor is the notion that Q1 channels form complexes with KCNE ␤-subunits with multiple stoichiometries (5,8). Thus, approaches that measure the average number of KCNE peptides in the Q1 channel complex at the cell surface are unable to readily discern between fixed and various stoichiometries.…”

A Carbohydrate Fraction, AIP1, fromArtemisia IwayomogiReduces the Action Potential Duration by Activation of Rapidly Activating Delayed Rectifier K+Channels in Rabbit Ventricular Myocytes

“…Both currents play an important role in the repolarization of action potentials, and congenital or acquired prolongation of the QT interval in ECG is often brought about by a loss of function in this system [5]. Excessive AP duration (APD) prolongation causes long QT syndrome, which is associated with torsades de pointes, a ventricular tachyarrhythmia that can degenerate into ventricular fibrillation and cause sudden death [6,7].…”

“…Therefore, an activator of IKr or IKs channels may prove useful in the treatment of long QT syndrome resulting from an excessive pharmacological block of these channels or from mutations in the genes that encode the channel proteins [6]. Artemisia iwayomogi (A. messer-schmidtiana var.…”