L-364,373 fails to activate the slow delayed rectifier K+ current in canine ventricular cardiomyocytes.
Activators of the slow delayed rectifier K+ current (I(Ks)) are promising tools to suppress ventricular arrhythmias originating from prolongation of action potentials. A recently synthesized compound, L-364,373, was shown to activate I(Ks) in ventricular cells isolated from guinea pigs and rabbits. Due to the interspecies differences known to exist in the properties of the delayed rectifier K+ currents, the effect of L-364,373 on I(Ks) was studied and compared with that of another I(Ks) activator mefenamic acid in canine ventricular myocytes. Mefenamic acid (100 microM) significantly increased the amplitude of the fully activated I(Ks) current, as well as the I(Ks) current tails, by shifting the voltage dependence of its activation towards negative voltages and increased the time constant for deactivation. In contrast, L-364,373, up to concentrations of 3 microM, failed to augment I(Ks) at any membrane potential studied, but slightly increased the time constant of deactivation. It is concluded that human studies are required to evaluate the therapeutically beneficial effects of I(Ks) activators. Rodent cardiac tissues are not suitable for this purpose.
Magyar
János
J
Department of Physiology, University of Debrecen, 4012, Debrecen, P.O. Box 22, Hungary.
Horváth
Balázs
B
Bányász
Tamás
T
Szentandrássy
Norbert
N
Birinyi
Péter
P
Varró
András
A
Szakonyi
Zsolt
Z
Fülöp
Ferenc
F
Nánási
Péter P
PP
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D051668:Delayed Rectifier Potassium Channels / Q000187:drug effects* / Q000502:physiology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles; D008528:Mefenamic Acid / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology
D051668:Delayed Rectifier Potassium Channels; C113498:L 364373; D001569:Benzodiazepines; D008528:Mefenamic Acid