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 μM) 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 μM, 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.