2 COMPONENTS OF CARDIAC DELAYED RECTIFIER K+ CURRENT - DIFFERENTIAL SENSITIVITY TO BLOCK BY CLASS-III ANTIARRHYTHMIC AGENTS

An envelope of tails test was used to show that the delayed rectifier K+ current (Ik) of guinea pig ventricular myocytes results from the activation of two outward K+ currents. One current was specifically blocked by the benzenesulfonamide antiarrhythmic agent, E-4031 (IC50 = 397 nM). The drug-sensitive current, "Ikr" exhibits prominent rectification and activates very rapidly relative to the slowly activating drug-insensitive current, "Iks." Iks, was characterized by a delayed onset of activation that occurs over a voltage range typical of the classically described cardiac IK. Fully activated Iks, measured as tail current after 7.5-s test pulses, was 11.4 times larger than the fully activated Ikr Ikr was also blocked by d-sotalol (100 µM), a less potent benzenesulfonamide Class III antiarrhythmic agent. The activation curve of Ikr had a steep slope (+7.5 mV) and a negative half-point (-21.5 mV) relative to the activation curve of Iks (slope = + 12.7 mV, half-point = + 15.7 mV). The reversal potential (Erev) of Ikr (-93 mV) was similar to EK (-94 mV for [K+]0 = 4 mM), whereas Erev of Iks was -77 mV. The time constants for activation and deactivation of Ikr made up a bell-shaped function of membrane potential, peaking between -30 and -40 mV (170 ms). The slope conductance of the linear portion of the fully activated Ikr-V relation was 22.5 S/F. Inward rectification of this relation occurred at potentials > -50 mV, resulting in a voltage-dependent decrease in peak Ikr at test potentials > 0 mV. Peak Ikr at 0 mV averaged 0.8 pA/pF (n = 21). Although the magnitude of Ikr was small relative to fully activated Ikr the two currents were of similar magnitude when measured during a relatively short pulse protocol (225 ms) at membrane potentials (-20 to + 20 mV) typical of the plateau phase of cardiac action potentials. © 1990, Rockefeller University Press., All rights reserved.