title: Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents.
abstract: 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 microM), 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+]o = 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 greater than -50 mV, resulting in a voltage-dependent decrease in peak IKr at test potentials greater than 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 IKs, 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.
authors.affiliation: Department of Pharmacology, Merck, Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: M C
authors.initials: MC
authors.lastname: Sanguinetti
authors.forename: N K
authors.initials: NK
authors.lastname: Jurkiewicz
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology*; D066298:In Vitro Techniques; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D008839:Microelectrodes; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D015737:Nisoldipine / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D015220:Calcium Channels; D010880:Piperidines; D015221:Potassium Channels; D011725:Pyridines; D015222:Sodium Channels; C063968:E 4031; D015737:Nisoldipine; D010042:Ouabain