The Journal of General Physiology, Vol 96, 195-215, Copyright © 1990 by The Rockefeller University Press

ARTICLES

Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents

MC Sanguinetti and NK Jurkiewicz
Department of Pharmacology, Merck, Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486.

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.
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				A. Peretz, H. Schottelndreier, L. B. Aharon-Shamgar, and B. Attali Modulation of homomeric and heteromeric KCNQ1 channels by external acidification J. Physiol., December 15, 2002; 545(3): 751 - 766. [Abstract] [Full Text] [PDF]

				A. N. Katchman, K. A. McGroary, M. J. Kilborn, C. A. Kornick, P. L. Manfredi, R. L. Woosley, and S. N. Ebert Influence of Opioid Agonists on Cardiac Human Ether-a-go-go-related Gene K+ Currents J. Pharmacol. Exp. Ther., November 1, 2002; 303(2): 688 - 694. [Abstract] [Full Text] [PDF]

				Y. Kurata, I. Hisatome, S. Imanishi, and T. Shibamoto Dynamical description of sinoatrial node pacemaking: improved mathematical model for primary pacemaker cell Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H2074 - H2101. [Abstract] [Full Text] [PDF]

				W. Han, W. Bao, Z. Wang, and S. Nattel Comparison of Ion-Channel Subunit Expression in Canine Cardiac Purkinje Fibers and Ventricular Muscle Circ. Res., November 1, 2002; 91(9): 790 - 797. [Abstract] [Full Text] [PDF]

				F. M. Mullins, S. Z. Stepanovic, R. R. Desai, A. L. George Jr., and J. R. Balser Extracellular Sodium Interacts with the HERG Channel at an Outer Pore Site J. Gen. Physiol., September 30, 2002; 120(4): 517 - 537. [Abstract] [Full Text] [PDF]

				S. Ohya, B. Horowitz, and I. A. Greenwood Functional and molecular identification of ERG channels in murine portal vein myocytes Am J Physiol Cell Physiol, September 1, 2002; 283(3): C866 - C877. [Abstract] [Full Text] [PDF]

				G.-R. Li, C.-P. Lau, A. Ducharme, J.-C. Tardif, and S. Nattel Transmural action potential and ionic current remodeling in ventricles of failing canine hearts Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1031 - H1041. [Abstract] [Full Text] [PDF]

				M. Mbai, S. Rajamani, and C. T January The anti-malarial drug halofantrine and its metabolite N-desbutylhalofantrine block HERG potassium channels Cardiovasc Res, September 1, 2002; 55(4): 799 - 805. [Abstract] [Full Text] [PDF]

				C.-E. Chiang, H.-N. Luk, T.-M. Wang, and P. Y.-A. Ding Effects of sildenafil on cardiac repolarization Cardiovasc Res, August 1, 2002; 55(2): 290 - 299. [Abstract] [Full Text] [PDF]

				J. J. Lynch Jr., J. J. Salata, A. A. Wallace, G. L. Stump, D. B. Gilberto, H. Jahansouz, N. J. Liverton, H. G. Selnick, and D. A. Claremon Antiarrhythmic Efficacy of Combined IKs and beta -Adrenergic Receptor Blockade J. Pharmacol. Exp. Ther., July 1, 2002; 302(1): 283 - 289. [Abstract] [Full Text] [PDF]

				M. Grunnet, T. Jespersen, H. B. Rasmussen, T. Ljungstrom, N. K Jorgensen, S.-P. Olesen, and D. A Klaerke KCNE4 is an inhibitory subunit to the KCNQ1 channel J. Physiol., July 1, 2002; 542(1): 119 - 130. [Abstract] [Full Text] [PDF]

				M. R. Finley, Y. Li, F. Hua, J. Lillich, K. E. Mitchell, S. Ganta, R. F. Gilmour Jr., and L. C. Freeman Expression and coassociation of ERG1, KCNQ1, and KCNE1 potassium channel proteins in horse heart Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H126 - H138. [Abstract] [Full Text] [PDF]

				M. Lecchi, E. Redaelli, B. Rosati, G. Gurrola, T. Florio, O. Crociani, G. Curia, R. R. Cassulini, A. Masi, A. Arcangeli, et al. Isolation of a Long-Lasting eag-Related Gene-Type K+ Current in MMQ Lactotrophs and Its Accommodating Role during Slow Firing and Prolactin Release J. Neurosci., May 1, 2002; 22(9): 3414 - 3425. [Abstract] [Full Text] [PDF]

				H. Matsuura, T. Ehara, W.-G. Ding, M. Omatsu-Kanbe, and T. Isono Rapidly and slowly activating components of delayed rectifier K+ current in guinea-pig sino-atrial node pacemaker cells J. Physiol., May 1, 2002; 540(3): 815 - 830. [Abstract] [Full Text] [PDF]

				K. Ishihara, D.-H. Yan, S. Yamamoto, and T. Ehara Inward rectifier K+ current under physiological cytoplasmic conditions in guinea-pig cardiac ventricular cells J. Physiol., May 1, 2002; 540(3): 831 - 841. [Abstract] [Full Text] [PDF]

				M. Vornanen, A. Ryokkynen, and A. Nurmi Temperature-dependent expression of sarcolemmal K+ currents in rainbow trout atrial and ventricular myocytes Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2002; 282(4): R1191 - R1199. [Abstract] [Full Text] [PDF]

				M. Weerapura, S. Nattel, D. Chartier, R. Caballero, and T. E Hebert A comparison of currents carried by HERG, with and without coexpression of MiRP1, and the native rapid delayed rectifier current. Is MiRP1 the missing link? J. Physiol., April 1, 2002; 540(1): 15 - 27. [Abstract] [Full Text] [PDF]

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