Tedisamil blocks the transient and delayed rectifier K+ currents in mammalian cardiac and glial cells

ID Dukes, L Cleemann and M Morad

Department of Physiology, University of Pennsylvania, Philadelphia.

The potassium currents in rat and guinea pig ventricular myocytes and mouse astrocytes were studied using tedisamil, a novel antiarrhythmic agent. A 1 to 20 microM dosage of tedisamil caused marked prolongation of the action potential in isolated rat ventricular myocytes, mimicking its reported effects on multicellular rat heart preparations. Under voltage clamp conditions, tedisamil caused a dose-dependent increase in the speed of inactivation of the transient outward K+ current (Ito), the predominant outward current in rat ventricular myocytes. In cardiac myocytes, the tedisamil block was neither use- nor voltage-dependent. The slow reversibility of drug action when applied from the outside, and its effectiveness when applied intracellularly, suggested an internal site of drug action. In guinea pig ventricular myocytes, tedisamil blocked the slowly developing time-dependent delayed rectifier K+ current (IK) over the same concentration range as that found for Ito in the rat myocytes. Tedisamil reduced this current without changing the characteristics of its slow (tau approximately 1 sec) activation. The effects of tedisamil on Ito and IK were independent of the phosphorylation state of the channel, as assessed by the equal effectiveness of the drug in the presence or absence of isoproterenol. Tedisamil also blocked the transient K+ current and the delayed rectifier current (IK) in mouse astrocytes over the same concentration range as that found in the cardiac myocytes and by a process that accelerated (transient K+ current) or mimicked (IK) inactivation. At concentrations of up to 50 microM, tedisamil had little effect on the time-dependent inward rectifier K+ current, or inward calcium current in rat or guinea pig ventricular myocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 254, Issue 2, pp. 560-569, 08/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				B. N. Singh and E. Aliot Newer antiarrhythmic agents for maintaining sinus rhythm in atrial fibrillation: simplicity or complexity? Eur. Heart J. Suppl., September 1, 2007; 9(suppl_G): G17 - G25. [Abstract] [Full Text] [PDF]

				D. A. Jacobson, C. R. Weber, S. Bao, J. Turk, and L. H. Philipson Modulation of the Pancreatic Islet beta-Cell-delayed Rectifier Potassium Channel Kv2.1 by the Polyunsaturated Fatty Acid Arachidonate J. Biol. Chem., March 9, 2007; 282(10): 7442 - 7449. [Abstract] [Full Text] [PDF]

				J. R. Ehrlich, C. Hoche, P. Coutu, C. Metz-Weidmann, W. Dittrich, S. H. Hohnloser, S. Nattel, and H. Gogelein Properties of a Time-Dependent Potassium Current in Pig Atrium: Evidence for a Role of Kv1.5 in Repolarization J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 898 - 906. [Abstract] [Full Text] [PDF]

				A. Royer, S. Demolombe, A. El Harchi, K. Le Quang, J. Piron, G. Toumaniantz, D. Mazurais, C. Bellocq, G. Lande, C. Terrenoire, et al. Expression of human ERG K+ channels in the mouse heart exerts anti-arrhythmic activity Cardiovasc Res, January 1, 2005; 65(1): 128 - 137. [Abstract] [Full Text] [PDF]

				J. Tamargo, R. Caballero, R. Gomez, C. Valenzuela, and E. Delpon Pharmacology of cardiac potassium channels Cardiovasc Res, April 1, 2004; 62(1): 9 - 33. [Abstract] [Full Text] [PDF]

				P. Dorian Antiarrhythmic Drug Therapy of Atrial Fibrillation: Focus on New Agents Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2003; 8(1_suppl): S27 - S31. [Abstract] [PDF]

				S. L. Bouter, S. Demolombe, A. Chambellan, C. Bellocq, F. Aimond, G. Toumaniantz, G. Lande, S. Siavoshian, I. Baro, A. L. Pond, et al. Microarray Analysis Reveals Complex Remodeling of Cardiac Ion Channel Expression With Altered Thyroid Status: Relation to Cellular and Integrated Electrophysiology Circ. Res., February 7, 2003; 92(2): 234 - 242. [Abstract] [Full Text] [PDF]

				K. Schroeder, B. Neagle, D. J. Trezise, and J. Worley IonworksTM Ht: A New High-Throughput Electrophysiology Measurement Platform J Biomol Screen, February 1, 2003; 8(1): 50 - 64. [Abstract] [PDF]

				M. R. Gralinski The Dog's Role in the Preclinical Assessment of QT Interval Prolongation Toxicol Pathol, January 1, 2003; 31(1_suppl): 11 - 16. [Abstract] [PDF]

				S.-S. Zhou, Z. Gao, L. Dong, Y.-F. Ding, X.-D. Zhang, Y.-M. Wang, J.-M. Pei, F. Gao, and X.-L. Ma Anion channels influence ECC by modulating L-type Ca2+ channel in ventricular myocytes J Appl Physiol, November 1, 2002; 93(5): 1660 - 1668. [Abstract] [Full Text] [PDF]

				S. A. Doggrell and V. Nand Effects of Tedisamil on Cardiovascular Tissues Isolated from Normoand Hypertensive Rats Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2001; 6(3): 261 - 272. [Abstract] [PDF]

				G. Lande, S. Demolombe, A. Bammert, A. Moorman, F. Charpentier, and D. Escande Transgenic mice overexpressing human KvLQT1 dominant-negative isoform Part II: Pharmacological profile Cardiovasc Res, May 1, 2001; 50(2): 328 - 334. [Abstract] [Full Text] [PDF]

				T.G Hammond, L Carlsson, A.S Davis, W.G Lynch, I MacKenzie, W.S Redfern, A.T Sullivan, and A.J Camm Methods of collecting and evaluating non-clinical cardiac electrophysiology data in the pharmaceutical industry: results of an international survey Cardiovasc Res, March 1, 2001; 49(4): 741 - 750. [Abstract] [Full Text] [PDF]

				H. Wang, H. Shi, L. Zhang, M. Pourrier, B. Yang, S. Nattel, and Z. Wang Nicotine Is a Potent Blocker of the Cardiac A-Type K+ Channels : Effects on Cloned Kv4.3 Channels and Native Transient Outward Current Circulation, September 5, 2000; 102(10): 1165 - 1171. [Abstract] [Full Text] [PDF]

				A. S. Lader, Y.-F. Xiao, C. R. O'Riordan, A. G. Prat, G. R. Jackson Jr., and H. F. Cantiello cAMP activates an ATP-permeable pathway in neonatal rat cardiac myocytes Am J Physiol Cell Physiol, July 1, 2000; 279(1): C173 - C187. [Abstract] [Full Text] [PDF]

				K M Fox, J R Henderson, J C Kaski, A Sachse, L Kuester, and S Wonnacott Antianginal and anti-ischaemic efficacy of tedisamil, a potassium channel blocker Heart, February 1, 2000; 83(2): 167 - 171. [Abstract] [Full Text]

				A. S. Lader, Y. Wang, G. R. Jackson Jr., S. C. Borkan, and H. F. Cantiello cAMP-activated anion conductance is associated with expression of CFTR in neonatal mouse cardiac myocytes Am J Physiol Cell Physiol, February 1, 2000; 278(2): C436 - C450. [Abstract] [Full Text] [PDF]

				J. R. Hume, D. Duan, M. L. Collier, J. Yamazaki, and B. Horowitz Anion Transport in Heart Physiol Rev, January 1, 2000; 80(1): 31 - 81. [Abstract] [Full Text] [PDF]

				J. A. Sanchez-Chapula Mechanism of Transient Outward K+ Channel Block by Disopyramide J. Pharmacol. Exp. Ther., August 1, 1999; 290(2): 515 - 523. [Abstract] [Full Text]

				S. Sorota Insights into the structure, distribution and function of the cardiac chloride channels Cardiovasc Res, May 1, 1999; 42(2): 361 - 376. [Abstract] [Full Text] [PDF]

				Z. Wang, J. Feng, H. Shi, A. Pond, J. M. Nerbonne, and S. Nattel Potential Molecular Basis of Different Physiological Properties of the Transient Outward K+ Current in Rabbit and Human Atrial Myocytes Circ. Res., March 19, 1999; 84(5): 551 - 561. [Abstract] [Full Text] [PDF]

				E. P. Baskin and J. J. Lynch Jr. Differential Atrial versus Ventricular Activities of Class III Potassium Channel Blockers J. Pharmacol. Exp. Ther., April 1, 1998; 285(1): 135 - 142. [Abstract] [Full Text]

				P. Bailly, J.-P. Benitah, M. Mouchoniere, G. Vassort, and P. Lorente Regional Alteration of the Transient Outward Current in Human Left Ventricular Septum During Compensated Hypertrophy Circulation, August 19, 1997; 96(4): 1266 - 1274. [Abstract] [Full Text]

				B. N. Singh Searching for the Ideal Class III Antiarrhythmic Agent: How Pure Should They Be? Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 1997; 2(4): 239 - 242. [PDF]

				M. Nemeth, A. Varro, L. Virag, O. Hala, D. Thormahlen, and J. Gyula Papp Frequency-dependent Cardiac Electrophysiologic Effects of Tedisamil: Comparison With Quinidine and Sotalol Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 1997; 2(4): 273 - 284. [Abstract] [PDF]

				N. K. Jurkiewicz, J. Wang, B. Fermini, M. C. Sanguinetti, and J. J. Salata Mechanism of Action Potential Prolongation by RP 58866 and Its Active Enantiomer, Terikalant: Block of the Rapidly Activating Delayed Rectifier K+ Current, IKr Circulation, December 1, 1996; 94(11): 2938 - 2946. [Abstract] [Full Text]

				A. F. James, T. Tominaga, Y. Okada, and M. Tominaga Distribution of cAMP-Activated Chloride Current and CFTR mRNA in the Guinea Pig Heart Circ. Res., August 1, 1996; 79(2): 201 - 207. [Abstract] [Full Text]

				M. C. Oz and S. Sorota Forskolin Stimulates Swelling-Induced Chloride Current, Not Cardiac Cystic Fibrosis Transmembrane-Conductance Regulator Current, in Human Cardiac Myocytes Circ. Res., June 1, 1995; 76(6): 1063 - 1070. [Abstract] [Full Text]

				K. Mori, Y. Hara, T. Saito, Y. Masuda, and H. Nakaya Anticholinergic Effects of Class III Antiarrhythmic Drugs in Guinea Pig Atrial Cells : Different Molecular Mechanisms Circulation, June 1, 1995; 91(11): 2834 - 2843. [Abstract] [Full Text]

				C. I. Berul and M. Morad Regulation of Potassium Channels by Nonsedating Antihistamines Circulation, April 15, 1995; 91(8): 2220 - 2225. [Abstract] [Full Text]