© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Effects of the chromanol 293B, a selective blocker of the slow, component of the delayed rectifier K+ current, on repolarization in human and guinea pig ventricular myocytes
aDepartment of Medicine and Research Center, Montreal Heart Institute, 5000 Bélanger Street E., Montreal, Quebec H1T 1C8, Canada
bDepartment of Medicine, University of Montreal, Montreal, Quebec, Canada
cDepartment of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
dThe Institute of Physiology, Eberhard-Karls-Universität Tübingen, Tübingen, Germany
eHoechst AG, Frankfurt, Germany
* Corresponding author. Tel.: +1 (514) 376 3330; Fax: +1 (514) 376 1355; E-mail: nattel@icm.umontreal.ca
Objectives: The slow component of the delayed rectifier K+ current (IKs) is believed to be important in cardiac repolarization, and may be a potential target for antiarrhythmic drugs, but its study has been limited by a lack of specific blockers. The chromanol derivate 293B blocks currents expressed by minK and not HERG in Xenopus oocytes, but little is known about its effects on native currents and action potentials. We aimed to establish the effects of 293B on K+, Na+ and Ca2+ currents and action potentials in human and guinea pig cardiomyocytes. Methods: Whole-cell patch clamp techniques were applied to assess the effects of 293B on isolated myocytes at 36°C. Results: Delayed rectifier current (IK) elicited by pulses to +60 mV from a holding potential of –50 mV in guinea pig myocytes was strongly inhibited by 293B (maximum inhibition 96.9±0.8%; 50% inhibitory concentration, EC50, 1.02 µM), but IK during pulses to –10 mV was unaffected (3.9±8.4% inhibition at 50 µM). Half-activation voltages, current-voltage relations, and current densities of drug-resistant and drug-sensitive IK correspond to those of IKr and IKs respectively. Inward rectifier K+ current, Na+ current and L-type Ca2+ current were unaffected by 293B. Transient outward current in human ventricular myocytes was inhibited by 293B at an EC50 of 24 µM, less than one twentieth the potency for IKs inhibition in guinea pig myocytes. While dofetilide prolonged action potential duration (APD) with strong reverse use dependence, 293B prolonged guinea pig and human ventricular APD to a similar fractional extent at all frequencies. Conclusions: 293B is a selective IKs blocker, and the frequency dependence of APD prolongation caused by this IKs blocker is different from that caused by IKr blockade: 293B may be an interesting tool to study the physiologic role of IKs and the antiarrhythmic potential of IKs blockade.
KEYWORDS Potassium channels; Action potential; Biophysics; Cardiac arrhythmias; Antiarrhythmic drugs
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T. Banyasz, B. Horvath, L. Virag, L. Barandi, N. Szentandrassy, G. Harmati, J. Magyar, S. Marangoni, A. Zaza, A. Varro, et al. Reverse rate dependency is an intrinsic property of canine cardiac preparations Cardiovasc Res, November 1, 2009; 84(2): 237 - 244. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Romero, E. Pueyo, M. Fink, and B. Rodriguez Impact of ionic current variability on human ventricular cellular electrophysiology Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1436 - H1445. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-C. Chang, A. S. Barth, T. Sasano, E. Kizana, Y. Kashiwakura, Y. Zhang, D. B. Foster, and E. Marban CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart PNAS, March 18, 2008; 105(11): 4477 - 4482. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Munoz, K. R. Grzeda, T. Desplantez, S. V. Pandit, S. Mironov, S. M. Taffet, S. Rohr, A. G. Kleber, and J. Jalife Adenoviral Expression of IKs Contributes to Wavebreak and Fibrillatory Conduction in Neonatal Rat Ventricular Cardiomyocyte Monolayers Circ. Res., August 31, 2007; 101(5): 475 - 483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Lerche, I. Bruhova, H. Lerche, K. Steinmeyer, A. D. Wei, N. Strutz-Seebohm, F. Lang, A. E. Busch, B. S. Zhorov, and G. Seebohm Chromanol 293B Binding in KCNQ1 (Kv7.1) Channels Involves Electrostatic Interactions with a Potassium Ion in the Selectivity Filter Mol. Pharmacol., June 1, 2007; 71(6): 1503 - 1511. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Xiao, L. Zhang, W. Han, Z. Wang, and S. Nattel Sex-based transmural differences in cardiac repolarization and ionic-current properties in canine left ventricles Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H570 - H580. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.-J. Chang, M.-J. Su, S.-C. Kuo, T.-P. Lin, and Y.-S. Lee Multiple Cellular Electrophysiological Effects of a Novel Antiarrhythmic Furoquinoline Derivative HA-7 [N-Benzyl-7-methoxy-2,3,4,9-tetrahydrofuro[2,3-b]quinoline-3,4-dione] in Guinea Pig Cardiac Preparations J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 380 - 391. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-X. Bai, J. Kurokawa, M. Tamagawa, H. Nakaya, and T. Furukawa Nontranscriptional Regulation of Cardiac Repolarization Currents by Testosterone Circulation, September 20, 2005; 112(12): 1701 - 1710. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Jost, L. Virag, M. Bitay, J. Takacs, C. Lengyel, P. Biliczki, Z. Nagy, G. Bogats, D. A. Lathrop, J. G. Papp, et al. Restricting Excessive Cardiac Action Potential and QT Prolongation: A Vital Role for IKs in Human Ventricular Muscle Circulation, September 6, 2005; 112(10): 1392 - 1399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Melnyk, J. R. Ehrlich, M. Pourrier, L. Villeneuve, T.-J. Cha, and S. Nattel Comparison of ion channel distribution and expression in cardiomyocytes of canine pulmonary veins versus left atrium Cardiovasc Res, January 1, 2005; 65(1): 104 - 116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-G. Ding, F. Toyoda, and H. Matsuura Regulation of Cardiac IKs Potassium Current by Membrane Phosphatidylinositol 4,5-Bisphosphate J. Biol. Chem., December 3, 2004; 279(49): 50726 - 50734. [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]
|
|
|
|
 |
|
 Y. Fukuda, S. Miyoshi, K. Tanimoto, K. Oota, K. Fujikura, M. Iwata, A. Baba, Y. Hagiwara, T. Yoshikawa, H. Mitamura, et al. Autoimmunity against the second extracellular loop of beta1-adrenergic receptors induces early afterdepolarization and decreases in K-channel density in rabbits J. Am. Coll. Cardiol., March 17, 2004; 43(6): 1090 - 1100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Nakashima, U. Gerlach, D. Schmidt, and S. Nattel In vivo electrophysiological effects of a selective slow delayed-rectifier potassium channel blocker in anesthetized dogs: potential insights into class III actions Cardiovasc Res, March 1, 2004; 61(4): 705 - 714. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Stengl, P. G A Volders, M. B Thomsen, R. L H M G Spatjens, K. R Sipido, and M. A Vos Accumulation of slowly activating delayed rectifier potassium current (IKs) in canine ventricular myocytes J. Physiol., September 15, 2003; 551(3): 777 - 786. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R Ehrlich, T.-J. Cha, L. Zhang, D. Chartier, P. Melnyk, S. H Hohnloser, and S. Nattel Cellular electrophysiology of canine pulmonary vein cardiomyocytes: action potential and ionic current properties J. Physiol., September 15, 2003; 551(3): 801 - 813. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G.A. Volders, M. Stengl, J. M. van Opstal, U. Gerlach, R. L.H.M.G. Spatjens, J. D.M. Beekman, K. R. Sipido, and M. A. Vos Probing the Contribution of IKs to Canine Ventricular Repolarization: Key Role for {beta}-Adrenergic Receptor Stimulation Circulation, June 3, 2003; 107(21): 2753 - 2760. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rocchetti, A. Besana, G. Mostacciuolo, P. Ferrari, R. Micheletti, and A. Zaza Diverse Toxicity Associated with Cardiac Na+/K+ Pump Inhibition: Evaluation of Electrophysiological Mechanisms J. Pharmacol. Exp. Ther., May 1, 2003; 305(2): 765 - 771. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. F. Bosch, A. C. Schneck, J. Kiehn, W. Zhang, A. Hambrock, B. W. Eigenberger, N. Rub, J. Gogel, C. Mewis, L. Seipel, et al. {beta}3-Adrenergic regulation of an ion channel in the heart--inhibition of the slow delayed rectifier potassium current IKs in guinea pig ventricular myocytes Cardiovasc Res, December 1, 2002; 56(3): 393 - 403. [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]
|
|
|
|
|
|
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. 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]
|
|
|
|
|
|
M. Lei, P. J Cooper, P. Camelliti, and P. Kohl Role of the 293b-sensitive, slowly activating delayed rectifier potassium current, iKs, in pacemaker activity of rabbit isolated sino-atrial node cells Cardiovasc Res, January 1, 2002; 53(1): 68 - 79. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kang, X.-L. Chen, L. Wang, and D. Rampe Interactions of the Antimalarial Drug Mefloquine with the Human Cardiac Potassium Channels KvLQT1/minK and HERG J. Pharmacol. Exp. Ther., October 1, 2001; 299(1): 290 - 296. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. MacVinish, Y. Guo, A.K. Dixon, R. D. Murrell-Lagnado, and A. W. Cuthbert XE991 Reveals Differences in K+ Channels Regulating Chloride Secretion in Murine Airway and Colonic Epithelium Mol. Pharmacol., October 1, 2001; 60(4): 753 - 760. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.E. Lacerda, J. Kramer, K.-Z. Shen, D. Thomas, and A.M. Brown Comparison of block among cloned cardiac potassium channels by non-antiarrhythmic drugs Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K23 - K30. [Abstract] [PDF]
|
|
|
|
|
|
Z. Lu, K. Kamiya, T. Opthof, K. Yasui, and I. Kodama Density and Kinetics of IKr and IKs in Guinea Pig and Rabbit Ventricular Myocytes Explain Different Efficacy of IKs Blockade at High Heart Rate in Guinea Pig and Rabbit: Implications for Arrhythmogenesis in Humans Circulation, August 21, 2001; 104(8): 951 - 956. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rocchetti, A. Besana, G. B Gurrola, L. D Possani, and A. Zaza Rate dependency of delayed rectifier currents during the guinea-pig ventricular action potential J. Physiol., August 1, 2001; 534(3): 721 - 732. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Kocic, Y. Hirano, and M. Hiraoka Ionic basis for membrane potential changes induced by hypoosmotic stress in guinea-pig ventricular myocytes Cardiovasc Res, July 1, 2001; 51(1): 59 - 70. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Han, Z. Wang, and S. Nattel Slow delayed rectifier current and repolarization in canine cardiac Purkinje cells Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1075 - H1080. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. W. Veldkamp Decrease of delayed rectifier currents in the subacute phase of infarction Cardiovasc Res, October 1, 2000; 48(1): 11 - 12. [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]
|
|
|
|
|
|
J. Merot, V. Probst, M. Debailleul, U. Gerlach, N. S. Moise, H. Le Marec, and F. Charpentier Electropharmacological characterization of cardiac repolarization in German shepherd dogs with an inherited syndrome of sudden death: abnormal response to potassium channel blockers J. Am. Coll. Cardiol., September 1, 2000; 36(3): 939 - 947. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. C.-H. Yang, M. W. Scherz, A. Bahinski, P. B. Bennett, and K. T. Murray Stereoselective Interactions of the Enantiomers of Chromanol 293B with Human Voltage-Gated Potassium Channels J. Pharmacol. Exp. Ther., September 1, 2000; 294(3): 955 - 962. [Abstract] [Full Text]
|
|
|
|
|
|
G.-R. Li, B. Yang, H. Sun, and C. M. Baumgarten Existence of a transient outward K+ current in guinea pig cardiac myocytes Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H130 - H138. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Pereon, S. Demolombe, I. Baro, E. Drouin, F. Charpentier, and D. Escande Differential expression of KvLQT1 isoforms across the human ventricular wall Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H1908 - H1915. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ono, S. Shibata, and T. Iijima Properties of the delayed rectifier potassium current in porcine sino-atrial node cells J. Physiol., April 1, 2000; 524(1): 51 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Varro, B. Balati, N. Iost, J. Takacs, L. Virag, D. A Lathrop, L. Csaba, L. Talosi, and J. G. Papp The role of the delayed rectifier component IKs in dog ventricular muscle and Purkinje fibre repolarization J. Physiol., February 15, 2000; 523(1): 67 - 81. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Dorian and D. Newman Rate dependence of the effect of antiarrhythmic drugs delaying cardiac repolarization: an overview Europace, January 1, 2000; 2(4): 277 - 285. [Abstract] [PDF]
|
|
|
|
|
|
P. G. A. Volders, K. R. Sipido, M. A. Vos, R. L. H. M. G. Spatjens, J. D. M. Leunissen, E. Carmeliet, and H. J. J. Wellens Downregulation of Delayed Rectifier K+ Currents in Dogs With Chronic Complete Atrioventricular Block and Acquired Torsades de Pointes Circulation, December 14, 1999; 100(24): 2455 - 2461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Lynch Jr, M. S. Houle, G. L. Stump, A. A. Wallace, D. B. Gilberto, H. Jahansouz, G. R. Smith, A. J. Tebben, N. J. Liverton, H. G. Selnick, et al. Antiarrhythmic Efficacy of Selective Blockade of the Cardiac Slowly Activating Delayed Rectifier Current, IKs, in Canine Models of Malignant Ischemic Ventricular Arrhythmia Circulation, November 2, 1999; 100(18): 1917 - 1922. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. M. Wilde, R. J. E. Jongbloed, P. A. Doevendans, D. R. Duren, R. N. W. Hauer, I. M. van Langen, J. P. van Tintelen, H. J. M. Smeets, H. Meyer, and J. L. M. C. Geelen Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1) J. Am. Coll. Cardiol., February 1, 1999; 33(2): 327 - 332. [Abstract] [Full Text] [PDF]
|
|