(Circulation. 1996;93:168-177.)
© 1996 American Heart Association, Inc.
Articles |
Regional Differences in Current Density and Rate-Dependent Properties of the Transient Outward Current in Subepicardial and Subendocardial Myocytes of Human Left Ventricle
Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 8-11, 1993, and published in abstract form in Circulation (1993;88[suppl I]:I-89).
From the Departments of Medicine I (M.N., G.S.) and Cardiovascular Surgery (P.Ü.), University of Munich, and the Department of Medicine III, University of Cologne (D.J.B.), Cologne, Germany.
Correspondence to Dr Michael Näbauer, Medizinische Klinik I, Klinikum Großhadern, 81377 Munich, Germany.
Background Recordings of outward currents in human ventricular myocytes revealed the presence of a large calcium-insensitive transient outward current. This current has been suggested to contribute significantly to regional electrophysiological heterogeneity in myocardial cells and tissue of several animal species and to cause electrical gradients across the ventricular wall.
Methods and Results The patch-clamp technique was used to record action potentials and outward currents in myocytes enzymatically isolated from thin subepicardial and subendocardial layers of human nonfailing and failing left ventricle. In all subepicardial cells studied, a calcium-insensitive transient outward current (Ito1) could be recorded with large density (10.6±1.08 pA/pF at 40 mV), whereas current density of Ito1 in subendocardial cells was fourfold smaller (2.63±0.31 pA/pF, P<.0001, nonfailing myocardium). In failing hearts, the density of Ito1 was significantly smaller in subepicardial cells (7.81±0.53 pA/pF, P=.012) but not different in subendocardial myocytes (2.01±0.23 pA/pF, P=.25). Rate-dependent reduction of peak Ito1 at a 2-Hz depolarization rate was minimal in subepicardial cells (to 92.3±1.9%), whereas peak Ito1 in subendocardial myocytes was almost suppressed at 2 Hz (reduction to 13.2±2.1%, P<.0001). The different rate-dependent reduction of the transient outward current was due to a much slower time course of recovery from inactivation in subendocardial cells. Kinetic data, including action potentials recorded at 35°C, allow assessment of the role of the transient outward current for electrical activity and transmural voltage gradients in human left ventricle.
Conclusions Marked regional differences in density and rate-dependent properties of the transient outward current exist in subendocardial and subepicardial layers in human left ventricular myocardium, causing transmural electrical gradients that are important for normal and pathological electrical behavior of the human heart. The difference in recovery rates of the transient outward current is a distinguishing feature between subepicardial and subendocardial myocytes.
Key Words: action potentials • electrophysiology • heart failure • ventricles
This article has been cited by other articles:
 |
|
 |
|
  C. Marionneau, S. Brunet, T. P. Flagg, T. K. Pilgram, S. Demolombe, and J. M. Nerbonne Distinct Cellular and Molecular Mechanisms Underlie Functional Remodeling of Repolarizing K+ Currents With Left Ventricular Hypertrophy Circ. Res., June 6, 2008; 102(11): 1406 - 1415. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Antzelevitch Role of spatial dispersion of repolarization in inherited and acquired sudden cardiac death syndromes Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2024 - H2038. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Antzelevitch Ionic, molecular, and cellular bases of QT-interval prolongation and torsade de pointes Europace, September 1, 2007; 9(suppl_4): iv4 - iv15. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Gaborit, S. Le Bouter, V. Szuts, A. Varro, D. Escande, S. Nattel, and S. Demolombe Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart J. Physiol., July 15, 2007; 582(2): 675 - 693. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Sartiani, E. Bettiol, F. Stillitano, A. Mugelli, E. Cerbai, and M. E. Jaconi Developmental Changes in Cardiomyocytes Differentiated from Human Embryonic Stem Cells: A Molecular and Electrophysiological Approach Stem Cells, May 1, 2007; 25(5): 1136 - 1144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kaab Tuning the Beat: Differential Expression of Ion Channels in the Sinus Node Circ. Res., December 8, 2006; 99(12): 1283 - 1284. [Full Text] [PDF]
|
|
|
|
|
|
S. N. Flaim, W. R. Giles, and A. D. McCulloch Contributions of sustained INa and IKv43 to transmural heterogeneity of early repolarization and arrhythmogenesis in canine left ventricular myocytes Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2617 - H2629. [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. S. Barth, R. Kuner, A. Buness, M. Ruschhaupt, S. Merk, L. Zwermann, S. Kaab, E. Kreuzer, G. Steinbeck, U. Mansmann, et al. Identification of a Common Gene Expression Signature in Dilated Cardiomyopathy Across Independent Microarray Studies J. Am. Coll. Cardiol., October 17, 2006; 48(8): 1610 - 1617. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Radicke, D. Cotella, E. M. Graf, U. Banse, N. Jost, A. Varro, G.-N. Tseng, U. Ravens, and E. Wettwer Functional modulation of the transient outward current Ito by KCNE {beta}-subunits and regional distribution in human non-failing and failing hearts Cardiovasc Res, September 1, 2006; 71(4): 695 - 703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Dong, X. Sun, A. A. Prinz, and H.-S. Wang Effect of simulated Ito on guinea pig and canine ventricular action potential morphology Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H631 - H637. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. N. Obreztchikova, K. W. Patberg, A. N. Plotnikov, N. Ozgen, I. N. Shlapakova, A. V. Rybin, E. A. Sosunov, P. Danilo Jr., E. P. Anyukhovsky, R. B. Robinson, et al. IKr contributes to the altered ventricular repolarization that determines long-term cardiac memory Cardiovasc Res, July 1, 2006; 71(1): 88 - 96. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wang, J. Cheng, R. W. Joyner, M. B. Wagner, and J. A. Hill Remodeling of Early-Phase Repolarization: A Mechanism of Abnormal Impulse Conduction in Heart Failure Circulation, April 18, 2006; 113(15): 1849 - 1856. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Jia and K. Takimoto Mitogen-Activated Protein Kinases Control Cardiac KChIP2 Gene Expression Circ. Res., February 17, 2006; 98(3): 386 - 393. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. L. Protsenko, S. M. Routkevitch, V. Y. Gur'ev, L. B. Katsnelson, O. Solovyova, O. N. Lookin, A. A. Balakin, P. Kohl, and V. S. Markhasin Hybrid duplex: a novel method to study the contractile function of heterogeneous myocardium Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2733 - H2746. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Patel and D. L. Campbell Transient outward potassium current, 'Ito', phenotypes in the mammalian left ventricle: underlying molecular, cellular and biophysical mechanisms J. Physiol., November 15, 2005; 569(1): 7 - 39. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. W. Patberg, M. N. Obreztchikova, S. F. Giardina, A. J. Symes, A. N. Plotnikov, J. Qu, P. Chandra, D. McKinnon, S. R. Liou, A. V. Rybin, et al. The cAMP response element binding protein modulates expression of the transient outward current: Implications for cardiac memory Cardiovasc Res, November 1, 2005; 68(2): 259 - 267. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Coronel, S. Casini, T. T. Koopmann, F. J.G. Wilms-Schopman, A. O. Verkerk, J. R. de Groot, Z. Bhuiyan, C. R. Bezzina, M. W. Veldkamp, A. C. Linnenbank, et al. Right Ventricular Fibrosis and Conduction Delay in a Patient With Clinical Signs of Brugada Syndrome: A Combined Electrophysiological, Genetic, Histopathologic, and Computational Study Circulation, November 1, 2005; 112(18): 2769 - 2777. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Nerbonne and R. S. Kass Molecular Physiology of Cardiac Repolarization Physiol Rev, October 1, 2005; 85(4): 1205 - 1253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. S. Maier, C. Wahl-Schott, W. Horn, S. Weichert, C. Pagel, S. Wagner, N. Dybkova, O. J. Muller, M. Nabauer, W.-M. Franz, et al. Increased SR Ca2+ cycling contributes to improved contractile performance in SERCA2a-overexpressing transgenic rats Cardiovasc Res, September 1, 2005; 67(4): 636 - 646. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Meregalli, A. A.M. Wilde, and H. L. Tan Pathophysiological mechanisms of Brugada syndrome: Depolarization disorder, repolarization disorder, or more? Cardiovasc Res, August 15, 2005; 67(3): 367 - 378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Sun and H.-S. Wang Role of the transient outward current (Ito) in shaping canine ventricular action potential - a dynamic clamp study J. Physiol., April 15, 2005; 564(2): 411 - 419. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Szentadrassy, T. Banyasz, T. Biro, G. Szabo, B. I. Toth, J. Magyar, J. Lazar, A. Varro, L. Kovacs, and P. P. Nanasi Apico-basal inhomogeneity in distribution of ion channels in canine and human ventricular myocardium Cardiovasc Res, March 1, 2005; 65(4): 851 - 860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L Winslow, S. Cortassa, and J. L Greenstein Using models of the myocyte for functional interpretation of cardiac proteomic data J. Physiol., February 15, 2005; 563(1): 73 - 81. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. F. McBride and C. M. White Critical Differences Among Beta-Adrenoreceptor Antagonists in Myocardial Failure: Debating the MERIT of COMET J. Clin. Pharmacol., January 1, 2005; 45(1): 6 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Berecki, J. G. Zegers, A. O. Verkerk, Z. A. Bhuiyan, B. de Jonge, M. W. Veldkamp, R. Wilders, and A. C. G. van Ginneken HERG Channel (Dys)function Revealed by Dynamic Action Potential Clamp Technique Biophys. J., January 1, 2005; 88(1): 566 - 578. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Zicha, L. Xiao, S. Stafford, T. J. Cha, W. Han, A. Varro, and S. Nattel Transmural expression of transient outward potassium current subunits in normal and failing canine and human hearts J. Physiol., December 15, 2004; 561(3): 735 - 748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Rithalia, P. M. Hopkins, and S. M. Harrison The Effects of Halothane, Isoflurane, and Sevoflurane on Ca2+ Current and Transient Outward K+ Current in Subendocardial and Subepicardial Myocytes from the Rat Left Ventricle Anesth. Analg., December 1, 2004; 99(6): 1615 - 1622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Jang, L. E.-C. Leong, L. T. Hoang, P. H. Wang, G. A. Gutman, and B. L. Semler Structurally Distinct Elements Mediate Internal Ribosome Entry within the 5'-Noncoding Region of a Voltage-gated Potassium Channel mRNA J. Biol. Chem., November 12, 2004; 279(46): 47419 - 47430. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. V. Doronin, I. A. Potapova, Z. Lu, and I. S. Cohen Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization J. Biol. Chem., November 12, 2004; 279(46): 48231 - 48237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Bellocq, R. Wilders, J.-J. Schott, B. Louerat-Oriou, P. Boisseau, H. Le Marec, D. Escande, and I. Baro A Common Antitussive Drug, Clobutinol, Precipitates the Long QT Syndrome 2 Mol. Pharmacol., November 1, 2004; 66(5): 1093 - 1102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Iyer, R. Mazhari, and R. L. Winslow A Computational Model of the Human Left-Ventricular Epicardial Myocyte Biophys. J., September 1, 2004; 87(3): 1507 - 1525. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Decher, A. S. Barth, T. Gonzalez, K. Steinmeyer, and M. C. Sanguinetti Novel KChIP2 isoforms increase functional diversity of transient outward potassium currents J. Physiol., June 15, 2004; 557(3): 761 - 772. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Patel, R. Parai, R. Parai, and D. L. Campbell Regulation of Kv4.3 voltage-dependent gating kinetics by KChIP2 isoforms J. Physiol., May 15, 2004; 557(1): 19 - 41. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E Conrath, R. Wilders, R. Coronel, J. M.T de Bakker, P. Taggart, J. R de Groot, and T. Opthof Intercellular coupling through gap junctions masks M cells in the human heart Cardiovasc Res, May 1, 2004; 62(2): 407 - 414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. H. W. J. ten Tusscher, D. Noble, P. J. Noble, and A. V. Panfilov A model for human ventricular tissue Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1573 - H1589. [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]
|
|
|
|
|
|
H. L Tan, C. R Bezzina, J. P.P Smits, A. O Verkerk, and A. A.M Wilde Genetic control of sodium channel function Cardiovasc Res, March 15, 2003; 57(4): 961 - 973. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Han, L. Zhang, G. Schram, and S. Nattel Properties of potassium currents in Purkinje cells of failing human hearts Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2495 - H2503. [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]
|
|
|
|
|
|
R. Kaprielian, R. Sah, T. Nguyen, A. D. Wickenden, and P. H. Backx Myocardial infarction in rat eliminates regional heterogeneity of AP profiles, Ito K+ currents, and [Ca2+]i transients Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1157 - H1168. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Xu, P. H. Dong, Z. Zhang, G. U. Ahmmed, and N. Chiamvimonvat Presence of a calcium-activated chloride current in mouse ventricular myocytes Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H302 - H314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Guo, H. Li, F. Aimond, D. C. Johns, K. J. Rhodes, J. S. Trimmer, and J. M. Nerbonne Role of Heteromultimers in the Generation of Myocardial Transient Outward K+ Currents Circ. Res., March 22, 2002; 90(5): 586 - 593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. Po, R. C. Wu, G. J. Juang, W. Kong, and G. F. Tomaselli Mechanism of alpha -adrenergic regulation of expressed hKv4.3 currents Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2518 - H2527. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B Huang, D Qin, and N El-Sherif Spatial alterations of Kv channels expression and K+ currents in post-MI remodeled rat heart Cardiovasc Res, November 1, 2001; 52(2): 246 - 254. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Decher, O. Uyguner, C. R Scherer, B. Karaman, M. Yuksel-Apak, A. E Busch, K. Steinmeyer, and B. Wollnik hKChIP2 is a functional modifier of hKv4.3 potassium channels: Cloning and expression of a short hKChIP2 splice variant Cardiovasc Res, November 1, 2001; 52(2): 255 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kaab and M. Nabauer Diversity of ion channel expression in health and disease Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K31 - K40. [Abstract] [PDF]
|
|
|
|
|
|
D. J. Huelsing, A. E. Pollard, and K. W. Spitzer Transient outward current modulates discontinuous conduction in rabbit ventricular cell pairs Cardiovasc Res, March 1, 2001; 49(4): 779 - 789. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. R Bezzina, M. B Rook, and A. A.M Wilde Cardiac sodium channel and inherited arrhythmia syndromes Cardiovasc Res, February 1, 2001; 49(2): 257 - 271. [Full Text] [PDF]
|
|
|
|
 |
|
 C.-C. Shieh, M. Coghlan, J. P. Sullivan, and M. Gopalakrishnan Potassium Channels: Molecular Defects, Diseases, and Therapeutic Opportunities Pharmacol. Rev., December 1, 2000; 52(4): 557 - 594. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Greenstein, R. Wu, S. Po, G. F. Tomaselli, and R. L. Winslow Role of the Calcium-Independent Transient Outward Current Ito1 in Shaping Action Potential Morphology and Duration Circ. Res., November 24, 2000; 87(11): 1026 - 1033. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-G. Shin, J. V. Barnett, P. Chang, S. Reddy, D. C. Drinkwater, R. N. Pierson, R. G. Wiley, and K. T. Murray Molecular heterogeneity of protein kinase C expression in human ventricle Cardiovasc Res, November 1, 2000; 48(2): 285 - 299. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Sipido, P. G. A. Volders, S. H. M. de Groot, F. Verdonck, F. Van de Werf, H. J. J. Wellens, and M. A. Vos Enhanced Ca2+ Release and Na/Ca Exchange Activity in Hypertrophied Canine Ventricular Myocytes : Potential Link Between Contractile Adaptation and Arrhythmogenesis Circulation, October 24, 2000; 102(17): 2137 - 2144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Guo, H. Li, B. London, and J. M. Nerbonne Functional Consequences of Elimination of Ito, f and Ito, s : Early Afterdepolarizations, Atrioventricular Block, and Ventricular Arrhythmias in Mice Lacking Kv1.4 and Expressing a Dominant-Negative Kv4 {alpha} Subunit Circ. Res., July 7, 2000; 87(1): 73 - 79. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Yu, J. Gao, H. Wang, R. Wymore, S. Steinberg, D. McKinnon, M. R. Rosen, and I. S. Cohen Effects of the Renin-Angiotensin System on the Current Ito in Epicardial and Endocardial Ventricular Myocytes From the Canine Heart Circ. Res., May 26, 2000; 86(10): 1062 - 1068. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Wickenden, R. Kaprielian, X.-M. You, and P. H. Backx The thyroid hormone analog DITPA restores Ito in rats after myocardial infarction Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1105 - H1116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
</ |