Biophysics and molecular biology of cardiac ion channels for the safety pharmacologist

Handbook of Experimental Pharmacology

Volumn 229, Issue , 2015, Pages 149-203

  Pugsley, M K ^a   Curtis, M J ^b   Hayes, E S ^c  

^a JANSSEN RESEARCH AND DEVELOPMENT   (United States)

^b ST THOMAS HOSPITAL   (United Kingdom)

^c NONE   (United States)

Author keywords

Activation; Atrial preparation; Biophysics; Calcium channel; Cardiac action potential; Channel kinetics; Comprehensive in vitro proarrhythmia assay; Delayed rectifier; Early afterdepolarisation; ECG; Hodgkin Huxley; ICHS7A; ICHS7B; In silico modelling; Inactivation; Inward rectifier; Langendorff heart; Purkinje fibre; Safety assessment; Sodium channel; Stem cells

Indexed keywords

DELAYED RECTIFIER POTASSIUM CHANNEL; INWARDLY RECTIFYING POTASSIUM CHANNEL; ION CHANNEL; NEW DRUG; VOLTAGE GATED CALCIUM CHANNEL; VOLTAGE GATED POTASSIUM CHANNEL;

ARTICLE; BIOASSAY; BIOPHYSICS; CHANNEL GATING; COMPUTER MODEL; DRUG INDUSTRY; DRUG QUALITY; DRUG SAFETY; DRUG SCREENING; ELECTROCARDIOGRAM; HEART ARRHYTHMIA; HEART ATRIUM; HEART DEPOLARIZATION; HEART MUSCLE CELL; HEART MUSCLE FIBER MEMBRANE POTENTIAL; HEART PROARRHYTHMIA; HODGKIN HUXLEY EQUATION; HUMAN; IN VITRO STUDY; ISOLATED HEART; MOLECULAR BIOLOGY; NONHUMAN; PARAMEDICAL PERSONNEL; PHARMACOLOGIST; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; PROTOCOL COMPLIANCE; PURKINJE FIBER; RISK ASSESSMENT; SAFETY PHARMACOLOGY; SIMULATION; TORSADE DES POINTES; TRANSLATIONAL RESEARCH; ACTION POTENTIAL; ANIMAL; DRUG EFFECTS; ELECTROCARDIOGRAPHY; HEART; MEMBRANE POTENTIAL; PHYSIOLOGY;

ACTION POTENTIALS; ANIMALS; BIOPHYSICS; DRUG EVALUATION, PRECLINICAL; ELECTROCARDIOGRAPHY; HEART; HUMANS; ION CHANNELS; MEMBRANE POTENTIALS; MOLECULAR BIOLOGY;

EID: 84934938361     PISSN: 01712004     EISSN: 18650325     Source Type: Book Series    
DOI: 10.1007/978-3-662-46943-9_7     Document Type: Article

References (139)

1. Aldrich RW, Corey DP, Stevens CF (1983) A reinterpretation of mammalian sodium channel gating based on single channel recording. Nature 306:436–441
2. Anon (2001) ICH S7A: Safety pharmacology studies for human pharmaceuticals. Fed Regist 66:36791–36792. Retrieved January 2015 at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm074959.pdf
3. Anon (2005) ICH S7B: The nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human biopharmaceuticals. Fed Regist 70:61133–61134. Retrieved January 2015 at: http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ucm074963.pdf
4. Antzelevitch C (2004) Arrhythmogenic mechanisms of QT prolonging drugs: Is QT prolongation really the problem? J Electrocardiol 37:15–24
5. Antzelevitch C, Shimizu W (2002) Cellular mechanisms underlying the long QT syndrome. Curr Opin Cardiol 17:43–51
6. Antzelevitch C, Sicouri S (1994) Clinical relevance of cardiac arrhythmias generated by afterdepolarizations. Role ofMcells in the generation of U Waves, triggered activity and torsade de pointes. J Am Coll Cardiol 23:259–277
7. Armstrong CM, Bezanilla F (1974) Charge movement associated with the opening and closing of the activation gates of the Na channels. J Gen Physiol 63:533–552
8. Armstrong CM, Hille B (1998) Voltage-gated ion channels and electrical excitability. Neuron 20:371–380
9. Armstrong CM, Bezanilla F, Rojas E (1973) Destruction of sodium conductance inactivation in squid axons perfused with pronase. J Gen Physiol 62:375–391
10. Ashcroft FM, Gribble FM (2000) New windows on the mechanism of action of K(ATP) channel openers. Trends Pharmacol Sci 11:439–445
11. Aubert M, Osterwalder R, Wagner B, Parrilla I, Cavero I, Doessegger L, Ertel EA (2006) Evaluation of the rabbit Purkinje fibre assay as an in vitro tool for assessing the risk of druginduced torsades de pointes in humans. Drug Saf 29:237–254
12. Authier S, Pugsley MK, Curtis MJ (2015) Hemodynamic assessment in safety pharmacology. In: Pugsley MK, Curtis MJ (eds) Principles of safety pharmacology. Springer, Heidelberg
13. Barrett TD, Walker MJA (1998) Glibenclamide does not prevent action potential shortening induced by ischemia in anesthetized rabbits but reduces ischemia-induced arrhythmias. J Mol Cell Cardiol 30:999–1008
14. Beatch GN, Abraham S, MacLeod BA, Yoshida NR, Walker MJ (1991) Antiarrhythmic properties of tedisamil (KC8857), a putative transient outward K+ current blocker. Br J Pharmacol 102:13–18
15. Bell RM, Mocanu MM, Yellon DM (2011) Retrograde heart perfusion: the Langendorff technique of isolated heart perfusion. J Mol Cell Cardiol 50:940–950
16. Binah O, Rosen MR (1992) Mechanisms of ventricular arrhythmias. Circulation 85:I25–I31
17. Bosch RF, Zeng X, Grammer JB, Popovic K, Mewis C, Kuhlkamp V (1999) Ionic mechanisms of electrical remodeling in human atrial fibrillation. Cardiovasc Res 44:121–131
18. Botting JH, Curtis MJ, Walker MJA (1985) Arrhythmias associated with myocardial ischaemia and infarction. Mol Aspects Med 8:311–422
19. Boyden PA, Hirose M, Dun W (2010) Cardiac Purkinje cells. Heart Rhythm 7:127–135
20. Boyett MR, Harrison SM, Janvier NC, McMorn SO, Owen JM, Shui Z (1996) A list of vertebrate cardiac ionic currents nomenclature, properties, function and cloned equivalents. Cardiovasc Res 32:455–481
21. Brack KE (2014) The heart’s ‘little brain’ controlling cardiac function in the rabbit. Exp Physiol. doi:10.1113/expphysiol.2014.080168
22. Case RB, Felix A, Castellana FS (1979) Rate of rise of myocardial pCO2 during early myocardial ischemia in the dog. Circ Res 45:324–330
23. Casimiro MC, Knollmann BC, Ebert SN, Vary JC Jr, Greene AE, Franz MR, Grinberg A, Huang SP, Pfeife K (2001) Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen Syndrome. Proc Natl Acad Sci USA 98:2526–25231
24. Catterall WA (1980) Neurotoxins that act on voltage-sensitive sodium channels in excitable membranes. Annu Rev Pharmacol Toxicol 20:15–43
25. Catterall WA (1993) Structure and function of voltage-gated ion channels. Trends Neurosci 16:500–506
26. Catterall WA (1995) Structure and function of voltage-gated ion channels. Annu Rev Biochem 64:493–531
27. Catterall WA (2001) A 3D view of sodium channels. Nature 409:988–991
28. Cavero I, Crumb W (2005) ICH S7B draft guideline on the non-clinical strategy for testing delayed cardiac repolarisation risk of drugs: a critical analysis. Expert Opin Drug Saf 4:509–530
29. Champeroux P, Viaud K, El Amrani AI, Fowler JS, Martel E, Le Guennec JY, Richard S (2005) Prediction of the risk of Torsade de Pointes using the model of isolated canine Purkinje fibres. Br J Pharmacol 144:376–485
30. Chiu SY (1977) Inactivation of sodium channels: second order kinetics in myelinated nerve. J Physiol 273:573–596
31. Clements-Jewery H, Curtis MJ (2014) The Langendorff preparation. In: Ardehali H, Bolli R, Losordo DW (eds) Manual of research techniques in cardiovascular medicine. Wiley Blackwell, Oxford
32. Clements-Jewery H, Hearse DJ, Curtis MJ (2007) Neutrophil ablation with anti-serum does not protect against phase 2 ventricular arrhythmias in anaesthetised rats with myocardial infarction. Cardiovasc Res 73:761–769
33. Clusin WT (2003) Calcium and cardiac arrhythmias: DADs, EADs, and alternans. Crit Rev Clin Lab Sci 40:337–375
34. Coraboeuf E, Carmeleit E (1982) Existence of two transient outward currents in sheep cardiac Purkinje fibers. Pflugers Arch 392:352–359
35. Corrias A, Giles W, Rodriguez B (2011) Ionic mechanisms of electrophysiological properties and repolarization abnormalities in rabbit Purkinje fibers. Am J Physiol Heart Circ Physiol 300: H1806–H1813
36. Curtis MJ (1998) Characterisation, utilisation and clinical relevance of isolated perfused heart models of ischaemia-induced ventricular fibrillation. Cardiovasc Res 39:194–215
37. Curtis MJ, Hancox JC, Farkas A, Wainwright CL, Stables CL, Saint DA, Clements-Jewery H, Lambiase PD, Billman GE, Janse MJ, Pugsley MK, Ng GN, Roden DM, Camm AJ, Walker MJA (2013) The Lambeth conventions (II): guidelines for the study of animal and human ventricular and supraventricular arrhythmias. Pharmacol Ther 139:213–248
38. Darpo B, Garnett C, Benson CT, Keirns J, Leishman D, Malik M et al (2014) Cardiac Safety Research Consortium: can the thorough QT/QTc study be replaced by early QT assessment in routine clinical pharmacology studies? Scientific update and a research proposal for a path forward. Am Heart J 168:262–272
39. Denac H, Mevissen M, Scholtysik G (2000) Structure, function and pharmacology of voltagegated sodium channels. Naunyn Schmiedebergs Arch Pharmacol 362:453–479
40. DePonti F, Poluzzi E, Cavalli A, Recanatini M, Montanaro N (2002) Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overview. Drug Saf 25:263–286
41. DeWaard M, Pragnel M, Campbell KP (1994) Ca2+ channel regulation by a conserved beta subunit domain. Neuron 13:495–503
42. DiFrancesco D, Noble D (1985) A model of cardiac electrical activity incorporating ionic pumps and concentration changes. Philos Trans R Soc Lond 307:353–398
43. Einthoven WE (1912) The different forms of the human electrocardiogram and their signification. Lancet 1:853–861
44. Ertel EA, Campbell KP, Harpold MM, Hofmann F, Mori Y et al (2000) Nomenclature of voltagegated calcium channels. Neuron 25:533–535
45. Farkas A, Coker SJ (2002) Limited induction of torsade de pointes by terikalant and erythromycin in an in vivo model. Eur J Pharmacol 449:143–153
46. Gibson JK, Bronson J, Palmer C, Numann R (2014) Adult human stem cell-derived cardiomyocytes detect drug-mediated changes on action potentials. J Pharmacol Toxicol Methods 70:255–267
47. Gintant GA (1995) Regional differences in IK density in canine left ventricle: role of IKs in electrical heterogeneity. Am J Physiol 268:H604–H613
48. Goineau S, Castagne´ V, Guillaume P, Froget G (2012) The comparative sensitivity of three in vitro safety pharmacology models for the detection of lidocaine-induced cardiac effects. J Pharmacol Toxicol Methods 66:52–58
49. Goldin AL (1993) Accessory subunits and sodium channel inactivation. Curr Opin Neurobiol 3:272–277
50. Goldin AL (2001) Resurgence of sodium channel research. Annu Rev Physiol 63:871–894
51. Grandi E, Pasqualini FS, Bers DM (2010) A novel computational model of the human ventricular action potential and Ca transient. J Mol Cell Cardiol 48:112–121
52. Guo W, Li H, London B, Nerbonne JM (2000) Functional consequences of elimination of i(to, f) and i(to, s): early afterdepolarizations, atrioventricular block, and ventricular arrhythmias in mice lacking Kv1.4 and expressing a dominant-negative Kv4 alpha subunit. Circ Res 87:73–79
53. Guo L, Dong Z, Guthrie H (2009) Validation of a guinea pig Langendorff heart model for assessing potential cardiovascular liability of drug candidates. J Pharmacol Toxicol Methods 60:130–151
54. Gussak I, Chaitman BR, Kopecky SL, Nerbonne JM (2000) Rapid ventricular repolarization in rodents: electrocardiographic manifestations, molecular mechanisms, and clinical insights. J Electrocardiol 33:159–170
55. Hamlin RL, Cruze CA, Mittelstadt SW, Kijtawornrat A, Keene BW, Roche BM, Nakayama T, Nakayama H, Hamlin DM, Arnold T (2004) Sensitivity and specificity of isolated perfused guinea pig heart to test for drug-induced lengthening of QTc. J Pharmacol Toxicol Methods 49:15–23
56. Han W, Wang Z, Nattel S (2000) A comparison of transient outward currents in canine cardiac Purkinje cells and ventricular myocytes. Am J Physiol 279:H466–H474
57. Hanck DA, Makielski JC, Sheets MF (1994) Kinetic effects of quaternary lidocaine block of cardiac sodium channels: a gating current study. J Gen Physiol 103:19–43
58. Hanson LA, Bass AS, Gintant G, Mittelstadt S, Rampe D, Thomas K (2006) ILSI-HESI cardiovascular safety subcommittee initiative: evaluation of three non-clinical models of QT prolongation. J Pharmacol Toxicol Methods 54:116–129
59. Hill JL, Gettes LS (1980) Effect of acute coronary artery occlusion on local myocardial extracellular K+ activity in swine. Circulation 61:769–778
60. Hille B (1992) Ionic channels of excitable membranes. Sinauer Associates, Sunderland Hodgkin AL
61. Huxley AF (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol 116:500–544
62. Hondeghem LM (1994) Computer aided development of antiarrhythmic agents with class IIIa properties. J Cardiovasc Electrophysiol 5:711–721
63. Hondeghem LM, Hoffmann P (2003) Blinded test in isolated female rabbit heart reliably identifies action potential duration prolongation and proarrhythmic drugs: importance of triangulation, reverse use dependence, and instability. J Cardiovasc Pharmacol 41:14–24
64. Hondeghem LM, Katzung BG (1977) Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta 472:373–398
65. Hoppe UC, Marban E, Johns DC (2001) Distinct gene-specific mechanisms of arrhythmia revealed by cardiac gene transfer of two long QT disease genes, HERG and KCNE1. Proc Natl Acad Sci USA 98:5335–5340
66. Hubbard JI, Llinas R, Quastel DMJ (1969) Electrophysiological analysis of synaptic transmission. Edward Arnold, London
67. Isom LL, De Jongh KS, Patton DE, Reber BF, Offord J, Charbonneau H, Walsh K, Goldin AL, Catterall WA (1992) Primary structure and functional expression of the beta 1 subunit of the rat brain sodium channel. Science 256:839–842
68. Jahnel U, Klemm P, Nawrath H (1994) Different mechanisms of the inhibition of the transient outward current in rat ventricular myocytes. Naunyn Schmiedebergs Arch Pharmacol 349:87–94
69. Ju YK, Saint DA, Gage PW (1992) Effects of lignocaine and quinidine on the persistent sodium current in rat ventricular myocytes. Br J Pharmacol 107:311–316
70. Khodorov B, Shishkove L, Peganov E, Revenko S (1976) Inhibition of sodium currents in frog Ranvier node treated with local anesthetics. Role of slow sodium inactivation. Biochim Biophys Acta 433:409–435
71. Kirsch GE, Trepakova ES, Brimecombe JC, Sidach SS, Erickson HD, Kochan MC, Shyjka LM, Lacerda AE, Brown AM (2004) Variability in the measurement of hERG potassium channel inhibition: effects of temperature and stimulus pattern. J Pharmacol Toxicol Methods 50:93–101
72. Klugbauer N, Lacinova L, Marais E, Hobom M, Hofmann F (1999) Molecular diversity of the calcium channel alpha2delta subunit. J Neurosci 19:684–691
73. Kuryshev YA, Wible BA, Gudz TI, Ramirez AN, Brown AM (2001) KChAP/Kvbeta1.2 interactions and their effects on cardiac Kv channel expression. Am J Physiol Cell Physiol 281:C290–C299
74. Kwak YG, Navarro-Polanco RA, Grobaski T, Gallagher DJ, Tamkunk MM (1999) Phosphorylation is required for alteration of kv1.5K(+) channel function by the Kvbeta1.3 subunit. J Biol Chem 274:25355–25361
75. Lawrence CL, Bridgland-Taylor MH, Pollard CE, Hammond TG, Valentin J-P (2006) A rabbit Langendorff heart proarrhythmia model: predictive value for clinical identification of Torsades de Pointes. Br J Pharmacol 149:845–860
76. Lee N, Authier S, Pugsley MK, Curtis MJ (2010) The continuing evolution of torsades de pointes liability testing methods: is there an end in sight? Toxicol Appl Pharmacol 243:146–153
77. Li H, Fuentes-Garcia J, Towbin JA (2000) Current concepts in long QT syndrome. Pediatr Cardiol 21:542–550
78. Lindgren S, Bass AS, Briscoe R, Bruse K, Friedrichs GS, Kallman M-J, Markgraf C, Patmore L, Pugsley MK (2008) Benchmarking safety pharmacology regulatory packages and best practice. J Pharmacol Toxicol Methods 58:99–109
79. Liu T, Brown BS, Wu Y, Antzelevitch C, Kowey PR, Yan GX (2006) Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias. Heart Rhythm 3:948–956
80. Lu HR, Mariën R, Saels A, De Clerck F (2000) Are there sex-specific differences in ventricular repolarization or in drug-induced early afterdepolarizations in isolated rabbit Purkinje fibers? J Cardiovasc Pharmacol 36:132–139
81. Lu HR, Mariën R, Saels A, De Clerck F (2001) Species plays an important role in drug-induced prolongation of action potential duration and early afterdepolarizations in isolated Purkinje fibers. J Cardiovasc Electrophysiol 12:93–102
82. Lu HR, Vlaminckx E, Gallacher DJ (2008) Choice of cardiac tissue in vitro plays an important role in assessing the risk of drug-induced cardiac arrhythmias in human: beyond QT prolongation. J Pharmacol Toxicol Methods 57:1–8
83. Luo C, Rudy Y (1991) A model of the ventricular action potential: depolarization, repolarization, and their interaction. Circ Res 68:1501–1526
84. MacKinnon R, Cohen SL, Kuo A, Lee A, Chait BT (1998) Structural conservation in prokaryotic and eukaryotic potassium channels. Science 280:106–109
85. Main MC, Bryant SM, Hart G (1998) Regional differences in action potential characteristics and membrane currents of guinea-pig left ventricular myocytes. Exp Physiol 83:747–761
86. Malik M, Camm AJ (2001) Evaluation of drug-induced QT Interval prolongation: implications for drug approval and labelling. Drug Saf 24:323–351
87. Mirams GR, Davies MR, Brough SJ, Cui Y, Gavaghan DJ, Abi-Gerges N (2014) Prediction of thorough QT study results using action potential simulations based on ion channel screens. J Pharmacol Toxicol Methods 70:246–254
88. Nakamura TY, Coetzee WA, Vega Saenz De Miera E, Artman M, Rudy B (1997) Modulation of Kv4 channels, key components of rat ventricular transient outward K+ current by PKC. Am J Physiol 273:H1775–H1786
89. Nalos L, Varkevisser R, Jonsson MK, Houtman MJ, Beekman JD et al (2012) Comparison of the IKr blockers moxifloxacin, dofetilide and E-4031 in five screening models of pro-arrhythmia reveals lack of specificity of isolated cardiomyocytes. Br J Pharmacol 165:467–478
90. Nerbonne JM (2000) Molecular basis of functional voltage-gated K+ channel diversity in the mammalian myocardium. J Physiol 525:285–298
91. O’Hara T, Virág L, Varro A, Rudy Y (2011) Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation. PLoS Comput Biol 7(5):e1002061. doi:10.1371/journal.pcbi.1002061
92. Pawson AJ, Sharman JL, Benson HE, Faccenda E, Alexander SP, Buneman OP, Davenport AP, McGrath JC, Peters JA, Southan C, Spedding M, Yu W, Harmar AJ, NC-IUPHAR (2014) The IUPHAR/BPS Guide to PHARMACOLOGY: an expert-driven knowledgebase of drug targets and their ligands. Nucleic Acids Res 42:D1098–D1106
93. Peng S, Lacerda AE, Kirsch GE, Brown AM, Bruening-Wright A (2010) The action potential and comparative pharmacology of stem cell-derived human cardiomyocytes. J Pharmacol Toxicol Methods 61:277–286
94. Puddu PE, Legrand J-C, Salle´ L, Rouet R, Ducroq J (2011) I(Kr) vs. I(Ks) blockade and arrhythmogenicity in normoxic rabbit Purkinje fibers: does it really make a difference? Fundam Clin Pharmacol 25:304–312
95. Pugsley MK (2002) Antiarrhythmic drug development: historical review and future perspective. Drug Dev Res 55:3–16
96. Pugsley MK, Quastel DMJ (1998) Basic cardiac electrophysiology. In: Pugsley MK, Walker MJA (eds) Methods in cardiac electrophysiology. CRC Press, Boca Raton, FL
97. Pugsley MK, Authier S, Curtis MJ (2008) Principles of safety pharmacology. Br J Pharmacol 154:1382–1399
98. Pugsley MK, Dalton JA, Authier S, Curtis MJ (2014) Safety pharmacology in 2014: new focus on non-cardiac methods and models. J Pharmacol Toxicol Methods 70:170–174
99. Ragsdale DS, McPhee JC, Scheuer T, Catterall WA (1996) Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+ channels. Proc Natl Acad Sci USA 93:9270–9275
100. Rasmusson RL, Morales MJ, Wang S, Liu S, Campbell DL, Brahmajothi MV, Strauss HC (1998) Inactivation of voltage-gated cardiac K+ channels. Circ Res 82:739–750
101. Rees SA, Curtis MJ (1995) Further investigations into the mechanism of antifibrillatory action of the specific IK1 blocker, RP58866, assessed using the rat dual coronary perfusion model. J Mol Cell Cardiol 27:2595–2606
102. Roberts R, Brugada R (2000) Genetic aspects of arrhythmias. Am J Med Genet 97:310–318
103. Rolf S, Haverkamp W, Borggrefe M, Musshoff U, Eckardt L, Mergenthaler J et al (2000) Effects of antiarrhythmic drugs on cloned cardiac voltage-gated potassium channels expressed in Xenopus oocytes. Naunyn Schmiedebergs Arch Pharmacol 362:22–31
104. Roy M, Dumaine R, Brown AM (1996) HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine. Circulation 94:817–823
105. Sager PT, Gintant G, Turner JR, Pettit S, Stockbridge N (2014) Rechanneling the cardiac proarrhythmia safety paradigm: a meeting report from the Cardiac Safety Research Consortium. Am Heart J 167:292–300
106. Saint DA (2007) The cardiac persistent sodium current: an appealing therapeutic target? Br J Pharmacol 153:1133–1142
107. Saint DA, Ju YK, Gage PW (1992) A persistent sodium current in rat ventricular myocytes. J Physiol 453:219–231
108. Sakura H, Bond C, Warren-Perry M, Horsley S, Kearney L, Tucker S, Adelman J, Turner R, Ashcroft FM (1995) Characterization and variation of a human inwardly-rectifying-K-channel gene (KCNJ6): a putative ATP-sensitive K-channel subunit. FEBS Lett 367:193–197
109. Sanguinetti MC, Jurkiewicz NK (1991) Delayed rectifier outward K+ current is composed of two currents in guinea pig atrial cells. Am J Physiol 260:H393–H399
110. Sato C, Ueno Y, Asai K, Takahashi K, Sato M, Engel A, Fujiyoshi Y (2001) The voltage-sensitive sodium channel is a bell-shaped molecule with several cavities. Nature 409:1047–1051
111. Schaper W, Schaper J, Winkler B (1986) The collateral circulation of the heart. J Mol Cell Cardiol 18:60
112. Sedmera D, Gourdie RG (2014) Why do we have Purkinje fibers deep in our heart? Physiol Res 63: S9–S18
113. Shah RR (2001) Drug-induced prolongation of the QT interval: why the regulatory concern? Fundam Clin Pharmacol 16:119–124
114. Snyders DJ (1999) Structure and function of cardiac potassium channels. Cardiovasc Res 42:377–390
115. Striessnig J (1999) Pharmacology, structure and function of cardiac L-type Ca2+ channels. Cell Physiol Biochem 9:242–269
116. Studenik CR, Zhou Z, January C (2001) Differences in action potential and early afterdepolarization properties in LQT2 and LQT3 models of long QT syndrome. Br J Pharmacol 132:85–92
117. Tanaka T, Tohyama S, Murata M, Nomura F, Kaneko T, Chen H, Hattori F, Egashira T, Seki T et al (2009) In vitro pharmacologic testing using human induced pluripotent stem cell-derived cardiomyocytes. Biochem Biophys Res Commun 385:497–502
118. ten Tusscher KH, Panfilov AV (2006) Cell model for efficient simulation of wave propagation in human ventricular tissue under normal and pathological conditions. Phys Med Biol 51:6141–6156
119. Topert C, Doring F, Derst C, Daut J, Grzeschik KH, Karschin A (2000) Cloning, structure and assignment to chromosome 19q13 of the human Kir2.4 inwardly rectifying potassium channel gene (KCNJ14). Mamm Genome 11:247–249
120. Vaughan Williams EM (1984) A classification of antiarrhythmic actions reassessed after a decade of new drugs. J Clin Pharmacol 24:129–147
121. Vidarsson H, Hyllner J, Sartipy P (2010) Differentiation of human embryonic stem cells to cardiomyocytes for in vitro and in vivo applications. Stem Cell Rev 6:108–120
122. Vos MA (2001) Preclinical evaluation of antiarrhythmic drugs: new drugs should be safe to be successful. J Cardiovasc Electrophysiol 12:1034–1036
123. Wang G, Dugas M, Ben Armah I, Honerjager P (1990) Interaction between DPI 201-106 enantiomers at the cardiac sodium channel. Mol Pharmacol 37:17–24
124. Wang Z, Yue L, White M, Pelletier G, Nattel S (1998) Differential distribution of inward rectifier potassium channel transcripts in human atrium versus ventricle. Circulation 98:2422–2428
125. Wang D, Patel C, Cui C, Yan GX (2008) Preclinical assessment of drug-induced proarrhythmias: Role of the arterially perfused rabbit left ventricular wedge preparation. Pharmacol Ther 119:141–151
126. Weiss JN, Venkatesh N (1993) Metabolic regulation of cardiac ATP-sensitive K+ channels. Cardiovasc Drugs Ther 7:499–505
127. West JW, Patton DE, Scheuer T, Wang Y, Goldin AL, Catterall WA (1992) A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation. Proc Natl Acad Sci U S A 89:10910–10914
128. Wickenden AD, Jegla TJ, Kaprielian R, Backx PH (1999) Regional contributions of Kv1.4, Kv4.2, and Kv4.3 to transient outward K+ current in rat ventricle. Am J Physiol 276:H1599–H1607
129. Williams BA, Dickenson DR, Beatch GN (1999) Kinetics of rate-dependent shortening of action potential duration in guinea-pig ventricle; effects of IK1 and IKr blockade. Br J Pharmacol 126:1426–1436
130. Wit AL, Rosen MR (1983) Pathophysiologic mechanisms of cardiac arrhythmias. Am Heart J 106:798–811
131. Wu MH, Su MJ, Sun SS (1999) Electrophysiological profile after inward rectifier K channel blockade by barium in isolated rabbit hearts. Altered repolarization and unmasked decremental conduction property. Europace 1:85–95
132. Xu H, Guo W, Nerbonne JM (1999) Four kinetically distinct depolarization-activated K+ currents in adult mouse ventricular myocytes. J Gen Physiol 113:661–678
133. Yan GX, Antzelevitch C (1996) Cellular basis for the electrocardiographic J wave. Circulation 93:372–379
134. Yan GX, Antzelevitch C (1998) Cellular basis for the normal T wave and the electrocardiographic manifestations of the long QT syndrome. Circulation 98:1928–1936
135. Yan GX, Shimizu W, Antzelevitch C (1998) Characteristics and distribution of M cells in arterially perfused canine left ventricular wedge preparations. Circulation 98:1921–1927
136. Yang T, Roden DM (1996) Extracellular potassium modulation of drug block of IKr. Implications for torsade de pointes and reverse use-dependence. Circulation 93:407–411
137. Yue L, Feng J, Gaspo R, Li GR, Wang Z, Nattel S (1997) Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ Res 81:512–525
138. Yue L, Feng J, Wang Z, Nattel S (1999) Adrenergic control of the ultrarapid delayed rectifier current in canine atrial myocytes. J Physiol 516:385–398
139. Zaza A, Belardinelli L, Shryock JC (2008) Pathophysiology and pharmacology of the cardiac “late sodium current”. Pharmacol Ther 119:326–339