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Biophysics and Molecular Biology of Cardiac Ion Channels for the Safety Pharmacologist

  • Chapter
Principles of Safety Pharmacology

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 229))

Abstract

Cardiac safety pharmacology is a continuously evolving discipline that uses the basic principles of pharmacology in a regulatory-driven process to generate data to inform risk/benefit assessment of a new chemical entity (NCE). The aim of cardiac safety pharmacology is to characterise the pharmacodynamic/pharmacokinetic (PK/PD) relationship of a drug’s adverse effects on the heart using continuously evolving methodology. Unlike Toxicology, safety pharmacology includes within its remit a regulatory requirement to predict the risk of rare cardiotoxic (potentially lethal) events such as torsades de pointes (TdP), which is statistically associated with drug-induced changes in the QT interval of the ECG due to blockade of I Kr or K v11.1 current encoded by hERG. This gives safety pharmacology its unique character. The key issues for the safety pharmacology assessment of a drug on the heart are detection of an adverse effect liability, projection of the data into safety margin calculation and clinical safety monitoring. This chapter will briefly review the current cardiac safety pharmacology paradigm outlined in the ICH S7A and ICH S7B guidance documents and the non-clinical models and methods used in the evaluation of new chemical entities in order to define the integrated risk assessment for submission to regulatory authorities. An overview of how the present cardiac paradigm was developed will be discussed, explaining how it was based upon marketing authorisation withdrawal of many non-cardiovascular compounds due to unanticipated proarrhythmic effects. The role of related biomarkers (of cardiac repolarisation, e.g. prolongation of the QT interval of the ECG) will be considered. We will also provide an overview of the ‘non-hERG-centric’ concepts utilised in the evolving comprehensive in vitro proarrhythmia assay (CIPA) that details conduct of the proposed ion channel battery test, use of human stem cells and application of in silico models to early cardiac safety assessment. The summary of our current understanding of the triggers of TdP will include the interplay between action potential (AP) prolongation, early and delayed afterdepolarisation and substrates for re-entry arrhythmias.

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References

  • Aldrich RW, Corey DP, Stevens CF (1983) A reinterpretation of mammalian sodium channel gating based on single channel recording. Nature 306:436–441

    Article  CAS  PubMed  Google Scholar 

  • 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

  • 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

  • Antzelevitch C (2004) Arrhythmogenic mechanisms of QT prolonging drugs: Is QT prolongation really the problem? J Electrocardiol 37:15–24

    Article  PubMed  Google Scholar 

  • Antzelevitch C, Shimizu W (2002) Cellular mechanisms underlying the long QT syndrome. Curr Opin Cardiol 17:43–51

    Article  PubMed  Google Scholar 

  • Antzelevitch C, Sicouri S (1994) Clinical relevance of cardiac arrhythmias generated by after-depolarizations. Role of M cells in the generation of U Waves, triggered activity and torsade de pointes. J Am Coll Cardiol 23:259–277

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Armstrong CM, Hille B (1998) Voltage-gated ion channels and electrical excitability. Neuron 20:371–380

    Article  CAS  PubMed  Google Scholar 

  • Armstrong CM, Bezanilla F, Rojas E (1973) Destruction of sodium conductance inactivation in squid axons perfused with pronase. J Gen Physiol 62:375–391

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ashcroft FM, Gribble FM (2000) New windows on the mechanism of action of K(ATP) channel openers. Trends Pharmacol Sci 11:439–445

    Article  Google Scholar 

  • 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 drug-induced torsades de pointes in humans. Drug Saf 29:237–254

    Article  CAS  PubMed  Google Scholar 

  • Authier S, Pugsley MK, Curtis MJ (2015) Hemodynamic assessment in safety pharmacology. In: Pugsley MK, Curtis MJ (eds) Principles of safety pharmacology. Springer, Heidelberg

    Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bell RM, Mocanu MM, Yellon DM (2011) Retrograde heart perfusion: the Langendorff technique of isolated heart perfusion. J Mol Cell Cardiol 50:940–950

    Article  CAS  PubMed  Google Scholar 

  • Binah O, Rosen MR (1992) Mechanisms of ventricular arrhythmias. Circulation 85:I25–I31

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Botting JH, Curtis MJ, Walker MJA (1985) Arrhythmias associated with myocardial ischaemia and infarction. Mol Aspects Med 8:311–422

    Article  Google Scholar 

  • Boyden PA, Hirose M, Dun W (2010) Cardiac Purkinje cells. Heart Rhythm 7:127–135

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Brack KE (2014) The heart's ‘little brain’ controlling cardiac function in the rabbit. Exp Physiol. doi:10.1113/expphysiol.2014.080168

    PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Catterall WA (1980) Neurotoxins that act on voltage-sensitive sodium channels in excitable membranes. Annu Rev Pharmacol Toxicol 20:15–43

    Article  CAS  PubMed  Google Scholar 

  • Catterall WA (1993) Structure and function of voltage-gated ion channels. Trends Neurosci 16:500–506

    Article  CAS  PubMed  Google Scholar 

  • Catterall WA (1995) Structure and function of voltage-gated ion channels. Annu Rev Biochem 64:493–531

    Article  CAS  PubMed  Google Scholar 

  • Catterall WA (2001) A 3D view of sodium channels. Nature 409:988–991

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chiu SY (1977) Inactivation of sodium channels: second order kinetics in myelinated nerve. J Physiol 273:573–596

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Clusin WT (2003) Calcium and cardiac arrhythmias: DADs, EADs, and alternans. Crit Rev Clin Lab Sci 40:337–375

    Article  CAS  PubMed  Google Scholar 

  • Coraboeuf E, Carmeleit E (1982) Existence of two transient outward currents in sheep cardiac Purkinje fibers. Pflugers Arch 392:352–359

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Curtis MJ (1998) Characterisation, utilisation and clinical relevance of isolated perfused heart models of ischaemia-induced ventricular fibrillation. Cardiovasc Res 39:194–215

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Denac H, Mevissen M, Scholtysik G (2000) Structure, function and pharmacology of voltage-gated sodium channels. Naunyn Schmiedebergs Arch Pharmacol 362:453–479

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • DeWaard M, Pragnel M, Campbell KP (1994) Ca2+ channel regulation by a conserved beta subunit domain. Neuron 13:495–503

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • Einthoven WE (1912) The different forms of the human electrocardiogram and their signification. Lancet 1:853–861

    Article  Google Scholar 

  • Ertel EA, Campbell KP, Harpold MM, Hofmann F, Mori Y et al (2000) Nomenclature of voltage-gated calcium channels. Neuron 25:533–535

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Gintant GA (1995) Regional differences in IK density in canine left ventricle: role of IKs in electrical heterogeneity. Am J Physiol 268:H604–H613

    CAS  PubMed  Google Scholar 

  • Goineau S, Castagné 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

    Article  CAS  PubMed  Google Scholar 

  • Goldin AL (1993) Accessory subunits and sodium channel inactivation. Curr Opin Neurobiol 3:272–277

    Article  CAS  PubMed  Google Scholar 

  • Goldin AL (2001) Resurgence of sodium channel research. Annu Rev Physiol 63:871–894

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Hill JL, Gettes LS (1980) Effect of acute coronary artery occlusion on local myocardial extracellular K+ activity in swine. Circulation 61:769–778

    Article  Google Scholar 

  • Hille B (1992) Ionic channels of excitable membranes. Sinauer Associates, Sunderland

    Google Scholar 

  • Hodgkin AL, Huxley AF (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol 116:500–544

    Article  Google Scholar 

  • Hondeghem LM (1994) Computer aided development of antiarrhythmic agents with class IIIa properties. J Cardiovasc Electrophysiol 5:711–721

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Hondeghem LM, Katzung BG (1977) Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta 472:373–398

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hubbard JI, Llinas R, Quastel DMJ (1969) Electrophysiological analysis of synaptic transmission. Edward Arnold, London

    Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Klugbauer N, Lacinova L, Marais E, Hobom M, Hofmann F (1999) Molecular diversity of the calcium channel alpha2delta subunit. J Neurosci 19:684–691

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Li H, Fuentes-Garcia J, Towbin JA (2000) Current concepts in long QT syndrome. Pediatr Cardiol 21:542–550

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Luo C, Rudy Y (1991) A model of the ventricular action potential: depolarization, repolarization, and their interaction. Circ Res 68:1501–1526

    Article  CAS  PubMed  Google Scholar 

  • MacKinnon R, Cohen SL, Kuo A, Lee A, Chait BT (1998) Structural conservation in prokaryotic and eukaryotic potassium channels. Science 280:106–109

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Malik M, Camm AJ (2001) Evaluation of drug-induced QT Interval prolongation: implications for drug approval and labelling. Drug Saf 24:323–351

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nerbonne JM (2000) Molecular basis of functional voltage-gated K+ channel diversity in the mammalian myocardium. J Physiol 525:285–298

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • O’Hara T, Virág L, Varró 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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Puddu PE, Legrand J-C, Sallé 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

    Article  CAS  PubMed  Google Scholar 

  • Pugsley MK (2002) Antiarrhythmic drug development: historical review and future perspective. Drug Dev Res 55:3–16

    Article  CAS  Google Scholar 

  • Pugsley MK, Quastel DMJ (1998) Basic cardiac electrophysiology. In: Pugsley MK, Walker MJA (eds) Methods in cardiac electrophysiology. CRC Press, Boca Raton, FL

    Google Scholar 

  • Pugsley MK, Authier S, Curtis MJ (2008) Principles of safety pharmacology. Br J Pharmacol 154:1382–1399

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Roberts R, Brugada R (2000) Genetic aspects of arrhythmias. Am J Med Genet 97:310–318

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Roy M, Dumaine R, Brown AM (1996) HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine. Circulation 94:817–823

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Saint DA (2007) The cardiac persistent sodium current: an appealing therapeutic target? Br J Pharmacol 153:1133–1142

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Saint DA, Ju YK, Gage PW (1992) A persistent sodium current in rat ventricular myocytes. J Physiol 453:219–231

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Schaper W, Schaper J, Winkler B (1986) The collateral circulation of the heart. J Mol Cell Cardiol 18:60

    Google Scholar 

  • Sedmera D, Gourdie RG (2014) Why do we have Purkinje fibers deep in our heart? Physiol Res 63:S9–S18

    PubMed  Google Scholar 

  • Shah RR (2001) Drug-induced prolongation of the QT interval: why the regulatory concern? Fundam Clin Pharmacol 16:119–124

    Article  Google Scholar 

  • Snyders DJ (1999) Structure and function of cardiac potassium channels. Cardiovasc Res 42:377–390

    Article  CAS  PubMed  Google Scholar 

  • Striessnig J (1999) Pharmacology, structure and function of cardiac L-type Ca2+ channels. Cell Physiol Biochem 9:242–269

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Vaughan Williams EM (1984) A classification of antiarrhythmic actions reassessed after a decade of new drugs. J Clin Pharmacol 24:129–147

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Vos MA (2001) Preclinical evaluation of antiarrhythmic drugs: new drugs should be safe to be successful. J Cardiovasc Electrophysiol 12:1034–1036

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Weiss JN, Venkatesh N (1993) Metabolic regulation of cardiac ATP-sensitive K+ channels. Cardiovasc Drugs Ther 7:499–505

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wit AL, Rosen MR (1983) Pathophysiologic mechanisms of cardiac arrhythmias. Am Heart J 106:798–811

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yan GX, Antzelevitch C (1996) Cellular basis for the electrocardiographic J wave. Circulation 93:372–379

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zaza A, Belardinelli L, Shryock JC (2008) Pathophysiology and pharmacology of the cardiac “late sodium current”. Pharmacol Ther 119:326–339

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Global Safety Pharmacology and Toxicology/Pathology, Janssen Pharmaceuticals LLC, 1000 Route 202 South, Raritan, NJ, 08869, USA

    Michael K. Pugsley

  2. Cardiovascular Division, Faculty of Life Sciences & Medicine, King’s College London, Rayne Institute, St Thomas’ Hospital, London, UK

    Michael J. Curtis

  3. Porolt, 3055 NW 57th Street, Seattle, WA, 98107, USA

    Eric S. Hayes

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  1. Michael K. Pugsley
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  2. Michael J. Curtis
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  3. Eric S. Hayes
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Correspondence to Michael K. Pugsley .

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Editors and Affiliations

  1. Drug Safety Sciences, Johnson & Johnson PR&D, Raritan, New Jersey, USA

    Michael K. Pugsley

  2. Cardiovascular Division, Faculty of Life Sciences & Medicine, St Thomas' Hospital, King's College London, Rayne Institute, London, United Kingdom

    Michael J Curtis

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Pugsley, M.K., Curtis, M.J., Hayes, E.S. (2015). Biophysics and Molecular Biology of Cardiac Ion Channels for the Safety Pharmacologist. In: Pugsley, M., Curtis, M. (eds) Principles of Safety Pharmacology. Handbook of Experimental Pharmacology, vol 229. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-46943-9_7

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