H J Witchel

Summary

Affiliation: University of Bristol
Country: UK

Publications

  1. ncbi request reprint Inhibitory actions of the selective serotonin re-uptake inhibitor citalopram on HERG and ventricular L-type calcium currents
    Harry J Witchel
    Cardiovascular Research Laboratories and Department of Physiology, School of Medical Sciences, Bristol, UK
    FEBS Lett 512:59-66. 2002
  2. pmc Inhibition of HERG K+ current and prolongation of the guinea-pig ventricular action potential by 4-aminopyridine
    J M Ridley
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK
    J Physiol 549:667-72. 2003
  3. pmc Inhibition of the HERG potassium channel by the tricyclic antidepressant doxepin
    R S Duncan
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol, BS8 1TD, UK
    Biochem Pharmacol 74:425-37. 2007
  4. ncbi request reprint Troubleshooting problems with in vitro screening of drugs for QT interval prolongation using HERG K+ channels expressed in mammalian cell lines and Xenopus oocytes
    Harry J Witchel
    Cardiovascular Research Laboratories, Department of Physiology, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK
    J Pharmacol Toxicol Methods 48:65-80. 2002
  5. ncbi request reprint The hERG potassium channel as a therapeutic target
    Harry J Witchel
    University of Bristol, School of Medical Sciences, Department of Physiology, Bristol, BS8 1TD, UK
    Expert Opin Ther Targets 11:321-36. 2007
  6. ncbi request reprint Psychotropic drugs, cardiac arrhythmia, and sudden death
    Harry J Witchel
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University of Bristol, Bristol, United Kingdom
    J Clin Psychopharmacol 23:58-77. 2003
  7. ncbi request reprint The low-potency, voltage-dependent HERG blocker propafenone--molecular determinants and drug trapping
    Harry J Witchel
    Cardiovascular Research Laboratories and Department of Physiology, School of Medical Sciences, University of Bristol, Bristol, BS8 1TD, UK
    Mol Pharmacol 66:1201-12. 2004
  8. ncbi request reprint Familial and acquired long qt syndrome and the cardiac rapid delayed rectifier potassium current
    H J Witchel
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University of Bristol, United Kingdom
    Clin Exp Pharmacol Physiol 27:753-66. 2000
  9. ncbi request reprint Time course and voltage dependence of expressed HERG current compared with native "rapid" delayed rectifier K current during the cardiac ventricular action potential
    J C Hancox
    Department of Physiology, School of Medical Sciences, University Walk, Bristol, BS8 1TD, UK
    Pflugers Arch 436:843-53. 1998
  10. ncbi request reprint Comparative effects of the short QT N588K mutation at 37 degrees C on hERG K+ channel current during ventricular, Purkinje fibre and atrial action potentials: an action potential clamp study
    M J McPate
    Department of Physiology and Pharmacology, Bristol Heart Institute, School of Medical Sciences, The University of Bristol, University Walk, Bristol, UK
    J Physiol Pharmacol 60:23-41. 2009

Collaborators

Detail Information

Publications32

  1. ncbi request reprint Inhibitory actions of the selective serotonin re-uptake inhibitor citalopram on HERG and ventricular L-type calcium currents
    Harry J Witchel
    Cardiovascular Research Laboratories and Department of Physiology, School of Medical Sciences, Bristol, UK
    FEBS Lett 512:59-66. 2002
    ..The effects of citalopram on both calcium current amplitude and the I(Ca,L) 'window' may help to explain citalopram's good cardiac safety profile, given its propensity to block HERG at excessive dosages...
  2. pmc Inhibition of HERG K+ current and prolongation of the guinea-pig ventricular action potential by 4-aminopyridine
    J M Ridley
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK
    J Physiol 549:667-72. 2003
    ..We conclude that by blocking the alpha-subunit of the IKr channel, millimolar concentrations of 4-AP can modulate ventricular repolarisation independently of any action on ITO,1...
  3. pmc Inhibition of the HERG potassium channel by the tricyclic antidepressant doxepin
    R S Duncan
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol, BS8 1TD, UK
    Biochem Pharmacol 74:425-37. 2007
    ..Notably, this study also establishes doxepin as an effective inhibitor of mutant (N588K) HERG channels responsible for variant 1 of the short QT syndrome...
  4. ncbi request reprint Troubleshooting problems with in vitro screening of drugs for QT interval prolongation using HERG K+ channels expressed in mammalian cell lines and Xenopus oocytes
    Harry J Witchel
    Cardiovascular Research Laboratories, Department of Physiology, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK
    J Pharmacol Toxicol Methods 48:65-80. 2002
    ..In Xenopus oocytes, endogenous chloride currents, insufficient superfusate flow, diminished HERG current and HERG current 'run up' may create difficulties...
  5. ncbi request reprint The hERG potassium channel as a therapeutic target
    Harry J Witchel
    University of Bristol, School of Medical Sciences, Department of Physiology, Bristol, BS8 1TD, UK
    Expert Opin Ther Targets 11:321-36. 2007
    ..Future developments will synthesise preclinical data on hERG with other criteria to determine net arrhythmogenic risk. Also, the molecular actions of hERG and its genetics will be elucidated in detail to allow clinical risk reduction...
  6. ncbi request reprint Psychotropic drugs, cardiac arrhythmia, and sudden death
    Harry J Witchel
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University of Bristol, Bristol, United Kingdom
    J Clin Psychopharmacol 23:58-77. 2003
    ....
  7. ncbi request reprint The low-potency, voltage-dependent HERG blocker propafenone--molecular determinants and drug trapping
    Harry J Witchel
    Cardiovascular Research Laboratories and Department of Physiology, School of Medical Sciences, University of Bristol, Bristol, BS8 1TD, UK
    Mol Pharmacol 66:1201-12. 2004
    ..This provides further evidence for the existence of gating-induced changes in the spatial location of Phe656 side chains...
  8. ncbi request reprint Familial and acquired long qt syndrome and the cardiac rapid delayed rectifier potassium current
    H J Witchel
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University of Bristol, United Kingdom
    Clin Exp Pharmacol Physiol 27:753-66. 2000
    ..Until such time, awareness of the QT-prolongation risk of particular agents is important for the clinician...
  9. ncbi request reprint Time course and voltage dependence of expressed HERG current compared with native "rapid" delayed rectifier K current during the cardiac ventricular action potential
    J C Hancox
    Department of Physiology, School of Medical Sciences, University Walk, Bristol, BS8 1TD, UK
    Pflugers Arch 436:843-53. 1998
    ....
  10. ncbi request reprint Comparative effects of the short QT N588K mutation at 37 degrees C on hERG K+ channel current during ventricular, Purkinje fibre and atrial action potentials: an action potential clamp study
    M J McPate
    Department of Physiology and Pharmacology, Bristol Heart Institute, School of Medical Sciences, The University of Bristol, University Walk, Bristol, UK
    J Physiol Pharmacol 60:23-41. 2009
    ..Changes in the timing of outward I(hERG) transients elicited by premature stimuli following AP commands indicate that SQT1 may alter the protection that hERG provides cardiac tissue against premature arrhythmogenic stimuli...
  11. ncbi request reprint Effects of the class III antiarrhythmic agent dofetilide (UK-68,798) on L-type calcium current from rabbit ventricular myocytes
    A A Paul
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, Bristol, UK
    J Pharm Pharmacol 53:1671-8. 2001
    ..The findings support the notion that dofetilide is a highly selective Class III antiarrhythmic agent, devoid of Class IV antiarrhythmic activity...
  12. ncbi request reprint Alteration of HERG current profile during the cardiac ventricular action potential, following a pore mutation
    J C Hancox
    Department of Physiology, School of Medical Sciences, University of Bristol, United Kingdom
    Biochem Biophys Res Commun 253:719-24. 1998
    ..These data provide a direct demonstration that rapid inactivation normally plays a critical role in determining both time-course and voltage dependence of HERG/I(Kr) -current during the cardiac ventricular AP...
  13. pmc Pharmacology of the short QT syndrome N588K-hERG K+ channel mutation: differential impact on selected class I and class III antiarrhythmic drugs
    M J McPate
    Cardiovascular Research Laboratories, Department of Physiology and Pharmacology, School of Medical Sciences, University of Bristol, Bristol, UK
    Br J Pharmacol 155:957-66. 2008
    ....
  14. ncbi request reprint Potent inhibition of human cardiac potassium (HERG) channels by the anti-estrogen agent clomiphene-without QT interval prolongation
    Kathryn H Yuill
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK
    Biochem Biophys Res Commun 318:556-61. 2004
    ....
  15. ncbi request reprint Preferential closed channel blockade of HERG potassium currents by chemically synthesised BeKm-1 scorpion toxin
    James T Milnes
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University of Bristol, University Walk, BS8 1TD, Bristol, UK
    FEBS Lett 547:20-6. 2003
    ..We conclude that synthetic BeKm-1 toxin blocks HERG preferentially through a closed (resting) state channel blockade mechanism, although some open channel blockade also occurs...
  16. ncbi request reprint Characterisation of recombinant HERG K+ channel blockade by the Class Ia antiarrhythmic drug procainamide
    John M Ridley
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, BS8 1TD, Bristol, UK
    Biochem Biophys Res Commun 306:388-93. 2003
    ..Thus, differences between the chemical structure of PROC and other Class Ia antiarrhythmic drugs may help provide insight into chemical determinants of blocking potency for agents that bind to open/activated HERG channels...
  17. ncbi request reprint Depleting serotonin enhances both cardiovascular and psychological stress reactivity in recovered patients with anxiety disorders
    Simon J C Davies
    Psychopharmacology Unit, University of Bristol, Whitson Street, Bristol BS1 8NY, United Kingdom
    J Clin Psychopharmacol 26:414-8. 2006
    ....
  18. ncbi request reprint Tryptophan depletion reverses the therapeutic effect of selective serotonin reuptake inhibitors in social anxiety disorder
    Spilios V Argyropoulos
    Psychopharmacology Unit, University of Bristol, Bristol, United Kingdom
    Biol Psychiatry 56:503-9. 2004
    ..The present study tested the hypothesis that temporary reduction in central 5-HT transmission, through acute tryptophan depletion, could reverse the therapeutic effect of the SSRIs in social anxiety disorder (SAD) patients...
  19. pmc Blockade of HERG potassium currents by fluvoxamine: incomplete attenuation by S6 mutations at F656 or Y652
    James T Milnes
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK
    Br J Pharmacol 139:887-98. 2003
    ..Fluvoxamine is therefore quite distinct in this regard from previously studied agents...
  20. pmc Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine
    Ashok A Paul
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol, BS8 1TD
    Br J Pharmacol 136:717-29. 2002
    ..40 microM. 7. Our data are consistent with FLEC, PROPAF and QUIN exerting I(HERG) blockade at clinically relevant concentrations. The rank potency as HERG blockers of the Class I drugs tested in this study was QUIN=PROPAF>FLEC>>LIG...
  21. pmc hERG1a/1b heteromeric currents exhibit amplified attenuation of inactivation in variant 1 short QT syndrome
    M J McPate
    Department of Physiology and Pharmacology, Bristol Heart Institute, School of Medical Sciences, The University of Bristol, University Walk, Bristol BS8 1TD, UK
    Biochem Biophys Res Commun 386:111-7. 2009
    ....
  22. ncbi request reprint Disopyramide is an effective inhibitor of mutant HERG K+ channels involved in variant 1 short QT syndrome
    Mark J McPate
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, University of Bristol, BS8 1TD, UK
    J Mol Cell Cardiol 41:563-6. 2006
    ..Disopyramide is associated with QT prolongation in normal use and our findings provide a rational basis for its evaluation as a treatment for SQT1...
  23. doi request reprint Investigating dynamic protocol-dependence of hERG potassium channel inhibition at 37 degrees C: Cisapride versus dofetilide
    James T Milnes
    Department of Physiology and Pharmacology, School of Medical Sciences, University Walk, Bristol, BS8 1TD, UK
    J Pharmacol Toxicol Methods 61:178-91. 2010
    ..Furthermore, it evaluated dynamic (pulse-by-pulse) protocol-dependence of hERG channel inhibition by these drugs...
  24. ncbi request reprint Erythromycin block of the HERG K+ channel: accessibility to F656 and Y652
    Rona S Duncan
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK
    Biochem Biophys Res Commun 341:500-6. 2006
    ..In computer models of the channel, erythromycin could make several direct contacts with F656, but not with Y652, in the open-state model, and erythromycin was unable to fit into a closed-state channel model...
  25. ncbi request reprint Clemastine, a conventional antihistamine, is a high potency inhibitor of the HERG K+ channel
    John M Ridley
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK
    J Mol Cell Cardiol 40:107-18. 2006
    ..The disparity between clemastine's potent IHERG inhibition and a lack of QT-prolongation in normal clinical use underscores the need to interpret HERG IC50 data for novel compounds in the context of information from other safety assays...
  26. ncbi request reprint The N588K-HERG K+ channel mutation in the 'short QT syndrome': mechanism of gain-in-function determined at 37 degrees C
    Mark J McPate
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK
    Biochem Biophys Res Commun 334:441-9. 2005
    ....
  27. ncbi request reprint High affinity HERG K(+) channel blockade by the antiarrhythmic agent dronedarone: resistance to mutations of the S6 residues Y652 and F656
    John M Ridley
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK
    Biochem Biophys Res Commun 325:883-91. 2004
    ..These findings demonstrate that high affinity drug blockade of I(HERG) can occur without a strong dependence on the Y652 and F656 aromatic amino-acid residues...
  28. ncbi request reprint Lidoflazine is a high affinity blocker of the HERG K(+)channel
    John M Ridley
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol BS8 1TD, United Kingdom
    J Mol Cell Cardiol 36:701-5. 2004
    ....
  29. ncbi request reprint Inhibition of ERK and JNK decreases both osmosensitive taurine release and cell proliferation in glioma cells
    Mark J Belsey
    Department of Pharmacology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK
    Neurochem Res 32:1940-9. 2007
    ....
  30. ncbi request reprint Moderately elevated plasma homocysteine impairs functional endothelial recovery following denudation of mouse carotid arteries
    Alastair L Miller
    Bristol Heart Institute, University of Bristol, Bristol, UK
    Metabolism 53:760-5. 2004
    ..69, P <.003). These data suggest that even modest homocysteinemia has a deleterious effect on the function of healed endothelium in mouse arteries. This may account for its adverse influence on chronic cardiovascular disease...
  31. ncbi request reprint hERG K+ channel blockade by the antipsychotic drug thioridazine: An obligatory role for the S6 helix residue F656
    James T Milnes
    Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK
    Biochem Biophys Res Commun 351:273-80. 2006
    ....
  32. ncbi request reprint Acquired QT interval prolongation and HERG: implications for drug discovery and development
    Keith Finlayson
    Fujisawa Institute of Neuroscience in Edinburgh, University of Edinburgh, 1 George Square, Edinburgh EH8 9JZ, UK
    Eur J Pharmacol 500:129-42. 2004
    ..Here we review the relationship between HERG, long QT syndrome and TdP, together with a summary of the associated regulatory issues, and developments in pre-clinical screening...