Table of Contents Author Guidelines Submit a Manuscript
BioMed Research International
Volume 2013, Article ID 872454, 18 pages
http://dx.doi.org/10.1155/2013/872454
Review Article

Hyperpolarization-Activated Current, , in Mathematical Models of Rabbit Sinoatrial Node Pacemaker Cells

Department of Anatomy, Embryology and Physiology, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands

Received 4 April 2013; Accepted 31 May 2013

Academic Editor: Mohamed Boutjdir

Copyright © 2013 Arie O. Verkerk and Ronald Wilders. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. H. Irisawa, H. F. Brown, and W. Giles, “Cardiac pacemaking in the sinoatrial node,” Physiological Reviews, vol. 73, no. 1, pp. 197–227, 1993. View at Google Scholar · View at Scopus
  2. M. R. Boyett, H. Honjo, and I. Kodama, “The sinoatrial node, a heterogeneous pacemaker structure,” Cardiovascular Research, vol. 47, no. 4, pp. 658–687, 2000. View at Publisher · View at Google Scholar · View at Scopus
  3. H. Satoh, “Sino-atrial nodal cells of mammalian hearts: ionic currents and gene expression of pacemaker ionic channels,” Journal of Smooth Muscle Research, vol. 39, no. 5, pp. 175–193, 2003. View at Publisher · View at Google Scholar · View at Scopus
  4. B. Couette, L. Marger, J. Nargeot, and M. E. Mangoni, “Physiological and pharmacological insights into the role of ionic channels in cardiac pacemaker activity,” Cardiovascular & Hematological Disorders, vol. 6, no. 3, pp. 169–190, 2006. View at Publisher · View at Google Scholar · View at Scopus
  5. H. Dobrzynski, M. R. Boyett, and R. H. Anderson, “New insights into pacemaker activity: promoting understanding of sick sinus syndrome,” Circulation, vol. 115, no. 14, pp. 1921–1932, 2007. View at Publisher · View at Google Scholar · View at Scopus
  6. V. A. Maltsev and E. G. Lakatta, “Normal heart rhythm is initiated and regulated by an intracellular calcium clock within pacemaker cells,” Heart Lung & Circulation, vol. 16, no. 5, pp. 335–348, 2007. View at Publisher · View at Google Scholar · View at Scopus
  7. M. E. Mangoni and J. Nargeot, “Genesis and regulation of the heart automaticity,” Physiological Reviews, vol. 88, no. 3, pp. 919–982, 2008. View at Publisher · View at Google Scholar · View at Scopus
  8. A. O. Verkerk, A. C. G. van Ginneken, and R. Wilders, “Pacemaker activity of the human sinoatrial node: role of the hyperpolarization-activated current, If,” International Journal of Cardiology, vol. 132, no. 3, pp. 318–336, 2009. View at Publisher · View at Google Scholar · View at Scopus
  9. E. G. Lakatta, V. A. Maltsev, and T. M. Vinogradova, “A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart's pacemaker,” Circulation Research, vol. 106, no. 4, pp. 659–673, 2010. View at Publisher · View at Google Scholar · View at Scopus
  10. H. Brown and D. DiFrancesco, “Voltage-clamp investigations of membrane currents underlying pace-maker activity in rabbit sino-atrial node,” Journal of Physiology, vol. 308, pp. 331–351, 1980. View at Google Scholar · View at Scopus
  11. D. DiFrancesco and P. Tortora, “Direct activation of cardiac pacemaker channels by intracellular cyclic AMP,” Nature, vol. 351, no. 6322, pp. 145–147, 1991. View at Publisher · View at Google Scholar · View at Scopus
  12. H. F. Brown, D. DiFrancesco, and S. J. Noble, “How does adrenaline accelerate the heart?” Nature, vol. 280, no. 5719, pp. 235–236, 1979. View at Google Scholar · View at Scopus
  13. A. Noma, H. Irisawa, and S. Kokobun, “Slow current systems in the A-V node of the rabbit heart,” Nature, vol. 285, no. 5762, pp. 228–229, 1980. View at Google Scholar · View at Scopus
  14. D. DiFrancesco, “A study of the ionic nature of the pace-maker current in calf Purkinje fibres,” Journal of Physiology, vol. 314, pp. 377–393, 1981. View at Google Scholar · View at Scopus
  15. F. Roubille and J. C. Tardif, “New therapeutic targets in cardiology: heart failure and arrhythmia: HCN channels,” Circulation, vol. 127, no. 19, pp. 1986–1996, 2013. View at Google Scholar
  16. N. J. Chandler, I. D. Greener, J. O. Tellez et al., “Molecular architecture of the human sinus node insights into the function of the cardiac pacemaker,” Circulation, vol. 119, no. 12, pp. 1562–1575, 2009. View at Publisher · View at Google Scholar · View at Scopus
  17. E. Schulze-Bahr, A. Neu, P. Friederich et al., “Pacemaker channel dysfunction in a patient with sinus node disease,” Journal of Clinical Investigation, vol. 111, no. 10, pp. 1537–1545, 2003. View at Publisher · View at Google Scholar · View at Scopus
  18. K. Ueda, K. Nakamura, T. Hayashi et al., “Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia,” Journal of Biological Chemistry, vol. 279, no. 26, pp. 27194–27198, 2004. View at Publisher · View at Google Scholar · View at Scopus
  19. R. Milanesi, M. Baruscotti, T. Gnecchi-Ruscone, and D. DiFrancesco, “Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel,” The New England Journal of Medicine, vol. 354, no. 2, pp. 151–157, 2006. View at Publisher · View at Google Scholar · View at Scopus
  20. E. Nof, D. Luria, D. Brass et al., “Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia,” Circulation, vol. 116, no. 5, pp. 463–470, 2007. View at Publisher · View at Google Scholar · View at Scopus
  21. A. Laish-Farkash, M. Glikson, D. Brass et al., “A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews,” Journal of Cardiovascular Electrophysiology, vol. 21, no. 12, pp. 1365–1372, 2010. View at Publisher · View at Google Scholar · View at Scopus
  22. P. A. Schweizer, N. Duhme, D. Thomas et al., “cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control,” Circulation: Arrhythmia and Electrophysiology, vol. 3, no. 5, pp. 542–552, 2010. View at Publisher · View at Google Scholar · View at Scopus
  23. N. Duhme, P. A. Schweizer, D. Thomas et al., “Altered HCN4 channel C-linker interaction is associated with familial tachycardia-bradycardia syndrome and atrial fibrillation,” European Heart Journal, 2013. View at Publisher · View at Google Scholar
  24. R. B. Robinson, P. R. Brink, I. S. Cohen, and M. R. Rosen, “If and the biological pacemaker,” Pharmacological Research, vol. 53, no. 5, pp. 407–415, 2006. View at Publisher · View at Google Scholar · View at Scopus
  25. C.-W. Siu, D. K. Lieu, and R. A. Li, “HCN-encoded pacemaker channels: from physiology and biophysics to bioengineering,” Journal of Membrane Biology, vol. 214, no. 3, pp. 115–122, 2006. View at Publisher · View at Google Scholar · View at Scopus
  26. M. R. Rosen, P. R. Brink, I. S. Cohen, and R. B. Robinson, “Biological pacemakers based on If,” Medical & Biological Engineering & Computing, vol. 45, no. 2, pp. 157–166, 2007. View at Publisher · View at Google Scholar · View at Scopus
  27. H. C. Cho and E. Marbán, “Biological therapies for cardiac arrhythmias: can genes and cells replace drugs and devices?” Circulation Research, vol. 106, no. 4, pp. 674–685, 2010. View at Publisher · View at Google Scholar · View at Scopus
  28. M. R. Rosen, R. B. Robinson, P. R. Brink, and I. S. Cohen, “The road to biological pacing,” Nature Reviews Cardiology, vol. 8, no. 11, pp. 656–666, 2011. View at Publisher · View at Google Scholar · View at Scopus
  29. R. Li, “Gene- and cell-based bio-artificial pacemaker: what basic and translational lessons have we learned?” Gene Therapy, vol. 19, no. 6, pp. 588–595, 2012. View at Google Scholar
  30. M. M. G. J. van Borren, A. O. Verkerk, R. Wilders et al., “Effects of muscarinic receptor stimulation on Ca2+ transient, cAMP production and pacemaker frequency of rabbit sinoatrial node cells,” Basic Research in Cardiology, vol. 105, no. 1, pp. 73–87, 2010. View at Publisher · View at Google Scholar · View at Scopus
  31. Y. Yaniv, S. Sirenko, B. D. Ziman, H. A. Spurgeon, V. A. Maltsev, and E. G. Lakatta, “New evidence for coupled clock regulation of the normal automaticity of sinoatrial nodal pacemaker cells: bradycardic effects of ivabradine are linked to suppression of intracellular Ca2+ cycling,” Journal of Molecular and Cellular Cardiology, 2013. View at Publisher · View at Google Scholar
  32. J. D. Lippiat, “Whole-cell recording using the perforated patch clamp technique,” Methods in Molecular Biology, vol. 491, pp. 141–149, 2008. View at Publisher · View at Google Scholar · View at Scopus
  33. H. Yu, J. Wu, I. Potapova et al., “MinK-related peptide 1: a β subunit for the HCN ion channel subunit family enhances expression and speeds activation,” Circulation Research, vol. 88, no. 12, pp. E84–E87, 2001. View at Google Scholar · View at Scopus
  34. N. Decher, F. Bundis, R. Vajna, and K. Steinmeyer, “KCNE2 modulates current amplitudes and activation kinetics of HCN4: influence of KCNE family members on HCN4 currents,” Pflügers Archiv European Journal of Physiology, vol. 446, no. 6, pp. 633–640, 2003. View at Publisher · View at Google Scholar · View at Scopus
  35. J. Qu, Y. Kryukova, I. A. Potapova et al., “MiRP1 modulates HCN2 channel expression and gating in cardiac myocytes,” Journal of Biological Chemistry, vol. 279, no. 42, pp. 43497–43502, 2004. View at Publisher · View at Google Scholar · View at Scopus
  36. W.-K. Ho, H. F. Brown, and D. Noble, “High selectivity of the if channel to Na+ and K+ in rabbit isolated sinoatrial node cells,” Pflügers Archiv European Journal of Physiology, vol. 426, no. 1-2, pp. 68–74, 1994. View at Google Scholar · View at Scopus
  37. A. M. Frace, F. Maruoka, and A. Noma, “Control of the hyperpolarization-activated cation current by external anions in rabbit sino-atrial node cells,” Journal of Physiology, vol. 453, pp. 307–318, 1992. View at Google Scholar · View at Scopus
  38. D. DiFrancesco, A. Ferroni, M. Mazzanti, and C. Tromba, “Properties of the hyperpolarizing-activated current (if) in cells isolated from the rabbit sino-atrial node,” Journal of Physiology, vol. 377, pp. 61–88, 1986. View at Google Scholar · View at Scopus
  39. A. C. G. van Ginneken and W. Giles, “Voltage clamp measurements of the hyperpolarization-activated inward current If in single cells from rabbit sino-atrial node,” Journal of Physiology, vol. 434, pp. 57–83, 1991. View at Google Scholar · View at Scopus
  40. A. O. Verkerk, H. M. den Ruijter, J. Bourier et al., “Dietary fish oil reduces pacemaker current and heart rate in rabbit,” Heart Rhythm, vol. 6, no. 10, pp. 1485–1492, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. A. M. Frace, F. Maruoka, and A. Noma, “External K+ increases Na+ conductance of the hyperpolarization-activated current in rabbit cardiac pacemaker cells,” Pflügers Archiv European Journal of Physiology, vol. 421, no. 2-3, pp. 97–99, 1992. View at Google Scholar · View at Scopus
  42. X. Yu, X.-W. Chen, P. Zhou et al., “Calcium influx through If channels in rat ventricular myocytes,” American Journal of Physiology Cell Physiology, vol. 292, no. 3, pp. C1147–C1155, 2007. View at Publisher · View at Google Scholar · View at Scopus
  43. G. Michels, M. C. Brandt, N. Zagidullin et al., “Direct evidence for calcium conductance of hyperpolarization-activated cyclic nucleotide-gated channels and human native If at physiological calcium concentrations,” Cardiovascular Research, vol. 78, no. 3, pp. 466–475, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. M. Biel, C. Wahl-Schott, S. Michalakis, and X. Zong, “Hyperpolarization-activated cation channels: from genes to function,” Physiological Reviews, vol. 89, no. 3, pp. 847–885, 2009. View at Publisher · View at Google Scholar · View at Scopus
  45. R. Männikkö, S. Pandey, H. P. Larsson, and F. Elinder, “Hysteresis in the voltage dependence of HCN channels: conversion between two modes affects pacemaker properties,” Journal of General Physiology, vol. 125, no. 3, pp. 305–326, 2005. View at Publisher · View at Google Scholar · View at Scopus
  46. E. M. Azene, T. Xue, E. Marbán, G. F. Tomaselli, and R. A. Li, “Non-equilibrium behavior of HCN channels: insights into the role of HCN channels in native and engineered pacemakers,” Cardiovascular Research, vol. 67, no. 2, pp. 263–273, 2005. View at Publisher · View at Google Scholar · View at Scopus
  47. F. Elinder, R. Männikkö, S. Pandey, and H. P. Larsson, “Mode shifts in the voltage gating of the mouse and human HCN2 and HCN4 channels,” Journal of Physiology, vol. 575, no. 2, pp. 417–431, 2006. View at Publisher · View at Google Scholar · View at Scopus
  48. A. Bruening-Wright and H. P. Larsson, “Slow conformational changes of the voltage sensor during the mode shift in hyperpolarization-activated cyclic-nucleotide-gated channels,” Journal of Neuroscience, vol. 27, no. 2, pp. 270–278, 2007. View at Publisher · View at Google Scholar · View at Scopus
  49. Y. F. Xiao, N. Chandler, H. Dobrzynski et al., “Hysteresis in human HCN4 channels: a crucial feature potentially affecting sinoatrial node pacemaking,” Acta Physiologica Sinica, vol. 62, no. 1, pp. 1–13, 2010. View at Google Scholar
  50. A. Noma, M. Morad, and H. Irisawa, “Does the “pacemaker current” generate the diastolic depolarization in the rabbit SA node cells?” Pflügers Archiv European Journal of Physiology, vol. 397, no. 3, pp. 190–194, 1983. View at Google Scholar · View at Scopus
  51. D. DiFrancesco, “The contribution of the “pacemaker” current (if) to generation of spontaneous activity in rabbit sino-atrial node myocytes,” Journal of Physiology, vol. 434, pp. 23–40, 1991. View at Google Scholar · View at Scopus
  52. M. Vassalle, “The pacemaker current (If) does not play an important role in regulating SA node pacemaker activity,” Cardiovascular Research, vol. 30, no. 2, p. 310, 1995. View at Google Scholar · View at Scopus
  53. S. L. Lipsius, J. Hüser, and L. A. Blatter, “Intracellular Ca2+ release sparks atrial pacemaker activity,” News in Physiological Sciences, vol. 16, no. 3, pp. 101–106, 2001. View at Google Scholar · View at Scopus
  54. D. DiFrancesco, “Serious workings of the funny current,” Progress in Biophysics and Molecular Biology, vol. 90, no. 1–3, pp. 13–25, 2006. View at Publisher · View at Google Scholar · View at Scopus
  55. S. Herrmann, J. Stieber, G. Stöckl, F. Hofmann, and A. Ludwig, “HCN4 provides a “depolarization reserve” and is not required for heart rate acceleration in mice,” The EMBO Journal, vol. 26, no. 21, pp. 4423–4432, 2007. View at Publisher · View at Google Scholar · View at Scopus
  56. D. Harzheim, K. H. Pfeiffer, L. Fabritz et al., “Cardiac pacemaker function of HCN4 channels in mice is confined to embryonic development and requires cyclic AMP,” The EMBO Journal, vol. 27, no. 4, pp. 692–703, 2008. View at Publisher · View at Google Scholar · View at Scopus
  57. E. G. Lakatta and D. DiFrancesco, “What keeps us ticking: a funny current, a calcium clock, or both?” Journal of Molecular and Cellular Cardiology, vol. 47, no. 2, pp. 157–170, 2009. View at Publisher · View at Google Scholar · View at Scopus
  58. A. O. Verkerk and R. Wilders, “Relative importance of funny current in human versus rabbit sinoatrial node,” Journal of Molecular and Cellular Cardiology, vol. 48, no. 4, pp. 799–801, 2010. View at Publisher · View at Google Scholar · View at Scopus
  59. D. DiFrancesco, “Considerations on the size of currents required for pacemaking,” Journal of Molecular and Cellular Cardiology, vol. 48, no. 4, pp. 802–803, 2010. View at Publisher · View at Google Scholar · View at Scopus
  60. V. A. Maltsev and E. G. Lakatta, “Funny current provides a relatively modest contribution to spontaneous beating rate regulation of human and rabbit sinoatrial node cells,” Journal of Molecular and Cellular Cardiology, vol. 48, no. 4, pp. 804–806, 2010. View at Publisher · View at Google Scholar · View at Scopus
  61. D. DiFrancesco and D. Noble, “The funny current has a major pacemaking role in the sinus node,” Heart Rhythm, vol. 9, no. 2, pp. 299–301, 2012. View at Publisher · View at Google Scholar · View at Scopus
  62. V. A. Maltsev and E. G. Lakatta, “The funny current in the context of the coupled-clock pacemaker cell system,” Heart Rhythm, vol. 9, no. 2, pp. 302–307, 2012. View at Publisher · View at Google Scholar · View at Scopus
  63. D. DiFrancesco and D. Noble, “Rebuttal: “The funny current in the context of the coupled clock pacemaker cell system”,” Heart Rhythm, vol. 9, no. 3, pp. 457–458, 2012. View at Publisher · View at Google Scholar · View at Scopus
  64. E. G. Lakatta and V. A. Maltsev, “Rebuttal: what If the shoe doesn't fit? “the funny current has a major pacemaking role in the sinus node”,” Heart Rhythm, vol. 9, no. 3, pp. 459–460, 2012. View at Publisher · View at Google Scholar · View at Scopus
  65. R. Wilders, “Computer modelling of the sinoatrial node,” Medical & Biological Engineering & Computing, vol. 45, no. 2, pp. 189–207, 2007. View at Publisher · View at Google Scholar · View at Scopus
  66. V. A. Maltsev and E. G. Lakatta, “Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model,” American Journal of Physiology Heart and Circulatory Physiology, vol. 296, no. 3, pp. H594–H615, 2009. View at Publisher · View at Google Scholar · View at Scopus
  67. S. Severi, M. Fantini, L. A. Charawi, and D. DiFrancesco, “An updated computational model of rabbit sinoatrial action potential to investigate the mechanisms of heart rate modulation,” Journal of Physiology, vol. 590, part 18, pp. 4483–4499, 2012. View at Google Scholar
  68. A. O. Verkerk, R. Wilders, R. Coronel, J. H. Ravesloot, and E. E. Verheijck, “Ionic remodeling of sinoatrial node cells by heart failure,” Circulation, vol. 108, no. 6, pp. 760–766, 2003. View at Publisher · View at Google Scholar · View at Scopus
  69. K. Yanagihara and H. Irisawa, “Inward current activated during hyperpolarization in the rabbit sinoatrial node cell,” Pflügers Archiv European Journal of Physiology, vol. 385, no. 1, pp. 11–19, 1980. View at Google Scholar · View at Scopus
  70. D. DiFrancesco and D. Noble, “Current If and its contribution to cardiac pacemaking,” in Neuronal and Cellular Oscillators, J. W. Jacklet, Ed., pp. 31–57, Marcel Dekker, New York, NY, USA, 1989. View at Google Scholar
  71. F. Maruoka, Y. Nakashima, M. Takano, K. Ono, and A. Noma, “Cation-dependent gating of the hyperpolarization-activated cation current in the rabbit sino-atrial node cells,” Journal of Physiology, vol. 477, no. 3, pp. 423–435, 1994. View at Google Scholar · View at Scopus
  72. D. DiFrancesco, “Characterization of the pace-maker current kinetics in calf Purkinje fibres,” Journal of Physiology, vol. 348, pp. 341–367, 1984. View at Google Scholar · View at Scopus
  73. A. L. Hodgkin and A. F. Huxley, “A quantitative description of membrane current and its application to conduction and excitation in nerve,” The Journal of Physiology, vol. 117, no. 4, pp. 500–544, 1952. View at Google Scholar · View at Scopus
  74. S. Dokos, B. Celler, and N. Lovell, “Ion currents underlying sinoatrial node pacemaker activity: a new single cell mathematical model,” Journal of Theoretical Biology, vol. 181, no. 3, pp. 245–272, 1996. View at Publisher · View at Google Scholar · View at Scopus
  75. H. Zhang, A. V. Holden, I. Kodama et al., “Mathematical models of action potentials in the periphery and center of the rabbit sinoatrial node,” American Journal of Physiology Heart and Circulatory Physiology, vol. 279, no. 1, pp. H397–H421, 2000. View at Google Scholar · View at Scopus
  76. S. S. Demir, J. W. Clark, C. R. Murphey, and W. R. Giles, “A mathematical model of a rabbit sinoatrial node cell,” American Journal of Physiology, vol. 266, no. 3, pp. C832–C852, 1994. View at Google Scholar · View at Scopus
  77. Y. Kurata, I. Hisatome, S. Imanishi, and T. Shibamoto, “Dynamical description of sinoatrial node pacemaking: improved mathematical model for primary pacemaker cell,” American Journal of Physiology Heart and Circulatory Physiology, vol. 283, no. 5, pp. H2074–H2101, 2002. View at Google Scholar · View at Scopus
  78. N. Sarai, S. Matsuoka, S. Kuratomi, K. Ono, and A. Noma, “Role of individual ionic current systems in the SA node hypothesized by a model study,” Japanese Journal of Physiology, vol. 53, no. 2, pp. 125–134, 2003. View at Publisher · View at Google Scholar · View at Scopus
  79. S. Matsuoka, N. Sarai, S. Kuratomi, K. Ono, and A. Noma, “Role of individual ionic current systems in ventricular cells hypothesized by a model study,” Japanese Journal of Physiology, vol. 53, no. 2, pp. 105–123, 2003. View at Publisher · View at Google Scholar · View at Scopus
  80. R. Wilders, H. J. Jongsma, and A. C. G. van Ginneken, “Pacemaker activity of the rabbit sinoatrial node. A comparison of mathematical models,” Biophysical Journal, vol. 60, no. 5, pp. 1202–1216, 1991. View at Google Scholar · View at Scopus
  81. Z.-W. Liu, A.-R. Zou, S. S. Demir, J. W. Clark, and R. D. Nathan, “Characterization of a hyperpolarization-activated inward current in cultured pacemaker cells from the sinoatrial node,” Journal of Molecular and Cellular Cardiology, vol. 28, no. 12, pp. 2523–2535, 1996. View at Publisher · View at Google Scholar · View at Scopus
  82. H. Honjo, M. R. Boyett, I. Kodama, and J. Toyama, “Correlation between electrical activity and the size of rabbit sino-atrial node cells,” Journal of Physiology, vol. 496, no. 3, pp. 795–808, 1996. View at Google Scholar · View at Scopus
  83. D. Noble, D. DiFrancesco, and J. C. Denyer, “Ionic mechanisms in normal and abnormal cardiac pacemaker activity,” in Neuronal and Cellular Oscillators, J. W. Jacklet, Ed., pp. 59–85, Marcel Dekker, New York, NY, USA, 1989. View at Google Scholar
  84. C. Altomare, B. Terragni, C. Brioschi et al., “Heteromeric HCN1-HCN4 channels: a comparison with native pacemaker channels from the rabbit sinoatrial node,” Journal of Physiology, vol. 549, no. 2, pp. 347–359, 2003. View at Google Scholar · View at Scopus
  85. A. Barbuti, M. Baruscotti, and D. DiFrancesco, “The pacemaker current: from basics to the clinics,” Journal of Cardiovascular Electrophysiology, vol. 18, no. 3, pp. 342–347, 2007. View at Publisher · View at Google Scholar · View at Scopus
  86. D. DiFrancesco and D. Noble, “Implications of the reinterpretation of iK2 for the modelling of the electrical activity of the pacemaker tissues in the heart,” in Cardiac Rate and Rhythm: Physiological, Morphological and Developmental Aspects, L. N. Boumann and H. J. Jongsma, Eds., pp. 93–128, Martinus Nijhoff, The Hague, The Netherlands, 1982. View at Google Scholar
  87. A. Zaza, R. B. Robinson, and D. DiFrancesco, “Basal responses of the L-type Ca2+ and hyperpolarization-activated currents to autonomie agonists in the rabbit sino-atrial node,” Journal of Physiology, vol. 491, no. 2, pp. 347–355, 1996. View at Google Scholar · View at Scopus
  88. S. Dokos, B. G. Celler, and N. H. Lovell, “Vagal control of sinoatrial rhythm: a mathematical model,” Journal of Theoretical Biology, vol. 182, no. 1, pp. 21–44, 1996. View at Publisher · View at Google Scholar · View at Scopus
  89. S. S. Demir, J. W. Clark, and W. R. Giles, “Parasympathetic modulation of sinoatrial node pacemaker activity in rabbit heart: a unifying model,” American Journal of Physiology, vol. 276, no. 6, pp. H2221–H2244, 1999. View at Google Scholar · View at Scopus
  90. H. Zhang, A. V. Holden, D. Noble, and M. R. Boyett, “Analysis of the chronotropic effect of acetylcholine on sinoatrial node cells,” Journal of Cardiovascular Electrophysiology, vol. 13, no. 5, pp. 465–474, 2002. View at Google Scholar · View at Scopus
  91. V. A. Maltsev and E. G. Lakatta, “A novel quantitative explanation for the autonomic modulation of cardiac pacemaker cell automaticity via a dynamic system of sarcolemmal and intracellular proteins,” American Journal of Physiology Heart and Circulatory Physiology, vol. 298, no. 6, pp. H2010–H2023, 2010. View at Publisher · View at Google Scholar · View at Scopus
  92. H. Zhang, T. Butters, I. Adeniran et al., “Modeling the chronotropic effect of isoprenaline on rabbit sinoatrial node,” Frontiers in Physiology, vol. 3, p. 241, 2012. View at Google Scholar
  93. D. DiFrancesco, “Dual allosteric modulation of pacemaker (f) channels by cAMP and voltage in rabbit SA node,” Journal of Physiology, vol. 515, no. 2, pp. 367–376, 1999. View at Google Scholar · View at Scopus
  94. A. Zaza, M. Micheletti, A. Brioschi, and M. Rocchetti, “Ionic currents during sustained pacemaker activity in rabbit sino-atrial myocytes,” Journal of Physiology, vol. 505, no. 3, pp. 677–688, 1997. View at Publisher · View at Google Scholar · View at Scopus