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Cardiac Drug Development Guide pp 27–46Cite as

The Role of Cardiac Pacemaker Currents in Antiarrhythmic Drug Discovery

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Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

Abstract

From even the most basic physiological observations, it is obvious that parts of the heart can generate their own intrinsic contractile rhythm. With the development of techniques to record electrical activity from tissues, it became clear that contraction of the heart is triggered by an action potential and that most areas of the heart can, under some circumstances, generate rhythmic action potentials, although it is cells in the sinoatrial node (SAN) that have the highest intrinsic frequency, and hence it is these cells that normally provide the drive for the rest of the heart. Even a single, isolated SAN cell will generate rhythmic action potentials separated by a period of slow diastolic depolarization. It is the diastolic depolarization that repeatedly drives the membrane potential towards threshold for action potential firing. The mechanism underlying this diastolic depolarization has been a subject of much puzzlement. By the 1970s, it was clear that to provide a slow depolarization, there must be a slow increase in net inward current, although it was not clear whether this came about as a consequence of the slow inactivation of an outward current (presumed to be a carried by potassium) or the slow activation of an inward current (1). Using the intracellular recording and voltage clamp techniques available at the time, it was difficult to resolve the different components of the current flowing during the diastolic depolarization (2–4). With the advent of patch-clamp techniques, coupled with techniques for preparation of isolated cells from various parts of the heart, resolution of individual currents became possible. The mechanism of the diastolic depolarization was greatly clarified by the discovery in pacemaker cells of an inward current that was activated by hyperpolarization (5–8).

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REFERENCES

  1. DiFrancesco, D. (1995) The onset and autonomic regulation of cardiac pacemaker activity: Relevance of the f current. Cardiovasc Res. 29, 449–456.

    PubMed  CAS  Google Scholar 

  2. Yanagihara, K. and Irisawa, H. (1980) Inward current activated during hyperpolarization in the rabbit sinoatrial node cell. Pflugers Arch. 385, 11–19.

    PubMed  CAS  Google Scholar 

  3. Brown, H. F., Giles, W., and Noble, S. J. (1977) Membrane currents underlying activity in frog sinus venosus. J. Physiol. 271, 783–816.

    PubMed  CAS  Google Scholar 

  4. DiFrancesco, D. (1981) A new interpretation of the pace-maker current in calf Purkinje fibres. J. Physiol. 314, 359–376.

    PubMed  CAS  Google Scholar 

  5. Brown, H. and DiFrancesco, D. (1980) Voltage-clamp investigations of membrane currents underlying pace-maker activity in rabbit sino-atrial node. J. Physiol. 308, 331–351.

    PubMed  CAS  Google Scholar 

  6. DiFrancesco, D. and Ojeda, C. (1980) Properties of the current if in the sino-atrial node of the rabbit compared with those of the current iK, in Purkinje fibres. J. Physiol. 308, 353–367.

    PubMed  CAS  Google Scholar 

  7. Irisawa, H. and Noma, A. (1984) Pacemaker currents in mammalian nodal cells. J. Mol. Cell Cardiol. 16, 777–781.

    PubMed  CAS  Google Scholar 

  8. Maylie, J. and Morad, M. (1984) Ionic currents responsible for the generation of pacemaker current in the rabbit sino-atrial node. J. Physiol. 355, 215–235.

    PubMed  CAS  Google Scholar 

  9. Bader, C. R., Macleish, P. R., and Schwartz, E. A. (1979) A voltage-clamp study of the light response in solitary rods of the tiger salamander. J. Physiol. 296, 1–26.

    PubMed  CAS  Google Scholar 

  10. DiFrancesco, D. (1993). Pacemaker mechanisms in cardiac tissue. Annu. Rev. Physiol. 55, 455–472.

    PubMed  CAS  Google Scholar 

  11. McCormick, D. A. and Pape, H. C. (1990) Properties of a hyperpolarization-activated cation current and its role in rhythmic oscillation in thalamic relay neurones. J. Physiol. 431, 291–318.

    PubMed  CAS  Google Scholar 

  12. Pape, H. C. (1996) Queer current and pacemaker: The hyperpolarization-activated cation current in neurons. Annu. Rev. Physiol. 58, 299–327.

    PubMed  CAS  Google Scholar 

  13. Maccaferri, G. and McBain, C. J. (1996) The hyperpolarization-activated current (Ih) and its contribution to pacemaker activity in rat CA1 hippocampal stratum oriens-alveus interneurones. J. Physiol. 497, 119–130.

    PubMed  CAS  Google Scholar 

  14. Luthi, A. and McCormick, D.A. (1998) H-current: Properties of a neuronal and network pacemaker. Neuron 21, 9–12.

    PubMed  CAS  Google Scholar 

  15. Demontis, G. C., Longoni, B., Barcaro, U., and Cervetto, L. (1999) Properties and functional roles of hyperpolarization-gated currents in guinea-pig retinal rods. J. Physiol. 515, 813–828.

    PubMed  CAS  Google Scholar 

  16. Magee, J. C. (1999) Dendritic Ih normalizes temporal summation in hippocampal CA1 neurons. Nat. Neurosci. 2, 848.

    PubMed  CAS  Google Scholar 

  17. Beaumont, V. and Zucker, R. S. (2000) Enhancement of synaptic transmission by cyclic AMP modulation of presynaptic Ih channels. Nat. Neurosci. 3, 133–141.

    PubMed  CAS  Google Scholar 

  18. Southan, A. P., Morris, N. P., Stephens, G. J., and Robertson, B. (2000) Hyperpolarization activated currents in presynaptic terminals of mouse cerebellar basket cells. J. Physiol. 526, 91–97.

    PubMed  CAS  Google Scholar 

  19. DiFrancesco, D. (1995) The pacemaker current (I(f)) plays an important role in regulating SA node pacemaker activity. Cardiovasc. Res. 30, 307–308.

    PubMed  CAS  Google Scholar 

  20. Vassalle, M. (1995) The pacemaker current (I(f)) does not play an important role in regulating SA node pacemaker activity. Cardiovasc. Res. 30, 309–310.

    PubMed  CAS  Google Scholar 

  21. Noble, D., Denyer, J. C., Brown, H. F., and DiFrancesco, D. (1992) Reciprocal role of the inward currents ib, Na and i(f) in controlling and stabilizing pacemaker frequency of rabbit sino-atrial node cells. Proc. R Soc. Lond. B Biol. Sci. 250, 199–207.

    CAS  Google Scholar 

  22. Liu, Y. M., Yu, H., Li, C. Z., Cohen, I. S., and Vassalle, M. (1998) Cesium effects on If and IK in rabbit sinoatrial node myocytes. Implications for SA node automaticity. J. Cardiovasc. Pharmacol. 32, 783–790.

    PubMed  CAS  Google Scholar 

  23. Baker, K., Warren, K. S., Yellen, G., and Fishman, M. C. (1997) Defective “pacemaker” current (Ih) in a zebrafish mutant with a slow heart rate. Proc. Natl. Acad. Sci. USA 94, 4554–4559.

    PubMed  CAS  Google Scholar 

  24. DiFrancesco, D., Ferroni, A., Mazzanti, M., and Tromba, C. (1986) Properties of the hyperpolarizing-activated current (if) in cells isolated from the rabbit sino-atrial node. J. Physiol. 377, 61–68.

    PubMed  CAS  Google Scholar 

  25. DiFrancesco, D. (1986) Characterization of single pacemaker channels in cardiac sinoatrial node cells. Nature 324, 470–473.

    PubMed  CAS  Google Scholar 

  26. DiFrancesco, D. and Tortora, P. (1991) Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature 351, 145–147.

    PubMed  CAS  Google Scholar 

  27. DiFrancesco, D. and Mangoni, M. (1994) Modulation of single hyperpolarization-activated channels (i(f)) by cAMP in the rabbit sino-atrial node. J. Physiol. 474, 473–482.

    PubMed  CAS  Google Scholar 

  28. Accili, E. A., Redaelli, G., and DiFrancesco, D. (1997) Differential control of the hyperpolarization-activated current (i(f)) by cAMP gating and phosphatase inhibition in rabbit sino-atrial node myocytes. J. Physiol. 500, 643–651.

    PubMed  CAS  Google Scholar 

  29. Chang, F., Cohen, I. S., DiFrancesco, D., Rosen, M. R., and Tromba, C. (1991) Effects of protein kinase inhibitors on canine Purkinje fibre pacemaker depolarization and the pacemaker current i(f). J. Physiol. 440, 367–384.

    PubMed  CAS  Google Scholar 

  30. Wu, J. Y., Yu, H., and Cohen, I. S. (2000) Epidermal growth factor increases i(f) in rabbit SA node cells by activating a tyrosine kinase. Biochim. Biophys. Acta. 1463, 1–19.

    Google Scholar 

  31. Renaudon, B., Lenfant, J., Decressac, S., and Bois, P. (2000) Thyroid hormone increases the conductance density of f-channels in rabbit sino-atrial node cells. Receptors Channels 7, 1–8.

    PubMed  CAS  Google Scholar 

  32. Hara, M., Liu, Y. M., Zhen, L., Cohen, I. S., Yu, H., Danilo P, Jr., et al. (1997) Positive chronotropic actions of parathyroid hormone and parathyroid hormone-related peptide are associated with increases in the current, I(f), and the slope of the pacemaker potential. Circulation 96, 3704–3709.

    PubMed  CAS  Google Scholar 

  33. DiFrancesco, D. and Tromba, C. (1988) Inhibition of the hyperpolarization-activated current (if) induced by acetylcholine in rabbit sino-atrial node myocytes. J. Physiol. 405, 477–491.

    PubMed  CAS  Google Scholar 

  34. Santoro, B. and Tibbs, G. R. (1999) The HCN gene family: Molecular basis of the hyperpolarization-activated pacemaker channels. Ann. NY Acad. Sci. 868, 741–764.

    PubMed  CAS  Google Scholar 

  35. Yu, H., Chang, F., and Cohen, I. S. (1995) Pacemaker current If in adult canine cardiac ventricular myocytes. J. Physiol. 485, 469–483.

    PubMed  CAS  Google Scholar 

  36. Santoro, B., Grant, S. G., Bartsch, D., and Kandel, E. R. (1997) Interactive cloning with the SH3 domain of N-src identifies a new brain specific ion channel protein, with homology to eag and cyclic nucleotide-gated channels. Proc. Natl. Acad. Sci. USA 94, 14,815–14,820.

    PubMed  CAS  Google Scholar 

  37. Ishii, T. M., Takano, M., Xie, L. H., Noma, A., and Ohmori, H. (1999) Molecular characterization of the hyperpolarization-activated cation channel in rabbit heart sinoatrial node. J. Biol. Chem. 274, 12,835–12,839.

    PubMed  CAS  Google Scholar 

  38. Ludwig, A., Zong, X., Jeglitsch, M., Hofmann, F., and Biel, M. (1998) A family of hyperpolarization-activated mammalian cation channels. Nature 393, 587–591.

    PubMed  CAS  Google Scholar 

  39. Santoro, B., Liu, D. T., Yao, H., Bartsch, D., Kandel, E. R., Siegelbaum, S. A., and Tibbs, G. R. (1998). Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain. Cell 93, 717–729.

    PubMed  CAS  Google Scholar 

  40. Vaccari, T., Moroni, A., Rocchi, M., Gorza, L., Bianchi, M. E., Beltrame, M., and DiFrancesco, D. (1999) The human gene coding for HCN2, the pacemaker channel of the heart. Biochim. Biophys. Acta. 1446, 419–425.

    PubMed  CAS  Google Scholar 

  41. Moroni, A., Barbuti, A., Altomare, C., Viscomi, C., Morgan, J., Baruscotti, M., and DiFrancesco, D. (2000) Kinetic and ionic properties of the human HCN2 pacemaker channel. Pflügers Arch. 439, 618–626.

    PubMed  CAS  Google Scholar 

  42. Clapham, D. E. (1998) Not so funny anymore: Pacing channels are cloned. Neuron 21, 5–7.

    PubMed  CAS  Google Scholar 

  43. Biel, M., Ludwig, A., Zong, X., and Hofmann, F. (1999) Hyperpolarization-activated cation channels: A multi-gene family. Rev. Physiol. Biochem. Pharmacol. 136, 165–181.

    PubMed  CAS  Google Scholar 

  44. Vaca, L., Stieber, J., Zong, X., Ludwig, A., Hofmann, F., and Biel, M. (2000) Mutations in the S4 domain of a pacemaker channel alter its voltage dependence. FEBS Lett. 479, 35–40.

    PubMed  CAS  Google Scholar 

  45. Doyle, D. A., Morais Cabral, J., Pfuetzner, R. A., Kuo, A., Gulbis, J. M., Cohen, S. L., et al. (1998) The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280, 69–77.

    PubMed  CAS  Google Scholar 

  46. Heginbotham, L., Lu, Z., Abramson, T., and MacKinnon, R. (1994) Mutations in the K+ channel signature sequence. Biophys. J. 66, 1061–1067.

    PubMed  CAS  Google Scholar 

  47. Zagotta, W. N. and Siegelbaum, S. A. (1996) Structure and function of cyclic nucleotidegated channels. Annu. Rev. Neurosci. 19, 235–263.

    PubMed  CAS  Google Scholar 

  48. Wainger, B. J., DeGennaro, M., Santoro, B., Siegelbaum, S. A., and Tibbs, G. R. (2001) Molecular mechanism of cAMP modulation of HCN pacemaker channels. Nature 411, 805–810.

    PubMed  CAS  Google Scholar 

  49. Ludwig, A., Zong, X., Stieber, J., Hullin, R., Hofmann, F., and Biel, M. (1999) Two pacemaker channels from human heart with profoundly different activation kinetics. EMBO J. 18, 2323–2329.

    PubMed  CAS  Google Scholar 

  50. Santoro, B., Chen, S., Luthi, A., Pavlidis, P., Shumyatsky, G. P., Tibbs, G. R., et al. (2000) Molecular and functional heterogeneity of hyperpolarization-activated pacemaker channels in the mouse CNS. J. Neurosci. 20, 5264–5275.

    PubMed  CAS  Google Scholar 

  51. Seifert, R., Scholten, A., Gauss, R., Mincheva, A., Lichter, P., and Kaupp, U. B. (1999) Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis. Proc. Natl. Acad. Sci. USA 96, 9391–9396.

    PubMed  CAS  Google Scholar 

  52. Yu, H., Wu, J., Potapova, I., Wymore, R. T., Holmes, B., Zuckerman, J., et al. (2001) MinK-related peptide 1: A beta subunit for the HCN ion channel subunit family enhances expression and speeds activation. Circ. Res. 88, E847–E87.

    Google Scholar 

  53. Maruoka, F., Nakashima, Y., Takano, M., Ono, K., and Noma, A. (1994) Cation-dependent gating of the hyperpolarization-activated cation current in the rabbit sino-atrial node cells. J. Physiol. 477, 423–435.

    PubMed  CAS  Google Scholar 

  54. Solomon, J. S. and Nerbonne, J. M. (1993) Two kinetically distinct components of hyperpolarization-activated current in rat superior colliculus-projecting neurons. J. Physiol. 469, 291–313.

    PubMed  CAS  Google Scholar 

  55. Chen, S., Wang, J., and Siegelbaum, S. A. (2001) Properties of hyperpolarization-activated pacemaker current defined by coassembly of HCN1 and HCN2 subunits and basal modulation by cyclic nucleotide. J. Gen. Physiol. 117, 491–504.

    PubMed  CAS  Google Scholar 

  56. Boyett, M. R., Honjo, H., and Kodama, I. (2000) The sinoatrial node, a heterogeneous pacemaker structure. Cardiovasc. Res. 47, 658–687.

    PubMed  CAS  Google Scholar 

  57. Shi, W., Wymore, R., Yu, H., Wu, J., Wymore, R. T., Pan, Z., et al. (1999) Distribution and prevalence of hyperpolarization-activated cation channel (HCN) mRNA expression in cardiac tissues. Circ. Res. 85, e1–e6.

    PubMed  CAS  Google Scholar 

  58. Zhang, H., Holden, A. V., and Boyett, M. R. (2000) Gradient model versus mosaic model of the sinoatrial node. Circulation 103, 584–588.

    Google Scholar 

  59. Nikmaram, M. R., Boyett, M. R., Kodama, I., Suzuki, R., and Honjo, H. (1997) Variation in effects of Cs+, UL-FS-49, and ZD-7288 within sinoatrial node. Am. J. Physiol. 272, H2782–H2792.

    PubMed  CAS  Google Scholar 

  60. Moosmang, S., Stieber, J., Zong, X., Biel, M., Hofmann, F., and Ludwig, A. (2001) Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues. Eur. J. Biochem. 268, 1646–1652.

    PubMed  CAS  Google Scholar 

  61. Monteggia, L. M., Eisch, A. J., Tang, M. D., Kaczmarek, L. K., and Nestler, E. J. (2000) Cloning and localization of the hyperpolarization-activated cyclic nucleotide-gated channel family in rat brain. Brain Res. Mol. Brain Res. 81, 129–139.

    PubMed  CAS  Google Scholar 

  62. Greenwood, I. A. and Prestwich, S. A. (2002) Characteristics of hyperpolarization-activated cation currents in portal vein smooth muscle cells. Am. J. Physiol. Cell Physiol. 282, C744–C753.

    PubMed  CAS  Google Scholar 

  63. Stevens, D. R., Seifert, R., Bufe, B., Muller, F., Kremmer, E., Gauss, R., et al. (2001) Hyperpolarization-activated channels HCN1 and HCN4 mediate responses to sour stimuli. Nature 413, 631–635.

    PubMed  CAS  Google Scholar 

  64. Boudoulas, H., Rittgers, S., Lewis, R., Leier, C., and Weissler, A. (1979) Changes in diastolic time with various pharmacologic agents: Implications for myocardial perfusion. Circulation 60, 164–169.

    PubMed  CAS  Google Scholar 

  65. Hoffman, J. (1990) Autoregulation and heart rate. Circulation 82, 1880–1881.

    PubMed  CAS  Google Scholar 

  66. Guth, B., Heusch, G., Seitelberger, R., and Ross, J. (1987) Elimination of exercise-induced regional myocardial dysfunction by a bradycardic agent in dogs with chronic coronary stenosis. Circulation 75, 661–669.

    PubMed  CAS  Google Scholar 

  67. O’Brien, P., Drage, D., Saeian, K., Brooks, H., and Warltier, D. (1992) Regional redistribution of myocardial perfusion by UL-FS49, a selective bradycardic agent. Am. Heart J. 123, 5665–5674.

    Google Scholar 

  68. Schlack, W., Ebel, D., Grunert, S., Halilovic, S., Meyer, O., and Thamer, V. (1998) Effect of heart rate reduction by 4-(N-ethyl-N-phenyl-amino)-1,2-dimethyl-6-(methyl-amino)pyrimidinium chloride on infarct size in dog. Arzneimittelforschung 48, 26–33.

    PubMed  CAS  Google Scholar 

  69. Indolfi, C., Guth, B. D., Miura, T., Miyazaki, S., Schulz, R., and Ross J. Jr. (1989) Mechanisms of improved ischemic regional dysfunction by bradycardia. Studies on UL-FS 49 in swine. Circulation 80, 983–993.

    PubMed  CAS  Google Scholar 

  70. Cerbai, E., Sartiani, L., DePaoli, P., Pino, R., Maccherini, M., Bizzarri, F., et al. (2001) The properties of the pacemaker current I(F)in human ventricular myocytes are modulated by cardiac disease. J. Mol. Cell Cardiol. 33, 441–448.

    PubMed  CAS  Google Scholar 

  71. Hoppe, U. C., Jansen, E., Sudkamp, M., and Beuckelmann, D. J. (1998) Hyperpolarization-activated inward current in ventricular myocytes from normal and failing human hearts. Circulation 97, 55–65.

    PubMed  CAS  Google Scholar 

  72. DiFrancesco, D. (1982) Block and activation of the pace-maker channel in calf purkinje fibres: effects of potassium, caesium and rubidium. J. Physiol. 329, 485–507.

    PubMed  CAS  Google Scholar 

  73. Zhou, Z. and Lipsius, S. L. (1992) Properties of the pacemaker current (If) in latent pacemaker cells isolated from cat right atrium. J. Physiol. 453, 503–523.

    PubMed  CAS  Google Scholar 

  74. BoSmith, R. E., Briggs, I., and Sturgess, N. C. (1993) Inhibitory actions of ZENECA ZD7288 on whole-cell hyperpolarization activated inward current (If) in guinea-pig dissociated sinoatrial node cells. Br. J. Pharmacol. 110, 343–349.

    PubMed  CAS  Google Scholar 

  75. Goethals, M., Raes A., and Van Bogaert, P. P. (1993) Use-dependent block of the pacemaker current I(f) in rabbit sinoatrial node cells by zatebradine (UL-FS 49). On the mode of action of sinus node inhibitors. Circulation 88, 2389–2401.

    PubMed  CAS  Google Scholar 

  76. Traunecker, W. and Walland, A. (1980) Haemodynamic and electrophysiologic actions of alinidine in the dog. Arch. Int. Pharmacodyn. Ther. 244, 58–72.

    PubMed  CAS  Google Scholar 

  77. Harron, D. W., Jady, K., Riddell, J. G., and Shanks, R. G. (1982) Effects of alinidine, a novel bradycardic agent, on heart rate and blood pressure in man. J. Cardiovasc. Pharmacol. 4, 213–220.

    PubMed  CAS  Google Scholar 

  78. Satoh, H. and Hashimoto, K. (1986) Electrophysiological study of alinidine in voltage clamped rabbit sino-atrial node cells. Eur. J. Pharmacol. 121, 211–219.

    PubMed  CAS  Google Scholar 

  79. Millar, J. S. and Williams, E. M. (1981) Pacemaker selectivity: Influence on rabbit atria of ionic environment and of alinidine, a possible anion antagonist. Cardiovasc. Res. 15, 335–350.

    PubMed  CAS  Google Scholar 

  80. Jaski, B. E. and Serruys, P. W. (1985) Anion-channel blockade with alinidine: A specific bradycardic drug for coronary heart disease without negative inotropic activity? Am. J. Cardiol. 56, 270–275.

    PubMed  CAS  Google Scholar 

  81. McPherson, G. A. and Angus, J. A. (1989) Phentolamine and structurally related compounds selectively antagonize the vascular actions of the K+ channel opener, cromromakalim. Br. J. Pharmacol. 97, 941–949.

    PubMed  CAS  Google Scholar 

  82. Streller, I. and Walland, A. (1990) Antiischemic effects of alinidine in paced isolated rat hearts. Basic Res Cardiol. 85, 71–77.

    PubMed  CAS  Google Scholar 

  83. Lang, U., Streller, I., and Walland, A. (1989) Alinidine antagonizes the myocardial effects of adenosine. Eur. J. Pharmacol. 164, 13–22.

    PubMed  CAS  Google Scholar 

  84. Lang, U. and Walland, A. (1989) Alinidine reverses the descending staircase of isolated rat atria by an antimuscarinic action. Naunyn Schmiedebergs Arch. Pharmacol. 339, 456–463.

    PubMed  CAS  Google Scholar 

  85. Takeda, M., Furukawa, Y., Ogiwara, Y., Saegusa, K., Haniuda, M., Akahane, K., et al. (1989) Effects on atrio-ventricular conduction of alinidine and falipamil injected into the AV node artery of the anesthetized dog. Arch. Int. Pharmacodyn Ther. 297, 39–48.

    PubMed  CAS  Google Scholar 

  86. Aidonidis, I., Brachmann, J., Rizos, I., Zacharoulis, A., Stavridis, I., Toutouzas, P., et al. (1995) Electropharmacology of the bradycardic agents alinidine and zatebradine (UL-FS 49) in a conscious canine ventricular arrhythmia model of permanent coronary artery occlusion. Cardiovasc. Drugs Ther. 9, 555–563.

    PubMed  CAS  Google Scholar 

  87. Boucher, M., Chassaing, C., and Chapuy, E. (1995) Cardiac electrophysiologic effects of alinidine, a specific bradycardic agent, in the conscious dog: Plasma concentration-response relations. J. Cardiovasc. Pharmacol. 25, 229–233.

    PubMed  CAS  Google Scholar 

  88. Meinertz, T., Kasper, W., and Jahnchen, E. (1987) Alinidine in heart patients: Electrophysiologic and antianginal actions. Eur. Heart J. 8, 109–114.

    PubMed  Google Scholar 

  89. Koenig, W., Stauch, M., Sund, M., Wanjura, D., and Henze, E. (1990) Hemodynamic effects of alinidine (ST 567) at rest and during exercise in patients with chronic congestive heart failure. Am. Heart J. 119, 1348–1354.

    PubMed  CAS  Google Scholar 

  90. Van de Werf, F., Janssens, L., Brzostek, T., Mortelmans, L., Wackers, F. J., Willems, G. M., et al. (1993) Short-term effects of early intravenous treatment with a beta-adrenergic blocking agent or a specific bradycardiac agent in patients with acute myocardial infarction receiving thrombolytic therapy. J. Am. Coll. Cardiol. 22, 407–416.

    PubMed  Google Scholar 

  91. Challinor-Rogers, J. L., Rosenfeldt, F. L., Du, X. J., and McPherson, G. A. (1997) Antiischemic and antiarrhythmic activities of some novel alinidine analogs in the rat heart. J. Cardiovasc. Pharmacol. 29, 499–507.

    PubMed  CAS  Google Scholar 

  92. Leitch, S. P., Sears, C. E., Brown, H. F., and Paterson, D. J. (1995) Effects of high potassium and the bradycardic agents ZD7288 and cesium on heart rate of rabbits and guinea pigs. J. Cardiovasc. Pharmacol. 25, 300–306.

    PubMed  CAS  Google Scholar 

  93. BoSmith, R. E., Briggs, I., and Sturgess, N. C. (1993) Inhibitory actions of Zeneca ZD7288 on whole-cell hyperpolarization activated inward current (If) in guinea-pig dissociated sinoatrial node cells. Br. J. Pharmacol. 110, 343–349.

    PubMed  CAS  Google Scholar 

  94. Rothberg, B. S., Shin, K. S., Phale, P. S., and Yellen, G. (2002) Voltage-controlled gating at the intracellular entrance to a hyperpolarization-activated cation channel. J. Gen. Physiol. 119, 83–91.

    PubMed  CAS  Google Scholar 

  95. Berger, F., Borchard, U., Gelhaar, R., Hafner, D., and Weis, T. (1994) Effects of the bradycardic agent ZD 7288 on membrane voltage and pacemaker current in sheep cardiac Purkinje fibres. Naunyn Schmiedebergs Arch Pharmacol. 350, 677–684.

    PubMed  CAS  Google Scholar 

  96. Briggs, I., BoSmith, R. E., and Heapy, C. G. (1994) Effects of Zeneca ZD7288 in comparison with alinidine and UL-FS 49 on guinea pig sinoatrial node and ventricular action potentials. J. Cardiovasc. Pharmacol. 24, 380–387.

    PubMed  CAS  Google Scholar 

  97. Harris, N. C. and Constanti, A. (1995) Mechanism of block by ZD 7288 of the hyperpolarization-activated inward rectifying current in guinea pig substantia nigra neurons in vitro. J. Neurophysiol. 7, 2366–2378.

    Google Scholar 

  98. Gasparini, S. and DiFrancesco, D. (1997) Action of the hyperpolarization-activated current (Ih) blocker ZD 7288 in hippocampal CA1 neurons. Pflugers Arch. 435, 99–106.

    PubMed  CAS  Google Scholar 

  99. Satoh, T. O. and Yamada, M. (2000) A bradycardiac agent ZD7288 blocks the hyperpolarization-activated current (I(h)) in retinal rod photoreceptors. Neuropharmacology 39, 1289–1291.

    Google Scholar 

  100. Hohnloser, S., Weirich, J., Homburger, H., and Antoni, H. (1982) Electrophysiological studies on effects of AQ-A 39 in the isolated guinea pig heart and myocardial preparations. Arzneimittelforschung 32, 730–734.

    PubMed  CAS  Google Scholar 

  101. Senges, J., Rizos, I., Brachmann, J., Anders, G., Jauernig, R., Hamman, H. D., et al. (1983) Effect of nifedipine and AQ-A 39 on the sinoatrial and atrioventricular nodes of the rabbit and their antiarrhythmic action on atrioventricular nodal reentrant tachycardia. Cardiovasc. Res. 17, 132–134.

    PubMed  CAS  Google Scholar 

  102. Kawada, M., Satoh, K., and Taira, N. (1984) Analyses of the cardiac action of the bradycardic agent, AQ-A 39, by use of isolated, blood-perfused dog-heart preparations. J. Pharmacol. Exp. Ther. 228, 484–490.

    PubMed  CAS  Google Scholar 

  103. Dammgen, J., Kadatz, R., and Diederen, W. (1981) Cardiovascular actions of 5,6-dimethoxy-2-(3-[(alpha-(3,4-dimethoxy) phenylethyl)-methylamino] propyl) phthalimidine (AQ-A 39), a specific bradycardic agent. Arzneimittelforschung 31, 666–670.

    PubMed  CAS  Google Scholar 

  104. Verdouw, P. D., Bom, H. P., and Bijleveld, R. E. (1983) Cardiovascular responses to increasing plasma concentrations of AQ-A 39 Cl, a new compound with negative chronotropic effects. Arzneimittelforschung 33, 702–706.

    PubMed  CAS  Google Scholar 

  105. Hilaire, J., Broustet, J. P., Colle, J. P., and Theron, M. (1983) Cardiovascular effects of AQ-A 39 in healthy volunteers. Br. J. Clin. Pharmacol. 16, 627–631.

    PubMed  CAS  Google Scholar 

  106. Siegl, P. K., Wenger, H. C., and Sweet, C. S. (1984) Comparison of cardiovascular responses to the bradycardic drugs, alinidine, AQ-A 39, and mixidine, in the anesthetized dog. J. Cardiovasc. Pharmacol. 6, 565–574.

    PubMed  CAS  Google Scholar 

  107. Gross, G. J., Daemmgen, J. W. (1986) Beneficial effects of two specific bradycardic agents AQ-A39 (falipamil) and AQ-AH 208 on reversible myocardial reperfusion damage in anesthetized dogs. J. Pharmacol. Exp. Ther. 238, 422–428.

    PubMed  CAS  Google Scholar 

  108. Gilfrich, H. J., Oberhoffer, M., and Witzke, J. (1987) Comparison of AQ-A 39 with propanolol and placebo in ischaemic heart disease. Eur. Heart J. 8(Suppl L), 147–151.

    PubMed  Google Scholar 

  109. Roth, W., Koss, F. W., Hallinan, D., Lambe, R., and Darragh, A. (1990) Pharmacokinetics of falipamil after intravenous administration to humans. J. Pharm. Sci. 79, 415–419.

    PubMed  CAS  Google Scholar 

  110. Osterrieder, W., Pelzer, D., Yang, Q. F., and Trautwein, W. (1981) The electrophysiological basis of the bradycardic action of AQA 39 on the sinoatrial node. Naunyn Schmiedebergs Arch Pharmacol. 317, 233–237.

    PubMed  CAS  Google Scholar 

  111. Boucher, M., Chassaing, C., Chapuy, E., and Duchene-Marullaz, P. (1994) Chronotropic cardiac effects of falipamil in conscious dogs: Interactions with the autonomic nervous system and various ionic conductances. J. Cardiovasc. Pharmacol. 23, 569–575.

    PubMed  CAS  Google Scholar 

  112. Lillie, C. and Kobinger, W. (1986) Investigations into the bradycardic effects of UL-FS 49 (1,3,4,5-tetrahydro-7,8-dimethoxy-3-[3-[[2-(3,4-dimethoxy-phenyl)ethyl]methyl-imino]propyl]-2H-3-benzazepin-2-on hydrochloride) in isolated guinea pig atria. J. Cardiovasc. Pharmacol. 8, 791–797.

    PubMed  CAS  Google Scholar 

  113. Johnston, W., Vinten-Johansen, J., Tommasi, E., and Little, W. (1991) ULFS-49 causes bradycardia without decreasing right ventricular systolic and diastolic performance. J. Cardiovasc. Pharmacol. 18, 528–534.

    PubMed  CAS  Google Scholar 

  114. Chen, Z. and Slinker, B. (1992) The sinus node inhibitor UL-FS 49 lacks significant inotropic effect. J. Cardiovasc. Pharmacol. 19, 264–271.

    PubMed  CAS  Google Scholar 

  115. Van Woerkens, L., van der Giessen, W., and Verdouw, P. (1992) The selective bradycardic effects of zatebradine (UL-FS 49) do not adversely affect left ventricular function in conscious pigs with chronic coronary artery occlusion. Cardiovasc. Drugs Ther. 6, 59–65.

    PubMed  Google Scholar 

  116. Breall, J., Watanabe, J., and Grossman, W. (1993) Effect of zatebradine on contractility, relaxation and coronary blood flow. J. Am. Coll. Cardiol. 21, 471–477.

    PubMed  CAS  Google Scholar 

  117. Pistchner, H., Muno, E., Vens-Cappel, F., Schulte, B., Schlepper, M., de Moura-Sieber, V., et al. Antiischemic, antianginal, and hemodynamic effects of ULFS 49 Cl (a new heart-rate-reducing agent) in patients with angiographically proven CAD, in Sinus Node Inhibitors: A New Concept in Angina Pectoris (Hjalmarson, Å., Remme, W., eds.), Springer, New York, 1991, pp. 45–53.

    Google Scholar 

  118. Baiker, W., Czako, E., Keck, M., and Nehmiz, G. Efficacy and duration of action of three doses of zatebradine (ULFS 49 Cl) in patients with chronic angina pectoris compared to placebo, in Sinus Node Inhibitors: A New Concept in Angina Pectoris (Hjalmarson, Å., Remme, W., eds.), Springer, New York, 1991, pp. 55–63.

    Google Scholar 

  119. Franke, H., Su CAPF, Schumacher, K., and Seiberling, M. (1987) Clinical pharmacology of two specific bradycardic agents. Eur. Heart J. 8(Suppl L), 91–98.

    PubMed  Google Scholar 

  120. Roth, W., Bauer, E., Heinzel, G., Cornelissen, P., van Tol, R., Jonkman, J., and Zuiderwijk, P. (1993) Zatebradine: pharmacokinetics of a novel heart-rate-lowering agent after intravenous infusion and oral administration to healthy subjects. J. Pharm. Sci. 82, 99–106.

    PubMed  CAS  Google Scholar 

  121. Kobinger, W. and Lillie, C. (1984) Cardiovascular characterization of UL-FS 49, 1,3,4,5-tetrahydro-7,8-dimethoxy-3-[3-][2-(3,4-dimethoxyphenyl)ethyl] methylimino]propyl]-2H-3-benzazepin-2-on hydrochloride, a new “specific bradycardic agent”. Eur. J. Pharmacol. 104, 9–18.

    PubMed  CAS  Google Scholar 

  122. Van Bogaert, P. P., Goethals, M., and Simoens, C. (1990) Use-and frequency-dependent blockade by UL-FS 49 of the if pacemaker current in sheep cardiac Purkinje fibres. Eur. J. Pharmacol. 187, 241–256.

    PubMed  Google Scholar 

  123. DiFrancesco, D. (1994) Some properties of the UL-FS 49 block of the hyperpolarization-activated current (i(f)) in sino-atrial node myocytes. Pflugers Arch. 427, 64–70.

    PubMed  CAS  Google Scholar 

  124. Doerr, T. and Trautwein, W. (1990) On the mechanism of the “specific bradycardic action” of the verapamil derivative UL-FS 49. Naunyn Schmiedebergs Arch Pharmacol. 341, 331–340.

    PubMed  CAS  Google Scholar 

  125. Thollon, C., Cambarrat, C., Vian, J., Prost, J. F., Peglion, J. L., and Vilaine, J. P. (1994) Electrophysiological effects of S 16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardiac preparations: Comparison with UL-FS 49. Br. J. Pharmacol. 112, 37–42.

    PubMed  CAS  Google Scholar 

  126. Perez, O., Gay, P., Franqueza, L., Carron, R., Valenzuela, C., Delpon, E., et al. (1995) Electromechanical effects of zatebradine on isolated guinea pig cardiac preparations. J. Cardiovasc. Pharmacol. 26, 46–54.

    PubMed  CAS  Google Scholar 

  127. Raberger, G., Krumpl, G., and Schneider, W. (1987) Effects of the bradycardic agent UL-FS 49 on exercise-induced regional contractile dysfunction in dogs. Int. J. Cardiol. 14, 343–354.

    PubMed  CAS  Google Scholar 

  128. Frishman, W. H., Pepine, C. J., Weiss, R. J., and Baiker, W. M. (1995) Addition of zatebradine, a direct sinus node inhibitor, provides no greater exercise tolerance benefit in patients with angina taking extended-release nifedipine: Results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. The Zatebradine Study Group. J. Am. Coll. Cardiol. 26, 305–312.

    PubMed  CAS  Google Scholar 

  129. Glasser, S. P., Michie, D. D., Thadani, U., and Baiker, W. M. (1997) Effects of zatebradine (ULFS 49 CL), a sinus node inhibitor, on heart rate and exercise duration in chronic stable angina pectoris. Zatebradine Investigators. Am. J. Cardiol. 79, 1401–1405.

    PubMed  CAS  Google Scholar 

  130. Valenzuela, C., Delpon, E., Franqueza, L., Gay, P., Perez, O., Tamargo, J., and Snyders, D. J. (1996) Class III antiarrhythmic effects of zatebradine. Time-, state-, use-, and voltage-dependent block of hKv1.5 channels. Circulation 94, 562–570.

    PubMed  CAS  Google Scholar 

  131. Bois, P., Bescond, J., Renaudon, B., and Lenfant, J. (1996) Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial node cells. Br. J. Pharmacol. 118, 1051–1057.

    PubMed  CAS  Google Scholar 

  132. Thollon, C., Bidouard, J. P., Cambarrat, C., Lesage, L., Reure, H., Delescluse, I., et al. (1997) Stereospecific in vitro and in vivo effects of the new sinus node inhibitor (+)-S 16257. Eur. J. Pharmacol. 339, 43–51.

    PubMed  CAS  Google Scholar 

  133. Simon, L., Ghaleh, B., Puybasset, L., Giudicelli, J. F., and Berdeaux, A. (1995) Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs. J. Pharmacol. Exp. Ther. 275, 659–666.

    PubMed  CAS  Google Scholar 

  134. Monnet, X., Ghaleh, B., Colin, P., de Curzon, O. P., Giudicelli, J. F., and Berdeaux, A. (2001) Effects of heart rate reduction with ivabradine on exercise-induced myocardial ischemia and stunning. J. Pharmacol. Exp. Ther. 299, 1133–1139.

    PubMed  CAS  Google Scholar 

  135. Carre, F., Denolle, T., Lecoz, F., Violet, I., Lerebours, G., and Gandon, J. M. (1995). First intravenous phase I of S 16257, a new bradycardic agent: Effects on the maximal exercise parameters. Thérapie 50, 377.

    Google Scholar 

  136. Duffull, S. B., Chabaud, S., Nony, P., Laveille, C., Girard, P., and Aarons, L. (2000) A pharmacokinetic simulation model for ivabradine in healthy volunteers. Eur. J. Pharm. Sci. 10, 285–294.

    PubMed  CAS  Google Scholar 

  137. Maesen, F. P., Smeets, J. J., van Noord, J. A., Nehmiz, G., Wald, F. D., and Cornelissen, P. J. (1994) Effect of zatebradine, a novel’ sinus node inhibitor,’ on pulmonary function compared to placebo. Pulm. Pharmacol. 7, 349–355.

    PubMed  CAS  Google Scholar 

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  1. Cellular Biophysics Laboratory, Department of Physiology, University of Adelaide, Adelaide, Australia

    David A. Saint

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  1. David A. Saint
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  1. Department of Pharmacology, Forest Research Institute, Jersey City, NJ

    Michael K. Pugsley

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Saint, D.A. (2003). The Role of Cardiac Pacemaker Currents in Antiarrhythmic Drug Discovery. In: Pugsley, M.K. (eds) Cardiac Drug Development Guide. Methods in Pharmacology and Toxicology. Humana Press. https://doi.org/10.1385/1-59259-404-2:27

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  • DOI: https://doi.org/10.1385/1-59259-404-2:27

  • Publisher Name: Humana Press

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