Selective pharmacological inhibition of the pacemaker channel isoforms (HCN1-4) as new possible therapeutical targets

Current Medicinal Chemistry

Volumn 18, Issue 24, 2011, Pages 3662-3674

  Koncz, I ^a   Szel T ^a   Jaeger, K ^a   Baczko I ^a   Cerbai, E ^c   Romanelli, M N ^c   Papp, J Gy ^a,b   Varro A ^a,b  

^a UNIVERSITY OF SZEGED   (Hungary)

^b INSTITUTE OF EXPERIMENTAL MEDICINE   (Hungary)

^c UNIVERSITY OF FLORENCE   (Italy)

Author keywords

Arrhythmogenesis; Clinical trials; HCN channel isoforms; Heart rate; Isoform selective phen ylalkylamines; Ivabradine; Myocardial ischaemia; Neuropathic pain; Sino atrial node

Indexed keywords

4 (N ETHYL N PHENYLAMINO) 1,2 DIMETHYL 6 (METHYLAMINO)PYRIMIDINIUM CHLORIDE; ACETYLCHOLINE; ALINIDINE; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; CALCIUM CHANNEL BLOCKING AGENT; CAPSAZEPINE; CARVEDILOL; CILOBRADINE; CLONIDINE; CYCLIC NUCLEOTIDE GATED CHANNEL; DKAH 269; EC 18; EC 4; FALIPAMIL; HYPERPOLARIZATION ACTIVATED CYCLIC NUCLEOTIDE GATED CHANNEL; ICID 7288; INHALATION ANESTHETIC AGENT; ISOFLURANE; IVABRADINE; KETAMINE; LAMOTRIGINE; LOPERAMIDE; MEL 57A; NEBIVOLOL; NITRATE; PHENCYCLIDINE; PROPOFOL; S 162572; ST 506; TRIMETAZIDINE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VERAPAMIL; YM 758; ZATEBRADINE;

ADRENERGIC SYSTEM; ANGINA PECTORIS; ARRHYTHMOGENESIS; ARTICLE; ATRIOVENTRICULAR BLOCK; BRONCHOSPASM; CARDIOVASCULAR DISEASE; CELL FUNCTION; CHANNEL GATING; CHOLINERGIC SYSTEM; CORONARY ARTERY ATHEROSCLEROSIS; CORONARY ARTERY SPASM; DEPRESSION; DRUG SELECTIVITY; ELECTROENCEPHALOGRAM; EPILEPSY; FATIGUE; FOOT EDEMA; GLUCOSE BLOOD LEVEL; HEADACHE; HEART ARRHYTHMIA; HEART ATRIUM FIBRILLATION; HEART FAILURE; HEART INFARCTION; HEART LEFT VENTRICLE FAILURE; HEART MUSCLE ISCHEMIA; HEART PACING; HEART RATE; HEMODYNAMIC PARAMETERS; HUMAN; HYPOTENSION; LIPID BLOOD LEVEL; MEMBRANE STEADY POTENTIAL; NEUROPATHIC PAIN; NONHUMAN; PACEMAKER; PATHOPHYSIOLOGY; PERIPHERAL NERVE INJURY; PSYCHOMOTOR PERFORMANCE; SEXUAL DYSFUNCTION; SIDE EFFECT; SINUS NODE; SPINAL GANGLION; ST SEGMENT ELEVATION MYOCARDIAL INFARCTION; STABLE ANGINA PECTORIS; STRUCTURE ACTIVITY RELATION; SYNAPTIC TRANSMISSION; THALAMUS; TREATMENT CONTRAINDICATION;

BENZAZEPINES; CARDIOVASCULAR AGENTS; CLINICAL TRIALS AS TOPIC; CYCLIC NUCLEOTIDE-GATED CATION CHANNELS; HEART DISEASES; HEART RATE; HUMANS; PROTEIN ISOFORMS; SINOATRIAL NODE;

EID: 80052001033     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/092986711796642427     Document Type: Article

References (148)

1. Moosmang, S.; Stieber, J.; Zong, X.; Biel, M.; Hofmann, F.; Ludwig, A. Cellular expression and functional characterization of four hyperpolarization- activated pacemaker channels in cardiac and neuronal tissues. Eur J. Biochem., 2001, 268, 1646-1652. (Pubitemid 32862698)
2. Brown, HF.; DiFrancesco, D.; Noble, SJ. How does adrenaline accelerate the heart? Nature, 1979, 280(5719), 235-236. (Pubitemid 9227914)
3. f) plays an important role in regulating SA node pacemaker activity. Cardiovasc Res., 1995, 30(2), 307-308.
4. Day, M.; Carr, DB.; Ulrich, S.; Ilijic, E.; Tkatch, T.; Surmeier, DJ. Dendritic excitability of mouse frontal cortex pyramidal neurons is shaped by the interaction among HCN, Kir2, and Kleak channels. J. Neurosci., 2005, 25(38), 8776-8787. (Pubitemid 41362056)
5. Ludwig, A.; Budde, T.; Stieber, J.; Moosmang, S.; Wahl, C.; Holthoff, K.; Langebartels, A.; Wotjak, C.; Munsch, T.; Zong, X.; Feil, S.; Feil, R.; Lancel, M.; Chien, KR.; Konnerth, A.; Pape, HC.; Biel, M.; Hofmann, F. Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2. EMBO J., 2003, 22, 216-224. (Pubitemid 36119427)
6. Fried, HU.; Kaupp, UB.; Müller, F. Hyperpolarization-activated and cyclic nucleotide-gated channels are differentially expressed in juxtaglomerular cells in the olfactory bulb of mice. Cell Tissue Res., 2010, 339(3), 463-479.
7. Wickenden, AD.; Maher, MP.; Chaplan, SR. HCN pacemaker channels and pain: a drug discovery perspective. Curr. Pharm. Des., 2009, 15, 2149-2168.
8. Fox, K.; Ford, I.; Steg, PG.; Tendera, M.; Ferrari, R. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet, 2008, 372(9641), 807-816.
9. f) in normal and failing human heart. J. Mol. Cell. Cardiol., 2008, 45(2), 289-299.
10. Tamura, A.; Ogura, T.; Uemura, H.; Reien, Y.; Kishimoto, T.; Nagai, T.; Komuro, I.; Miyazaki, M.; Nakaya, H. Effects of antiarrhythmic drugs on the hyperpolarization-activated cyclic nucleotide-gated channel current. J Pharmacol Sci., 2009, 110, 150-159.
11. f inhibition: a novel mechanism of action. Eur. Heart J. Suppl., 2003, 5(suppl. G), 19-25.
12. Lakatta, EG.; DiFrancesco, D. What keeps us ticking: a funny current, a calcium clock, or both? J. Mol. Cell. Cardiol., 2009, 47, 157-170.
13. f) by cAMP in the rabbit sino-atrial node. J. Physiol., 1994, 474(3), 473-482. (Pubitemid 24060780)
14. f at physiological calcium concentrations. Cardiovasc. Res., 2008, 78, 466-475. (Pubitemid 351769763)
15. Tardif, JC. Heart rate and atherosclerosis. Eur. Heart J. Suppl., 2009, 11(suppl. D), 8-12.
16. Berdeaux, A.; Drieu la Rochelle, C.; Richard, V.; Giudicelli JF. Opposed responses of large and small coronary arteries to propranolol during exercise in dogs. Am. J. Physiol., 1991, 261(2), 265-270.
17. Van de Werf, F.; Bax, J.; Betriu, A.; Blomstrom-Lundqvist, C.; Crea, F.; Falk, V.; Filippatos, G.; Fox, K.; Huber, K.; Kastrati, A.; Rosengren, A.; Steg, PG.; Tubaro, M.; Verheugt, F.; Weidinger, F.; Weis, M. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation. Eur. Heart J., 2008, 29, 2909-2945.
18. Yu, FH.; Yarov-Yarovoy, V.; Gutman, GA.; Catterall, WA. Overview of molecular relationships in the voltage-gated ion channel superfamily. Pharmacol. Rev., 2005, 57, 387-395. (Pubitemid 43036430)
19. Accili, EA.; Proenza, C.; Baruscotti, M.; DiFrancesco, D. From funny current to HCN channels: 20 years of excitation. News Physiol. Sci., 2002, 17, 32-37.
20. Tran, N.; Proenza C.; Macri V.; Petigara F.; Sloan E.; Samler S.; et al. A conserved domain in the NH2 terminus important for assembly and functional expression of pacemaker channels. J. Biol. Chem., 2002, 5, 26-35.
21. Bucchi, A.; Baruscotti, M.; Robinson, RB.; DiFrancesco, D. Modulation of rate by autonomic agonists in SAN cells involves changes in diastolic depolarization and the pacemaker current. J. Mol. Cell. Cardiol., 2007, 43, 39-48. (Pubitemid 46898426)
22. Chen, J.; Mitcheson, JS.; Tristani-Firouzi, M.; Lin, M.; Sanguinetti, MC. The S4-S5 linker couples voltage sensing and activation of pacemaker channels. Proc. Natl. Acad. Sci. U. S. A., 2001, 98, 11277-11282. (Pubitemid 32928719)
23. Giorgetti, A.; Carloni, P.; Mistrik, P.; Torre, V. A homology model of the pore region of HCN channels. Biophy. J., 2005, 89, 932-944. (Pubitemid 41098979)
24. Laio, A.; Torre, V. Physical origin of selectivity in ionic channels of biological membranes. Biophys. J., 1999, 76, 129-148. (Pubitemid 29202444)
25. + channel signature sequence. Biophys. J., 1994, 66, 1061-1067. (Pubitemid 24106352)
26. Much, B.; Wahl-Schott, C.; Zong, X.; Schneider, A.; Baumann, L.; Moosmang, S.; Ludwig, A.; Biel, M. Role of subunit heteromerization and N-linked glycosylation in the formation of functional hyperpolarization-activated cyclic nucleotide-gated channels. J. Biol. Chem., 2003, 278, 43781-43786. (Pubitemid 37346006)
27. Shin, KS.; Rothberg, BS.; Yellen, G. Blocker state dependence and trapping in hyperpolarization-activated cation channels: evidence for an intracellular activation gate. J. Gen. Physiol., 2001, 117, 91-101. (Pubitemid 32423749)
28. Armstrong, CM.; Binstock, L. Anomalous rectification in the squid giant axon injected with tetraethylammonium chloride. J. Gen. Physiol., 1965, 48, 859-872.
29. +-induced anomalous rectification in squid giant axons. J Gen Physiol., 1966, 50(2), 491-503.
30. Armstrong, CM. Inactivation of the potassium conductance and related phenomena caused by quaternary ammonium ion injection in squid axons. J. Gen. Physiol., 1969, 54(5), 553-575.
31. Zhong, H.; Molday, LL.; Molday, RS.; Yau, K W. The heteromeric cyclic nucleotide-gated channel adopts a 3A:1B stoichiometry. Nature, 2002, 420, 193-198. (Pubitemid 35340125)
32. Zhong, H.; Lai, J.; Yau, K W. Selective heteromeric assembly of cyclic nucleotide-gated channels. Proc. Natl. Acad. Sci. USA., 2003, 100, 5509-5513. (Pubitemid 36542735)
33. Zhou, L.; Siegelbaum, SA. Gating of HCN channels by cyclic nucleotides; residue contacts that underlie ligand binding, selectivity, and efficacy. Structure, 2007, 15, 655-670. (Pubitemid 46874082)
34. Decher, N.; Chen, J.; Sanguinetti, MC. Voltage-dependent gating of hyperpolarization-activated, cyclic nucleotide-gated pacemaker channels: molecular coupling between the S4-S5 and C-linkers. J. Biol. Chem., 2004, 279, 13859-13865. (Pubitemid 38468918)
35. Zagotta, WN.; Olivier, NB.; Black, KD.; Young, EC.; Olson, R.; Gouaux, E. Structural basis for modulation and agonist specificity of HCN pacemaker channels. Nature, 2003, 425, 200-205. (Pubitemid 37150901)
36. Waigner, BJ.; DeGennaro, M.; Santoro, B.; Siegelbaum, SA.; Tibbs, GR. Molecular mechanism of cAMP modulation of HCN pacemaker channels. Nature, 2001, 411, 805-810. (Pubitemid 32588104)
37. Craven, KB.; Zagotta, WN. Salt bridges and gating in the COOH-terminal region of HCN2 and CNGA1 channels. J. Gen. Physiol., 2004, 124, 663-677. (Pubitemid 39628134)
38. DiFrancesco, D. Funny channels in the control of cardiac rhythm and mode of action of selective blockers. Pharm. Res., 2006, 53, 399-406. (Pubitemid 43729047)
39. 2+ releases during diastolic depolarization of sinoatrial pacemaker cells do not require membrane depolarization. Circ. Res., 2004, 94, 802-809. (Pubitemid 38451742)
40. f does not play an important role in regulating SA node pacemaker activity. Cardiovasc Res., 1995, 30(2), 309-310.
41. f inhibitor, in stable angina: a randomized, doubleblind, multicentered, placebo-controlled trial. Circulation, 2003, 107, 817-823.
42. Mackaay, AJ.; Op't Hof, T.; Bleeker, WK.; Jongsma, HJ.; Bouman, LN. Interaction of adrenaline and acetylcholine on cardiac pacemaker function. Functional inhomogeneity of the rabbit sinus node. J. Pharmacol. Exp. Ther., 1980, 214(2), 417-422. (Pubitemid 10049056)
43. f) in rabbit sino-atrial node myocytes. J. Physiol., 1988, 405, 493-510.
44. f) in cells isolated from the rabbit sinoatrial node. J. Physiol., 1986, 377, 61-88. (Pubitemid 16072722)
45. Thuringer, D.; Lauribe, P.; Escande, D. A hyperpolarization-activated inward current in human myocardial cells. J. Mol. Cell. Card., 1992, 24(5), 451-455.
46. f, in ventricular myocytes isolated from hypertensive rats. J. Physiol., 1994, 481(3), 585-591.
47. Pape, HC. Queer current and pacemaker: the hyperpolarization-activated cation current in neurons. Annu. Rev. Physiol., 1996, 58, 299-327.
48. DiFrancesco, D.; Tortora, P. Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature, 1991, 351, 145-147. (Pubitemid 21896552)
49. DiFrancesco, D. Dual allosteric modulation of pacemaker (f) channels by cAMP and voltage in rabbit SA node. J. Physiol., 1999, 515(2), 367-376. (Pubitemid 29129208)
50. DiFrancesco, D. Pacemaker mechanisms in cardiac tissue. Annu. Rev. Physiol., 1993, 55, 455-472. (Pubitemid 23102141)
51. Baruscotti, M.; Bucchi, A.; DiFrancesco, D. Physiology and pharmacology of the cardiac pacemaker ("funny") current. Pharm. & Ther., 2005, 107, 59-79. (Pubitemid 40800408)
52. f in the human sinoatrial node. Eur. Heart J., 2007, 20, 2472-2478. (Pubitemid 47614280)
53. Qu, J.; Kryukova, Y.; Potapova, IA.; Doronin, SV.; Larsen, M.; Krishnamurthy, G.; Cohen, IS.; Robinson, RB. MiRP1 modulates HCN2 channel expression and gating in cardiac myocytes. J. Biol. Chem., 2004, 279, 43497-43502. (Pubitemid 39390649)
54. f) by cAMP gating and phosphatase inhibition in rabbit sino-atrial node myocytes. J. Physiol., 1997, 500.3, 643-651. (Pubitemid 27207826)
55. Gravante, B.; Barbuti, A.; Milanesi, R.; Zappi, I.; Viscomi, C.; DiFrancesco, D. Interaction of the pacemaker channel HCN1 with filamin A. J. Biol. Chem., 2004, 279, 43847-43853. (Pubitemid 39390691)
56. Suh, BC.; Hille, B. Regulation of ion channels by phosphatidylinositol 4,5-bisphosphate. Curr. Opin. Neurobiol., 2005, 15, 370-378. (Pubitemid 40806451)
57. Barbuti, A.; Gravante, B.; Riolfo, M.; Milanesi, R.; Terragni, B.; Di-Francesco, D. Localization of pacemaker channels in lipid rafts regulates channel kinetics. Circ. Res., 2004, 94, 1325-1331. (Pubitemid 38724478)
58. DiFrancesco, D. The role of the funny current in pacemaker activity. Circ. Res., 2010, 106, 434-446.
59. Kobinger, W.; Lillie, C. Specific bradycardic agents - a novel pharmacological class? Eur. Heart J., 1987, Suppl. L, 7-15. (Pubitemid 18088407)
60. Satoh, H.; Hashimoto, K. Electrophysiological study of alinidine in voltage clamped rabbit sino-atrial node cells. Eur. J. Pharmacol., 1986, 121(2), 211-219.
61. Briggs, I.; BoSmith, RE.; Heapy, CG. Effects of Zeneca ZD 7288 in comparison with alinidine and UL-FS 49 on guinea pig sinoatrial node and ventricular action potentials. J. Cardiovasc. Pharm., 1994, 24, 380-387. (Pubitemid 24260517)
62. Kobinger, W. Editorial: History of 'specific bradycardic agents'. Eur. Heart J., 1987, Suppl. L, 5-6. (Pubitemid 18088406)
63. Osterrieder, W.; Pelzer, D.; Yang, QF.; Trautwein W. The electrophysiological basis of the bradycardic action of AQA 39 on the sinoatrial node. Naunyn Schmiedebergs Arch Pharmacol., 1981, 317(3), 233-237. (Pubitemid 11030944)
64. Boucher, M.; Chassaing, C.; Chapuy, E. Cardiac electrophysiological effects of falipamil in the conscious dog: comparison with alinidine. Eur. J. Pharmacol., 1996, 306(1-3), 93-98. (Pubitemid 26200129)
65. f)) in sino-atrial node myocytes. Pflugers Arch, 1994, 427(1-2), 64-70. (Pubitemid 24131555)
66. Valenzuela, C.; Delpon, E.; Franqueza, L.; BS; Gay, P.; Perez, O.; Tamargo, J.; Snyders D.J. Class III Antiarrhythmic Effects of Zatebradine. Circulation, 1996, 94, 562-570.
67. Thollon, C.; Cambarrat, C.; Vian, J.; Prost, J-F.; Peglion, J.; Vilaine, J. 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. 1994, 112, 37-42. (Pubitemid 24151700)
68. Frishman, WH.; Pepine, CJ.; Weiss, RJ.; Baiker, WM. 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., 1995, 26(2), 305-312.
69. Satoh, TO.; Yamada, M. Multiple inhibitory effects of zatebradine (UL-FS49) on the electrophysiological properties of retinal rod photoreceptors. Pflugers Arch., 2002, 443(4), 532-540. (Pubitemid 34185057)
70. f) by cilobradine and zatebradine. Eur. J. Pharmacol., 2003, 478(2-3), 161-171. (Pubitemid 37315735)
71. Baruscotti, M.; Barbuti, A.; Bucchi, A. The cardiac pacemaker current. J. Mol. Cell. Cardiol., 2010, 48, 55-64.
72. f) in guinea-pig dissociated sinoatrial node cells. B r. J. Pharmacol., 1993, 110, 343-349. (Pubitemid 23257802)
73. h) blocker ZD 7288 in hippocampal CA1 neurons. Pflugers Arch., 1997, 435(1), 99-106. (Pubitemid 28068744)
74. Harris, NC.; Constanti, A. Mechanism of block by ZD 7288 of the hyperpolarization-activated inward rectifying current in guinea pig substantia nigra neurons in vitro. J. Neurophysiol., 1995, 74(6), 2366-2378. (Pubitemid 26012299)
75. Williams, SR.; Turner, JP.; Hughes, SW.; Crunelli, V. On the nature of anomalous rectification in thalamocortical neurones of the cat ventrobasal thalamus in vitro. J. Physiol., 1997, 505(3), 727-747. (Pubitemid 28022371)
76. (f) inhibition in cardiovascular diseases. Adv. Pharmacol., 2010, 59, 53-92.
77. Reiffen, M.; Eberlien, W.; Müller, P.; Psiorz, M.; Noll, K.; Heider, J.; Lillie, C.; Kobinger, W.; Luger, P. Specific Bradycardic Agents. Chemistry, pharmacology, and structure-activity relationships of substituted benzazepinones, a new class of compounds exerting antiischemic properties. J. Med. Chem., 1990, 33, 1496-1504. (Pubitemid 20148390)
78. Bomhard, A.; Reiffen, M.; Heider, J.; Psiorz, M.; Lillie, C. Specific bradycardic agents. 2. Heteroaromatic modifications in the side chain of specific bradycardic benzazepinones: chemistry, pharmacology, and structure-activity relationships. J. Med. Chem., 1991, 34, 942-947.
79. Kubota, H.; Kakefuda, A.; Watanabe, T.; Taguchi, Y.; Ishii, N.; Masuda, N.; Sakamoto, S.; Tsukamoto, S. (±)-2-(3-Piperidyl)-1,2,3,4- tetrahydroisoquinolines as a new class of specific bradycardic agents. Bioorg. Med. Chem. Lett., 2003, 13, 2155-2158. (Pubitemid 36694295)
80. Kakefuda, A.; Watanabe, T.; Taguchi, Y.; Masuda, N.; Tanaka, A.; Yanagisawa, I. Synthesis and pharmacological evaluation of 2-(3-Piperidyl)-1,2, 3,4-tetrahydroisoquinoline derivatives as specific bradycardic agents. Chem. Pharm. Bull., 2003, 51, 390-398. (Pubitemid 41694812)
81. f channel inhibitory activity. J. Med. Chem., 2003, 46(22), 4728-4740. (Pubitemid 37271621)
82. Kubota, H.; Watanabe, T.; Kakefuda, A.; Masuda, N.; Wada, K.; Ishii, N.; Sakamoto, S.; Tsukamoto, S. Synthesis and pharmacological evaluation of N-acyl-1,2,3,4-tetrahydroisoquinoline derivatives as novel specific bradycardic agents. Bioorg. Med. Chem., 2004, 12(5), 871-882. (Pubitemid 38251279)
83. Kubota, H.; Watanabe, T.; Kakefuda, A.; Masuda, N.; Wada, K.; Ishii, N.; Sakamoto, S.; Tsukamoto, S. Synthesis and pharmacological evaluation of piperidinoalkanoyl-1,2,3,4-tetrahydroisoquinoline derivatives as novel specific bradycardic agents. Bioorg. Med. Chem. Lett., 2004, 14(12), 3049-3052. (Pubitemid 38624560)
84. Bisi, A.; Rampa, A.; Budriesi, R.; Gobbi, S.; Belluti, F.; Ioan, P.; Valoti, E.; Chiarini, A.; Valenti, P. Cardiovascular hybrid drugs: new benzazepinone derivatives as bradycardic agents endowed with selective b1-non-competitive antagonism. Bioorg. Med. Chem., 2003, 11, 1353-1361. (Pubitemid 36293529)
85. f channel blockers. Bioorg. Med. Chem. Lett., 2001, 11, 2351-2354. (Pubitemid 32781697)
86. Romanelli, M. N.; Cerbai, E.; Dei, S.; Guandalini, L.; Martelli, C.; Martini, E.; Scapecchi, S.; Teodori, E.; Mugelli, A. Design, synthesis and preliminary biological evaluation of Zatebradine analogues as potential blockers of the hyperpolarization-activated current. Bioorg. Med. Chem., 2005, 13, 1211-1220. (Pubitemid 40164605)
87. Kobinger, W.; Lillie, C. AQ-A 39 (5,6-dimethoxy-2-[3[[alpha-(3,4- dimethoxy)-phenylethyl]methylamino]propyl]phtalimidine), a specific bradycardic agent with direct action on the heart. Eur. J. Pharmacol., 1981, 72, 153-164. (Pubitemid 11072493)
88. Delpon, E.; Valenzuela, C.; Perez, O.; Franqueza, L.; Gay, P.; Snyders, D. J.; Tamargo, J. Mechanism of block of a human cloned potassium channel by the enantiomers of a new bradycardic agent: S-16257-2 and S-16260-2. B r. J. Pharmacol., 1996, 117, 1293-1301. (Pubitemid 26105355)
89. Bois, P.; Bescond, J.; Renaudon, B.; Lenfant, J. Mode of action of brady-cardic agent, S 16257, on ionic currents of rabbit sinoatrial node cells. B r. J. Pharmacol., 1996, 118, 1051-1057. (Pubitemid 26261281)
90. Wahl-Schott, C.; Biel, M. HCN channels: structure, cellular regulation and physiological function. Cell Mol. Life Sci., 2009, 66(3), 470-494.
91. El-Kholy, W.; MacDonald, P. E.; Fox, J. M.; Bhattacharjee, A.; Xue, T.; Gao, X.; Zhang, Y.; Stieber, J.; Li, R. A.; Tsushima, R. G.; Wheeler, M. B. Hyperpolarization-activated cyclic nucleotide-gated channels in pancreatic beta-cells. Mol. Endocrinol., 2007, 21, 753-764.
92. Hurtado, R.; Bub, G.; Herzlinger, D. The pelvis-kidney junction contains HCN3, a hyperpolarization-activated cation channel that triggers ureter peristalsis. Kidney Int., 2010, 77, 500-508.
93. Satoh, T.-O.; Yamada, M. Multiple inhibitory effects of zatebradine (UL-FS 49) on the electrophysiological properties of retinal rod photoreceptors. Pflügers Arch. Eur. J. Physiol., 2002, 443, 532-540. (Pubitemid 34185057)
94. Maher, M. P.; Wu, N.-T.; Guo, H.-Q.; Dubin, A. E.; Chaplan, S. R.; Wickenden, A. D. HCN channels as targets for drug discovery. Comb. Chem. High Throughput Screen., 2009, 12, 64-72.
95. Lee, Y. T.; Vasilyev, D. V.; Shan, Q. J.; Dunlop, J.; Mayer, S.; Bowlby, M. R. Novel pharmacological activity of loperamide and CP-339,818 on human HCN channels characterized with an automated electrophysiology assay. Eur. J. Pharmacol., 2008, 581, 97-104.
96. Shin, K. S.; Rothberg, B. S.; Yellen, G. Blocker state dependence and trapping in hyperpolarization-activated cation channels: evidence for an intracellular activation gate. J. Gen. Physiol., 2001, 117, 91-101. (Pubitemid 32423749)
97. Cheng, L.; Kinard, K.; Rajamani, R.; Sanguinetti, M. C. Molecular mapping of the binding site for a blocker of hyperpolarization-activated, cyclic nucleotide-modulated pacemaker channels. J. Pharmacol. Exp. Ther., 2007, 322, 931-939. (Pubitemid 47295784)
98. Chan, Y.-C.; Wang, K.; Au, K. W.; Lau, C.-P.; Tse, H.-F.; Li, R. A. Probing the bradycardic drug binding receptor of HCN-encoded pacemaker channels. Pflugers Arch. - Eur. J. Physiol., 2009, 459, 25-38.
99. Ludwig, A.; Zong, X.; Hofmann, F.; Biel, M. Structure and function of cardiac pacemaker channels. Cell Physiol. Biochem., 1999, 9, 179-186.
100. Stieber, J.; Wieland, K.; Stockl, G.; Ludwig, A.; Hofmann, F. Bradycardic and proarrhythmic properties of sinus node inhibitors. Mol. Pharmacol., 2006, 69, 1328-1337.
101. Bucchi, A.; Tognati, A.; Milanesi, R.; Baruscotti, M.; DiFrancesco, D. Properties of ivabradine-induced block of HCN1 and HCN4 pacemaker channels. J. Physiol. 2006, 572.2, 335-346.
102. Demontis, G. C.; Gargini, C.; Paoli, T. G.; Cervetto, L. Selective HCN1 channels inhibition by ivabradine in mouse rod photoreceptors. Invest. O-phthalmol. Vis. Sci., 2009, 50, 1948-1955.
103. Swedberg, K.; Komajda, M.; Böhm, M.; Borer, JS.; Ford, I.; Dubost-Brama, A.; Lerebours, G.; Tavazzi, L.; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet, 2010, 376(9744), 875-885.
104. Melchiorre, M.; Del Lungo, M.; Guandalini, L.; Martini, E.; Dei, S.; Manetti, D.; Scapecchi, S.; Teodori, E.; Sartiani, L.; Mugelli, A.; Cerbai, E.; Romanelli, M. N. Design, synthesis, and preliminary biological evaluation of new isoform-selective f-current blockers. J. Med. Chem., 2010, 53(18), 6773-6777.
105. Romanelli, M. N.; Mugelli, A.; Cerbai, E.; Sartiani, L.; Del Lungo, M.; Melchiorre, M. Isoform-selective HCN blockers. WO2011/000915 A1 (Application number WO2010EP59369 01 July 2010).
106. Cerbai, E.; Romanelli, M. N.; Varro, A. manuscript in preparation
107. f current inhibitor ivabradine. A new therapeutic approach to ischemic heart disease. Pharm. Res., 2006, 53, 424-434. (Pubitemid 43729045)
108. Thollon, C.; Bidouard, JP.; Cambarrat, C.; Lesage, L.; Reure, H.; Delescluse, I.; Vian, J.; Peglion, JL.; Vilaine, J P. Stereospecific in vitro and in vivo effects of the new sinus node inhibitor (+)-S16257. Eur. J. Pharmacol., 1997, 339, 43-51. (Pubitemid 28015430)
109. f current inhibitor. Eur. Heart J. Suppl., 2003, 5(suppl. G), 26-35.
110. f channels by ivabradine. J Gen Physiol., 2002, 120(1), 1-13. (Pubitemid 34755772)
111. Heusch, G.; Schulz, R. The role of heart rate and the benefits of heart rate reduction in acute myocardial ischaemia. Eur. Heart J. Suppl., 2007, 9(F), 8-14.
112. f current inhibitor ivabradine: safety considerations. Adv. Cardiol., 2006, 43, 79-96. (Pubitemid 44290165)
113. f inhibitor, in stable angina. Circ. 2003, 107, 817-823. (Pubitemid 36241038)
114. Joannides, R.; Moore, N.; Iacob, M.; Compagnon, P.; Lerebours, G.; Menard, JF.; Thuillez, C. Comparative effects of ivabradine, a selective heart rate-lowering agent, and propranolol on systemic and cardiac haemodynamics at rest and during exercise. B r. J. Clin. Pharmacol., 2005, 61(2), 127-137. (Pubitemid 43382606)
115. (f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur. Heart J., 2005, 26(23), 2529-2536. (Pubitemid 41677303)
116. f current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4-month, randomized, placebo-controlled trial. Eur. Heart J., 2009, 30(5), 540-548.
117. f inhibition help after myocardial infarction? Dialogues in Cardiovascular Medicine, 2006, Vol.11 No.1., 36-41. (Pubitemid 43810946)
118. Couvreur, N.; Tissier, R.; Pons, S.; Chetboul, V.; Gouni, V.; Bruneval, P.; Mandet, C.; Pouchelon, J-L.; Berdeaux, A.; Ghaleh, B. Chronic heart rate reduction with ivabradine improves systolic function of the reperfused heart through a dual mechanism involving a direct mechanical effect and a long-term increase in FKBP12/12.6 expression. Eur. Heart J., 2010, 31, 1529-1537.
119. Heusch, G.; Skyschally, A.; Gres, P.; van Caster, P.; Schilawa, D.; Schulz, R. Improvement of regional myocardial blood flow and function and reduction of infarct size with ivabradine: protection beyond heart rate reduction. Eur. Heart J., 2008, 29, 2265-2275.
120. Ceconi, C.; Comini, L.; Suffredini, S.; Stillitano, F.; Bouly, M.; Cerbai, E.; Mugelli, A.; Ferrari, R. Heart rate reduction with ivabradine prevents the global phenotype of left ventricular remodeling. Am. J. Physiol. Heart Circ. Physiol., 2011, 300(1), H366-373.
121. Baruscotti, M.; Bucchi, A.; Viscomi, C.; Mandelli, G.; Consalez, G.; Gnecchi-Rusconi, T.; Montano, N.; Casali, KR.; Micheloni, S.; Barbuti, A.; Di-Francesco D. Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene HCN4. Proc. Natl. Acad. Sci. USA, 2011, 108, 1705-1710.
122. Thollon, C.; Bedut, S.; Villeneuve, N.; Cogé, F.; Piffard, L.; Guillaumin, J-P.; Brunel-Jacquemin, C.; Chomarat, P.; Boutin, J-A.; Peglion, J-L.; Vilaine, J-P. Use-dependent inhibition of hHCN4 by ivabradine and relationship with reduction in pacemaker activity. B r. J. Pharmacol., 2007, 150, 37-46. (Pubitemid 46094667)
123. Dobrzynski, H.; Nikolski, VP.; Sambelashvili, AT.; Greener, ID.; Yamamoto, M.; Boyett, MR.; Efimov, IR. Site of origin and molecular substrate of atrioventricular junctional rhythm in the rabbit heart. Circ. Res., 2003, 93, 1102-1110. (Pubitemid 37485042)
124. Gaborit, N.; Le Bouter, S.; Szuts, V.; Varro, A.; Escande, D.; Nattel, S.; Demolombe, S. Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart. J. Physiol., 2007, 582, 675-693. (Pubitemid 47040552)
125. Ludwig, A.; Zong, X.; Stieber, J.; Hullin, R.; Hofmann, F.; Biel, M. Two pacemaker channels from human heart with profoundly different activation kinetics. EMBO J., 1999, 18, 2323-2329. (Pubitemid 29213266)
126. f), in ventricular myocytes from human failing heart. Circulation, 1997, 95, 568-571. (Pubitemid 27063029)
127. Hoppe, UC.; Jansen, E.; Südkamp, M.; Beuckelmann, DJ. Hyperpolarization-activated inward current in ventricular myocytes from normal and failing human hearts. Circulation, 1998, 97, 55-65. (Pubitemid 28036155)
128. f) in human ventricular myocytes are modulated by cardiac disease. J. Mol. Cell. Cardiol., 2001, 33, 441-448. (Pubitemid 32539001)
129. f to cardiac arrhythmias. Circulation, 2005, 111, 399-404. (Pubitemid 40204422)
130. Campbell, JN.; Meyer, RA. Mechanisms of neuropathic pain. Neuron, 2006, 52(1), 77-92. (Pubitemid 44466361)
131. Jarvis, MF.; Boyce-Rustay, JM. Neuropathic pain: models and mechanisms. Curr. Pharm. Des., 2009, 15, 1711-1716.
132. Jiang, YQ.; Sun, Q.; Tu, HY.; Wan, Y. Characteristics of HCN channels and their participation in neuropathic pain. Neurochem Res., 2008, 33, 1979-1989.
133. h via adenylyl cyclase. Neuron, 1994, 13(1), 179-186.
134. Moosmang, S.; Biel, M.; Hofmann, F.; Ludwig, A. Differential distribution of four hyperpolarization-activated cation channels in mouse brain. Biol Chem., 1999, 380(7-8), 975-980. (Pubitemid 29412758)
135. Biel, M.; Wahl-Schott, C.; Michalakis, S.; Zong, X. Hyperpolarization- activated cation channels: from genes to function. Physiol. Rev., 2009, 89(3), 847-885.
136. Sun, Q.; Xing, GG.; Tu, HY.; Han, JS.; Wan, Y. Inhibition of hyperpolarization-activated current by ZD7288 suppresses ectopic discharges of injured dorsal root ganglion neurons in a rat model of neuropathic pain. Brain Res., 2005, 1032, 63-69. (Pubitemid 40170309)
137. h by analgesic lop-eramide in rat DRG neurons. J. Neurophysiol., 2007, 97, 3713-3721. (Pubitemid 47084782)
138. Jung, S.; Jones, TD.; Lugo, JN Jr.; Sheerin, AH.; Miller, JW.; D'Ambrosio, R.; Anderson, AE.; Poolos, NP. Progressive dendritic HCN channelopathy during epileptogenesis in the rat pilocarpine model of epilepsy. J. Neurosci., 2007, 27(47), 13012-13021. (Pubitemid 350159594)
139. Jung, S.; Bullis, JB.; Lau, IH.; Jones, TD.; Warner, LN.; Poolos, NP. Downregulation of dendritic HCN channel gating in epilepsy is mediated by altered phosphorylation signaling. J. Neurosci., 2010, 30(19), 6678-6688.
140. Poolos, NP.; Migliore, M.; Johnston, D. Pharmacological upregulation of hchannels reduces the excitability of pyramidal neuron dendrites. Nat. Neurosci., 2002, 5, 767-774. (Pubitemid 34827595)
141. h blockers have a potential of antiepileptic effects. Epilepsia, 2003, 44, 20-24. (Pubitemid 36733616)
142. h contributes to propofol-induced inhibition of mouse cortical pyramidal neurons. J. Neurophysiol., 2005, 94, 3872-3883. (Pubitemid 41691753)
143. h in HCN1 knockout mice. J. Neurophysiol., 2009, 101, 129-140.
144. Chen, X.; Shu, S.; Bayliss, DA. HCN1 channel subunits are a molecular
145. Gill, CH.; Randall, A.; Bates, SA.; Hill, K.; Owen, D.; Larkman, PM.; Cairns, W.; Yusaf, SP.; Murdock, P.R.; Strijbos, PJ.; Powell, AJ.; Benham, CD.; Davies, CH. Characterization of the human HCN1 channel and its inhibition by capsazepine. Br. J. Pharmacol., 2004, 143, 411-421. (Pubitemid 39424830)
146. Tanabe, M. Inhibition of hyperpolarization-activated cation currents by phencyclidine and some sigma ligands in rat hippocampal CA1 pyramidal neurons in vitro. Neuropharm., 2007, 53(3), 406-414. (Pubitemid 47212251)
147. Bischoff, U.; Bräu, ME.; Vogel, W.; Hempelmann, G.; Olschewski, A. Local anaesthetics block hyperpolarization-activated inward current in rat small dorsal root ganglion neurones. Br. J. Pharmacol., 2003, 139(7), 1273-1280. (Pubitemid 37026410)
148. f inhibition: therapeutic utility from clinical trials. Eur. Heart J., 2005, Suppl. S7 (suppl H), 22-28.