Cardiac sarcolemmal ion channels and transporters as possible targets for antiarrhythmic and positive inotropic drugs: Strategies of the past-perspectives of the future

Current Pharmaceutical Design

Volumn 10, Issue 20, 2004, Pages 2411-2427

  Varro, Andras ^a   Nanasi, Péter P ^b   Acsai, Karoly ^a   Virag, Laszlo ^a   Papp, Julius Gy ^a,c  

^a UNIVERSITY OF SZEGED   (Hungary)

^b UNIVERSITY OF DEBRECEN   (Hungary)

^c INSTITUTE OF EXPERIMENTAL MEDICINE   (Hungary)

Author keywords

Action potential; Antiarrhythmic drugs; Ca current; Cardiac myocytes; Human cardiac cells; Ion channels; K current; Positive inotropic drugs

Indexed keywords

4 AMINOPYRIDINE; ADENOSINE TRIPHOSPHATASE (POTASSIUM SODIUM); AMIODARONE; ANTIARRHYTHMIC AGENT; AZIMILIDE; BARIUM ION; BENZODIAZEPINE DERIVATIVE; BERTOSAMIL; BETA ADRENERGIC RECEPTOR; CALCIUM ION; CARRIER PROTEIN; CYCLIC AMP; DISOPYRAMIDE; DOFETILIDE; DRONEDARONE; ENCAINIDE; FLECAINIDE; IBUTILIDE; INOTROPIC AGENT; ION; ION CHANNEL; POTASSIUM CHANNEL BLOCKING AGENT; POTASSIUM ION; QUINIDINE; SODIUM CALCIUM EXCHANGE PROTEIN; SODIUM CHANNEL BLOCKING AGENT; SODIUM ION; SODIUM PROTON EXCHANGE PROTEIN; SOTALOL; TEDISAMIL; UNINDEXED DRUG;

ANTIARRHYTHMIC ACTIVITY; CELLULAR DISTRIBUTION; DOSE RESPONSE; DRUG BLOOD LEVEL; DRUG MECHANISM; DRUG TARGETING; GAP JUNCTION; HEART ATRIUM FIBRILLATION; HEART DISEASE; HEART FAILURE; HEART MUSCLE CELL; HEART MUSCLE FIBER MEMBRANE; HEART VENTRICLE TACHYCARDIA; HUMAN; INOTROPISM; ION CURRENT; NONHUMAN; PRIORITY JOURNAL; PROTEIN TARGETING; REVIEW; RISK ASSESSMENT; TORSADE DES POINTES; TREATMENT FAILURE;

ANIMALS; ANTI-ARRHYTHMIA AGENTS; BIOLOGICAL TRANSPORT; CARDIOTONIC AGENTS; EVALUATION STUDIES; HUMANS; ION CHANNELS; MYOCYTES, CARDIAC; SARCOLEMMA;

EID: 3242887895     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/1381612043383836     Document Type: Review

References (130)

1. Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989; 321: 406-12.
2. Waldo AL, Camm AJ, deRuyter H, Friedman PL, MacNeil DJ, Pitt B, et al. Survival with oral d-sotalol in patients with left ventricular dysfunction after myocardial infarction: rationale, design and methods (the SWORD Trial). Am J Cardiol 1995; 75: 1023-27.
3. + channel diversity in the mammalian myocardium. J Physiol (Lond) 2000; 525: 285-98.
4. Van Wagoner DR, Nerbonne JM. Molecular basis of electrical remodelling in atrial fibrillation. J Mol Cell Cardiol 2000; 32: 1101-17.
5. Rosati B, Pan Z, Lypen S, Wang HS, Cohen I, Dixon JE, et al. Regulation of KChIP2 potassium channel β subunit gene expression underlies the gradient of transient outward current in canine and human ventricle. J Physiol (Lond) 2001; 533: 119-25.
6. Kr channel. J Gen Physiol 1996; 107: 611-19.
7. ks in dog ventricular muscle and purkinje fibre repolarization. J Physiol (Lond) 2000; 523: 67-81.
8. c and action potential duration. Br J Pharmacol 2001, 32: 101-110.
9. Ks, to canine ventricular repolarization. Key role for β-adrenergic receptor stimulation. Circulation 2003; 107: 2753-60.
10. Wang Z, Yue L, White M, Pelletier M, Nattel S. Differential distribution of inward rectifier potassium channel transcripts in human atrium versus ventricle. Circ Res 1998; 98: 2422-28.
11. + current similar to Kv1.5 cloned channel currents. Circ Res 1993; 73: 1061-76.
12. Yue L, Feng J, Li GR, Nattel S. Characterization of an ultrarapid delayed rectifier potassium channel involved in canine atrial repolarization. J Physiol (Lond) 1996; 496: 647-62.
13. ACh in atrial fibrillation using a mouse knockout model. J Am Coll Cardiol 2001; 37: 2136-43.
14. Bosch RF, Zeng X, Grammer JB, Popovic K, Mewis C, Kühlkamp V. Ionic mechanism of electrical remodelling in human atrial fibrillation. Cardiovasc Res 1999; 44: 121-31.
15. ACh down-regulation in chronic human atrial fibrillation. decrease in GIRK4 mRNA correlates with reduced muscarinic receptor-mediated shortening of action potentials. Circulation 2001; 104: 134.
16. Nattel S, Li D. Ionic remodelling in the heart. Pathophysiological significance and new therapeutic opportunities for atrial fibrillation. Circ Res 2000; 87: 440-47.
17. Kääb S, Dixon J, Duc J, Ashen D, Näbauer M, Beuckelmann DJ, et al. Molecular basis of transient outward potassium current downregulation in human heart failure. Circulation 1998; 99: 1383-93.
18. Pogwizd SM, Schlotthauer K, Li L, Yuan W, Bers D. Arrhythmogenesis and contractile dysfunction in heart failure. Roles of sodium-calcium exchange, inward rectifier potassium current, and residual β-adrenergic responsiveness. Circ Res 2001; 88: 1159-67.
19. + currents in dogs with chronic complete atrioventricular block and acquired torsades de pointes. Circulation 1999; 100: 2455-61.
20. Hondeghem LM, Katzung BG. Antiarrhythmic agents: the modulated receptor mechanism of action of sodium and calcium channel-blocking drugs. Annu Rev Pharmacol Toxicol 1984; 24: 387-423.
21. Grant AO. Mechanisms of action of antiarrhythmic drugs: from ion channel blockage to arrhythmia termination. PACE 1997; 20: 432-44.
22. Courtney KR. Sodium channel blockers: the size/solubility hypothesis. Mol Pharmacol 1990; 37: 855-9.
23. Campbell TJ. Resting and rate-dependent depression of maximum rate of depolarization (Vmax) in guinea pig ventricular action potentials by mexiletine, disopyramide, and encainide. J Cardiovasc Pharmacol 1983, 5: 291-6.
24. Courtney K. Interval-dependent effects of small antiarrhythmic drugs on excitability of guinea-pig myocardium. J Mol Cell Cardiol 1980; 12: 1273-86.
25. Sicouri S, Moro S, Litovsky S, Elizari MZ, Antzelevitch C. Chronic amiodarone reduces transmural dispersion of repolarization in the canine heart. J Cardiovasc Electrophysiol 1997; 8: 1269-79.
26. Julian DG, Camm AJ, Frangin G, Janse MJ, Munoz A, Schwartz PJ, et al. Randomised trial of effect of amiodarone on mortality in patients with left ventricular dysfunction after recent myocardial infarction: EMIAT. Lancet 1997; 349: 667-74.
27. Van Opstal JM, Schoenmakers M, Verduyn SC, De Groot M, Leunissen JDM, Van der Hulst FF, et al. Chronic amiodarone evokes no torsade de pointes arrhythmias despite QT lengthening in an animal model of acquired long-QT syndrome. Circulation 2001; 104: 2722-27.
28. Vaughan-Williams EM. Classification of anti-dysrhythmic drugs. Pharmacol Ther [B] 1975; 1: 115-38.
29. Merot J, Charpentier F, Poirier JM, Coutris G, Weissenburger J. Effects of chronic treatment by amiodarone on transmural heterogeneity of canine ventricular repolarization in vivo: interaction with acute sotalol. Cardiovasc Res 1999; 44: 303-14.
30. + current by dofetilide. Circ Res 2001; 71: 75-83.
31. Walsh KB, Begenish TB, Kass RS. Beta-adrenergic modulation of cardiac ion channels, differential temperature-sensivity of potassium and calcium currents. J Gen Physiol 1989; 93: 841-54.
32. Kr blockade: implications for the antifibrillatory efficacy of potassium channel blocking agents. J Am Coll Cardiol 1995; 25: 1609-14.
33. Ks play and important role in the repolarization in normal human ventricular muscle? Circulation 1999; 100: 2611.
34. Biliczki P, Virág L, Iost N, Papp JGy, Varró A. Interaction of different potassium channels in cardiac repolarization in dog ventricular preparations: role of repolarozation reserve. Br J Pharmacol 2002; 137: 361-8.
35. + current on repolarisation in human and guinea pig ventricular myocytes. Cardiovasc Res 1998; 38: 441-50.
36. + currents in rabbit heart purkinje cells. J Physiol (Lond) 1998; 508: 811-23.
37. Ks in guinea pig ventricular myocytes. Circulation 1996; 94: 1-529.
38. Roden DM, Lazzara R, Rosen M, Schwartz PJ, Towbin J, Vincent M. Multiple mechanisms in the long -QT syndrome current knowledge, gaps, and future directions. Circulation 1996; 94: 1996-2012.
39. Priori SG, Napolitano C, Bloise R, Schwartz PJ. Low penetrance in the long QT syndrome: the importance of molecular diagnosis. Eur Heart J 1998; 19: 24.
40. Roden DM. Taking the "idio" out of "idiosyncratic": predicting Torsades de Pointes. PACE 1998; 21: 1029-34.
41. Pinto JMB, Boyden PA. Electrical remodeling in ischemia and infarction. Cardiovasc Res 1999; 42: 284-97.
42. Varró A, Iost N, Virág L, Lengyel C, Pacher P, Kecskeméti V, et al. Diabetes attenuates the repolarization reserve in rabbit heart. PACE 2003; 26: S136.
43. + currents. Mol Pharmacol 1998; 53: 220-30.
44. Ks corrects abnormal repolarization in rabbit models of acquired LQT2 and ventricular hypertrophy. Am J Physiol 2002; 283: H664-70.
45. t0l in cardiac electrogenesis. Br J Pharmacol 1999; 126: 251-63.
46. Litovsky SH, Antzelevitch C. Rate dependence of action potential duration and refiractoriness in canine ventricular endocardium differs from that of epicardium: role of the transient outward current. J Am Coll Cardiol 1989; 14: 1053-66.
47. 10l in shaping action potential morphology and duration. Circ Res 2000; 87: 1026-33.
48. Hoppe UC, Marbán E, Johns DC. Molecular dissection of cardiac repolarization by in vivo Kv4.3 gene transfer. J Clin Invest 2000; 8: 105.
49. + current in rabbit and human atrial myocytes. Circ Res 1999; 84: 551-61.
50. Feng J, Wang Z, Li GR, Nattel S. Effects of class III antiarrhythmic drugs on transient outward and ultra-rapid delayed rectifier currents in human atrial myocytes. J Pharmacol Exp Ther 1997; 281: 384-92.
51. Wettwer E, Himmel HM, Amos GJ, Li Q, Metzger F, Ravens U. Mechanism of block by tedisamil of transient outward current in human ventricular subepicardial myocytes. Br J Pharmacol 1999; 125: 659-66.
52. Di Diego JM, Cordeiro JM, Goodrow RJ, Fish M, Zygmund AC, Perez J, et al. Ionic and cellular basis for the predominance of the Brugada syndrome phenotype in males. Circulation 2002: 106: 2004-11.
53. Wang Z, Fermini B, Nattel S. Mechanism of flecainide's rate-dependent actions on action potential duration in canine atrial tissue. J Pharmacol Exp Ther 1993; 267: 2.
54. 2+ in guinea pig ventricular muscles. Am J Physiol 1986; 251: 24-33.
55. Nattel S, Matthews C, De Blasio E, Han W, Li D, Yue L. Dose dependence of 4-aminopyridine plasma concentrations and electrophysiological effects in dogs. Potential relevance to ionic mechanism in vivo. Circ Res 2000; 101: 1179-84.
56. Anyukhovsky EP, Rosenshtraukh LV. Electrophysiological responses of canine atrial endocardium and epicardium to acetylcholine and 4-aminopyridine, Cardiovasc Res 1999; 43: 364-70.
57. Yue L, Feng JL, Wang Z, Nattel S. Effects of ambasilide, quinidine, flecainide and verapamil on ultra-rapid delayed rectifier potassium currents in canine atrial myocytes. Cardiovasc Res 2000; 46: 151-61.
58. + current in human atrial myocytes. Br J Pharmacol 1997; 122: 291-301.
59. Franqueza L, Valenzuela C, Delpón E, Longobardo M, Caballero R, Tamargo J. Effects of propafenone and 5-hydroxy-propafenone on hKv1.5 channels. Br J Pharmacol 1998; 125: 969-78.
60. Valenzuela C, Delpón E, Franqueza L, Gay P, Pérez O, Tamargo J, et al. Class III antiarrhythmic effects of zatebradine, time-, state-, use-, and voltage-dependent block of hKv1.5 channels. Circ Res 1996; 94: 562-70.
61. Kr (dofetilide/ibutilide) in electrically remodelled atria of the goat. Circulation 2003; 108: IV-84.
62. Hara Y, Nakaya H. SD-3212 a new class I and IV antiarrhythmic drug: a potent inhibitor of the muscarinic acetylcholine-receptor-operated potassium current in gguinea pig atrial cells. Br J Pharmacol 1995; 116: 2750-56.
63. Watanabe Y, Hara Y, Amagawa M, Nakaya H. Inhibitory Effect of amiodarone on the muscarinic acetylcholine receptor-operated potassium current in guinea pig atrial Cells. J Pharmacol Exp Ther 1996; 279: 617-24.
64. Mori K, Hara J, Masuda Y, Nakaya H. Anticholinergic effects of class III antiarrhythmic drugs in guinea pig atrial cells: different molecular mechanisms. Circulation 1995; 91: 2834-43.
65. + current in guinea pig atrial cells. J Cardiovasc Pharmacol 2000; 36: 802-5.
66. Németh M, Varró A, Thormählen D, Papp JGy. Tedisamil is a potent blocker of ATP-sensitive potassium channels in cardiac muscle. Exp Clin Cardiol 1997; 2: 37-40.
67. Wu B, Sato T, Kiyosue T, Arita M. Blockade of 2,4-dinitrophenol induced ATP-sensitive potassium current in guinea pig ventricular myocytes by class 1 antiarrhythmic drugs. Cardiovasc Res 1992, 26: 1095-101.
68. Tosaki A, Szerdahelyi P, Engelman RM, Das DK. Potassium channel openers and blockers: do they posses proarrhythmic or antiarrhythmic activity in ischaemic and reperfused rat hearts? J Pharmacol Exp Ther 1993; 267: 1355-62.
69. Hoffmann D, Opie HL. Potassium channel blockade and acute myocardial infarction: implications for management of the non-insulin requiring diabetic patient. Eur Heart J 1993; 14: 1585-9.
70. Gross GJ, Auchampach JA. Blockade or ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. Circ Res 1992; 70: 223-33.
71. Gögelein H, Hartung J, Englert HC, Schölkens BA. HMR 1883, a novel cardioselective inhibitor or the ATP-sensitive potassium channel. Part I: Effects oil cardiomyocytes, coronary flow and pancreatic β-cells. J Pharmacol Exp Ther 1998; 286: 1453-64.
72. Delpon E, Valenzuela C, Perez O, Franqueza L, Gay P, Snyders DJ, et al. Mechanisms of block of a human cloned potassium channel by the enantiomers of a new bradycardic agent: S-16257-2 and S-16260-2. Br J Pharmacol 1996; 117: 1293-301.
73. Dhein S, Schott M, Tudyka T, Piecha D, Gottwald E, Klaus W. Antiarrhythmic peptides: a new antiarrhythmic principle. Exp Clin Cardiol 1997; 2: 51-8.
74. Xing D, Kjolbye AL, Peterson J.S, Harlow KW, Martins JB. Does novel gap junction opener ZP123 prevents focal ventricular tachycardia induction? PACE 2003; 26: S135.
75. +-exchange inhibitor HOE 642 on intracellular pH, calcium and sodium in isolated rat ventricular myocytes. Pflügers Arch 1996; 433: 26-34.
76. Scholz W, Albus U, Counillon L, Gögelein H, Lang HJ, Ling W, et al. Protective effects of HOE 642, a selective sodium-hydrogen exchange subtype 1 inhibitor, on cardiac ischaemia and reperfusion. Cardiovasc Res 1995; 29: 260-8.
77. 2+ exchanger, attenuates reperfusion injury in the in vitro and in vivo cerebral ischemic models. J Pharmacol Exp Ther 2001; 298: 249-56.
78. 2+ exchanger inhibitors SEA0400 and KB-R7943. Am J Physiol 2003; 284: H903-10.
79. Malecot CO, Bers DM, Katzung BG. Biphasic contractions induced by milrinone at low temperature in ferret ventricular muscle: role of the sarcoplasmic reticulum and transmembrane calcium influx. Circ Res 1986; 59: 151-62.
80. Bechem M, Hoffmann H. The molecular mode of action of the Ca agonist (-) BAY K 8644 in the cardiac Ca channel. Pflügers Arch 1993; 424: 343-53.
81. Salzmann R, Bormann G, Herzig JW, Markstein R, Scholtysik G. Pharmacological actions of APP 201-533, a novel cardiotonic agent. J Cardiovasc Pharmacol 1985; 7: 588-96.
82. Kondo N, Shibata S, Kodoma I, Yamada K. Electrical and mechanical effects of amrinone isolated guinea pig ventricular muscle. J Cardiovasc Pharmacol 1983; 5: 903-12.
83. West GA., Isenberg G, Belardinelly L. Antagonism of forskolin effects by adenosine in isolated hearts and ventricular myocytes. Am J Physiol 1986; 250: M769-77.
84. Müller-Beckmann B, Freud P, Honerjager P, Kling L, Rüegg JC. In vitro investigations on a new positive inotropic and vasodilatating angent (BM 14.478) that increases myocardial cyclic AMP content and myofibrillar calcium sensitivity. J Cardiovasc Pharmacol 1988; 11: 8-16.
85. Endoh M. Mechanisms of action of novel cardiotonic agents. J Cardiovasc Pharmacol 2002; 40: 323-38.
86. Mewes T, Dutz S, Ravens U, Jakobs KH. Activation of calcium currents in cardiac myocytes by empty β-adrenoceptors. Circulation 1993; 88: 2916-22.
87. Brunkhorst D, Leyden H, Meyer W, Nigbur R, Schmidt-Schumacher C, Scholz H. Relation of positive inotropic and chronotropic effects of pimobendan, UD-CG 212 Cl, milrinone and other phosphodiesterase inhibitors to phosphodiesterase III inhibition in guinea pig heart. Naunyn Schmiedebergs Arch Pharmacol 1989; 339: 575-83.
88. 1) in cells isolated from the rabbit sino-atrial node. J Physiol 1986; 377: 61-88.
89. Chang F, Gao J, Tromba C, Cohen I, DiFrancesco D. Acetylcholine reverses effects of beta-agonists oil pacemaker currents in canine cardiac Purkinje fibers, but has no direct action. A difference between primary and secondary pacemakers. Circ Res 1990, 66: 633-6.
90. Walsh KB, Begenisich TB, Kass RS. Beta adrenergic modulation of cardiac ion channels. Differenctial temperature sensitivity of potassium and calcium currents. J Gen Physiol 1989; 93: 841-54.
91. + current by isoprenaline in bull-frog atrial myocytes. J Physiol 1989; 415: 233-49.
92. Harwey RD, Hume JR. Autonomic regulation of a chloride current in heart. Science 1989; 244: 983-985.
93. 2+ channels. Nature 1983; 303: 535-7.
94. Rampe D, Lacerda A. A new site for activation of cardiac calcium channels defined by the nondihydropyridine FPL 64176. J Pharmacol Exp Ther 1991; 259: 982-7.
95. 2+ channel activators, BAY K 8644 and FPL64176. J Pharmacol Exp Ther 1993; 265: 1125-30.
96. Hess P, Lansman JB, Tsien RW. Different modes of Ca channel gating behaviour favored by dihydropyridine Ca agonists and antagonists. Nature 1984; 311: 538-44.
97. Hoffmann BF, Goodman LS, Gilman A. Digitalis and allied cardiac glycosides. In: Goodman LS, Gilman A, editors. The pharmacological basis of therapeutics. 7th ed. New York: MacMillan, 1985; p. 716-48.
98. Glynn IM. The action of cardiac glycosides oil ion movements. Pharmacol Rev 1964; 16: 381-407.
99. Eisner DA, Ledereer WJ. Na/Ca exchange: stoichiometry and electrogenicity. Am J Physiol 1985; 248: 189-202.
100. Falk RT, Cohen IS. Membrane current following activity in canine cardiac Purkinje fibers. J Gen Physiol 1984; 83: 771-99.
101. Vassalle M. Contribution of the Na/K pump to the membrane potential. Experimentia 1987; 43: 1135-40.
102. Kassenbaum DG. Electrophysiological effects of strophantidin in the heart. J Pharmacol Exp Ther 1963; 140: 329-38.
103. Edmands RE, Greenspan K, Fisch C. An electrophysiologic correlate of ouabain inotropy in canine cardiac muscle. Circ Res 1967; 21: 515-24.
104. Isenberg G, Trautwein W. The effect of dihydro-ouabain and lithium ions on the outward current in cardiac Purkinje fibers. Pflügers Arch 1974; 350: 41-54.
105. Eisner DA, Vaughan-Jones RD. Do calcium-activated potassium channels exist in the heart? Cell Calcium 1983; 4: 371-86.
106. Luk HN, Carmeliet E. Na activated K current in cardiac cells: rectification, open probability, block and in digitalis toxicity. Pflügers Arch 1990; 309: 354-6.
107. Ferrier GR, Saunders JH, Mendez C. A cellular mechanism for generation of ventricular arrhythmias by acetylstrophantidin. Circ Res 1973; 32: 600-9.
108. Kass RS, Lederer WJ, Tsien RW, Weingart R. Role of calcium ions in transient invward currents and aftercontractions induced by strophantidin in cardiac Purkinje fibres. J Physiol 1978; 281: 187-208.
109. Karagueuzian HS, Katzung BG. Voltage clamp studies of transient inward current and mechanical oscillations induced by ouabain in ferret papillary muscle. J Physiol 1982; 327: 255-71.
110. 2+ release channels: a possible role in cardiac inotropy. Br J Pharmacol 1993; 108: 1043-50.
111. Sagawa T, Sagawa K, Kelly JE, Tsushima RG, Wasserstrom JA. Activation of cardiac ryanodine receptors by cardiac glycosides. Am J Physiol 2002; 282: H1118-26.
112. Catteral WA. Neurotoxins that act on voltage sensitive sodium channels in excitable membranes. Ann Rev Pharmacol Toxicol 1980; 20: 15-43.
113. Isenberg G, Ravens U. The effects of Anemonia sulcata toxin (ATXII) on membrane currents of isolated mammalian myocytes. J Physiol 1984; 357: 127-49.
114. Buggisch D, Isenberg G, Ravens U, Scholtysik G. The role of sodium channels in the effects of the cardiotonic compound DPI 201-106 on contractility and membrane potentials in isolated mammalian heart preparations. Eur J Pharmacol 1985; 118: 303-11.
115. Wang G, Dugas M, Ben-Armach I, Henerjager P. Interaction between DPI 201-106 enantiomers at the cardiac sodium channels. Mol Pharmacol 1990; 37: 17-24.
116. + channels by DPI 201-106. J Membran Biol 1986, 89: 163-72.
117. Nilius B, Vereecke J, Carmeliet E. Properties of the bursting Na channel in the presence of DPI 201-106 ill guinea pig ventricular myocytes. Pflügers Arch 1989; 413: 234-41.
118. Krafle DS, Volberg WA, Dillon K, Ezrin AM. Expression of cardiac Na channels with appropriate physiological and pharmacological properties in Xenopus oocytes. Proc Natl Acad Sci USA 1991, 88: 4071-4.
119. Scholtysik G, Salzmann R, Berthold R, Herzig JW, Quast U, Markstein R. DPI 201-106, a novel cardioactive agent. Combination of cAMP-independent positive inotropic, negative chronotropic, action potential prolonging and coronary dilatory properties. Naunyn Schmiedebergs Arch Pharmacol 1985; 329: 316-25.
120. Groschner K, Ulle P, Brunner F, Kukovetz WR. Interaction of DPI 201-106 with cardiac muscarinic receptors. Eur J Pharmacol 1989; 159: 125-31.
121. 2+ current by the enantiomers of DPI 201-106 and BDF 8784. Br J Pharmacol 1991, 104: 490-4.
122. Novosel D, Hof A, Zeierhut W, Hof RP. Proarrhythmic effects of DPI 201-106 elicited with programmed electrical stimulation: a comparison with sotalol. J Cardiovasc Pharmacol 1993; 21: 967-72.
123. Ozaki T, Uematsu T, Nagashima S, Nishimoto M, Nakashima M. Effects of DPI 201-106, a novel cardiotonic agent, on haemodynamics, cardiac electrophysiology and arrhythmias induced by programmed ventricular stimulation in dogs with subacute myocardial infarction: a comparative study with dobutamine. Naunyn Schmiedebergs Arch Pharmacol 1991; 344: 478-87.
124. Ravens U, Wettwer E, Pfeiffer T, Himmel H, Armah B. Characterization of the effect of the new inotropic agent BDF 9148 in isolated papillary muscles and myocytes of the guinea pig heart. Br J Pharmacol 1991; 104: 1019-23.
125. Kawamura A, Wahler GM, Solaro RJ. RWJ-24517, a positive inotropic agent, has novel effects oil action potentials in guinea pig myocardium. J Cardiovasc Pharmacol 1993; 22: 519-25.
126. Pogwizd SM, Bers DM. Calcium Cycling in heart failure: the arrhythmia connection. J Cardiovasc Electrophysiol 2002, 13: 88-91.
127. Pogwizd SM. Clinical potential of sodium-calcium exchanger inhibitors as antiarrhythmic agents. Drugs 2003; 63: 439-52.
128. Li Y, Harte WE. A review of molecular modeling approaches to pharmacophore models and structure-activity relationships of ion channel modulators in CNS. Curr Pharm Design 2002, 8(2): 99-110.
129. Lombardi F, Terranova P. Hypertension and Concurrent arrhythmias. Curr Pharm Design 2003; 9(21): 1703-13.
130. Takano H, Ohtsuka M, Akazawa H, Toko H, Harada M, Hasegawa H, Nagai T, Komuro I. Pleiotropic effects of cytokines oil acute myocardial infarction: G-CSF as a novel therapy for acute myocardial infarction. Curr Pharm Design 2003; 9(14): 1121-7.