The therapeutic potential of novel cardiotonic agents

Expert Opinion on Investigational Drugs

Volumn 12, Issue 5, 2003, Pages 735-750

  Endoh, Masao ^a  

^a YAMAGATA UNIVERSITY   (Japan)

Author keywords

Ca2+ sensitisers; Cardiac E C coupling; Levosimendan; Myofilament Ca2+ sensitivity; Novel cardiotonic agents; PDE3 inhibitors; Pimobendan

Indexed keywords

1,3,5,6 TETRAHYDRO 5 METHYL 6 PHENYL 3,6 METHANO 1,5 BENZODIAZOCINE 2,4 DIONE; 4,5 DIHYDRO 6 [4 (4 PYRIDYLAMINO)PHENYL] 3(2H) PYRIDAZINONE; 5 [1 (3,4 DIMETHOXYBENZOYL) 1,2,3,4 TETRAHYDRO 6 QUINOLYL] 3,6 DIHYDRO 6 METHYL 2H 1,3,4 THIADIAZIN 2 ONE; 6 (3 DIMETHYLAMINOPROPIONYL)FORSKOLIN; AMRINONE; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; BETA ADRENERGIC RECEPTOR STIMULATING AGENT; CALCIUM ANTAGONIST; CALCIUM ION; CALCIUM SENSITIZER; CARDIOTONIC AGENT; CYCLIC AMP DEPENDENT PROTEIN KINASE; DENOPAMINE; DIGITALIS; DOBUTAMINE; DOPAMINE; FORSKOLIN; GINGEROL; ISOPRENALINE; LEVOSIMENDAN; LOPRINONE; MILRINONE; N HYDROXY 5,6 DIMETHOXY 2 BENZO[B]THIOPHENECARBOXIMIDAMIDE; NORADRENALIN; PHOSPHODIESTERASE INHIBITOR; PIMOBENDAN; PIPERANOMETOZINE; UK 1745; UNCLASSIFIED DRUG; UNINDEXED DRUG; XAMOTEROL;

CALCIUM MOBILIZATION; CELL DEATH; CLINICAL TRIAL; CONGESTIVE HEART FAILURE; DOWNSTREAM PROCESSING; DRUG DOSE REGIMEN; DRUG EFFICACY; DRUG RESEARCH; DRUG SAFETY; DRUG SYNTHESIS; HEART ARRHYTHMIA; HEART LEFT VENTRICLE OVERLOAD; HEART MUSCLE CELL; HEART MUSCLE INJURY; HUMAN; MYOFILAMENT; NAUSEA AND VOMITING; NONHUMAN; OUTCOMES RESEARCH; PLASMA HALF LIFE; REGULATORY MECHANISM; REVIEW; TACHYCARDIA;

3',5'-CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; ADRENERGIC BETA-AGONISTS; CALCIUM; CARDIOTONIC AGENTS; CLINICAL TRIALS; HEART FAILURE, CONGESTIVE; HUMANS; MICROFILAMENTS; MYOCARDIUM; PHOSPHODIESTERASE INHIBITORS;

EID: 0038355215     PISSN: 13543784     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543784.12.5.735     Document Type: Review

References (177)

1. KATZ AM: Heart Failure - Pathophysiology, Molecular Biology, and Clinical Management (1st Ed.). Lippincott Williams & Wilkins, Philadelphia (2000).
2. KRUM H: New and emerging pharmacological strategies in the management of chronic heart failure. Curr. Opin. Pharmacol. (2001) 1:126-133.
3. CHIN BS, LIP GY: New pharmacological strategies for the treatment of heart failure. Curr. Opin. Investig. Drugs (2001) 2:923-928.
4. YOUNG JB: New therapeutic choices in the management of acute congestive heart failure. Rev. Cardiovasc. Med. (2001) 2(Suppl. 2):S19-S24.
5. DOGGRELL SA, BROWN L: Present and future pharmacotherapy for heart failure. Expert Opin. Pharmacother. (2002) 3:915-930.
6. FARAH AE, ALOUSI AA, SCHWARZ RP Jr: Positive inotropic agents. Ann. Rev. Pharmacol. Toxicol. (1984) 24:275-328.
7. PITT B, ZANNAD F, REMME WJ et al.: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N. Engl. J. Med. (1999) 341:709-717.
8. PACKER M, CATS AJ, FOWLER MB et al.: Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N. Engl. J. Med. (2001) 344:1651-1658.
9. SMITH ES 3rd, TRUSSELL S, MENCER LJ: Prevention of heart failure. Curr. Opin. Cardiol. (2002) 17:512-517.
10. PACKER M, CARVER JR, RODEHEFFER RJ et al.: Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N. Engl. J. Med. (1991) 325:1468-1475.
11. LEIER CV, BINKLEY PF: Parenteral inotropic support for advanced congestive heart failure. Prog. Cardiovasc. Dis. (1998) 41:207-224.
12. HATZIZACHARIAS A, MAKRIS T, KRESPI P et al.: Intermittent milrinone effect on long-term hemodynamic profile in patients with severe congestive heart failure. Am. Heart J. (1999) 138(2, Pt 1):191-192.
13. ENDOH M, HORI M: Basic pharmacology and clinical application of new positive inotropic agents. Drugs Today (1993) 29:29-56.
14. SCHOLZ H, MEYER W: Phosphodiesterase-inhibiting properties of newer inotropic agents. Circulation (1986) 73:III99-III108.
15. SOLARO RJ: Modulation of activation of cardiac myofilaments by β-adrenergic agonists. In: Modulation of Cardiac Calcium Sensitivity: A New Approach to Increasing the Strength of the Heart. JA Lee, DG Allen (Eds), Oxford University Press, New York (1993):160-177.
16. ENDOH M: The effects of various drugs on the myocardial inotropic response. Gen. Pharmacol. (1995) 26:1-31.
17. ++ as an inotropic mechanism. Circulation (1986) 73:III85-III98.
18. 2+ sensitization as mechanisms of action of physiological interventions and inotropic agents in intact myocardial cells. Jpn. Heart J. (1998) 39:1-44.
19. ENDOH M: Regulation of myocardial contractility by a downstream mechanism. Circ. Res. (1998) 83:230-232.
20. LEE JA, ALLEN DG: Calcium sensitisers: mechanisms of action and potential usefulness as inotropes. Cardiovasc. Res. (1997) 36:10-20.
21. YUE DT, HERZIG S, MARBAN E: α-Adrenergic stimulation of calcium channels occurs by potentiation of high-activity gating modes. Proc. Natl. Acad. Sci. USA (1990) 87:753-757.
22. 2+ channel currents but not for the negative shift of activation. FEBS Lett. (2001) 489:87-91.
23. HAIN J, ONOUE H, MAYRLEITNER M et al.: Phosphorylation modulates the function of the calcium release channel of sarcoplasmic reticulum from cardiac muscle. J. Biol. Chem. (1995) 270:2074-2081.
24. TADA M, KATZ AM: Phosphorylation of the sarcoplasmic reticulum and sarcolemma. Ann. Rev. Physiol. (1982) 44:401-423.
25. HAGEMANN D, KUSCHEL M, KURAMOCHI T et al.: Frequency-encoding Thr17 phospholamban phosphorylation is independent of Ser16 phosphorylation in cardiac myocytes. J. Biol. Chem. (2000) 275:22532-22536.
26. WESTFALL MV, TURNER I, ALBAYYA FP et al.: Troponin I chimera analysis of the cardiac myofilament tension response to protein kinase A. Am. J. Physiol. (2001) 280:C324-C332.
27. WINEGRAD S: Cardiac myosin binding protein C. Circ. Res. (1999) 84:1117-1126.
28. 2+ release during excitation-contraction coupling in cardiac myocytes. Circ. Res. (2001) 88:794-801.
29. ++ transients. J. Pharmacol. Exp. Ther. (1993) 265:1292-1300.
30. HABUCHI Y, YAMAMOTO T, NISHIO M et al.: Modulation of L-type Ca current by denopamine, a nonparenteral partial β1 stimulant, in rabbit ventricular cells. Naunyn Schmiedebergs Arch. Pharmacol. (1996) 354:437-443.
31. ENDOH M: Mechanisms of novel cardiotonic agents developed to treat the failing heart syndrome. In: New Horizons for Failing Heart Syndrome. S Sasayama (Ed.), Springer, Tokyo (1996):187-208.
32. KUROSAWA H, NARITA H, KABURAKI M et al.: Prolongation of the life span of cardiomyopathic hamster by the adrenergic β1-selective partial agonist denopamine. Jpn. J. Pharmacol. (1996) 72:325-333.
33. NISHIO R, MATSUMORI A, SHIOI T et al.: Denopamine, a β1-adrenergic agonist, prolongs survival in a murine model of congestive heart failure induced by viral myocarditis: suppression of tumor necrosis factor-α production in the heart. J. Am. Coll. Cardiol. (1998) 32:808-815.
34. GOMEZ AM, VALDIVIA HH, CHENG H et al.: Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science (1997) 276:800-806.
35. SUGAWARA H, SAKURAI K, ATSUMI H et al.: Differential alteration of cardiotonic effects of EMD 57033 and β-adrenoceptor agonists in volume-overload rabbit ventricular myocytes. J. Card. Fail. (2000) 6:338-349.
36. max to Pressure-Volume Area. MM LeWinter, H Suga, MW Watkin (Eds), Kluwer Academic Publishers, Boston, USA (1995):171-199.
37. RECHTMAN MP, VAN DER ZYPP A, MAJEWSKI H: Amrinone reduces ischaemia-reperfusion injury in rat heart. Eur. J. Pharmacol. (2000) 402:255-262.
38. CHANANI NK, COWAN DB, TAKEUCHI K et al.: Differential effects of amrinone and milrinone upon myocardial inflammatory signaling. Circulation (2002) 106(12, Suppl. 1):1284-1289.
39. BRISTOW MR, HERSHBERGER RE, PORT JD et al.: β 1- and β 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium. Mol. Pharmacol. (1989) 35:295-303.
40. SANBE A, TAKEO S: Diminished responsiveness to cardiac β 1-adrenoceptor agonists in rats with chronic heart failure following myocardial infarction. Biol. Pharm. Bull. (1995) 18:1362-1366.
41. SANBE A, TAKEO S: Effects of NKH477, a water-soluble forskolin derivative, on cardiac function in rats with chronic heart failure after myocardial infarction. J. Pharmacol. Exp. Ther. (1995) 274:120-126.
42. SATO S, SATO N, KUDEJ RK et al.: β-adrenergic receptor signalling in stunned myocardium of conscious pigs. J. Mol. Cell. Cardiol. (1997) 29:1387-1400.
43. TOYA Y, SCHWENCKE C, ISHIKAWA Y: Forskolin derivatives with increased selectivity for cardiac adenylyl cyclase. J. Mol. Cell. Cardiol. (1998) 30:97-108.
44. HOSONO M, TAKAHIRA T, FUJITA A et al.: Cardiovascular and adenylate cyclase stimulant properties of NKH477, a novel water-soluble forskolin derivative. J. Cardiovasc. Pharmacol. (1992) 19:625-634.
45. + current in ventricular myocytes. Am. J. Physiol. (1994) 266:H1551-H1557.
46. HIRASAWA A, AWAJI T, HOSONO M et al.: Effects of a new forskolin derivative, NKH477, on canine ventricular arrhythmia models. J. Cardiovasc. Pharmacol. (1993) 22:847-851.
47. ISHIZUKA O, HOSONO M, NAKAMURA K: Profile of cardiovascular effects of NKH477, a novel forskolin derivative, assessed in isolated, blood-perfused dog heart preparations: comparison with isoproterenol. J. Cardiovasc. Pharmacol. (1992) 20:261-267.
48. MIYAKE R, YOSHIDA H, TANONAKA K et al.: Characterization of positive inotropic effect of colforsin daropate [correction of dapropate] hydrochloride, a water-soluble forskolin derivative, in isolated adult rat cardiomyocytes. Can. J. Physiol. Pharmacol. (1999) 77:225-234. [Published erratum appears in Can. J. Physiol. Pharmacol. (1999) 77(7):551].
49. FUJITA A, TAKAHIRA T, HOSONO M et al.: Improvement of drug-induced cardiac failure by NKH477, a novel forskolin derivative, in the dog heart-lung preparation. Jpn. J. Pharmacol. (1992) 58:375-381.
50. SAWAKI S, FURUKAWA Y, INOUE Y et al.: Zatebradine attenuates cyclic AMP-related positive chronotropic but not inotropic responses in isolated, perfused right atria of the dog. Clin. Exp. Pharmacol. Physiol. (1995) 22:29-34.
51. LECHAT P, PACKER M, CHALON S et al.: Clinical effects of β-adrenergic blockade in chronic heart failure: a meta-analysis of double-blind, placebo-controlled, randomized trials. Circulation (1998) 98:1184-1191.
52. PACKER M, FOWLER MB, ROECKER EB et al.: Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation (2002) 106:2194-2196.
53. YOSHIKAWA T, BABA A, SUZUKI M et al.: Effectiveness of carvedilol alone versus carvedilol + pimobendan for severe congestive heart failure. For the Keio Interhospital Cardiology Study (KICS) Group. Am. J. Cardiol. (2000) 85:1495-1497; A7.
54. LOWES BD, SIMON MA, TSVETKOVA TO et al.: Inotropes in the β-blocker era. Clin. Cardiol. (2000) 23:III11-III16.
55. SAWADA H, ENDOH M: Pharmacological characterization of effects of UK-1745, a novel cardiotonic agent with β-adrenoceptor-blocking action, in aequorin-loaded canine right ventricular muscle. J. Mol. Cell. Cardiol. (1999) 31:1047-1062.
56. 2+ channels. Nature (1983) 303:535-537.
57. 2+ channels. Trends Pharmacol. Sci. (1988) 9:257-261.
58. MCCALL E, HRYSHKO LV, STIFFEL VM et al.: Possible functional linkage between the cardiac dihydropyridine and ryanodine receptor: acceleration of rest decay by Bay K 8644. J. Mol. Cell. Cardiol. (1996) 28:79-93.
59. SATOH H, HAYASHI H, BLATTER LA et al.: Bay K 8644 increases resting calcium spark frequency in ferret ventricular myocytes. Heart Vessels (1997) (Suppl. 12):58-61.
60. 2+ spark frequency in ferret ventricular myocytes independent of Ca influx: contrast with caffeine and ryanodine effects. Circ. Res. (1998) 83:1192-1204.
61. 2+ cross signaling between DHP and ryanodine receptors in rat ventricular myocytes. Am. J. Physiol. (1999) 276:H1178-H1189.
62. SAGAWA T, NISHIO M, SAGAWA K et al.: Activation of purified cardiac ryanodine receptors by dihydropyridine agonists. Am. J. Physiol. (2001) 280:H1201-H1207.
63. OHIZUMI Y: Application of physiologically active substances isolated from natural resources to pharmacological studies. Jpn. J. Pharmacol. (1997) 73:263-289.
64. 2+-pumping ATPase in skeletal and cardiac sarcoplasmic reticulum. Biochim. Biophys. Acta (1987) 903:96-102.
65. ++-pumping adenosine triphosphatase of sarcoplasmic reticulum, in guinea pig atrial muscle. J. Pharmacol. Exp. Ther. (1988) 246:667-673.
66. HOBAI IA, O'ROURKE B: Decreased sarcoplasmic reticulum calcium content is responsible for defective excitation-contraction coupling in canine heart failure. Circulation (2001) 103:1577-1584.
67. MAIER LS, SCHWAN C, SCHILLINGER W et al.: Gingerol, isoproterenol and ouabain normalize impaired post-rest behavior but not force-frequency relation in failing human myocardium. Cardiovasc. Res. (2000) 45:913-924.
68. 2+ sensitizers - update 2001. Cardiovasc. Drugs Ther. (2001) 15:397-403.
69. 2+-specific sites of cardiac troponin and troponin C. J. Biol. Chem. (1980) 255:9635-9640.
70. LI G, MARTIN AF, SOLARO RJ: Localization of regions of troponin I important in deactivation of cardiac myofilaments by acidic pH. J. Mol. Cell. Cardiol. (2001) 33:1309-1320.
71. SATA M, SUGIURA S, YAMASHITA H et al.: Dynamic interaction between cardiac myosin isoforms modifies velocity of actomyosin sliding in vitro. Circ. Res. (1993) 73:696-704.
72. SOLARO RJ, GAMBASSI G, WARSHAW DM et al.: Stereoselective actions of thiadiazinones on canine cardiac myocytes and myofilaments. Cicr. Res. (1993) 73:981-990.
73. SOLARO RJ, RARICK HM: Troponin and tropomyosin: proteins that switch on and tune in the activity of cardiac myofilaments. Circ. Res. (1998) 83:471-480.
74. 2+-activated myofilament tension in adult cardiac myocytes. Circ. Res. (2000) 86:470-477.
75. 2+ sensitizer EMD 57033 and cardiac troponin I inhibitory peptide. Biochemistry (2000) 39:8782-8790.
76. 2+ sensitizing drug EMD 57033. J. Biol. Chem. (2001) 276:25456-25466.
77. 2+ concentration in mammalian cardiac muscles. Jpn. Heart J. (1996) 37:143-152.
78. 2+ sensitizer Org-30029 reverses acidosis- and BDM-induced contractile depression in canine myocardium. Am. J. Physiol. (1996) 271:H1829-H1839.
79. LEE JA, SHAH N, WHITE J et al.: A novel thiadiazinone derivative fully reverses acidosis-induced depression of force in cardiac muscle by a calcium-sensitizing effect. Clin. Sci. (1993) 84:141-144.
80. TRINES SA, SMITS CA, VAN DER MOER J et al.: Calcium sensitizer EMD 57033, but not the β1-adrenoceptor agonist dobutamine, increases mechanical efficiency in stunned myocardium. J. Cardiovasc. Pharmacol. (2002) 39:61-72.
81. TSUTSUI H, KINUGAWA S, IDE T et al.: Positive inotropic effects of calcium sensitizers on normal and failing cardiac myocytes. J. Cardiovasc. Pharmacol. (2001) 37:16-24.
82. HAGEMEIJER F: Calcium sensitization with pimobendan: pharmacology, haemodynamic improvement, and sudden death in patients with chronic congestive heart failure. Eur. Heart J. (1993) 14:551-566.
83. 2+ activation and the inotropic effect of pimobendan: comparison with milrinone. Circ. Res. (1988) 63:911-922.
84. SCHELD HH, FRITSCHE R, SCHLEPPER M et al.: Pimobendan increases calcium sensitivity of skinned human papillary muscle fibers. J. Clin. Pharmacol. (1989) 29:360-366.
85. BÖHM M, MORANO I, PIESKE B et al.: Contribution of cAMP-phosphodiesterase inhibition and sensitization of the contractile proteins for calcium to the inotropic effect of pimobendan in the failing human myocardium. Circ. Res. (1991) 68:689-701.
86. SATA M, SUGIURA S, YAMASHITA H et al.: Pimobendan directly sensitizes reconstituted thin filament to slide on cardiac myosin. Eur. J. Pharmacol. (1995) 290:55-59.
87. 2+ current and developed tension in guinea-pig ventricular myocytes and papillary muscle: comparison with IBMX, milrinone, and cilostazol. Cardiovasc. Drugs Ther. (1999) 13:105-11
88. MATSUMORI A, NUNOKAWA Y, SASAYAMA S: Pimobendan inhibits the activation of transcription factor NF-κB: a mechanism which explains its inhibition of cytokine production and inducible nitric oxide synthase. Life Sci. (2000) 67:2513-2519.
89. OHTE N, CHENG CP, SUZUKI M et al.: The cardiac effects of pimobendan (but not amrinone) are preserved at rest and during exercise in conscious dogs with pacing-induced heart failure. J. Pharmacol. Exp. Ther. (1997) 282:23-31.
90. LUBSEN J, JUST H, HJALMARSSON AC et al.: Effect of pimobendan on exercise capacity in patients with heart failure: main results from the Pimobendan in Congestive Heart Failure (PICO) trial. Heart (1996) 76:223-231.
91. ISHIKI R, ISHIHARA T, IZAWA H et al.: Acute effects of a single low oral dose of pimobendan on left ventricular systolic and diastolic function in patients with congestive heart failure. J. Cardiovasc. Pharmacol. (2000) 35:897-905.
92. THE EFFECT OF PIMOBENDAN ON CHRONIC HEART FAILURE STUDY: Effects of pimobendan on adverse cardiac events and physical activities in patients with mild to moderate chronic heart failure: the effects of pimobendan on chronic heart failure study (EPOCH study). Circ. J. (2002) 66:149-157.
93. MATHEW L, KATZ SD: Calcium sensitizing agents in heart failure. Drug Aging (1998) 12:191-204.
94. 2+ sensitivity of cardiac myofibrils and sarcoplasmic reticulum in guinea pig heart. Circ. Res. (1995) 77:107-113.
95. HAIKALA H, KAIVOLA J, NISSINEN E et al.: Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan. J. Mol. Cell. Cardiol. (1995) 27:1859-1866.
96. LEVIJOKI J, POLLESELLO P, KAIVOLA J et al.: Further evidence for the cardiac troponin C mediated calcium sensitization by levosimendan: structure-response and binding analysis with analogs of levosimendan. J. Mol. Cell. Cardiol. (2000) 32:479-491.
97. HAIKALA H, NISSINEN E, ETEMADZADEH E et al.: Troponin C-mediated calcium sensitization induced by levosimendan does not impair relaxation. J. Cardiovasc. Pharmacol. (1995) 25:794-801.
98. KLEEREKOPER Q, PUTKEY JA: Drug binding to cardiac troponin C. J. Biol. Chem (1999) 274:23932-23939.
99. ENDOH M: Mechanisms of action of novel cardiotonic agents. J. Cardiovasc. Pharmacol. (2002) 40:323-338.
100. HAIKALA H, LEVIJOKI J, LINDEN IB: Troponin C-mediated calcium sensitization by levosimendan accelerates the proportional development of isometric tension. J. Mol. Cell. Cardiol. (1995) 27:2155-2165.
101. HASENFUSS G, PIESKE B, CASTELL M et al.: Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium. Circulation (1998) 98:2141-2147.
102. YOKOSHIKI H, KATSUBE Y, SUNAGAWA M et al.: The novel calcium sensitizer levosimendan activates the ATP-sensitive K+ channel in rat ventricular cells. J. Pharmacol. Exp. Ther. (1997) 283:375-383.
103. 2+ sensitizer, activates the glibenclamide-sensitive K+ channel in rat arterial myocytes. Eur. J. Pharmacol. (1997) 333:249-259.
104. ATP channel opener. Eur. J. Pharmacol. (2001) 428:311-314.
105. DU TOIT EF, MULLER CA, MCCARTHY J et al.: Levosimendan: effects of a calcium sensitizer on function and arrhythmias and cyclic nucleotide levels during ischemia/reperfusion in the Langendorff-perfused guinea pig heart. J. Pharmacol. Exp. Ther. (1999) 290:505-514.
106. SLAWSKY MT, COLUCCI WS, GOTTLIEB SS et al.: Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Study Investigators. Circulation (2000) 102:2222-2227.
107. KIVIKKO M, LEHTONEN L, COLUCCI WS: Sustained hemodynamic effects of intravenous levosimendan. Circulation (2003) 107:81-86.
108. TAKAHASHI R, TALUKDER MA, ENDOH M: Inotropic effects of OR-1896, an active metabolite of levosimendan, on canine ventricular myocardium. Eur. J. Pharmacol. (2000) 400:103-112.
109. TAKAHASHI R, TALUKDER MA, ENDOH M: Effects of OR-1896, an active metabolite of levosimendan, on contractile force and aequorin light transients in intact rabbit ventricular myocardium. J. Cardiovasc. Pharmacol. (2000) 36:118-125.
110. 2+ sensitizer levosimendan in human myocardium. Am. J. Physiol. (2002) 282:H131-H137.
111. FOLLATH F, CLELAND JG, JUST H et al.: Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet (2002) 360:196-202.
112. GOMES UC, CLELAND JG: Heart failure update. Eur. J. Heart. Fail. (1999) 1:301-302.
113. CLELAND JG, MCGOWAN J: Levosimendan: a new era for inodilator therapy for heart failure? Curr. Opin. Cardiol. (2002) 17:257-265.
114. KITADA Y, NARIMATSU A, SUZUKI R et al.: Does the positive inotropic action of a novel cardiotonic agent, MCI-154, involve mechanisms other than cyclic AMP? J. Pharmacol. Exp. Ther. (1987) 243:639-645.
115. ++ sensitivity of the contractile system by MCI-154, a novel cardiotonic agent, in chemically skinned fibers from the guinea pig papillary muscles. J. Pharmacol. Exp. Ther. (1987) 243:633-638.
116. 2+ sensitivity of reconstituted thin filament. A study using a novel in vitro motility assay technique. Circ. Res. (1995) 76:626-633.
117. ABE Y, SEKIOKA K, ISHISU R et al.: Restoration of ischemic contractile failure of indo-1-loaded guinea pig heart by a calcium sensitizer, MCI-154. J. Pharmacol. Exp. Ther. (1996) 279:47-55.
118. WARREN SE, KIHARA Y, PESATURO J et al.: Inotropic and lusitropic effects of MCI-154 (6-[4-(4′-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone) on human myocardium. J. Mol. Cell. Cardiol. (1989) 21:1037-1045.
119. 2+ activation of skinned human myocardium. Eur. J. Pharmacol. (1989) 165:305-308.
120. ++-regulated interactions between troponin subunits from bovine heart. J. Pharmacol. Exp. Ther. (1994) 270:831-839.
121. ++ binding by MCI-154, a novel cardiotonic agent. J. Pharmacol. Exp. Ther. (1989) 250:272-277.
122. BETHKE T, MEYER W, SCHMITZ W et al.: High selectivity for inhibition of phosphodiesterase III and positive inotropic effects of MCI-154 in guinea pig myocardium. J. Cardiovasc. Pharmacol. (1993) 21:847-855.
123. ABE Y, ISHISU R, ONISHI K et al.: Calcium sensitization in perfused beating guinea pig heart by a positive inotropic agent MCI-154. J. Pharmacol. Exp. Ther. (1996) 276:433-439.
124. 2+ sensitizer, decreases the oxygen cost of contractility in isolated canine hearts. Am. J. Physiol. (1997) 273:H1688-H1695.
125. 2+ sensitizer, MCI-154, on the myocardial oxygen consumption-cardiac output relation in patients with left ventricular dysfunction after myocardial infarction: comparison with dobutamine and phosphodiesterase inhibitor. Am. Heart J. (1997) 133:283-289.
126. 2+ sensitizer' MIC-154. Scand. Cardiovasc. J. (2002) 36:172-179.
127. TERAMURA S, YAMAKADO T, MAEDA M et al.: Effects of MCI-154, a calcium sensitizer, on left ventricular systolic and diastolic function in pacing-induced heart failure in the dog. Circulation (1997) 95:732-739.
128. 2+ sensitization with a new cardiotonic agent, MCI-154, on diseased human hearts. Cardiovasc. Res. (1995) 30:915-922.
129. HAEUSLER G, JONAS P, MINCK KO et al.: In vivo evidence of positive inotropism of EMD 57033 through calcium sensitization. J. Cardiovasc. Pharmacol. (1997) 29:647-655.
130. LUES I, BEIER N, JONAS R et al.: The two mechanisms of action of racemic cardiotonic EMD 53998, calcium sensitization and phosphodiesterase inhibition, reside in different enantiomers. J. Cardiovasc. Pharmacol. (1993) 21:883-892.
131. TOBIAS AH, SLINKER BK, KIRKPATRICK RD et al.: Functional effects of EMD-57033 in isovolumically beating isolated rabbit hearts. Am. J. Physiol. (1996) 271:H51-H58.
132. SENZAKI H, ISODA T, PAOLOCCI N et al.: Improved mechanoenergetics and cardiac rest and reserve function of in vivo failing heart by calcium sensitizer EMD-57033. Circulation (2000) 101:1040-1048.
133. ++ sensitizers impair cardiac relaxation in failing human myocardium. J. Pharmacol. Exp. Ther. (1997) 280:247-254.
134. ISHISU R, ABE Y, ONISHI K et al.: Differential effects of EMD-53998 on calcium-pressure relationship in normal and ischemic guinea pig heart. Am. J. Physiol. (1996) 271:H311-H319.
135. GRANDIS DJ, DELNIDO PJ, KORETSKY AP: Functional and energetic effects of the inotropic agents EMD-57033 and BAPTA on the isolated rat heart. Am. J. Physiol. (1995) 269:C472-C479.
136. POPPING S, MRUCK S, FISCHER Y et al.: Economy of contraction of cardiomyocytes as influenced by different positive inotropic interventions. Am. J. Physiol. (1996) 271:H357-H364.
137. HEROLD P, HERZIG JW, WENK P et al.: 5-Methyl-6-phenyl-1,3,5,6-tetrahydro-3,6-methano-1,5-benzodiazocine- 2,4-dione (BA 41899): representative of a novel class of purely calcium-sensitizing agents. J. Med. Chem. (1995) 38:2946-2954.
138. ZIMMERMANN N, BOKNIK P, GAMS E et al.: Positive inotropic effects of the calcium sensitizer CGP 48506 in guinea pig myocardium. J. Pharmacol. Exp. Ther. (1996) 277:1572-1578.
139. WOLSKA BM, KITADA Y, PALMITER KA et al.: CGP-48506 increases contractility of ventricular myocytes and myofilaments by effects on actin-myosin reaction. Am. J. Physiol. (1996) 270:H24-H32.
140. NEUMANN J, ESCHENHAGEN T, GRUPP IL et al.: Positive inotropic effects of the calcium sensitizer CGP 48506 in failing human myocardium. J. Pharmacol. Exp. Ther. (1996) 277:1579-1585.
141. 2+ sensitizing agent, and (+)-5-(1-(3,4-dimethoxybenzoyl -1,2,3,4-tetrahydroquinolin-6-yl)- 6-methyl-3, 6-dihydro-2H-1,3,4-thiadiazin-2-one on skinned fibres and isolated ventricular strips. Arzneimittelforschung (1996) 46:586-593.
142. 2+ sensitizers EMD 57033 and CGP 48506 on cross-bridge cycling in human myocardium. J. Pharmacol. Exp. Ther. (2000) 295:1284-1290.
143. 2+-independent mechanisms in porcine skinned trabeculae. Cardiovasc. Res. (1996) 32:411-421.
144. 2+ sensitizers caffeine and CGP 48506 on the relaxation rate of rat skinned cardiac trabeculae. Circ. Res. (1997) 80:682-687.
145. SLINKER BK, WU Y, GREEN HW et al.: Overall cardiac functional effect of positive inotropic drugs with differing effects on relaxation. J. Cardiovasc. Pharmacol. (2000) 36:1-13.
146. SLINKER BK, GREEN HW, WU Y etal.: Relaxation effect of CGP-48506, EMD-57033, and dobutamine in ejecting and isovolumically beating rabbit hearts. Am. J. Physiol. (1997) 273:H2708-H720.
147. ZIMMERMANN N, BOKNIK P, GAMS E et al.: Calcium sensitization as new principle of inotropic therapy in end-stage heart failure? Eur. J. Cardiothorac. Surg. (1998) 14:70-75.
148. COTTNEY J, LOGAN R, MARSHALL R et al.: Org 30029: a new cardiotonic agent possessing both phosphodiesterase inhibitory and calcium-sensitizing properties. Cardiovasc. Drug Rev. (1990) 8:179-202.
149. MILLER DJ, STEELE DS: The 'calcium sensitising' effects of ORG30029 in saponin- or Triton-skinned rat cardiac muscle. Br. J. Pharmacol. (1990) 100:843-849.
150. SHAHID M, NICHOLSON CD: Comparison of cyclic nucleotide phosphodiesterase isoenzymes in rat and rabbit ventricular myocardium: positive inotropic and phosphodiesterase inhibitory effects of Org 30029, milrinone and rolipram. Naunyn Schmiedebergs Arch. Pharmacol. (1990) 342:698-705.
151. GRANDIS DJ, MACGOVAN GA, KORETSKY AP: Comparison of the effects of ORG 30029, dobutamine and high perfusate calcium on function and metabolism in rat heart. J. Mol. Cell. Cardiol. (1998) 30:2605-2612.
152. STAMM C, FRIEHS I, COWAN DB et al.: Dopamine treatment of postischemic contractile dysfunction rapidly induces calcium-dependent pro-apoptotic signaling. Circulation (2002) 106(12, Suppl. 1):1290-1298.
153. KAWABATA Y, ENDOH M: Effects of the positive inotropic agent Org 30029 on developed force and aequorin light transients in intact canine ventricular myocardium. Circ. Res. (1993) 72:597-606.
154. ++ sensitizing action. 3rd communication: stereoselectivity of the enantiomers in cardiovascular effects. Arzneimittelforschung (1999) 49:412-419.
155. ++ sensitizer with no chronotropic activity in mammalian cardiac muscle. J. Pharmacol. Exp. Ther. (1998) 287:214-222.
156. ++ sensitizing action. 2nd communication: in vivo cardiovascular effects and bioavailability in dogs. Arzneimittelforschung (1999) 49:407-411.
157. ++ sensitizing action. 1st communication: phosphodiesterase III inhibitory effect and class III antiarrhythmic effect in guinea-pig heart. Arzneimittelforschung (1999) 49:398-406.
158. 2+ transients in aequorin-loaded right-ventricular papillary muscles and indo-1-loaded single ventricular cardiomyocytes of the rabbit. J. Mol. Cell. Cardiol. (1998) 30:1115-1128.
159. ENDOH M, SHIBASAKI T, SATOH H et al.: Different mechanisms involved in the positive inotropic effects of benzimidazole derivative UD-CG 115 BS (pimobendan) and its demethylated metabolite UD-CG 212 Cl in canine ventricular myocardium. J. Cardiovasc. Pharmacol. (1991) 17:365-375.
160. 2+ sensitizing effect of (+)-enantiomer EMD 57033 on diastolic function but not on systolic function in rabbit ventricular cardiomyocytes. Jpn. J. Pharmacol. (1999) 80:55-65.
161. LEE JA, ALLEN DG: EMD 53998 sensitizes the contractile proteins to calcium in intact ferret ventricular muscle. Circ. Res. (1991) 69:927-936.
162. HIGASHIYAMA A, WATKINS MW, CHEN Z et al.: Effects of EMD 57033 on contraction and relaxation in isolated rabbit hearts. Circulation (1995) 92:3094-3104.
163. GAMBASSI G, CAPOGROSSI MC, KLOCKOW M et al.: Enantiomeric dissection of the effects of the inotropic agent, EMD 53998, in single cardiac myocytes. Am. J. Physiol. (1993) 264:H728-H738.
164. STRAUSS JD, ZEUGNER C, RÜEGG JC: The positive inotropic calcium sensitizer EMD 53998 antagonizes phosphate action on cross-bridges in cardiac skinned fibers. Eur. J. Pharmacol. (1992)
165. BRUNKHORST D, VAN DER LEYEN H, MEYER W et al.: 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) 339:575-583.
166. RAASMAJA A: Biochemical mechanisms of the novel cardiotonic agent OR-1259. J. Mol. Cell. Cardiol. (1991) 23:S.129.
167. BETHKE T, MEYER W, SCHMITZ W et al.: Phosphodiesterase III inhibition by MCI-154 and other cardiotonic drugs in relation to force of contraction, cAMP content and calcium sensitization in the heart. Eur. J. Pharmacol. (1990) 183:783-784.
168. 2+ mediated through α- and β-adrenoceptors. Circ. Res. (1998) 62:247-265.
169. ENDOH M: Dual inhibition of myocardial function through muscarinic and adenosine receptors in the mammalian heart. J. Appl. Cardiol. (1987) 2:213-230.
170. ENDOH M, YANAGISAWA T, MORITA T et al.: Differential effects of sulmazole (AR-L 115 BS) on contractile force and cyclic AMP levels in canine ventricular muscle: comparison with MDL 17,043. J. Pharmacol. Exp. Ther. (1985) 234:267-273.
171. BOKNIK P, NEUMANN J, KASPAREIT G et al.: Mechanisms of the contractile effects of levosimendan in the mammalian heart. J. Pharmacol. Exp. Ther. (1997) 280:277-283.
172. 2+ sensitivity induced by UD-CG 212 Cl, an active metabolite of pimobendan, in canine ventricular myocardium. J. Cardiovasc. Pharmacol. (2001) 37:209-218.
173. ENDOH M, YANAGISAWA T, TAIRA N et al.: EfFects of new inotropic agents on cyclic nucleotide metabolism and calcium transients in canine ventricular muscle. Circulation (1986) 73:III117-III133.
174. HAIKALA H, KAHEINEN P, LEVIJOKI J et al.: The role of cAMP- and cGMP-dependent protein kinases in the cardiac actions of the new calcium sensitizer, levosimendan. Cardiovasc. Res. (1997) 34:536-546.
175. MORANO I: Tuning the human heart molecular motors by myosin light chains. J. Mol. Med. (1999) 77:544-555.
176. THE DIGITALIS INVESTIGATION GROUP: The effect of digoxin on mortality and morbidity in patients with heart failure. N. Engl. J. Med. (1997) 336:525-533.
177. 2+. Ann. Med. (2002) 34:248-258.