The therapeutic potential of novel cardiotonic agents

Bibliography

• KATZ AM: Heart Failure — Pathophysiology, Molecular Biology, and Clinical Management (1st Ed.). Lippincott Williams & Wilkins, Philadelphia (2000).
   Google Scholar
• ••Recent advances of heart failure researchfrom molecular and cellular mechanisms to clinical and therapeutic aspects are covered, providing a balanced view of the disease.
   Google Scholar
• KRUM H: New and emerging pharmacological strategies in the management of chronic heart failure. Curl: Opin. Phannacol (2001) 1:126–133.
   PubMedGoogle Scholar
• CHIN BS, LIP GY: New pharmacological strategies for the treatment of heart failure. CLIFF. Opin. Investig. Drugs (2001) 2:923–928.
   PubMedGoogle Scholar
• YOUNG JB: New therapeutic choices inthe management of acute congestive heart failure. Rev Cardiovasc. Med. (2001) 2\(Suppl. 2):S19–S24.
   Google Scholar
• DOGGRELL SA, BROWN L: Present andfuture pharmacotherapy for heart failure. Expert Opin. Pharmacother: (2002) 3:915–930.
   PubMedGoogle Scholar
• FARAH AE, ALOUSI AA, SCHWARZ RP Jr: Positive inotropic agents. Ann. Rev Pharmacol Toxicol (1984) 24:275–328.
   PubMed Web of Science ®Google Scholar
• ••Landmark of the development of novelcardiotonic agents, describing necessity based on the state-of-the-art and perspectives.
   Google Scholar
• 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. Med. (1999) 341:709–717.
   PubMed Web of Science ®Google Scholar
• ••Clinical study showing the importance ofthe involvement of aldosterone in progress of heart failure syndrome.
   Google Scholar
• 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. I Med. (2001) 344:1651–1658.
   Google Scholar
• SMITH ES 3rd, TRUSSELL S, MENCER LJ: Prevention of heart failure. Curr. Opin. Cardiol (2002) 17:512–517.
   PubMed Web of Science ®Google Scholar
• 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. I Med. (1991) 325:1468–1475.
   PubMed Web of Science ®Google Scholar
• ••Important clinical study showing thatlong-term treatment with oral milrinone, a selective PDE3 inhibitor, is harmful to the prognosis of heart failure patients.
   Google Scholar
• LEIER CV, BINKLEY PF: Parenteral inotropic support for advanced congestive heart failure. Frog. Cardiovasc. Dis. (1998) 41:207–224.
   PubMed Web of Science ®Google Scholar
• 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 (1999) 138(2, Pt 1):191–192.
   Google Scholar
• ENDOH M, HORI M: Basic pharmacology and clinical application of new positive inotropic agents. Drugs Today (1993) 29:29–56.
   Google Scholar
• SCHOLZ H, MEYER W: Phosphodiesterase-inhibiting properties of newer inotropic agents. Circulation (1986) 73:11199–111108.
   Google Scholar
• SOLARO RJ: Modulation of activation of cardiac myofilaments by P-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.
   Google Scholar
• ENDOH M: The effects of various drugs on the myocardial inotropic response. Gen. Pharmacol. (1995) 26:1–31.
   PubMedGoogle Scholar
• BLINKS JR, ENDOH M: Modification of myofibrillar responsiveness to Ca++ as an inotropic mechanism. Circulation (1986) 73:11185–11198.
   Google Scholar
• ••Cardiotonic agents are classified first basedon their mechanism of action, acting on the central, upstream and downstream mechanisms of the cardiac E-C coupling.
   Google Scholar
• ENDOH M: Changes in intracellular Ca2+ mobilization and Ca2+ sensitization as mechanisms of action of physiological interventions and inotropic agents in intact myocardial cells. fpn. Heart (1998) 39:1–44.
   Web of Science ®Google Scholar
• ENDOH M: Regulation of myocardial contractility by a downstream mechanism. Circ. Res. (1998) 83:230–232.
   PubMed Web of Science ®Google Scholar
• LEE JA, ALLEN DG: Calcium sensitisers: mechanisms of action and potential usefulness as inotropes. Cardiovasc. Res. (1997) 36:10–20.
   PubMed Web of Science ®Google Scholar
• YUE DT, HERZIG S, MARBAN E: a-Adrenergic stimulation of calcium channels occurs by potentiation of high-activity gating modes. Proc. Natl. Acad. Sci. USA (1990) 87:753–757.
   PubMed Web of Science ®Google Scholar
• NAGURO I, NAGAO T, ADACHI-AKAHANE S: Ser1901 of al C subunit is required for the PKA-mediated enhancement of L-type Ca2+ channel currents but not for the negative shift of activation. FEBS Lett. (2001) 489:87–91.
   PubMed Web of Science ®Google Scholar
• HAIN J, ONOUE H, MAYRLEITNER M et al.: Phosphorylation modulates the function of the calcium release channel of sarcoplasmic reticulum from cardiac muscle. Biol. Chem. (1995) 270:2074–2081.
   Web of Science ®Google Scholar
• TADA M, KATZ AM: Phosphorylation of the sarcoplasmic reticulum and sarcolemma. Ann. Rev Physiol. (1982) 44:401–423.
   PubMed Web of Science ®Google Scholar
• ••Important article reviewing the functionalsignificance of phosphorylation of regulatory proteins.
   Google Scholar
• HAGEMANN D, KUSCHEL M, KURAMOCHI T et al.: Frequency-encoding Thr17 phospholamban phosphorylation is independent of Ser16 phosphorylation in cardiac myocytes. Biol. Chem. (2000) 275:22532–22536.
   Web of Science ®Google Scholar
• WESTFALL MV, TURNER I, ALBAYYA FP et al.: Troponin I chimera analysis of the cardiac myofilament tension response to protein kinase A. Am. .1. Physiol. (2001) 280:C324–C332.
   Google Scholar
• •Domain of TnI that plays an important role in regulation of Ca2+ sensitivity was differentiated by means of chimera analysis.
   Google Scholar
• WINEGRAD S: Cardiac myosin binding protein C. Circ. Res. (1999) 84:1117–1126.
   PubMed Web of Science ®Google Scholar
• •Perspectives for potential regulatory role of MyBP-C are discussed in detail based on current findings.
   Google Scholar
• SONG LS, WANG SQ, XIAO RP et al.: P-Adrenergic stimulation synchronizes intracellular Ca2+ release during excitation-contraction coupling in cardiac myocytes. Circ. Res. (2001) 88:794–801.
   PubMed Web of Science ®Google Scholar
• KOHI M, NOROTA I, TAKANASHI M et al.: On the mechanism of action of the I3-1 partial agonist denopamine in regulation of myocardial contractility: effects on myocardial a adrenoceptors and intracellular Ca ++ transients. Pharmacol. Exp. Ther. (1993) 265:1292–1300.
   PubMed Web of Science ®Google Scholar
• HABUCHI Y, YAMAMOTO T, NISHIO M et al: Modulation of L-type Ca current by denopamine, a nonparenteral partial 131 stimulant, in rabbit ventricular cells. Naunyn Schmiedebergs Arch. Pharmacol. (1996) 354:437–443.
   PubMed Web of Science ®Google Scholar
• 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.
   Google Scholar
• KUROSAWA H, NARITA H, KABURAKI M et al.: Prolongation of the life span of cardiomyopathic hamster by the adrenergic IM-selective partial agonist denopamine. fpn. Pharmacol. (1996) 72:325–333.
   Web of Science ®Google Scholar
• NISHIO R, MATSUMORI A, SHIOI T et al: Denopamine, a IM-adrenergic agonist, prolongs survival in a murine model of congestive heart failure induced by viral myocarditis: suppression of tumor necrosis factor-a production in the heart. Am. Coll. Cardiol. (1998) 32:808–815.
   PubMed Web of Science ®Google Scholar
• GOMEZ AM, VALDIVIA HH, CHENG H et al.: Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science (1997) 276:800–806.
   PubMed Web of Science ®Google Scholar
• •Potential subcellular mechanisms for defective E-C coupling were proposed based on the dysfunction of CICR detected by alteration of Ca2+ sparks.
   Google Scholar
• SUGAWARA H, SAKURAI K, ATSUMI H et al.: Differential alteration of cardiotonic effects of EMD 57033 and I3-adrenoceptor agonists in volume-overload rabbit ventricular myocytes. Card. Fail. (2000) 6:338–349.
   PubMed Web of Science ®Google Scholar
• ENDOH M: Calcium signaling and pharmacology of cardiotonic agents. In: Cardiac Energetics: From E to Pressure-Volume Area. MM LeWinter, H Suga, MW Watkin (Eds), Kluwer Academic Publishers, Boston, USA (1995):171–199.
   Google Scholar
• RECHTMAN MP, VAN DER ZYPP A, MAJEWSKI H: Amrinone reduces ischaemia-reperfusion injury in rat heart. Eur. Pharmacol. (2000) 402:255–262.
   PubMed Web of Science ®Google Scholar
• 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.
   Google Scholar
• BRISTOW MR, HERSHBERGER RE, PORT JD et al.: 131- and 13 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium. Mol. Pharmacol. (1989) 35:295–303.
   PubMed Web of Science ®Google Scholar
• SANBE A, TAKEO S: Diminished responsiveness to cardiac 13 1-adrenoceptor agonists in rats with chronic heart failure following myocardial infarction. Biol. Pharm. Bull. (1995) 18:1362–1366.
   PubMed Web of Science ®Google Scholar
• SANBE A, TAKEO S: Effects of NKH477, a water-soluble forskolin derivative, on cardiac function in rats with chronic heart failure after myocardial infarction. Pharmacol. Exp. Ther. (1995) 274:120–126.
   PubMed Web of Science ®Google Scholar
• SATO S, SATO N, KUDEJ RK et al: P-adrenergic receptor signalling in stunned myocardium of conscious pigs. Mol. Cardiol. (1997) 29:1387–1400.
   PubMed Web of Science ®Google Scholar
• TOYA Y, SCHWENCKE C, ISHIKAWA Y: Forskolin derivatives with increased selectivity for cardiac adenylyl cyclase. Ma Cell. Cardiol (1998) 30:97–108.
   PubMed Web of Science ®Google Scholar
• HOSONO M, TAKAHIRA T, FUJITA A et al: Cardiovascular and adenylate cyclase stimulant properties of NKH477, a novel water-soluble forskolin derivative. Cardiovasc. Pharmacol (1992) 19:625–634.
   PubMed Web of Science ®Google Scholar
• HARADA K, IIJIMA T: Differential modulation by adenylate cyclase of Ca2+ and delayed K+ current in ventricular myocytes. Am. .1. Physiol (1994) 266:H1551–H1557.
   PubMed Web of Science ®Google Scholar
• HIRASAWA A, AWAJI T, HOSONO M et al: Effects of a new forskolin derivative, NKH477, on canine ventricular arrhythmia models. Cardiovasc. Phannacol (1993) 22:847–851.
   PubMed Web of Science ®Google Scholar
• ISHIZUKA 0, 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. Cardiovasc. Pharmacol (1992) 20:261–267.
   PubMed Web of Science ®Google Scholar
• 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. Physiol Phannacol (1999) 77:225-234. [Published erratum appears in Can. I Physiol Phannacol (1999) 77(7):551].
   Google Scholar
• FUJITA A, TAKAHIRA T, HOSONO M et at Improvement of drug-induced cardiac failure by NKH477, a novel forskolin derivative, in the dog heart-lung preparation. fpn. I Pharmacol (1992) 58:375–381.
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• LECHAT P, PACKER M, CHALON S et al.: Clinical effects of P-adrenergic blockade in chronic heart failure: a meta-analysis of double-blind, placebo-controlled, randomized trials. Circulation (1998) 98:1184–1191.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• •Survival study with carvedilol.
   Google Scholar
• 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.
   Google Scholar
• LOWES BD, SIMON MA, TSVETKOVA TO et al.: Inotropes in the P-blocker era. Clin. Cardiol (2000) 23:11111–11116.
   Google Scholar
• SAWADA H, END OH M: Pharmacological characterization of effects of UK-1745, a novel cardiotonic agent with P-adrenoceptor-blocking action, in aequorin-loaded canine right ventricular muscle. Ma Cell. Cardiol (1999) 31:1047–1062.
   PubMed Web of Science ®Google Scholar
• SCHRAMM M, THOMAS G, TOWART R et al.: Novel dihydropyridines with positive inotropic action through activation of Ca2+ channels. Nature (1983) 303:535–537.
   PubMed Web of Science ®Google Scholar
• •First report on the Ca2+ agonist Bay K 8644.
   Google Scholar
• BECHEM M, HEBISCH S, SCHRAMM M: Ca2+ agonists: new sensitive probes for Ca2+ channels. Trends Phannacol Sci. (1988) 9:257–261.
   Web of Science ®Google Scholar
• 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 8644.1 Ma Cell. Cardiol (1996) 28:79–93.
   Google Scholar
• 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.
   Google Scholar
• SATOH H, KATOH H, VELEZ P et al.:Bay K 8644 increases resting Ca2+ spark frequency in ferret ventricular myocytes independent of Ca influx: contrast with caffeine and ryanodine effects. Circ. Res. (1998) 83:1192–1204.
   PubMed Web of Science ®Google Scholar
• ADACHI-AKAHANE S, CLEEMANN L, MORAD M: BAY K 8644 modifies Ca2+ cross signaling between DHP and ryanodine receptors in rat ventricular myocytes. Am. Physiol (1999) 276:H1178–H1189.
   PubMed Web of Science ®Google Scholar
• SAGAWA T, NISHIO M, SAGAWA K et al.: Activation of purified cardiac ryanodine receptors by dihydropyridine agonists. Am.j Physiol (2001) 280:H1201–H1207.
   Web of Science ®Google Scholar
• OHIZUMI Y: Application of physiologically active substances isolated from natural resources to pharmacological studies. fpn..1. Pharmacol (1997) 73:263–289.
   Google Scholar
• KOBAYASHI M, SHOJI N, OHIZUMI Y:Gingerol, a novel cardiotonic agent, activates the Ca2+-pumping ATPase in skeletal and cardiac sarcoplasmic reticulum. Biochim. Biophys. Acta (1987) 903:96–102.
   PubMed Web of Science ®Google Scholar
• KOBAYASHI M, ISHIDA Y, SHOJI N et al.: Cardiotonic action of [8] -gingerol, an activator of the Ca++-pumping adenosine triphosphatase of sarcoplasmic reticulum, in guinea pig atrial muscle. I Phannacol Exp. Ther. (1988) 246:667–673.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• •Role of SR Ca2+ in contractile dysfunction in heart failure.
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• ENDOH M: Mechanism of action of Ca2+sensitizers - update 2001. Cardiovasc. Drugs Ther. (2001) 15:397–403.
   PubMed Web of Science ®Google Scholar
• JOHNSON JD, COLLINS JH, ROBERTSON SP et al.: A fluorescent probe study of Ca2+ binding to the Ca2+-specific sites of cardiac troponin and troponin C. I Biol. Chem. (1980) 255:9635–9640.
   Web of Science ®Google Scholar
• LI G, MARTIN AF, SOLARO RJ: Localization of regions of troponin I important in deactivation of cardiac myofilaments by acidic pH. 1 MM. Cell. Cardiol (2001) 33:1309–1320.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• SOLARO RJ, GAMBASSI G, WARSHAW DM et al.: Stereoselective actions of thiadiazinones on canine cardiac 746 myocytes and myofilaments. Circ. Res. (1993) 73:981–990.
   PubMed Web of Science ®Google Scholar
• ••Stereoselective separation of Ca2+ sensitising and PDE3 inhibitory action.
   Google Scholar
• SOLARO RI, RARICK HM: Troponin and tropomyosin: proteins that switch on and tune in the activity of cardiac myofilaments. Circ. Res. (1998) 83:471–480.
   PubMed Web of Science ®Google Scholar
• WESTFALL MV, ALBAYYA FP, TURNER II, METZGER JM: Chimera analysis of troponin I domains that influence Ca2±-activated myofilament tension in adult cardiac myocytes. Circ. Res. (2000) 86:470–477.
   PubMed Web of Science ®Google Scholar
• •Identification of functional domains of TnI by means of chimera analysis.
   Google Scholar
• LI MX, SPYRACOPOULOS L, BEIER N et al: Interaction of cardiac troponin C with Ca2+ sensitizer EMD 57033 and cardiac troponin I inhibitory peptide. Biochemistry (2000) 39:8782–8790.
   PubMed Web of Science ®Google Scholar
• WANG X, LI MX, SPYRACOPOULOS L et al.: Structure of the C-domain of human cardiac troponin C in complex with the Ca2+ sensitizing drug EMD 57033. J. Biol. Chem. (2001) 276:25456–25466.
   PubMed Web of Science ®Google Scholar
• ••EMD 57033 has specific binding domainin C-terminus of cTnC.
   Google Scholar
• KURIHARA S, KOMUKAI K: Cross-bridge-dependent changes in the intracellular Ca2+ concentration in mammalian cardiac muscles. fpn. Heart .1. (1996) 37:143-152.
   Google Scholar
• WATANABE A, TOMOIKE H, END OH M: Ca2+ sensitizer Org-30029 reverses acidosis- and BDM-induced contractile depression in canine myocardium. Am. .1. Physiol (1996) 271:H1829–H1839.
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• TRINES SA, SMITS CA, VAN DER MOER J et al.: Calcium sensitizer EMD 57033, but not the 31-adrenoceptor agonist dobutamine, increases mechanical efficiency in stunned myocardium. Cardiovasc. Pharmacol (2002) 39:61–72.
   Google Scholar
• TSUTSUI H, KINUGAWA S, IDE T et al: Positive inotropic effects of calcium sensitizers on normal and failing cardiac myocytes. Cardiovasc. Pharmacol (2001) 37:16–24.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• FUJINO K, SPERELAKIS N, SOLARO RI: Sensitization of dog and guinea pig heart myofilaments to Ca2+ activation and the inotropic effect of pimobendan: comparison with milrinone. Circ. Res. (1988) 63:911–922.
   PubMed Web of Science ®Google Scholar
• SCHELD HH, FRITSCHE R, SCHLEPPER M et al.: Pimobendan increases calcium sensitivity of skinned human papillary muscle fibers. I Gin. Pharmacol (1989) 29:360–366.
   Web of Science ®Google Scholar
• BOHM 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.
   PubMed Web of Science ®Google Scholar
• SATA M, SUGIURA S, YAMASHITA H et al.: Pimobendan directly sensitizes reconstituted thin filament to slide on cardiac myosin. Eui: Pharmacol (1995) 290:55–59.
   PubMed Web of Science ®Google Scholar
• MATSUI K, KIYOSUE T, WANG IC et al.: Effects of pimobendan on the L-type Ca2+ current and developed tension in guinea-pig ventricular myocytes and papillary muscle: comparison with IBMX, milrinone, and cilostazol. Cardiovasc. Drugs Thec (1999) 13:105–113.
   PubMed Web of Science ®Google Scholar
• MATSUMORI A, NUNOKAWA Y, SASAYAMA S: Pimobendan inhibits the activation of transcription factor NF-icB: a mechanism which explains its inhibition of cytokine production and inducible nitric oxide synthase. Life Sci. (2000) 67:2513–2519.
   PubMed Web of Science ®Google Scholar
• 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. I Pharmacol Exp. Thec (1997) 282:23–31.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• •Clinical study with pimobendan.
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• 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. (2002) 66:149–157.
   Web of Science ®Google Scholar
• MATHEW L, KATZ SD: Calcium sensitizing agents in heart failure. Drug Aging (1998) 12:191–204.
   PubMed Web of Science ®Google Scholar
• EDES I, KISS E, KITADA Y et al: Effects of levosimendan, a cardiotonic agent targeted to troponin C, on cardiac function and on phosphorylation and Ca2+ sensitivity of cardiac myofibrils and sarcoplasmic reticulum in guinea pig heart. Circ. Res. (1995) 77:107–113.
   PubMed Web of Science ®Google Scholar
• HAIKALA H, KAIVOLA J, NISSINEN E et al: Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan. MM. Cell. Cardiol (1995) 27:1859–1866.
   PubMed Web of Science ®Google Scholar
• 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. MM. Cell. Cardiol (2000) 32:479–491.
   PubMed Web of Science ®Google Scholar
• •Levosimendan binding to TnC may be responsible for Ca2+-sensitising action.
   Google Scholar
• HAIKALA H, NISSINEN E, ETEMADZADEH E et al.: Troponin C-mediated calcium sensitization induced by levosimendan does not impair relaxation. Cardiovasc. Pharmacol (1995) 25:794–801.
   PubMed Web of Science ®Google Scholar
• KLEEREKOPER Q, PUTKEY JA: Drug binding to cardiac troponin C. I Biol. Chem. (1999) 274:23932–23939.
   Web of Science ®Google Scholar
• ENDOH M: Mechanisms of action of novel cardiotonic agents. J. Cardiovasc. Pharmacol (2002) 40:323–338.
   PubMed Web of Science ®Google Scholar
• HAIKALA H, LEVIJOKI J, LINDEN IB: Troponin C-mediated calcium sensitization by levosimendan accelerates the proportional development of isometric tension. J. MM. Cell. Cardiol (1995) 27:2155–2165.
   PubMed Web of Science ®Google Scholar
• HASENFUSS G, PIESKE B, CASTELL M et al.: Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human 747 myocardium. Circulation (1998) 98:2141–2147.
   PubMed Web of Science ®Google Scholar
• YOKOSHIKI H, KATSUBE Y, SUNAGAWA M et al: The novel calcium sensitizer levosimendan activates the ATP-sensitive K+ channel in rat ventricular cells. Pharmacol. Exp. Ther. (1997) 283:375–383.
   PubMed Web of Science ®Google Scholar
• YOKOSHIKI H, KATSUBE Y, SUNAGAWA M et al.: Levosimendan, a novel Ca2+ sensitizer, activates the glibenclamide-sensitive K+ channel in rat arterial myocytes. Ear: Pharmacol. (1997) 333:249–259.
   PubMed Web of Science ®Google Scholar
• KOPUSTINSKIENE DM, POLLESELLO P, SARIS NE: Levosimendan is a mitochondrial KAT channel opener. Eur.j Pharmacol. (2001) 428:311–314.
   PubMed Web of Science ®Google Scholar
• 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. Pharmacol. Exp. Ther. (1999) 290:505–514.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• KIVIKKO M, LEHTONEN L, COLUCCI WS: Sustained hemodynamic effects of intravenous levosimendan. Circulation (2003) 107:81–86.
   PubMed Web of Science ®Google Scholar
• TAKAHASHI R, TALUKDER MA, ENDOH M: Inotropic effects of OR-1896, an active metabolite of levosimendan, on canine ventricular myocardium. Ear: J. Pharmacol. (2000) 400:103–112.
   Google Scholar
• 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. Cardiovasc. Pharmacol. (2000) 36:118–125.
   PubMed Web of Science ®Google Scholar
• BRIXIUS K, REICKE S, SCHWINGER RH: Beneficial effects of the Ca2+ sensitizer levosimendan in human myocardium. Am. J. Physial (2002) 282:H131–H137.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• GOMES UC, CLELAND JG: Heart failure update. Eur. J. Heart Fail (1999) 1:301–302.
   PubMed Web of Science ®Google Scholar
• CLELAND JG, MCGOWAN J: Levosimendan: a new era for inodilator therapy for heart failure? Curt: Opin. Cardiol. (2002) 17:257–265.
   Web of Science ®Google Scholar
• 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? Pharmacol. Exp. Ther. (1987) 243:639–645.
   PubMed Web of Science ®Google Scholar
• KITADA Y, NARIMATSU A, MATSUMURA N et al.: Increase in Ca-FE 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. The]: (1987) 243:633–638.
   Google Scholar
• SATA M, SUGIURA S, YAMASHITA H et al: MCI-154 increases Ca2+ sensitivity of reconstituted thin filament. A study using a novel M vitro motility assay technique. Circ. Res. (1995) 76:626–633.
   Google Scholar
• •Ca2±-sensitising action of MCI-154 requires Ca2+ regulation of thin filament.
   Google Scholar
• 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-154.1 Pharmacol. Exp. The]: (1996) 279:47–55.
   Google Scholar
• WARREN SE, KIHARA Y, PESATURO J et al.: Inotropic and lusitropic effects of MCI-154 (6- [4- (4'-pyridy0 aminophenyl] - 4, 5-dihydro-3 (2H)-pyridazinone) on human myocardium. j Mol. Cell. Cardiol. (1989) 21:1037–1045.
   PubMed Web of Science ®Google Scholar
• PERREAULT CL, BROZOVICH FV, RANSIL BJ et al: Effects of MCI-154 on Ca2+ activation of skinned human myocardium. Ear: Pharmacol. (1989) 165:305–308.
   PubMed Web of Science ®Google Scholar
• LIAO R, GWATHMEY JK: Effects of MCI-154 and caffeine on Ca-regulated interactions between troponin subunits from bovine heart. J. Pharmacol. Exp. The]: (1994) 270:831–839.
   Google Scholar
• KITADA Y, KOBAYASHI M, NARIMATSU A et al.: Potent stimulation of myofilament force and adenosine triphosphatase activity of canine cardiac muscle through a direct enhancement of troponin C Ca ++ binding by MCI-154, a novel cardiotonic agent. J. Pharmacol. Exp. Ther. (1989) 250:272–277.
   PubMed Web of Science ®Google Scholar
• 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. Cardiovasc. Pharmacol. (1993) 21:847–855.
   PubMed Web of Science ®Google Scholar
• 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. The]: (1996) 276:433–439.
   Google Scholar
• ONISHI K, SEKIOKA K, ISHISU R et at: MCI-154, a Ca2+ sensitizer, decreases the oxygen cost of contractility in isolated canine hearts. Am. J. Physiol (1997) 273:H1688–H1695.
   PubMed Web of Science ®Google Scholar
• TAKAOKA H, TAKEUCHI M, HATA K et al.: Beneficial effects of a Ca2+ 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.
   PubMed Web of Science ®Google Scholar
• KORVALD C, NORDHAUG DO, STEENSTRUD T et al.: Vasodilation and mechanoenergetic inefficiency dominates the effect of the `Ca2+ sensitizer' MIC-154. Scand. Cardiovasc. J. (2002) 36:172–179.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• MORI M, TAKEUCHI M, TAKAOKA H et al.: Lusitropic effects of a Ca2+ sensitization with a new cardiotonic agent, MCI-154, on diseased human hearts. Cardiovasc. Res. (1995) 30:915–922.
   PubMed Web of Science ®Google Scholar
• HAEUSLER G, JONAS R, MINCK KO et al.: In vivo evidence of positive inotropism of EMD 57033 through calcium sensitization. J. Cardiovasc. Pharmacol. (1997) 29:647–655.
   PubMed Web of Science ®Google Scholar
• 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. Cardiovasc. Pharmacol. (1993) 21:883–892.
   PubMed Web of Science ®Google Scholar
• TOBIAS AH, SLINKER BK, KIRKPATRICK RD et al.: Functional effects of EMD-57033 in isovolumically beating isolated rabbit hearts. Am. Physiol (1996) 271:H51–H58.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• HAJJAR R.J, SCHMIDT U, HELM P et al: Ca++sensitizers impair cardiac relaxation in failing human myocardium. Pharmacol Exp. The]: (1997) 280:247–254.
   PubMed Web of Science ®Google Scholar
• •Impairment of cardiac relaxation by Ca2+ sensitisers.
   Google Scholar
• 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. Physic] (1996) 271:H311–H319.
   Web of Science ®Google Scholar
• GRANDIS DJ, DELNIDO PJ, KORETSKY AP: Functional and energetic effects of the inotropic agents EMD-57033 and BAPTA on the isolated rat heart. Am. Physiol (1995) 269:C472–C479.
   PubMed Web of Science ®Google Scholar
• POPPING S, MRUCK S, FISCHER Y et al.: Economy of contraction of cardiomyocytes as influenced by different positive inotropic interventions. Am. Physiol (1996) 271:H357–H364.
   PubMed Web of Science ®Google Scholar
• HEROLD P, HERZIG JW, WENK P et al: 5-Methy1-6-pheny1-1,3,5,6-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.
   PubMed Web of Science ®Google Scholar
• ZIMMERMANN N, BOKNIK P, GAMS E et al.: Positive inotropic effects of the calcium sensitizer CGP 48506 in guinea pig myocardium. I Pharmacol Exp. Ther. (1996) 277:1572–1578.
   PubMed Web of Science ®Google Scholar
• •CGP 48506 is a pure Ca2+ sensitiser.
   Google Scholar
• WOLSKA BM, KITADA Y, PALMITER KA et al.: CGP-48506 increases contractility of ventricular myocytes and myofilaments by effects on actin-myosin reaction. Am.,/ Physic] (1996) 270:H24–H32.
   PubMed Web of Science ®Google Scholar
• NEUMANN J, ESCHENHAGEN T, GRUPP IL et al.: Positive inotropic effects of the calcium sensitizer CGP 48506 in failing human myocardium. Pharmacol Exp. The]: (1996) 277:1579–1585.
   Google Scholar
• HERZIG JW, CHIESI M, DEPERSIN H et al: Ca2+ sensitization in idiopathic dilated human myocardium. Differential in vitro effects of (+)-(5-methy1-6-pheny1)-1,3,5,6- tetrahydro-3,6-methano-1,5- benzodiazocine-2,4-dione, a novel purely Ca2+ sensitizing agent, and (+) 5 (1 (3,4 dimethoxybenzoyfl -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.
   Google Scholar
• BRIXIUS K, MEHLHORN U, BLOCH W et al.: Different effect of the Ca2+ sensitizers EMD 57033 and CGP 48506 on cross-bridge cycling in human myocardium. Pharmacol Exp. Ther. (2000) 295:1284–1290.
   PubMed Web of Science ®Google Scholar
• PALMER S, DI BELLO S, DAVENPORT SL et al.: The novel inotropic agent CGP 48506 alters force primarily by Ca2+-independent mechanisms in porcine skinned trabeculae. Cardiovasc. Res. (1996) 32:411–421.
   PubMed Web of Science ®Google Scholar
• PALMER S, KENTISH JC: Differential effects of the Ca2+ sensitizers caffeine and CGP 48506 on the relaxation rate of rat skinned cardiac trabeculae. Circ. Res. (1997) 80:682–687.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• SLINKER BK, GREEN HW, WU Y et al.: Relaxation effect of CGP-48506, EMD-57033, and dobutamine in ejecting and isovolumically beating rabbit hearts. Am. J. Physic] (1997) 273:H2708–H720.
   Web of Science ®Google Scholar
• ZIMMERMANN N, BOKNIK P, GAMS E et al.: Calcium sensitization as new principle of inotropic therapy in end-stage heart failure? Ear: Cardiothorac. Surg. (1998) 14:70–75.
   Web of Science ®Google Scholar
• 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.
   Google Scholar
• MILLER DJ, STEELE DS: The 'calcium sensitising' effects of 0RG30029 in saponin- or Triton-skinned rat cardiac muscle. Br. J. Pharmacol (1990) 100:843–849.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• GRANDIS DJ, MACGOWAN GA, KORETSKY AP: Comparison of the effects of ORG 30029, dobutamine and high perfusate calcium on function and metabolism in rat heart. MM. Cell. Cardiol (1998) 30:2605–2612.
   PubMed Web of Science ®Google Scholar
• 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.
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• •Org 30029 is a Ca2+sensitiser with the highest efficacy in the dog.
   Google Scholar
• SUGAWARA H, HINO M, YOSHIMURA A et at: Investigation on SCH00013, a novel cardiotonic agent with Ca++ sensitizing action. 3rd communication: stereoselectivity of the enantiomers in cardiovascular effects. Arzneimittelforschung (1999) 49:412–419.
   Google Scholar
• SUGAWARA H, END OH M: A novel cardiotonic agent SCH00013 acts as a Ca++ sensitizer with no chronotropic activity in mammalian cardiac muscle. J. Pharmacol Exp. Ther. (1998) 287:214–222.
   PubMed Web of Science ®Google Scholar
• YOSHIMURA A, KOIDE Y, YOSHIOKA K et al.: Investigation on SCH00013, a novel cardiotonic agent with Ca ++ sensitizing action. 2nd communication: in vivo cardiovascular effects and bioavailability in dogs. Arzneimittelforschung (1999) 49:407–411.
   Google Scholar
• HINO M, SUGAWARA H, YOSHIMURA A et at: Investigation on SCH00013, a novel cardiotonic agent with Ca++ sensitizing action. 1st communication: phosphodiesterase III inhibitory effect and class III antiarrhythmic effect in guinea-pig heart. Arzneimittelforschung (1999) 49:398–406.
   Google Scholar
• SATO S, TALUKDER MA, SUGAWARA H et al.: Effects of levosimendan on myocardial contractility and Ca2+ transients in aequorin-loaded right-ventricular papillary muscles and indo- 1-loaded single ventricular cardiomyocytes of the rabbit. J. MM. Cell. Cardiol (1998) 30:1115–1128.
   PubMed Web of Science ®Google Scholar
• •The positive inotropic effect of levosimendan is susceptible to carbachol, a muscarinic agonist.
   Google Scholar
• 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. Cardiovasc. Pharinacol (1991) 17:365–375.
   PubMed Web of Science ®Google Scholar
• SUGAWARA H, ENDOH M: (-)-Enantiomer EMD 57439 antagonizes the Ca2+ sensitizing effect of (+)-enantiomer EMD 57033 on diastolic function but not on systolic function in rabbit ventricular cardiomyocytes. "ph. Pharinacol (1999) 80:55–65.
   Google Scholar
• LEE JA, ALLEN DG: EMD 53998 sensitizes the contractile proteins to calcium in intact ferret ventricular muscle. Circ. Res. (1991) 69:927–936.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• 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. Physic] (1993) 264:H728–H738.
   Web of Science ®Google Scholar
• STRAUSS JD, ZEUGNER C, ROEGG JC: The positive inotropic calcium sensitizer EMD 53998 antagonizes phosphate action on cross-bridges in cardiac skinned fibers. Eur: Pharmacol (1992) 227:437–441.
   PubMed Web of Science ®Google Scholar
• 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.
   Google Scholar
• RAASMAJA A: Biochemical mechanisms of the novel cardiotonic agent OR-1259. J. MM. Cell. Cardiol (1991) 23:S.129.
   Google Scholar
• 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. Pharmacol (1990) 183:783–784.
   Web of Science ®Google Scholar
• ENDOH M, BLINKS JR: Actions of sympathomimetic amines on the Ca2+ transients and contractions of rabbit myocardium: reciprocal changes in myofibrillar responsiveness to Ca2+ mediated through a- and P-adrenoceptors. Circ. Res. (1988) 62:247–265.
   PubMed Web of Science ®Google Scholar
• •First report on the receptor-mediated Ca2+ sensitisation.
   Google Scholar
• ENDOH M: Dual inhibition of myocardial function through muscarinic and adenosine receptors in the mammalian heart. I Appl. Cardiol (1987) 2:213–230.
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• BOKNIK P, NEUMANN J, KASPAREIT G et al.: Mechanisms of the contractile effects of levosimendan in the mammalian heart. Pharmacol Exp. Ther: (1997) 280:277–283.
   PubMed Web of Science ®Google Scholar
• TAKAHASHI R, ENDOH M: Increase in myofibrillar Ca2+ sensitivity induced by UD-CG 212 Cl, an active metabolite of pimobendan, in canine ventricular myocardium. Cardiovasc. Pharmacol (2001) 37:209–218.
   PubMed Web of Science ®Google Scholar
• 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) 73:111117–111133.
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• MORANO I: Tuning the human heart molecular motors by myosin light chains. J. MM. Med. (1999) 77:544–555.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• ARTEAGA GM, KOBAYASHI T, SOLARO JR: Molecular actions of drugs that sensitize cardiac myofilaments to Ca2+. Ann. Med. (2002) 34:248–258.
   PubMed Web of Science ®Google Scholar