American Journal of Medical Case Reports
ISSN (Print): 2374-2151 ISSN (Online): 2374-216X Website: Editor-in-chief: Samy, I. McFarlane
Open Access
Journal Browser
American Journal of Medical Case Reports. 2014, 2(3), 57-74
DOI: 10.12691/ajmcr-2-3-5
Open AccessReview Article

A Review on Study of Various Ionotropic Calcium Sensitizing Drugs in Congestive Heart Failure Treatment

Mohammad Asif1,

1Department of Pharmacy, GRD(PG)IMT, Dehradun, India

Pub. Date: April 11, 2014

Cite this paper:
Mohammad Asif. A Review on Study of Various Ionotropic Calcium Sensitizing Drugs in Congestive Heart Failure Treatment. American Journal of Medical Case Reports. 2014; 2(3):57-74. doi: 10.12691/ajmcr-2-3-5


Acute Heart failure (AHF), clinical signs of low cardiac output, therapy with positive inotropic drug for cardiac care is mandatory. Three classes of inotropic drugs are currently available, like β-adrenergic agonists (especially dobutamine), phosphodiesterase (PDE) inhibitors (such as milrinone) and Ca2+ sensitizers (levosimendan). The mechanisms of action of these drugs, and important issues regarding their clinical indications and potential risks associated with their use are studied. Oral inotropes did not always improve mortality of the patients with heart failure (HF) partly because of possible direct toxic effects of these agents on myocytes, exacerbating arrhythmias, enhancing neurohormonal activity. Ca2+ sensitizers such as pimobendan and levosimendan were improve even mortality of the patients with HF through increasing cardiac contractility (CC) without a rise in (Ca2+)i. However, these agents disappoint our expectations. We need the development of the agents which has more specific effect of Ca2+ sensitizing.

calcium sensitizers ionotrpic heart failure

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit


[1]  Vilas-Boas F. Modern approach to the treatment of decompensated heart failure. Expert Rev Cardiovasc Ther. 2009 Feb; 7(2): 159-67.
[2]  Tadano N, Morimoto S, Takahashi-Yanaga F, Miwa Y, Ohtsuki I, Sasaguri T. Propyl gallate, a strong antioxidant, increases the Ca2+ sensitivity of cardiac myofilament. J Pharmacol Sci. 2009 Mar; 109(3): 456-8.
[3]  Meyer K, Klocke RC, Schipke JD, Gams E, Korbmacher B. Ca2+ sensitizer superior to catecholamine during myocardial stunning? Eur J Cardiothorac Surg. 2008 Aug; 34(2): 326-31.
[4]  Varro A, Papp JG. Classification of positive inotropic actions based on electrophysiologic characteristics: where should calcium sensitizers be placed? J Cardiovasc Pharmacol. 1995; 26 Suppl 1: S32-44.
[5]  Sakata Y. Clinical significance of calcium sensitizer. Clin Calcium. 2013 Apr; 23(4): 575-82.
[6]  Giglioli C, Cecchi E, Landi D, Chiostri M, Spini V, Valente S, Gensini GF, Romano SM. Levosimendan produces an additional clinical and hemodynamic benefit in patients with decompensated heart failure successfully submitted to a fluid removal treatment. Congest Heart Fail. 2012 Jan-Feb; 18(1): 47-53.
[7]  Robertson IM, Sun YB, Li MX, Sykes BD. A structural and functional perspective into the mechanism of Ca2+-sensitizers that target the cardiac troponin complex. J Mol Cell Cardiol. 2010 Dec; 49(6): 1031-41.
[8]  Rusca M, Liaudet L.Inotropic agents for treatment of acute heart failure syndromes in intensive care. Rev Med Suisse. 2009 Dec 9; 5(229): 2512-5.
[9]  van Hees HW, Andrade Acuña G, Linkels M, Dekhuijzen PN, Heunks LM. Levosimendan improves calcium sensitivity of diaphragm muscle fibres from a rat model of heart failure. Br J Pharmacol. 2011 Feb; 162(3): 566-73.
[10]  Follath F. Newer treatments for decompensated heart failure: focus on levosimendan. Drug Des Devel Ther. 2009 Sep 21; 3: 73-8.
[11]  Parissis JT, Andreadou I, Bistola V, Paraskevaidis I, Filippatos G, Kremastinos DT. Novel biologic mechanisms of levosimendan and its effect on the failing heart. Expert Opin Investig Drugs. 2008 Aug; 17(8): 1143-50.
[12]  Endoh M. Cardiac Ca2+ signaling and Ca2+ sensitizers. Circ J. 2008 Dec; 72(12): 1915-25.
[13]  Endoh M. Could Ca2+ sensitizers rescue patients from chronic congestive heart failure? Br J Pharmacol. 2007 Apr; 150(7): 826-8.
[14]  Antoniades C, Tousoulis D, Koumallos N, Marinou K, Stefanadis C. Levosimendan: beyond its simple inotropic effect in heart failure. Pharmacol Ther. 2007 May; 114(2): 184-97.
[15]  Kasikcioglu HA, Uyarel H, Tartan Z, Kasikcioglu E, Ozturk R, Cam N. Do calcium sensitizers affect right ventricular functions in patients with chronic heart failure? Int J Cardiol. 2007 May 31; 118(2): 246-8.
[16]  Papp JG, Pollesello P, Varró AF, Végh AS. Effect of levosimendan and milrinone on regional Myocardial ischemia/reperfusion-induced arrhythmias in dogs. J Cardiovasc Pharmacol Ther. 2006 Jun; 11(2): 129-35.
[17]  Endoh M. Signal transduction and Ca2+ signaling in intact myocardium. J Pharmacol Sci. 2006; 100(5): 525-37.
[18]  González-Chon O, García López SM, Chacón Mercado MA, Arias Sánchez EA, Vega Zapata RE. Levosimendan: a new strategy in the treatment of heart failure. Arch Cardiol Mex. 2005 Jul-Sep; 75 Suppl 3: S3-130-9.
[19]  Perrone SV, Kaplinsky EJ. Calcium sensitizer agents: a new class of inotropic agents in the treatment of decompensated heart failure. Int J Cardiol. 2005 Sep 1; 103(3): 248-55.
[20]  Haikala H, Pollesello P. Calcium sensitivity enhancers. IDrugs. 2000 Oct; 3(10): 1199-205.
[21]  Bonnefoy E, Trindade PT. Levosimendan, a revolution in the world of inotropic agents?. Rev Med Suisse. 2005 May 25; 1(21): 1425-6, 1428-9.
[22]  Andersen GO, Eritsland J, Bjørnerheim R, Kløw NE, Jonassen A, Mangschau A. Cardiogenic shock-new therapeutic strategies. Tidsskr Nor Laegeforen. 2005 May 19; 125(10): 1318-21.
[23]  Bultas J, Karetová D. New trends in pharmacotherapy of cardiovascular diseases. Vnitr Lek. 2004 Oct; 50 Suppl 1:S37-58.
[24]  Ng TM. Levosimendan, a new calcium-sensitizing inotrope for heart failure. Pharmacotherapy. 2004 Oct; 24(10): 1366-84.
[25]  Sorsa T, Pollesello P, Rosevear PR, Drakenberg T, Kilpeläinen I. Stereoselective binding of levosimendan to cardiac troponin C causes Ca2+-sensitization. Eur J Pharmacol. 2004 Feb 13; 486(1): 1-8.
[26]  Ishikawa T, O-Uchi J, Mochizuki S, Kurihara S. Evaluation of the cross-bridge-dependent change in the Ca2+ affinity of troponin C in aequorin-injected ferret ventricular muscles. Cell Calcium. 2005 Feb; 37(2): 153-62.
[27]  Papp Z, Van Der Velden J, Borbély A, Edes I, Stienen GJ. Effects of Ca2+-sensitizers in permeabilized cardiac myocytes from donor and end-stage failing human hearts. J Muscle Res Cell Motil. 2004; 25(3): 219-24.
[28]  Chen HZ, Cui XL, Zhao HC, Zhao LY, Lu JY, Wu BW. Inotropic effects of MCI-154 on rat cardiac myocytes. Sheng Li Xue Bao. 2004 Jun 25; 56(3): 301-5.
[29]  Andréka P, Nádházi Z, Vándor L, Takács E, Szánthó G, Kónya L, Tulassay Z. New medical therapies for the treatment of systolic heart failure. Orv Hetil. 2003 Oct 19; 144(42): 2053-62.
[30]  Follath F. Levosimendan in patients with low-output heart failure: lessons from the LIDO trial. Ital Heart J. 2003 May; 4 Suppl 2: 34S-38S.
[31]  Erhardt LR. Is calcium sensitization the best strategy to improve myocardial contractility in acute heart failure? Ital Heart J. 2003 May;4 Suppl 2: 27S-33S.
[32]  Lehmann A, Boldt J, Kirchner J. The role of Ca2+-sensitizers for the treatment of heart failure. Curr Opin Crit Care. 2003 Oct; 9(5): 337-44.
[33]  Endoh M. Mechanisms of action of novel cardiotonic agents. J Cardiovasc Pharmacol. 2002 Sep; 40(3): 323-38.
[34]  Burger AJ, Burger MR, Aronson D. New therapies for the treatment of congestive heart failure. Drugs Today (Barc). 2002 Jan; 38(1): 31-48.
[35]  Sasayama S. Inotropic agents. Nihon Rinsho. 2003 May; 61(5): 807-14.
[36]  Nawarskas JJ, Anderson JR. Levosimendan: a unique approach to the treatment of heart failure. Heart Dis. 2002 Jul-Aug; 4(4): 265-71.
[37]  Brixius K, Reicke S, Reuter H, Schwinger RH. Effects of the Ca2+ sensitizers EMD 57033 and CGP 48506 on myocardial contractility and Ca2+ transients in human ventricular and atrial myocardium. Z Kardiol. 2002 Apr; 91(4): 312-8.
[38]  Teerlink JR. The development of new medical treatments for acute decompensated heart failure. Heart Fail Monit. 2002; 2(4): 129-37.
[39]  Endoh M, Sugawara H, Mineshima M. Pharmacology of SCH00013: a novel Ca2+ sensitizer. Cardiovasc Drug Rev. 2001 Winter; 19(4): 345-66.
[40]  Endoh M. Mechanism of action of Ca2+ sensitizers--update 2001. Cardiovasc Drugs Ther. 2001 Sep; 15(5): 397-403.
[41]  Bonnet D. Treatment of chronic heart failure in the child. Arch Pediatr. 2001 Dec; 8(12): 1379-82.
[42]  Ishitani T, Hattori Y, Sakuraya F, Onozuka H, Makino T, Matsuda N, Gando S, Kemmotsu O. Effects of Ca2+ sensitizers on contraction, [Ca2+]i transient and myofilament Ca2+ sensitivity in diabetic rat myocardium: potential usefulness as inotropic agents. J Pharmacol Exp Ther. 2001 Aug; 298(2): 613-22.
[43]  Brixius K, Hoischen S, Zobel C, Lasek K, Schwinger RH. The Ca2+ sensitizers CGP 48506 and EMD 57033, but not the Na(+) channel modulator BDF 9148, prolong relaxation in isolated cardiomyocytes of the guinea pig. Z Kardiol. 2001 Apr; 90(4): 286-91.
[44]  Wang X, Li MX, Spyracopoulos L, Beier N, Chandra M, Solaro RJ, Sykes BD. Structure of the C-domain of human cardiac troponin C in complex with the Ca2+ sensitizing drug EMD 57033. J Biol Chem. 2001 Jul 6; 276(27): 25456-66.
[45]  Tsutsui H, Kinugawa S, Ide T, Hayashidani S, Suematsu N, Satoh S, Nakamura R, Egashira K, Takeshita A. Positive inotropic effects of calcium sensitizers on normal and failing cardiac myocytes. J Cardiovasc Pharmacol. 2001 Jan; 37(1): 16-24.
[46]  Auslender M. New drugs in the treatment of heart failure. Prog Pediatr Cardiol. 2000 Nov 4; 12(1): 119-124.
[47]  Lipshultz SE. Ventricular dysfunction clinical research in infants, children and adolescents. Prog Pediatr Cardiol. 2000 Nov 4; 12(1): 1-28.
[48]  Brixius K, Mehlhorn U, Bloch W, Schwinger RH. Different effect of the Ca2+ sensitizers EMD 57033 and CGP 48506 on cross-bridge cycling in human myocardium. J Pharmacol Exp Ther. 2000 Dec; 295(3): 1284-90.
[49]  Myrmel T, Korvald C. New aspects of myocardial oxygen consumption. Invited review. Scand Cardiovasc J. 2000 Jun; 34(3): 233-41.
[50]  Slinker BK, Wu Y, Green HW 3rd, Kirkpatrick RD, Campbell KB. Overall cardiac functional effect of positive inotropic drugs with differing effects on relaxation. J Cardiovasc Pharmacol. 2000 Jul; 36(1): 1-13.
[51]  de Zeeuw S, Trines SA, Krams R, Verdouw PD, Duncker DJ. Cardiovascular profile of the calcium sensitizer EMD 57033 in open-chest anaesthetized pigs with regionally stunned myocardium. Br J Pharmacol. 2000 Apr; 129(7): 1413-22.
[52]  Wahr PA, Metzger JM. Role of Ca2+ and cross-bridges in skeletal muscle thin filament activation probed with Ca2+ sensitizers. Biophys J. 1999 Apr; 76(4): 2166-76.
[53]  Kleerekoper Q, Putkey JA. Drug binding to cardiac troponin C. J Biol Chem. 1999 Aug 20; 274(34): 23932-9.
[54]  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. Jpn J Pharmacol. 1999 May; 80(1): 55-65.
[55]  Soei LK, de Zeeuw S, Krams R, Duncker DJ, Verdouw PD. Ca2+ sensitization and diastolic function of normal and stunned porcine myocardium. Eur J Pharmacol. 1999 Dec 10; 386(1): 55-67.
[56]  Bowman P, Haikala H, Paul RJ. Levosimendan, a calcium sensitizer in cardiac muscle, induces relaxation in coronary smooth muscle through calcium desensitization. J Pharmacol Exp Ther. 1999 Jan; 288(1): 316-25.
[57]  Zimmermann N, Boknik P, Gams E, Herzig JW, Neumann J, Scholz H. Calcium sensitization as new principle of inotropic therapy in end-stage heart failure? Eur J Cardiothorac Surg. 1998 Jul; 14(1): 70-5.
[58]  Teramura S, Yamakado T. Calcium sensitizers in chronic heart failure: inotropic interventions-reservation to preservation. Cardiologia. 1998 Apr; 43(4): 375-85.
[59]  Endoh M. Changes in intracellular Ca2+ mobilization and Ca2+ sensitization as mechanisms of action of physiological interventions and inotropic agents in intact myocardial cells. Jpn Heart J. 1998 Jan; 39(1): 1-44.
[60]  Schwinger RH, Erdmann E. Therapy of heart failure. II. Therapy of chronic heart failure. Fortschr Med. 1997 Jun 10; 115(16):36-8, 41-5.
[61]  Goto Y, Hata K. Mechanoenergetic effect of pimobendan in failing dog hearts. Heart Vessels. 1997; Suppl 12:103-5.
[62]  Holubarsch C. New inotropic concepts: rationale for and differences between calcium sensitizers and phosphodiesterase inhibitors. Cardiology. 1997; 88 Suppl 2:12-20.
[63]  Sasayama S. Inotropic agents in the treatment of heart failure: despair or hope? Cardiovasc Drugs Ther. 1997 Jan; 10(6):703-9.
[64]  Hajjar RJ, Schmidt U, Helm P, Gwathmey JK. Ca++ sensitizers impair cardiac relaxation in failing human myocardium. J Pharmacol Exp Ther. 1997 Jan; 280(1):247-54.
[65]  Hata K, Goto Y, Futaki S, Takasago T, Saeki A, Nishioka T, Suga H. Effects of milrinone and sulmazole on left ventricular mechanoenergetics in canine hearts. J Card Fail. 1996 Sep; 2(3): 203-13.
[66]  Uhlmann R, Schwinger RH, Lues I, Erdmann E. EMD 53998 acts as Ca(2+)-sensitizer and phosphodiesterase III-inhibitor in human myocardium. Basic Res Cardiol. 1995 Sep-Oct; 90(5):365-71.
[67]  Haikala H, Nissinen E, Etemadzadeh E, Levijoki J, Lindén IB. Troponin C-mediated calcium sensitization induced by levosimendan does not impair relaxation. J Cardiovasc Pharmacol. 1995 May; 25(5):794-801.
[68]  Hasenfuss G, Pieske B, Kretschmann B, Holubarsch C, Alpert NR, Just H. Effects of calcium sensitizers on intracellular calcium handling and myocardial energetics. J Cardiovasc Pharmacol. 1995;26 Suppl 1:S45-51.
[69]  Ravens U, Himmel HM, Flüss M, Davia K, Harding SE. Phosphodiesterase inhibition and Ca2+ sensitization. Mol Cell Biochem. 1996 Apr 12-26; 157(1-2):245-9.
[70]  Haikala H, Linden IB. Mechanisms of action of calcium-sensitizing drugs. J Cardiovasc Pharmacol. 1995; 26 Suppl 1:S10-9.
[71]  Haikala H, Levijoki J, Lindén IB. Troponin C-mediated calcium sensitization by levosimendan accelerates the proportional development of isometric tension. J Mol Cell Cardiol. 1995 Oct; 27(10): 2155-65.
[72]  Nielsen-Kudsk JE, Aldershvile J. Will calcium sensitizers play a role in the treatment of heart failure? J Cardiovasc Pharmacol. 1995; 26 Suppl 1:S 77-84.
[73]  Lehtonen L, Mills-Owens P, Akkila J. Safety of levosimendan and other calcium sensitizers. J Cardiovasc Pharmacol. 1995; 26 Suppl 1: S70-6.
[74]  Hasenfuss G. New cardiotonic/inodilator agents: energetic aspects. Z Kardiol. 1992; 81 Suppl 4: 57-63.
[75]  Haikala H, Kaivola J, Nissinen E, Wall P, Levijoki J, Lindén IB. Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan. J Mol Cell Cardiol. 1995 Sep; 27(9): 1859-66.
[76]  Solaro RJ. Troponin C-troponin I interactions and molecular signalling in cardiac myofilaments. Adv Exp Med Biol. 1995; 382: 109-15.
[77]  Endoh M. The effects of various drugs on the myocardial inotropic response. Gen Pharmacol. 1995 Jan; 26(1): 1-31.
[78]  Endoh M. Ca2+ sensitizers. Tanpakushitsu Kakusan Koso. 2000 Apr; 45(6 Suppl): 859-67.
[79]  Webster KA, Bodi I, McNamara JP, Tracy M, Discher DJ, Bishopric NH. Negative lusitropy and abnormal calcium handling in hypoxic cardiac myocytes exposed to the calcium-sensitizer EMD 53998. J Mol Cell Cardiol. 1993 Jul; 25(7): 747-51.
[80]  Ohizumi Y. Tendency of development on novel type of cardiotonic drugs. Nihon Rinsho. 1993 May; 51(5): 1299-304.
[81]  Lamont C, Miller DJ. Calcium sensitizing action of carnosine and other endogenous imidazoles in chemically skinned striated muscle. J Physiol. 1992 Aug; 454: 421-34.
[82]  Ovaska M, Taskinen J. A model for human cardiac troponin C and for modulation of its Ca2+ affinity by drugs. Proteins. 1991; 11(2): 79-94.
[83]  Hgashiyama A, Watkins MW, Chen Z, LeWinter MM. Effects of EMD 57033 on contraction and relaxation in isolated rabbit hearts. Circulation. 1995 Nov 15; 92(10): 3094-104.
[84]  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 May; 80(5): 682-7.
[85]  Ochala J. Ca2+ sensitizers: An emerging class of agents for counterbalancing weakness in skeletal muscle diseases? Neuromuscul Disord. 2010 Feb; 20(2): 98-101.
[86]  van Zwieten PA. Current and newer approaches in the drug treatment of congestive heart failure. Cardiovasc Drugs Ther. 1997 Jan; 10(6): 693-702.
[87]  Vegh A, Papp JG, Udvary E, Kaszala K. Hemodynamic effects of calcium-sensitizing agents. J Cardiovasc Pharmacol. 1995; 26 Suppl 1: S20-31.