Pharmacology of levosimendan: A new myofilament calcium sensitizer

Paul S. Pagel, Heimo Haikala, Pertti J. Pentikäinen, Marja Leena Toivonen, Markku S. Nieminen, Lasse Lehtonen, Julian Gy Papp, David C. Warltier

Research output: Review article

24 Citations (Scopus)


Levosimendan, a new myofilament Ca2+ sensitizer, enhances myocardial contractility by selectively stabilizing the Ca2+ bound conformation of cTnC in a Ca2+-dependent manner. In contrast to other myofilament Ca2+ sensitizers, levosimendan does not alter Ca2+ affinity of cTnC or myosin ATPase activity. Levosimendan-induced inhibition of PDE III may contribute to the positive inotropic actions of this drug at higher concentrations. Myofilament Ca2+ sensitization and stabilization of the Ca2+-bound conformation of cTnC may theoretically delay relaxation. Levosimendan, however, has been demonstrated to enhance relaxation of cardiac muscle. In addition to positive inotropic effects, levosimendan causes venous and arterial vasodilation and improves indices of diastolic performance in the presence of normal left ventricular function. In experimental models of and in patients with left ventricular dysfunction, levosimendan causes beneficial reductions in left ventricular preload and afterload and augments contractility and diastolic function without producing reflex increases in heart rate and myocardial oxygen consumption. Levosimendan potentiates the positive inotropic effects of dopamine, enhances left ventricular-arterial coupling and mechanical efficiency, and improves the contractile function of stunned myocardium. Levosimendan has a high margin of safety in experimental animals. The toxicity of levosimendan in experimental animals is associated with exacerbation of the pharmacological effects. High doses of levosimendan may adversely affect the establishment and maintenance of pregnancy. Levosimendan does not produce mutagenic effects during organogenesis. Levosimendan is rapidly absorbed from the gastrointestinal tract and has high bioavailability, The elimination half-life of levosimendan is approximately 1 h in patients with heart failure and is not altered in the presence of renal insufficiency. Levosimendan is metabolized by hepatic glutathione conjunction or reduction by intestinal bacteria and is excreted in the urine and feces. High doses of levosimendan may cause headaches and dizziness in healthy volunteers, and to a lesser extent, in patients with congestive heart failure via peripheral vasodilation. The incidence of other adverse drug effects, including hypotension, tachycardia, and palpitations, is low. The clinical utility and safety of levosimendan in patients with congestive heart failure require further investigation.

Original languageEnglish
Pages (from-to)286-316
Number of pages31
JournalCardiovascular Drug Reviews
Issue number3
Publication statusPublished - jan. 1 1996

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

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    Pagel, P. S., Haikala, H., Pentikäinen, P. J., Toivonen, M. L., Nieminen, M. S., Lehtonen, L., Papp, J. G., & Warltier, D. C. (1996). Pharmacology of levosimendan: A new myofilament calcium sensitizer. Cardiovascular Drug Reviews, 14(3), 286-316.