Pharmacology of levosimendan: A new myofilament calcium sensitizer

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

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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
Volume14
Issue number3
Publication statusPublished - 1996

Fingerprint

Myofibrils
Pharmacology
Calcium
Heart Failure
simendan
Vasodilation
Pregnancy Maintenance
Myocardial Stunning
Safety
Organogenesis
Left Ventricular Dysfunction
Dizziness
Myosins
Left Ventricular Function
Tachycardia
Feces
Oxygen Consumption
Pharmaceutical Preparations
Hypotension

Keywords

  • Calcium sensitizers
  • Cardiac stimulants
  • Heart failure
  • Inodilators
  • Levosimendan

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Pharmacology

Cite this

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

Pharmacology of levosimendan : A new myofilament calcium sensitizer. / Pagel, Paul S.; Haikala, Heimo; Pentikäinen, Pertti J.; Toivonen, Marja Leena; Nieminen, Markku S.; Lehtonen, Lasse; Papp, J.; Warltier, David C.

In: Cardiovascular Drug Reviews, Vol. 14, No. 3, 1996, p. 286-316.

Research output: Contribution to journalArticle

Pagel, PS, Haikala, H, Pentikäinen, PJ, Toivonen, ML, Nieminen, MS, Lehtonen, L, Papp, J & Warltier, DC 1996, 'Pharmacology of levosimendan: A new myofilament calcium sensitizer', Cardiovascular Drug Reviews, vol. 14, no. 3, pp. 286-316.
Pagel PS, Haikala H, Pentikäinen PJ, Toivonen ML, Nieminen MS, Lehtonen L et al. Pharmacology of levosimendan: A new myofilament calcium sensitizer. Cardiovascular Drug Reviews. 1996;14(3):286-316.
Pagel, Paul S. ; Haikala, Heimo ; Pentikäinen, Pertti J. ; Toivonen, Marja Leena ; Nieminen, Markku S. ; Lehtonen, Lasse ; Papp, J. ; Warltier, David C. / Pharmacology of levosimendan : A new myofilament calcium sensitizer. In: Cardiovascular Drug Reviews. 1996 ; Vol. 14, No. 3. pp. 286-316.
@article{9dd493ff456843dcb5e73c809a655ca2,
title = "Pharmacology of levosimendan: A new myofilament calcium sensitizer",
abstract = "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.",
keywords = "Calcium sensitizers, Cardiac stimulants, Heart failure, Inodilators, Levosimendan",
author = "Pagel, {Paul S.} and Heimo Haikala and Pentik{\"a}inen, {Pertti J.} and Toivonen, {Marja Leena} and Nieminen, {Markku S.} and Lasse Lehtonen and J. Papp and Warltier, {David C.}",
year = "1996",
language = "English",
volume = "14",
pages = "286--316",
journal = "Cardiovascular Drug Reviews",
issn = "0897-5957",
publisher = "Neva Press, Inc.",
number = "3",

}

TY - JOUR

T1 - Pharmacology of levosimendan

T2 - A new myofilament calcium sensitizer

AU - Pagel, Paul S.

AU - Haikala, Heimo

AU - Pentikäinen, Pertti J.

AU - Toivonen, Marja Leena

AU - Nieminen, Markku S.

AU - Lehtonen, Lasse

AU - Papp, J.

AU - Warltier, David C.

PY - 1996

Y1 - 1996

N2 - 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.

AB - 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.

KW - Calcium sensitizers

KW - Cardiac stimulants

KW - Heart failure

KW - Inodilators

KW - Levosimendan

UR - http://www.scopus.com/inward/record.url?scp=0029808961&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029808961&partnerID=8YFLogxK

M3 - Article

AN - SCOPUS:0029808961

VL - 14

SP - 286

EP - 316

JO - Cardiovascular Drug Reviews

JF - Cardiovascular Drug Reviews

SN - 0897-5957

IS - 3

ER -