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Pharmacological Mechanisms Contributing to the Clinical Efficacy of Levosimendan (2005)

Papp, Zoltán ; Csapó, Kálmán ; Pollesello, Piero ; [et al.]

Oxford, UK : Blackwell Publishing Ltd

Cardiovascular drug reviews 23 (2005), S. 0

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ISSN: 1527-3466

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Medicine

Notes: Acute decompensation of chronic heart failure is a direct life-threatening situation with short-term mortality approaching 30%. A number of maladaptive changes are amplified within the cardiovascular system during the progression of chronic heart failure that makes the decompensation phase difficult to handle. Levosimendan is a new Ca2+-sensitizer for the treatment of acutely decompensated heart failure that has proved to be effective during the decompensation of chronic heart failure and acute myocardial infarction. Levosimendan differs from other cardiotonic agents that are used for acute heart failure in that it utilizes a unique dual mechanism of action: Ca2+-sensitization through binding to troponin C in the myocardium, and the opening of ATP-sensitive K+ channels in vascular smooth muscle. In general, these mechanisms evoke positive inotropy and vasodilation. Clinical studies suggested long-term benefits on mortality following short-term administration. It may, therefore, be inferred that levosimendan has additional effects on the cardiovascular system that are responsible for the prolongation of survival. Results of pre-clinical and clinical investigations suggest that the combination of levosimendan-induced cardiac and vascular changes has favorable effects on the coronary, pulmonary and peripheral circulations. Redistribution of the circulating blood offers an improved hemodynamic context for the development of a positive inotropic effect through Ca2+-sensitization of the contractile filaments, without a proportionate increase in myocardial oxygen consumption or the development of arrhythmias. Activation of ATP-sensitive K+ channels, both on sarcolemma and mitochondria, may protect against myocardial ischemia, and decreased levels of cytokines may prevent the development of further myocardial remodeling. Collectively, these effects of levosimendan shift the disturbed cardiovascular parameters towards normalization, thereby halting the perpetuation of the vicious cycle of heart failure progression. This may contribute to stabilization of the circulation and improved life expectancy of patients with chronic heart failure.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1111/j.1527-3466.2005.tb00158.x

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The role of phospholamban in the regulation of calcium transport by cardiac sarcoplasmic reticulum (1990)

Davis, Bruce A. ; Edes, Istvan ; Gupta, Ramesh C. ; [et al.]

Springer

Molecular and cellular biochemistry 99 (1990), S. 83-88

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ISSN: 1573-4919

Keywords: cardiac ; sarcoplasmic reticulum ; phospholamban ; calcium transport ; protein kinase ; phosphatase

Source: Springer Online Journal Archives 1860-2000

Topics: Biology , Chemistry and Pharmacology , Medicine

Notes: Abstract The calcium transport mechanism of cardiac sarcoplasmic reticulum (SR) is regulated by a phosphoregulatory mechanism involving the phosphorylation-dephosphorylation of an integral membrane component, termed phospholamban. Phospholamban, a 27,000 Da proteolipid, contains phosphorylation sites for three independent protein kinases: 1) cAMP-dependent, 2) Ca2+-calmodulin-dependent, and 3) Ca2+-phospholipid-dependent. Phosphorylation of phospholamban by any one of these kinases is associated with stimulation of the calcium transport rates in isolated SR vesicles. Dephosphorylation of phosphorylated phospholamban results in the reversal of the stimulatory effects produced by the protein kinases. Studies conducted on perfused hearts have shown that during exposure to beta-adrenergic agents, a good correlation exists between the in situ phosphorylation of phospholamban and the relaxation of the left ventricle. Phosphorylation of phospholamban in situ is also associated with stimulation of calcium transport rates by cardiac SR, similar to in vitro findings. Removal of beta-adrenergic agents results in the reversal of the inotropic response and this is associated with dephosphorylation of phospholamban. These findings indicate that a phospho-regulatory mechanism involving phospholamban may provide at least one of the controls for regulation of the contractile properties of the myocardium.