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. 2022 Nov 29;396(4):669–682. doi: 10.1007/s00210-022-02348-7

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© The Author(s) 2022

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — Scheme: Potential mechanism(s) of action of levosimendan in the human and mouse cardiomyocytes. Stimulation of the activity of β-adrenoceptors (β-AR) by endogenous noradrenaline or exogenous isoprenaline leads via stimulatory GTP-binding proteins (G_s) to an increase of adenylyl cyclase (AC) activity. Adenylyl cyclase increases the formation of 3′,5′-cyclic adenosine monophosphate (cAMP) that stimulates cAMP-protein kinase (PKA). PKA phosphorylates and thus activates phospholamban (PLB) at the amino acid serine 16, the inhibitory subunit of troponin (TnI), the ryanodine receptor (RYR) and the L-type calcium channel (LTCC). The formed cAMP can be degraded to inactive 5′-AMP and pyrophosphate by isoenzymes of the phosphodiesterase family of proteins (PDE). Cilostamide and rolipram (bottom: structural formulae) inactivate phosphodiesterases 3 and 4, respectively. The β-adrenoceptor is blocked by β-adrenoceptor blockers like timolol or propranolol. Calcium cations (Ca²⁺) are stored on calsequestrin (CSQ) in the sarcoplasmic reticulum and are released via RYR from the sarcoplasmic reticulum (SR). These released calcium cations bind to troponin C on thin myofilaments, and as a result, systolic force is augmented. Typical calcium sensitizers like EMD57033 act by generating at a given level of free Ca²⁺ more force of contraction. In cardiac diastole, Ca²⁺ concentrations fall because Ca²⁺ is pumped into the SR via the SR calcium ATPase (SERCA). The activity of SERCA is increased when phospholamban is phosphorylated on amino acid serine 16. Levosimendan (bottom: structural formula) might act via increasing the sensitivity for calcium cations of troponin C in the thin myofilaments or might inhibit phosphodiesterases in the heart