Mechanisms of the Contractile Effects of Levosimendan in the Mammalian Heart1

  1. Peter Bokník,
  2. Joachim Neumann,
  3. Grit Kaspareit2,
  4. Wilhelm Schmitz,
  5. Hasso Scholz2,
  6. Ute Vahlensieck and
  7. Norbert Zimmermann2,3
  1. Institut für Pharmakologie und Toxikologie der Westfälischen Wilhelms-Universität, Münster, Federal Republic of Germany

    Abstract

    In spontaneously beating guinea pig right atria, levosimendan (LS, or R-[[-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl]-hydrazono]propanedinitrile) exerted a positive chronotropic effect starting at 0.1 μM. In electrically driven guinea pig left atria, LS (0.1–10 μM) increased force of contraction without changing time parameters of contraction. In electrically driven right papillary muscles, LS (0.1–10 μM) enhanced force of contraction without affecting time parameters of contraction. The maximal effect on force of contraction at 10 μM amounted to 130 ± 8.6% of predrug value. The positive inotropic effect of LS in papillary muscles was greatly diminished by additionally applied carbachol. In [32P]-labeled guinea pig ventricular cardiomyocytes, LS increased the phosphorylation state of phospholamban, the inhibitory subunit of troponin and C-protein. The maximal effect at 1 μM amounted to 134 ± 8.6%, 124 ± 4.2% and 121 ± 8% of control for phospholamban, the inhibitory subunit of troponin and C-protein, respectively. LS (1 μM) increased cAMP content from 6.3 ± 0.3 to 8.1 ± 0.3 pmol/mg protein in guinea pig ventricular cardiomyocytes. Furthermore, whole-cell patch-clamp studies were performed in guinea pig ventricular cardiomyocytes. In this setup, 10 μM LS increased the amplitude of L-type Ca++ current to 402 ± 86% of predrug value.

    Footnotes

    • Send reprint requests to: Dr. Peter Boknı́k, Institut für Pharmakologie und Toxikologie der Westfälischen Wilhelms-Universität, Domagkstraβe 12, D-48129 Münster, Germany.

    • ↵1 This work was supported by the Deutsche Forschungsgemeinschaft.

    • ↵2 Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Martinistraβe 52, D-20246, Federal Republic of Germany.

    • ↵3 Present address: Klinik für Thorax- und Kardiovaskuläre Chirurgie, Heinrich Heine-Universität, Moorenstraβe 5, D-40001 Düsseldorf, Federal Republic of Germany.

    • Abbreviations:
      CP
      C-protein
      DMSO
      dimethyl sulfoxide
      LS
      levosimendan
      MLC
      myosin light chains
      PDE
      phosphodiesterase
      PLB
      phospholamban
      SDS
      sodium dodecyl sulfate
      SDS-PAGE
      sodium dodecyl sulfate polyacrylamide gel electrophoresis
      Tnl
      inhibitory subunit of troponin
      GPVC
      [32P]-labeled guinea pig ventricular cardiomyocytes
      • Received January 17, 1996.
      • Accepted September 6, 1996.
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    1. JPET January 1, 1997 vol. 280 no. 1 277-283
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