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Vol. 280, Issue 1, 277-283, 1997

Mechanisms of the Contractile Effects of Levosimendan in the Mammalian Heart1

Peter Bokník, Joachim Neumann, Grit Kaspareit2, Wilhelm Schmitz, Hasso Scholz2, Ute Vahlensieck and Norbert Zimmermann2 3

Institut für Pharmakologie und Toxikologie der Westfälischen Wilhelms-Universität, Münster, Federal Republic of Germany

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.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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