P. Boknik et al., MECHANISMS OF THE CONTRACTILE EFFECTS OF LEVOSIMENDAN IN THE MAMMALIAN HEART, The Journal of pharmacology and experimental therapeutics, 280(1), 1997, pp. 277-283
In spontaneously beating guinea pig right atria, levosimendan (LS, or
3-pyridazinyl)-phenyl]-hydrazono]propanedinitrile) exerted a positive
chronotropic effect starting at 0.1 mu M. In electrically driven guine
a pig left atria, LS (0.1-10 mu M) increased force of contraction with
out changing time parameters of contraction. In electrically driven ri
ght papillary muscles, LS (0.1-10 mu M) enhanced force of contraction
without affecting time parameters of contraction. The maximal effect o
n force of contraction at 10 mu M amounted to 130 +/- 8.6% of predrug
value. The positive inotropic effect of LS in papillary muscles was gr
eatly diminished by additionally applied carbachol. In [P-32]-labeled
guinea pig ventricular cardiomyocytes, LS increased the phosphorylatio
n state of phospholamban, the inhibitory subunit of troponin and C-pro
tein. The maximal effect at 1 mu M amounted to 134 +/- 8.6%, 124 +/- 4
.2% and 121 +/- 8% of control for phospholamban, the inhibitory subuni
t of troponin and C-protein, respectively. LS (1 mu M) 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 studie
s were performed in guinea pig ventricular cardiomyocytes. In this set
up, 10 mu M LS increased the amplitude of L-type Ca++ current to 402 /- 86% of predrug value.