MECHANISMS OF THE CONTRACTILE EFFECTS OF LEVOSIMENDAN IN THE MAMMALIAN HEART

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.