Inotropic effects of OR-1896, an active metabolite of levosimendan, on canine ventricular myocardium

We performed experiments in dog ventricular trabeculae loaded with aequorin to elucidate the mechanism of positive inotropic effect of (R)-N-[4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenyl]-acetamide (OR-1896), an active metabolite of (R)-([4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono)-propanedinitrile (levosimendan). Concentration-response curve for OR-1896 was biphasic: positive inotropic effect of OR-1896 reached a plateau at 10(-5) M (1st phase) and the concentration-response curve became steeper at 10(-3) M and higher (2nd phase). Maximum response of the Ist phase was 29% of maximal response to isoproterenol and associated with an increase in Ca2+ transients of 13% of the maximal response to isoproterenol. For a given increase in force, the increase in Ca2+ transients by OR-1896 was lower than that induced by elevation of [Ca2+](o). The positive inotropic effect of OR-1896 was not associated with impairment of relaxation and it was abolished by carbachol. In conclusion, OR-1896 has a positive inotropic effect partly due to an increase in myofibrillar Ca2+ sensitivity that is exerted via cross-talk with signal transduction mediated by cAMP. (C) 2000 Elsevier Science B.V. All rights reserved.