EFFECTS OF LEVOSIMENDAN ON MYOCARDIAL-CONTRACTILITY AND OXYGEN-CONSUMPTION

Levosimendan is hypothesized to be primarily a calcium sensitizer in v itro. Therefore, its inotropic action may be similar in both the norma l and the congestive heart failure (CHF) state, and it may be associat ed with a decreased energetic cost of inotropism in vivo. To test thes e hypotheses, we gave levosimendan to cross-circulated isolated hearts from normal (n = Il)and CHF (n = 7, 4-week rapid pacing) dogs. Peak i sovolumic left ventricular pressure at an end-diastolic pressure of 5 mm Hg (P-max,P-5) measured by an intraventricular balloon was 120 +/- 15 mm Hg in normal dogs, and it was increased by similar to 40% in res ponse to similar to 0.63 mu M levosimendan. in CHF dogs, base-line P-m ax,P-5 was only 60 +/- 12 mm Hg (P < .01 compared to normals), and sim ilar to 8.4 mu M levosimendan (P < .05) was required to increase P-max ,P-5 by similar to 40%. The inotropic actions were associated with inc reases in unloaded myocardial oxygen consumption by comparable amounts in normal and failing hearts. The blunted inotropic response in CHF a nd the energetic cost of inotropism were also comparable to those obta ined with isoproterenol. In other studies, there was no significant in otropic action of levosimendan in Langendorff-perfused rat hearts (n = 5), and intracellular calcium concentration, estimated by macroinject ed aequorin, in ferret hearts (n = 2) increased dose-dependently. Thes e findings suggest that inotropic actions of levosimendan in vivo may be mediated in part by factors other than calcium sensitization.