INFLUENCE OF THE NOVEL INOTROPIC AGENT LEVOSIMENDAN ON ISOMETRIC TENSION AND CALCIUM CYCLING IN FAILING HUMAN MYOCARDIUM

Background-Levosimendan was shown to increase calcium sensitivity by a novel mechanism and to inhibit phosphodiesterase III activity in anim al myocardium. Methods and Results-We investigated the influence of le vosimendan on isometric contractions and calcium transients (aequorin method) in muscle strips from human hearts with and-stage failing dila ted or ischemic cardiomyopathy (n=27). Data were compared with the eff ects of the phosphodiesterase inhibitor milrinone (n=9). The average m aximum increase in twitch tension was 47+/-14% (range, 6% to 150%) at a levosimendan concentration of 0.8+/-0.3 mu mol/L (P<0.01). This was associated with significant increases in maximum rates of tension rise and fall and decreases in times to peak tension, to 50% relaxation, a nd to 95% relaxation. In aequorin-loaded muscles, levosimendan 10(-6) mol/L increased average tension by 50% (P<0.02), associated with a non significant increase in aequorin light (16%). With milrinone 10(-5) mo l/L, average tension increased by 58% and aequorin light by 49% (P<0.0 5). In those muscle strips with pronounced inotropic effects (>50% inc rease in tension), there was a comparable and pronounced increase in a equorin light with both agents. However, in muscle strips with weak in otropic responses (<50% increase in tension), the increase in light wa s significantly higher with milrinone than with levosimendan. Conclusi ons-Levosimendan has inotropic and lusitropic actions in failing human myocardium. Comparison with the phosphodiesterase inhibitor milrinone indicates that in case of pronounced inotropic stimulation, the modes of action of the two agents may be similar (phosphodiesterase inhibit ion), whereas small inotropic effects of levosimendan may result predo minantly from calcium sensitization.