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Levosimendan has been reported to increase cardiac Ca(2+) sensitivity, thereby not enhancing intracellular Ca(2+) or diastolic tension. This may be advantageous for the treatment of heart failure patients. Therefore, the present study investigates the mode of action of levosimendan in both failing and nonfailing (NF) human myocardium. The effects of levosimendan on contractile force, Ca(2+) transient (fura 2), and the force-frequency relationship (0.5-3 Hz) were studied in left ventricular terminally failing [dilated cardiomyopathy (DCM; n = 18)] and nonfailing (NF) myocardium (donor hearts, n = 6). Levosimendan (0.03-10 micromol/l) increased contractile force in NF (EC(50): 0.38 micromol/l). In left ventricular failing myocardium, levosimendan only increased force after prestimulation with isoprenaline (0.1 micromol/l, EC(50) levosimendan: 0.062 micromol/l) or after elevation of the extracellular Ca(2+) concentration from 1.8 to 3.2 mmol/l. After application of isoprenaline, levosimendan shortened relaxation and contraction kinetics. Levosimendan did not change the systolic Ca(2+) transient but it improved the force-frequency relationship in DCM. In conclusion, levosimendan improves contraction in failing human myocardium under conditions with already increased intracellular Ca(2+).