© 1995 American Heart Association, Inc.
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Effects of Levosimendan, a Cardiotonic Agent Targeted to Troponin C, on Cardiac Function and on Phosphorylation and Ca2+ Sensitivity of Cardiac Myofibrils and Sarcoplasmic Reticulum in Guinea Pig Heart
From the Second Department of Medicine (I.E.) and the Departments of Physiology (E.K.) and Pharmacology (J.G.P.), Albert Szent-Györgyi Medical University, Szeged, Hungary; the Department of Pharmacology and Cell Biophysics (E.G.K.), University of Cincinnati (Ohio); and the Department of Physiology and Biophysics (Y.K., F.M.P., R.J.S.), University of Illinois at Chicago.
Correspondence to R. John Solaro, PhD, Department of Physiology and Biophysics (M/C 901), College of Medicine, University of Illinois at Chicago, 901 S Wolcott Ave, Chicago, IL 60612-7342.
Abstract A new cardiotonic agent, (R)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl] hydrazono]propanedinitrile (Levosimendan), has been developed and screened for its ability to bind to cardiac troponin C. In perfused hearts, low concentrations of 0.03 or 0.1 µmol/L Levosimendan increased +dP/dt, but did not affect the speed of relaxation and produced only a slight increase in spontaneous heart rate in the hearts perfused with 0.1 µmol/L of the drug. In these same hearts, perfusion with 0.03 µmol/L Levosimendan did not alter the 32P incorporation into troponin I or C protein, whereas a slight but significant increase was noted for phospholamban, with no detectable change in tissue cAMP levels. Administration of 0.1 or 0.3 µmol/L Levosimendan significantly increased myocardial cAMP levels as well as the phosphorylation of phospholamban, troponin I, and C protein. Levosimendan (0.03 to 10 µmol/L) reversibly increased force generated by detergent-extracted fiber bundles over a range of submaximally activating free Ca2+ concentrations with no significant effect on maximum force or on Ca2+ binding to myofilament troponin C. There was no direct effect of Levosimendan on Ca2+ uptake by vesicles of sarcoplasmic reticulum (SR). In contrast, under conditions optimal for cAMP-dependent phosphorylation, Levosimendan slightly but significantly lowered the concentration of Ca2+, yielding half-maximal uptake rates by the SR vesicles. Our results indicate that at low concentrations Levosimendan acts preferably as a Ca2+ sensitizer, whereas at higher concentrations its action as a phosphodiesterase inhibitor contributes to the positive inotropic effect.
Key Words: Levosimendan • troponin C • cardiac contractility
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