Affiliation:
1. 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.
Abstract
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
32
P 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 Ca
2+
concentrations with no significant effect on maximum force or on Ca
2+
binding to myofilament troponin C. There was no direct effect of Levosimendan on Ca
2+
uptake by vesicles of sarcoplasmic reticulum (SR). In contrast, under conditions optimal for cAMP-dependent phosphorylation, Levosimendan slightly but significantly lowered the concentration of Ca
2+
, yielding half-maximal uptake rates by the SR vesicles. Our results indicate that at low concentrations Levosimendan acts preferably as a Ca
2+
sensitizer, whereas at higher concentrations its action as a phosphodiesterase inhibitor contributes to the positive inotropic effect.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
225 articles.
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