Levosimendan increases L-type Ca(2+) current via phosphodiesterase-3 inhibition in human cardiac myocytes

To evaluate the potency of levosimendan, a newly developed cardiotonic agent, as a phosphodiesterase-3 inhibitor, we examined its effects on the L-type Ca(2+) current (I(Ca,L)) in single human atrial cells using the whole-cell voltage-clamp method. Levosimendan significantly increased I(Ca,L) in a concentration-dependent manner (E(max), 139.0 +/- 1.8%; EC(50), 54 +/- 3.6 nM). The increase in I(Ca,L) induced by 1 microM levosimendan was significantly greater in human atrial cells (136.7 +/- 11.0%, n=8) than in rabbit atrial cells (23.5 +/- 3.5%, n=6) (depolarization to +10 mV in each case). In rat atrial and ventricular cells, I(Ca,L) was unaffected by 1-10 microM levosimendan. These results indicate that the selective phosphodiesterase-3 inhibitor levosimendan increases cardiac-cell I(Ca,L) significantly more strongly in human than in rabbit and rat. It seems likely that the positive inotropic effect of levosimendan on the human myocardium depends on an increase in I(Ca,L) that is modulated by adenosine 3'5'-cyclic monophosphate (cAMP)-dependent phosphorylation.