Levosimendan increases L-type Ca2+ 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 Ca2+ current (I-Ca,I-L) in single human atrial cells using the whole-cell voltage-clamp method. Levosimendan significantly increased I-Ca,I-L in a concentration-dependent manner (E-max 139.0 +/- 1.8%; EC50, 54 +/- 3.6 nM). The increase in I-Ca,I-L induced by 1 muM 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,I-L was unaffected by 1 - 10 muM levosimendan. These results indicate that the selective phosphodiesterase-3 inhibitor levosimendan increases cardiac-cell I-Ca,I-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,I-L that is modulated by adenosine 3' 5' -cyclic monophosphate (cAMP)-dependent phosphorylation. (C) 2002 Elsevier Science B.V. All rights reserved.