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.
Ajiro
Youichi
Y
The Heart Institute of Japan, Tokyo Women's Medical University, 8-1 Kawada-cho, Tokyo 162-8666, Shinjuku, Japan.
Hagiwara
Nobuhisa
N
Katsube
Yasuhiro
Y
Sperelakis
Nicholas
N
Kasanuki
Hiroshi
H
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004594:Electrophysiology; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D011817:Rabbits; D000077464:Simendan
D020746:Calcium Channels, L-Type; D006835:Hydrazones; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D000077464:Simendan; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D015056:1-Methyl-3-isobutylxanthine