Potassium channel-related relaxation by levosimendan in the human internal mammary artery

Levosimendan is a potent inotropic and vasodilator drug used in the treatment of decompensated heart failure. There is no study on in vitro effects of levosimendan in human isolated arteries.

We investigated the effect of levosimendan on contractile tone of human isolated internal mammary artery (IMA). The responses in IMA were recorded isometrically by a force-displacement transducer in isolated organ baths. Levosimendan was added to organ baths either at rest or after precontraction with phenylephrine (1 micromol/L). Levosimendan-induced relaxations were tested in the presence of cyclooxygenase inhibitor indomethacin (10 micromol/L), nitric oxide synthase inhibitor N122-nitro-L-arginine methyl ester (100 micromol/L), large-conductance calcium-activated potassium-channel inhibitor tetraethylammonium (1 mmol/L), adenosine triphosphate-sensitive potassium-channel inhibitor glibenclamide (10 micromol/L), and voltage-sensitive potassium-channel inhibitor 4-aminopyridine (1 mmol/L).

Levosimendan (10 nmol/L to 3 micromol/L) produced potent relaxation in human IMA (maximal effect, 75.3% +/- 4.9% of phenylephrine maximum contraction, 6.8 +/- 0.1, n = 15; -log10 of 50% effective concentration). Vehicle had no significant relaxant effect. The relaxation to levosimendan is not affected by either potassium-channel inhibitors (tetraethylammonium and 4-aminopyridine) or cyclooxygenase and nitric oxide synthase inhibitors. Glibenclamide (10 micromol/L) inhibited levosimendan-induced relaxation significantly (p < 0.01).

Levosimendan effectively and directly decreases the tone of IMA. The mechanism of levosimendan-induced relaxation in IMA appears in part to be adenosine triphosphate-sensitive potassium-channel opening action. Levosimendan may be a cardiovascular protective agent by its relaxing action on the major arterial graft, IMA.