Potassium Channels in the Vasodilating Action of Levosimendan on the Human Umbilical Artery

Objective: Levosimendan is a calcium-sensitizing agent and indoilator working via potassium channels, which is under current investigation in the treatment of heart failure. We investigated the type of potassium channels that play a role on the dilatating effect of levosimendan on the contractile tones of the isolated human umbilical artery (HUA).

Methods: The response in the HUA was recorded isometrically by a force displacement transducer in isolated organ baths. Levosimendan was added to organ baths after precontraction with serotonin (5-HT, 1 μM). Levosimendan-induced relaxations were tested in the presence of the large conductive Ca²⁺-activated K⁺ channel inhibitor tetraethylammonium (TEA, 1 mM), the adenosine triphosphate (ATP)-sensitive K⁺ channel inhibitor glibenclamide (GLI, 10 μM), and the voltage-sensitive K⁺ channel inhibitor 4-aminopyridine (4-AP, 1 mM). All experiments were performed in solutions containing the cyclooxygenase inhibitor indomethacin (10 μM) and the nitric oxide synthase inhibitor L-NAME (100 μM).

Results: Levosimendan (10 nM to 3 μM) produced potent relaxation in the HUA. Vehicle had no significant relaxant effect. The relaxation of levosimendan was not affected by the K⁺ channel inhibitor, GLI. However, 4-AP (1 mM) and TEA (1 mM) inhibited levosimendan-induced relaxation significantly (P <.05).

Conclusion: These results show that levosimendan effectively and directly decreases the tone of the HUA. The mechanism of this levosimendan-relaxation in the HUA appears in part to be due to voltage-gated and large conductance Ca²⁺-activated K⁺ channel opening action.