The Novel Calcium Sensitizer Levosimendan Activates the ATP-Sensitive K⁺ Channel in Rat Ventricular Cells1

Abstract

Levosimendan, a new Ca⁺⁺-sensitizing and positive inotropic agent, was reported to act as a coronary vasodilator and protect ischemic myocardium. To elucidate the mechanisms of these actions, the possible electrophysiological effects of levosimendan on isolated rat ventricular cells were examined by the patch-clamp technique with whole-cell and single-channel recordings. Levosimendan (3 and 10 μM) markedly shortened action potential duration and activated an outward current at potentials positive to −70 mV. The increased current was abolished by glibenclamide, a blocker of the ATP-sensitive K⁺ (K_ATP) current. Stimulation of K_ATP current was dose dependent, with an EC₅₀value of 4.7 μM; a maximal effect occurred at 30 μM. The L-type Ca⁺⁺ current was not affected by levosimendan (0.2–10 μM). In single-channel current recording in open cell-attached patches, K_ATP channels, which had been inhibited by 0.3 mM ATP, were activated by levosimendan. However, levosimendan did not stimulate the K_ATP channels that exhibited high spontaneous activity in ATP-free solution. Levosimendan also could not stimulate K_ATP channels that had rundown in ATP-free solution. However, levosimendan could stimulate rundown K_ATP channels that were reactivated by nucleotide diphosphates. K_ATPchannels inhibited by 0.5 mM AMP-PNP, a nonhydrolyzable ATP analog, were not stimulated by levosimendan; however, the channels were stimulated by levosimendan in the presence of 30 to 50 μM ADP. Levosimendan stimulates cardiac K_ATP channels that are suppressed by intracellular ATP. It appears that levosimendan acts synergistically with nucleotide diphosphates. These properties of levosimendan may help protect ischemic myocardium because activation of K_ATP channels by levosimendan would likely occur in ischemic regions in which intracellular ADP concentration is increased and intracellular ATP concentration is decreased.