The novel calcium sensitizer levosimendan activates the ATP-sensitive K+ channel in rat ventricular cells

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 mu M) 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 EC50 value of 4.7 mu M; a maximal effect occurred at 30 mu M. The L-type Ca++ current was not affected by levosimendan (0.2-10 mu M). 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-ATP channels 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 mu M 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.