TY - JOUR T1 - The Novel Calcium Sensitizer Levosimendan Activates the ATP-Sensitive K<sup>+</sup> Channel in Rat Ventricular Cells JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 375 LP - 383 VL - 283 IS - 1 AU - Hisashi Yokoshiki AU - Yasuhiro Katsube AU - Masanori Sunagawa AU - Nicholas Sperelakis Y1 - 1997/10/01 UR - http://jpet.aspetjournals.org/content/283/1/375.abstract N2 - 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+ (KATP) current. Stimulation of KATP 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, KATP channels, which had been inhibited by 0.3 mM ATP, were activated by levosimendan. However, levosimendan did not stimulate the KATP channels that exhibited high spontaneous activity in ATP-free solution. Levosimendan also could not stimulate KATP channels that had rundown in ATP-free solution. However, levosimendan could stimulate rundown KATP channels that were reactivated by nucleotide diphosphates. KATPchannels 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 KATP 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 KATP channels by levosimendan would likely occur in ischemic regions in which intracellular ADP concentration is increased and intracellular ATP concentration is decreased. The American Society for Pharmacology and Experimental Therapeutics ER -