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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 283; no. 1; p. 375
• Main Authors: Yokoshiki, H, Katsube, Y, Sunagawa, M, Sperelakis, N
• Format: Journal Article
• Language: English
• Published: United States 01-10-1997
• Subjects: Action Potentials - drug effects; Adenosine Diphosphate - pharmacology; Adenosine Triphosphate - pharmacology; Animals; Calcium - metabolism; Calcium Channels - drug effects; Cardiotonic Agents - pharmacology; Heart - drug effects; Heart - physiology; Heart Ventricles; Hydrazones - pharmacology; Potassium Channels - drug effects; Potassium Channels - physiology; Pyridazines - pharmacology; Rats; Rats, Sprague-Dawley
• ISSN: 0022-3565

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 microM) 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 microM; a maximal effect occurred at 30 microM. The L-type Ca++ current was not affected by levosimendan (0.2-10 microM). 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 microM 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.