title: The novel calcium sensitizer levosimendan activates the ATP-sensitive K+ channel in rat ventricular cells.
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 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.
authors.affiliation: Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Ohio 45267-0576, USA. yokoshh@ucbeh.san.uc.edu
authors.forename: H
authors.initials: H
authors.lastname: Yokoshiki
authors.forename: Y
authors.initials: Y
authors.lastname: Katsube
authors.forename: M
authors.initials: M
authors.lastname: Sunagawa
authors.forename: N
authors.initials: N
authors.lastname: Sperelakis
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles; D006835:Hydrazones / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077464:Simendan
chemical_list: D015220:Calcium Channels; D002316:Cardiotonic Agents; D006835:Hydrazones; D015221:Potassium Channels; D011724:Pyridazines; D000077464:Simendan; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D002118:Calcium