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Vol. 283, Issue 1, 375-383, 1997
Department of Molecular and Cellular Physiology, College of
Medicine, University of Cincinnati, Cincinnati, Ohio
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 EC50
value 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. KATP
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 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.
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