THE NOVEL CALCIUM SENSITIZER LEVOSIMENDAN ACTIVATES THE ATP-SENSITIVEK+ 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 myocar dium. To elucidate the mechanisms of these actions, the possible elect rophysiological effects of levosimendan on isolated rat ventricular ce lls were examined by the patch-clamp technique with whole-cell and sin gle-channel recordings. Levosimendan (3 and 10 mu M) markedly shortene d action potential duration and activated an outward current at potent ials positive to -70 mV. The increased current was abolished by gliben clamide, a blocker of the ATP-sensitive K+ (K-ATP) current. Stimulatio n 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 rec ording in open cell-attached patches, K-ATP, channels, which had been inhibited by 0.3 mM ATP, were activated by levosimendan. However, levo simendan did not stimulate the K-ATP channels that exhibited high spon taneous activity in ATP-free solution. Levosimendan also could not sti mulate K-ATP channels that had rundown in ATP-free solution. However, levosimendan could stimulate rundown K-ATP channels that were reactiva ted by nucleotide diphosphates. K-ATP channels inhibited by 0.5 mM AMP -PNP, a nonhydrolyzable ATP analog, were not stimulated by levosimenda n; however, the channels were stimulated by levosimendan in the presen ce of 30 to 50 mu M ADP. Levosimendan stimulates cardiac K-ATP channel s that are suppressed by intracellular ATP. it appears that levosimend an acts synergistically with nucleotide diphosphates. These properties of levosimendan may help protect ischemic myocardium because activati on of K-ATP channels by levosimendan would likely occur in ischemic re gions in which intracellular ADP concentration is increased and intrac ellular ATP concentration is decreased.