LEVOSIMENDAN, A NOVEL CA2-SENSITIVE K+ CHANNEL IN RAT ARTERIAL MYOCYTES( SENSITIZER, ACTIVATES THE GLIBENCLAMIDE)

The electrophysiological effect of levosimendan, a novel Ca2+-sensitiz ing positive inotropic agent and vasodilator, was examined on rat mese nteric arterial myocytes using the patch clamp technique. Resting pote ntial was significantly hyperpolarized with levosimendan, with an EC50 of 2.9 mu M and maximal effect (19.5 +/- 3.5 mV; n = 12) at 10 mu M L evosimendan (10 mu M) significantly increased the whole-cell outward c urrent. The currents intersected close to the calculated E-K (-84 mV), suggesting that the activated current was a K+ current. Hyperpolariza tion and stimulation of K+ current by levosimendan were not prevented by 30 mu M H-7 (a non-specific inhibitor of protein kinases) and 100 n M charybdotoxin (a blocker of Ca2+-activated K+ channels), but were ab olished by 10 mu M glibenclamide. In single-channel current recording in open cell-attached patches, two types of K+ channels were observed having conductances of 26 and 154 pS. The 154 pS channels were not aff ected by levosimendan and glibenclamide. The 26 pS channels were evoke d in one-fourth of the patches when 10 mu M levosimendan (and 0.1 mM U DP) was added (at -60 mV) and channel activity was abolished by gliben clamide. The mean open probability of the 26 pS channels was 0.094 +/- 0.017 (n = 9), and the mean open time (at -60 mV) was 6.6 ms in the p resence of UDP and levosimendan. Although significant hyperpolarizatio n (4.7 +/- 1.5 mV, n = 8) was observed at 1 mu M levosimendan, the sam e concentration did not affect Ca2+ channel currents (n = 10). In summ ary, levosimendan hyperpolarized the arterial myocytes, probably throu gh activation of a glibenclamide-sensitive K+ channel. This mechanism may contribute to the vasodilating action of levosimendan. (C) 1997 El sevier Science B.V.