title: Levosimendan, a novel Ca2+ sensitizer, activates the glibenclamide-sensitive K+ channel in rat arterial myocytes.
abstract: The electrophysiological effect of levosimendan, a novel Ca(2+)-sensitizing positive inotropic agent and vasodilator, was examined on rat mesenteric arterial myocytes using the patch clamp technique. Resting potential was significantly hyperpolarized with levosimendan, with an EC50 of 2.9 microM and maximal effect (19.5 +/- 3.5 mV; n = 12) at 10 microM. Levosimendan (10 microM) significantly increased the whole-cell outward current. The currents intersected close to the calculated EK (-84 mV), suggesting that the activated current was a K+ current. Hyperpolarization and stimulation of K+ current by levosimendan were not prevented by 30 microM H-7 (a non-specific inhibitor of protein kinases) and 100 nM charybdotoxin (a blocker of Ca(2+)-activated K+ channels), but were abolished by 10 microM 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 affected by levosimendan and glibenclamide. The 26 pS channels were evoked in one-fourth of the patches when 10 microM levosimendan (and 0.1 mM UDP) was added (at -60 mV) and channel activity was abolished by glibenclamide. 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 presence of UDP and levosimendan. Although significant hyperpolarization (4.7 +/- 1.5 mV, n = 8) was observed at 1 microM levosimendan, the same concentration did not affect Ca2+ channel currents (n = 10). In summary, levosimendan hyperpolarized the arterial myocytes, probably through activation of a glibenclamide-sensitive K+ channel. This mechanism may contribute to the vasodilating action of levosimendan.
authors.affiliation: Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, OH 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: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D018999:Charybdotoxin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005905:Glyburide / Q000494:pharmacology*; D006835:Hydrazones / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008638:Mesenteric Arteries / Q000187:drug effects; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects*; D011724:Pyridazines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D000077464:Simendan; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D006835:Hydrazones; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D011724:Pyridazines; D014665:Vasodilator Agents; D018999:Charybdotoxin; D000077464:Simendan; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D005905:Glyburide