Levosimendan increases diastolic coronary flow in isolated guinea-pig heart by opening ATP-sensitive potassium channels.
Levosimendan, a novel calcium sensitizer developed for the treatment of acute heart failure, is an inodilator that increases coronary flow. Because it was recently shown that levosimendan stimulates potassium current through K(ATP) channels in isolated rat arterial cells, our aim was to assess whether the levosimendan-induced increase in coronary flow is due to the opening of the K(ATP) channels in coronary smooth muscle. The effect of levosimendan on the diastolic coronary flow velocity (DCFV) was measured in the Langendorff perfused spontaneously beating guinea-pig heart in the absence and presence of glibenclamide. Pinacidil was used as a reference compound, and the protein kinase C inhibitor bisindolylmaleimide was used to study the dilatory effect of levosimendan when the K(ATP) channels in smooth muscle are not inhibited by PKC-dependent phosphorylation. Levosimendan (0.01-1 microM) increased DCFV concentration-dependently and was noncompetitively antagonized by 0.1 microM glibenclamide, whereas pinacidil was inhibited competitively by glibenclamide. In the presence of glibenclamide the positive inotropic and chronotropic effects of levosimendan were unaltered. The effect of bisindolylmaleimide and levosimendan on DCFV was additive. The results indicate that levosimendan induced coronary vasodilation through the opening of the K(ATP) channels. Levosimendan and pinacidil probably have different binding sites on the K(ATP) channels. The additive effect of bisindolylmaleimide and levosimendan on the increase of DCFV suggests that the latter binds to the unphosphorylated form of the channel.
Kaheinen
P
P
Orion Pharma, Drug Discovery and Pharmacology, Cardiovascular Research, Espoo, Finland. petri.kaheinen@orionpharma.com
Pollesello
P
P
Levijoki
J
J
Haikala
H
H
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006835:Hydrazones / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000378:metabolism; D020110:Pinacidil / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D011724:Pyridazines / Q000494:pharmacology*; D000077464:Simendan; D014665:Vasodilator Agents / Q000494:pharmacology*
D006835:Hydrazones; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D011724:Pyridazines; D014665:Vasodilator Agents; D000077464:Simendan; D020110:Pinacidil; D005905:Glyburide