Comparison of the vasorelaxing effect of cromakalim and the new inodilator, levosimendan, in human isolated portal vein

In the present study the vasorelaxing capacity of cromakalim, an ATP-sensitive potassium-channel (K-ATP channel) activator, and that of levosimendan, a new positive inotropic and vasodilating drug with calcium sensitizing and potassium-channel-activating properties, were compared in human isolated portal vein. Based on the 50% effective concentrations (EC50), levosimendan was found to be about 16-fold more potent (EC50=0.28 +/- 0.03 mu M) as a relaxing agent than cromakalim (EC50=4.53 +/- 0.12 mu M) in noradrenaline-precontracted portal venous preparations. Glibenclamide, the known inhibitor of K-ATP channels, was able to prevent the cromakalim-induced venodilation completely. Glibenclamide (15 mu M) decreased the quasi-maximal effect of levosimendan (at 1.27 mu M by about 60%) and also the effects of those submicromolar concentrations of the inodilator (at 0.1 mu M by 23%, at 0.3 mu M by 27% and at 0.7 mu M by 19%, on average) which were therapeutically effective in preliminary human studies. These findings indicate that, in the human portal vein, both cromakalim and levosimendan are powerful vasorelaxants and that a considerable part of the relaxing effect induced by levosimendan is of cromakalim type.