Comparison of the Vasorelaxing Effect of Cromakalim and the New Inodilator, Levosimendan, in Human Isolated Portal Vein

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Abstract
In the present study the vasorelaxing capacity of cromakalim, an ATP-sensitive potassium-channel (KATP 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 = 0.281 ± 0.03 μM) as a relaxing agent than cromakalim (EC50 = 4.53 ± 0.12 μM) in noradrenaline-precontracted portal venous preparations. Glibenclamide, the known inhibitor of KATP channels, was able to prevent the cromakalim-induced venodilation completely. Glibenclamide (15 μM) decreased the quasi-maximal effect of levosimendan (at 1.27 μM by about 60%) and also the effects of those submicromolar concentrations of the inodilator (at 0.1 μM by 23%, at 0.3 μM by 27% and at 0.7 μM 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.