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 microM) as a relaxing agent than cromakalim (EC50 = 4.53+/-0.12 microM) in noradrenaline-precontracted portal venous preparations. Glibenclamide, the known inhibitor of KATP channels, was able to prevent the cromakalim-induced venodilation completely. Glibenclamide (15 microM) decreased the quasi-maximal effect of levosimendan (at 1.27 microm by about 60%) and also the effects of those submicromolar concentrations of the inodilator (at 0.1 microM by 23%, at 0.3 microM by 27% and at 0.7 microM 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.

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The involvement of potassium channels in the venodilating capacity of the inodilator levosimendan in human saphenous vein preparations was investigated. Levosimendan caused relaxation with 50% effective concentration (EC50) of 0.32 +/- 0.04 microM in isolated veins contracted by 5-hydroxytryptamine. Fifteen microM glibenclamide, a blocker of the ATP-sensitive potassium channels (K(ATP)), partially inhibited the relaxing effect of the inodilator. In the presence of iberiotoxin, the selective blocker of large conductance calcium-activated potassium channels (BK(Ca)), levosimendan induced contraction with EC50 of 0.21 +/- 0.06 microM. We presume that levosimendan dilates human saphenous veins by interacting with hyperpolarizing potassium channels (K(ATP) and BK(Ca)).

Introduction In addition to nitric oxide (NO), it is thought that an endothelium-derived hyperpolarizing factor (EDHF) plays an important role in the relaxation of penile arteries. Recently, it has been shown that C-type natriuretic peptide (CNP) shows the characteristics of EDHF in systemic small arteries. Aim To investigate the mechanism involved in CNP-evoked vasodilatation and to address whether CNP is an EDHF in human penile resistance arteries. Methods Erectile tissue was obtained in connection with transsexual operations. Intracavernous penile resistance arteries were isolated and mounted in microvascular myographs for recording of isometric tension. Membrane potential was recorded by the use of a small glass electrode inserted in the smooth muscle layer. Main Outcome Measure In vitro evidence for hyperpolarization and vasorelaxation induced by CNP. Results Acetylcholine (ACh) and CNP hyperpolarized smooth muscle membrane potential in resting penile resistance arteries. In penile small arteries incubated with inhibitors of NO synthase and cyclooxygenase and contracted with phenylephrine, ACh and CNP evoked concentration-dependent relaxations with maximum of 56±6% and 71±6%, respectively. Addition of a combination of blockers of small- and intermediate-conductance calcium-activated K+ channels, apamin plus charybdotoxin, respectively, and a combination thought to block the smooth muscle response of EDHF-type relaxation, barium plus ouabain, markedly reduced ACh- and CNP-evoked relaxation. Iberiotoxin, a blocker of big-conductance calcium-activated K+ channels inhibited the vasorelaxant responses evoked by ACh and CNP. A selective natriuretic peptide receptor type C (NPR-C) agonist, C-atrial natriuretic factor4−23 (cANF4−23), induced relaxations with less maximum response compared to CNP. Conclusion The present findings suggest that CNP possesses the characteristics of an EDHF in human penile resistance arteries. By activation of natriuretic peptide receptor type B and NPR-C receptors, CNP causes relaxation by activation, respectively, of large-conductance calcium-activated K+ channels and Na+/K+-adenosine triphosphatase (ATPase), and barium-sensitive inward rectifier K+ channels. Modulation of the CNP pathway opens for new treatment modalities of erectile dysfunction.

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