title: Effects of phosphodiesterase (PDE) inhibitors on human ether-a-go-go related gene (hERG) channel activity.
abstract: It is presumed that phosphodiesterase (PDE) inhibitors have two mechanisms for inhibition of hERG currents in the acute applications to cells: direct channel block, and downregulation of human ether-a-go-go related gene (hERG) activities by PKA-dependent pathway mediated phosphorylation through their inhibitory effects against PDE enzymes. However, it is unknown whether PDE inhibition contributes to the inhibitory effects of PDE inhibitors on hERG currents. This study examined the effects of various PDE inhibitors on hERG currents using both the whole-cell and perforated patch-clamp techniques in hERG transfected CHO-K1 cells. The study also investigated the contribution of the PKA-dependent pathway to the inhibitory effects of PDE inhibitors on hERG currents. Of the PDE inhibitors tested, vinpocetine, erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), vesnarinone, rolipram and dipyridamole decreased hERG currents in a concentration-dependent manner. Vinpocetine and vesnarinone markedly decreased the hERG current with an IC (50)of 0.13 and 20.6 microm, respectively, at comparatively low concentrations. Furthermore, vinpocetine caused a cumulative block of hERG currents. Milrinone, amrinone and zaprinast had no effect on the hERG current up to 100 microm. Of the PDE3 inhibitors (vesnarinone, amrinone and milrinone), only vesnarinone showed an hERG inhibitory effect. The inhibitory effects of vinpocetine and vesnarinone were not significantly affected by the co-application of protein kinase inhibitors. Furthermore, the protein kinase activators had no effect on hERG currents. It is concluded that vinpocetine and vesnarinone block the hERG channel directly, and that the inhibitory effect on intracellular PDE in the PKA-dependent pathway may not be involved in the inhibition of hERG currents in hERG transfected CHO-K1 cells.
authors.affiliation: Shin Nippon Biomedical Laboratories Ltd, Drug Safety Research Laboratories, 2438 Miyanoura, Kagoshima 891-1394, Japan. yunomae-kiyokazu@snbl.co.jp
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Yunomae
authors.forename: Satoko
authors.initials: S
authors.lastname: Ichisaki
authors.forename: Junko
authors.initials: J
authors.lastname: Matsuo
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nagayama
authors.forename: Koichiro
authors.initials: K
authors.lastname: Fukuzaki
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Nagata
authors.forename: Go
authors.initials: G
authors.lastname: Kito
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000676:Amrinone / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004176:Dipyridamole / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D000072237:ERG1 Potassium Channel; D020536:Enzyme Activators / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes; D008564:Membrane Potentials / Q000187:drug effects; D020105:Milrinone / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology; D011719:Pyrazines; D011804:Quinolines / Q000494:pharmacology; D020889:Rolipram / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection; D014748:Vinca Alkaloids / Q000494:pharmacology
chemical_list: D000072237:ERG1 Potassium Channel; D020536:Enzyme Activators; D051638:Ether-A-Go-Go Potassium Channels; D007527:Isoenzymes; C000606913:KCNH2 protein, human; D010726:Phosphodiesterase Inhibitors; D047428:Protein Kinase Inhibitors; D011688:Purinones; D011719:Pyrazines; D011804:Quinolines; D014748:Vinca Alkaloids; C013983:vinpocetine; C010192:9-(2-hydroxy-3-nonyl)adenine; C041667:vesnarinone; D004176:Dipyridamole; D017868:Cyclic AMP-Dependent Protein Kinases; D010727:Phosphoric Diester Hydrolases; C011145:zaprinast; D000225:Adenine; D020105:Milrinone; D000676:Amrinone; D020889:Rolipram