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Effects of phosphodiesterase (PDE) inhibitors on human ether‐a‐go‐go related gene (hERG) channel activity
Author(s) -
Yunomae Kiyokazu,
Ichisaki Satoko,
Matsuo Junko,
Nagayama Shinichi,
Fukuzaki Koichiro,
Nagata Ryoichi,
Kito Go
Publication year - 2006
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.1201
Subject(s) - herg , vinpocetine , milrinone , rolipram , pharmacology , phosphodiesterase , chemistry , amrinone , protein kinase a , patch clamp , phosphodiesterase 3 , biochemistry , potassium channel , phosphorylation , enzyme , biophysics , biology , endocrinology , receptor , inotrope
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 µ m , 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 µ m . 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. Copyright © 2006 John Wiley & Sons, Ltd.