Pimobendan inhibits the activation of transcription factor NF-kappaB: a mechanism which explains its inhibition of cytokine production and inducible nitric oxide synthase.
Pimobendan, an inhibitor of phosphodiesterase III with calcium sensitizing properties, inhibits the production of cytokines and nitric oxide. In the present study, the effects of pimobendan and other inotropic agents on the activation of transcription factor NF-kappaB were examined. Pimobendan significantly decreased the expression of luciferase protein in A549 cells transfected with the NF-kappaB reporter plasmid, stimulated with interleukin (IL)-1beta, tumor necrosis factor-alpha, or phorbol 12-myristate 13 acetate. However, high concentrations of amrinone, vesnarinone, or NKH 477 decreased promoter activity only slightly. Electrophoretic mobility shift assay also showed inhibition of NF-kappaB activation by pimobendan. Pimobendan possesses the unique property of inhibiting NF-kappaB, which may be independent of phosphodiesterase inhibition.
Matsumori
A
A
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan. amat@kuhp.kyoto-u.ac.jp
Nunokawa
Y
Y
Sasayama
S
S
D000676:Amrinone / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D005576:Colforsin / Q000031:analogs & derivatives* / Q000494:pharmacology; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011719:Pyrazines; D011724:Pyridazines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002316:Cardiotonic Agents; D016207:Cytokines; D007375:Interleukin-1; D016328:NF-kappa B; D010726:Phosphodiesterase Inhibitors; D011719:Pyrazines; D011724:Pyridazines; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; C041648:pimobendan; C041667:vesnarinone; D008156:Luciferases; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000676:Amrinone; D013755:Tetradecanoylphorbol Acetate