Abstract
Objective:
The purpose of this study was to investigate the effects of vesnarinone on nitric oxide (NO) synthesis in cardiac myocytes.
Methods:
We measured the accumulation of nitrite, a stable oxidation product of NO synthase (iNOS) protein in cultured neonatal rat cardiac myocytes.
Results:
Incubation of the cultures with interleukin-1 beta (IL-1 beta; 10 ng/ml) and tumor necrosis factor alpha (TNF alpha; 10 ng/ml) caused a marked increase in nitrite production. Although vesnarinone by itself showed no effect on nitrite accumulation, it enhanced cytokine-induced nitrite production by cardiac myocytes in a dose-dependent manner. The effect of vesnarinone was completely abolished in the presence of NG-monomethyl-L-arginine or actinomycin D. The vesnarinone-induced nitrite production was accompanied by increased iNOS protein expression. In the presence of dibutyryl-cAMP, cytokine-induced nitrite accumulation was further increased, but the stimulatory effect on vesnarinone on nitrite accumulation was diminished. The effect of vesnarinone was also inhibited by Rp-8-Br-cAMPS, a competitive inhibitor of protein kinase A, in a dose-dependent manner.
Conclusions:
These findings indicate that vesnarinone increases NO synthesis in cytokine-stimulated cardiac myocytes, at least partially through a cAMP-dependent pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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8-Bromo Cyclic Adenosine Monophosphate / analogs & derivatives
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8-Bromo Cyclic Adenosine Monophosphate / pharmacology
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Analysis of Variance
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Animals
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Animals, Newborn
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Bucladesine / pharmacology
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Cardiotonic Agents / pharmacology*
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Cells, Cultured
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Culture Media, Conditioned / chemistry
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Cyclic AMP-Dependent Protein Kinase Type II
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Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
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Dactinomycin / pharmacology
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Dose-Response Relationship, Drug
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Interleukin-1 / pharmacology
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Myocardium / metabolism*
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Nitric Oxide / biosynthesis*
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Nitric Oxide Synthase / analysis
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Nitric Oxide Synthase / antagonists & inhibitors
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Nitric Oxide Synthase Type II
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Nitrites / analysis
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Protein Synthesis Inhibitors / pharmacology
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Pyrazines
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Quinolines / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Thionucleotides / pharmacology
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Tumor Necrosis Factor-alpha / pharmacology
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omega-N-Methylarginine / pharmacology
Substances
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8-bromoadenosine-3',5'-cyclic monophosphorothioate
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Cardiotonic Agents
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Culture Media, Conditioned
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Interleukin-1
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Nitrites
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Protein Synthesis Inhibitors
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Pyrazines
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Quinolines
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Thionucleotides
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Tumor Necrosis Factor-alpha
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Dactinomycin
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8-Bromo Cyclic Adenosine Monophosphate
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omega-N-Methylarginine
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Nitric Oxide
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vesnarinone
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Bucladesine
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, rat
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Cyclic AMP-Dependent Protein Kinase Type II
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Cyclic AMP-Dependent Protein Kinases