Abstract
Simendans are novel agents used in the treatment of decompensated heart failure. They sensitize troponin C to calcium and open ATP-sensitive potassium channels and have been shown to reduce cardiac myocyte apoptosis. The aim of the present study was to evaluate whether simendans reduce pulmonary eosinophilia and regulate eosinophil apoptosis. Bronchoalveolar lavage (BAL) eosinophilia was evaluated in ovalbumin-sensitized mice. Effects of simendans on apoptosis in isolated human eosinophils were assessed by relative DNA fragmentation assay, annexin V-binding, and morphological analysis. Dextrosimendan [(+)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazono]propanedinitrile] reduced ovalbumin-induced BAL-eosinophilia in sensitized mice. Levosimendan [(–)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile] and dextrosimendan reversed interleukin (IL)-5-afforded survival of human eosinophils by inducing apoptosis in vitro. Even high concentrations of IL-5 were not able to overcome the effect of dextrosimendan. Dextrosimendan further enhanced spontaneous apoptosis as well as that induced by CD95 ligation, without inducing primary necrosis. Dextrosimendan-induced DNA fragmentation was shown to be dependent on caspase and c-Jun NH2-terminal kinase activation, whereas extracellular signal-regulated kinase, p38 mitogen-activated kinase, and ATP-sensitive potassium channels seemed to play no role in its actions. Taken together, our results show that simendans possess antieosinophilic activity and may be useful for the treatment of eosinophilic inflammation.
Footnotes
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This study was supported by the Tampere Tuberculosis Foundation, by the Finnish Anti-Tuberculosis Association Foundation (Finland), by the Academy of Finland, by the Medical Research Fund of Tampere University Hospital (Finland), by OrionPharma Ltd. (Finland), and by the National Technology Agency (TEKES, Finland).
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R.T., E.N., M.R., and H.H. are current employees of Orion Corporation.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.124057.
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ABBREVIATIONS: IL, interleukin; levosimendan, (–)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile; dextrosimendan, (+)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazono]propanedinitrile; BAL, bronchoalveolar lavage; JNK, c-Jun NH2-terminal kinase; DMSO, dimethyl sulfoxide; l-JNKI1, GRKKRRQRRR-PP-RPKRPTTLNLFPQVPRSQD-amide; l-TAT, RKKRRQRRR-amide, negative control for l-JNKI1; fmk, fluoromethyl ketone; Z-Asp-CH2-DCB, benzyloxycarbonyl-Asp-CH2COC-dichlorobenzene; PD098059, 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4 pyridyl)-1H-imidazole; PI, propidium iodide; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; KATP, ATP-sensitive potassium channel.
- Received April 5, 2007.
- Accepted July 6, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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