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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Antieosinophilic Activity of Simendans

The Immunopharmacology Research Group, Medical School, University of Tampere (H.K., X.Z., E.M.) and Department of Respiratory Medicine (H.K.) and Research Unit (E.M.), Tampere University Hospital, Tampere, Finland; Seinajoki Central Hospital, Seinajoki, Finland (H.K.); Orion Corporation, Espoo, Finland (R.T., M.R., H.H., E.N.); and Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (X.Z.)

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.

Address correspondence to: Dr. Hannu Kankaanranta, Department of Respiratory Medicine, Seinajoki Central Hospital, Hanneksenrinne 7, FIN-60220 Seinajoki, Finland. E-mail: hannu.kankaanranta{at}epshp.fi