Circulation, Vol 89, 955-958, Copyright © 1994 by American Heart Association
A Matsumori, T Shioi, T Yamada, S Matsui and S Sasayama
BACKGROUND: Vesnarinone, a quinolinone derivative, is a recently
synthesized positive inotropic agent that has been shown to dramatically
improve the survival of patients with heart failure. However, the mechanism
of action of vesnarinone remains unknown. Reversible neutropenia
complicated with vesnarinone therapy suggests that vesnarinone may modulate
the production of cytokines. Because tumor necrosis factor (TNF)-alpha and
other cytokines have been shown to depress myocardial contractility, we
investigated the effects of vesnarinone on the production of various
cytokines. METHODS AND RESULTS: We studied the effects of vesnarinone on
cytokine production by lipopolysaccharide (LPS)-stimulated whole blood from
seven patients with heart failure and from five healthy volunteers.
Heparinized blood was diluted in RPMI and stimulated with LPS. Vesnarinone
was added in a range of 1 to 30 micrograms/mL, the blood was incubated for
24 hours, and interleukin (IL)-1 alpha, IL-1 beta, IL-6, TNF-alpha,
interferon (IFN)-gamma, and granulocyte colony-stimulating factor (G-CSF)
were measured by an enzyme-linked immunosorbent assay. LPS stimulation
induced a more prominent increase in TNF-alpha in patients with heart
failure than in healthy volunteers. Vesnarinone inhibited the production of
TNF-alpha and IFN-gamma both in healthy volunteers and in patients with
heart failure. IL-1 alpha and IL-1 beta were also suppressed in healthy
volunteers, but this response was variable, and a significant reduction was
not seen in patients with heart failure. Marked inhibition of G-CSF and
other cytokines by vesnarinone was observed in one patient who had
developed neutropenia as a result of vesnarinone therapy. CONCLUSIONS:
Although the number of study patients was small and the results are
preliminary, these findings provide evidence that vesnarinone plays an
important role in the regulation of cytokines and suggest that the
reduction of cytokine release may contribute to the beneficial effects of
the drug in the treatment of heart failure. Furthermore, the measurement of
cytokines may be useful in predicting the occurrence of neutropenia, which
has been occasionally reported in patients treated with vesnarinone.
ARTICLES
Vesnarinone, a new inotropic agent, inhibits cytokine production by stimulated human blood from patients with heart failure
Department of Internal Medicine, Faculty of Medicine, Kyoto University, Japan.
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