Vesnarinone and amrinone reduce the systemic inflammatory response syndrome

Takeuchi, Koh; Nido, Pedro J. del; Ibrahim, Andra E.; Cao-Danh, Hung; Friehs, Ingeborg; Glynn, Paul; Poutias, Dimitrios; Cowan, Douglas B.; McGowan, Francis X.

doi:10.1016/s0022-5223(99)70436-8

Cited by 34 publications

(7 citation statements)

References 22 publications

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“…In keeping with previous studies with iNOS inhibitors, these findings suggest that NO production during endotoxemia is not a primary cause of systemic hypotension (14,15). Our data of induced iNOS activity in the rabbit heart are in keeping with previous findings by Takeuchi et al (16). Moreover, increased cardiac content of cyclic guanosine 3',5'-monophosphate, likely caused by iNOS activation, was found in rabbit cardiac myocytes incubated for 6 hrs with LPS (17).…”

Section: Discussionsupporting

confidence: 93%

Species-specific modulation of the nitric oxide pathway after acute experimentally induced endotoxemia

Bachetti

Pasini

Suzuki

et al. 2003

Critical Care Medicine

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Section: Discussionsupporting

confidence: 93%

Species-specific modulation of the nitric oxide pathway after acute experimentally induced endotoxemia

Bachetti

Pasini

Suzuki

et al. 2003

Critical Care Medicine

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“…This agent exhibits potent immunomodulatory activity, as indicated by the suppression of NK cell activity (2,3), endotoxin-induced production of inflammatory cytokines (4 -10), and nitric oxide synthase from macrophages (11,12) and cardiac myocytes (11,13), and it abrogate E-selectin expression in endothelial cells (5). These immunosuppressive effects of vesnarinone have been suggested to contribute to its activity against CHF (9), prolongation of cardiac allograft survival (14,15), and suppression of systemic inflammation (16). Vesnarinone also causes agranulocytosis by impairing stromal functions and cytokine inhibition (17,18) and inhibits immune-mediated hepatic injury (19).…”

Section: -Piperazinyl]-2(1h)-quinolinone; Also Called Opc-8212mentioning

confidence: 99%

Vesnarinone Suppresses TNF-Induced Activation of NF-κB, c-Jun Kinase, and Apoptosis

Manna

Aggarwal

2000

The Journal of Immunology

161

180

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Vesnarinone, a synthetic quinolinone derivative used in the treatment of cardiac failure, exhibits immunomodulatory, anti-inflammatory, and cell growth regulatory properties. The mechanisms underlying these properties are not understood, but due to the critical role of nuclear transcription factor NF-κB in these responses, we hypothesized that vesnarinone must modulate NF-κB activation. We investigated the effect of vesnarinone on NF-κB activation induced by inflammatory agents. Vesnarinone blocked TNF-induced activation of NF-κB in a concentration- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of IκBα, an inhibitor of NF-κB. The effects of vesnarinone were not cell type specific, as it blocked TNF-induced NF-κB activation in a variety of cells. NF-κB-dependent reporter gene transcription activated by TNF was also suppressed by vesnarinone. The TNF-induced NF-κB activation cascade involving TNF receptor 1-TNF receptor associated death domain-TNF receptor associated factor 2 NF-κB-inducing kinase-IKK was interrupted at the TNF receptor associated factor 2 and NF-κB-inducing kinase sites by vesnarinone, thus suppressing NF-κB reporter gene expression. Vesnarinone also blocked NF-κB activation induced by several other inflammatory agents, inhibited the TNF-induced activation of transcription factor AP-1, and suppressed the TNF-induced activation of c-Jun N-terminal kinase and mitogen-activated protein kinase kinase. TNF-induced cytotoxicity, caspase activation, and lipid peroxidation were also abolished by vesnarinone. Overall, our results indicate that vesnarinone inhibits activation of NF-κB and AP-1 and their associated kinases. This may provide a molecular basis for vesnarinone’s ability to suppress inflammation, immunomodulation, and growth regulation.

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“…Indeed, several in vitro studies 10 -12 have shown that vesnarinone suppresses the production of TNF-␣ and IL-6 in various human cell lines, including peripheral lymphocytes, monocytes, T-cell lines, and microglial cells. Moreover, an in vivo study 23 of endotoxemia in rabbits showed that IV vesnarinone reduced the circulating levels of TNF-␣. Although the reasons for the discrepancy between the previous in vitro/in vivo findings are not clear, there are several possible explanations.…”

Section: Discussionmentioning

confidence: 99%

Effects of Vesnarinone on Peripheral Circulating Levels of Cytokines and Cytokine Receptors in Patients With Heart Failure

Deswal

Petersen

Feldman

et al. 2001

Chest

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Vesnarinone and amrinone reduce the systemic inflammatory response syndrome

Cited by 34 publications

References 22 publications

Species-specific modulation of the nitric oxide pathway after acute experimentally induced endotoxemia

Species-specific modulation of the nitric oxide pathway after acute experimentally induced endotoxemia

Vesnarinone Suppresses TNF-Induced Activation of NF-κB, c-Jun Kinase, and Apoptosis

Effects of Vesnarinone on Peripheral Circulating Levels of Cytokines and Cytokine Receptors in Patients With Heart Failure

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