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EXPERIMENTAL STUDIES

Pimobendan inhibits the production of proinflammatory cytokines and gene expression of inducible nitric oxide synthase in a murine model of viral myocarditis

^a Department of Cardiovascular Medicine, Kyoto University, Kyoto, Japan

Manuscript received June 22, 1998; revised manuscript received November 5, 1998, accepted December 22, 1998.

Reprint requests and correspondence: Dr. Akira Matsumori, Department of Cardiovascular Medicine, Kyoto University, 54 Kawaracho, Shogoin, Sakyo-ku, Kyoto 606-8397, Japan.
amat{at}kuhp.kyoto-u.ac.jp

OBJECTIVES

This study was designed to examine the effects of pimobendan in a murine model of viral myocarditis in relation to proinflammatory cytokine production and nitric oxide (NO) synthesis by inducible NO synthase (iNOS) in the heart.

BACKGROUND

Pimobendan has been recently confirmed to improve both acute and chronic heart failure. Since the modulation of myocardial necrosis and contractile dysfunction by various proinflammatory cytokines may be partially mediated by the production of nitric oxide, the effects of pimobendan on the production of proinflammatory cytokines and NO were investigated in an animal model of viral myocarditis involving heart failure.

METHODS

DBA/2 mice were inoculated with the encephalomyocarditis virus. To observe its effect on survival up to 14 days, pimobendan (0.1 mg/kg or 1 mg/kg) or vehicles were given from the day of virus inoculation (day 0) orally once daily. The effects of pimobendan on histological changes, cytokine production, NO production and iNOS gene expression in the heart were studied in mice treated either with pimobendan, 1 mg/kg or with vehicles only, and sacrificed seven days after virus inoculation.

RESULTS

The survival of mice improved in a dose-dependent fashion such that a significant difference (p < 0.02) was found between the higher-dose pimobendan group (20 of 30 [66.7%]) and the control group (11 of 30 [36.7%]). Histological scores for cellular infiltration (1.1 ± 0.1 vs. 2.0 ± 0.0, p < 0.001), intracardiac tumor necrosis factor (TNF)- (18.2 ± 1.8 vs. 35.8 ± 4.2 pg/mg heart, p < 0.001) and interleukin (IL)-1ß (9.3 ± 1.2 vs. 26.6 ± 7.1 pg/mg heart, p < 0.01) were significantly lower in the mice given pimobendan versus those of the control mice. Interleukin-6 levels (7.1 ± 0.8 vs. 9.2 ± 1.9 pg/mg heart) were also lower in the mice treated with pimobendan. Furthermore, intracardiac NO production was significantly (p < 0.001) less in the pimobendan group (0.165 ± 0.004 nmol/mg heart) than in the control group (0.291 ± 0.051 nmol/mg heart), and intracardiac iNOS gene expression in the mice given pimobendan was 74% lower than it was in the control animals (p < 0.01).

CONCLUSIONS

These findings suggest that the beneficial effects of pimobendan in viral myocarditis are partially mediated by the inhibition of both proinflammatory cytokine production and NO synthesis by iNOS.

Abbreviations and Acronyms   cAMP = cyclic adenosine monophosphate   EMC = encephalomyocarditis   iNOS = inducible nitric oxide synthase   IL = interleukin   LPS = lipopolysaccharide   mRNA = messenger RNA   NO = nitric oxide   PDE = phosphodiesterase   TNF = tumor necrosis factor

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