(Circulation. 1999;100:1823-1829.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Contribution of Endothelin-1 to Myocardial Injury in a Murine Model of Myocarditis
Acute Effects of Bosentan, an Endothelin Receptor Antagonist
From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan.
Correspondence to Akira Matsumori, MD, PhD, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Kawaracho Shogoin, Sakyo-ku, Kyoto 606-8397, Japan. E-mail amat{at}kuhp.kyoto-u.ac.jp
Background—Endothelin (ET) is one of the most important contributing factors in the pathophysiology of cardiovascular diseases. However, little is known about its role in myocarditis.
Methods and Results—Four-week-old DBA/2 mice were inoculated with the encephalomyocarditis virus. Expression levels of ET-converting enzyme-1 (ECE-1) and prepro-ET-1 mRNA were significantly increased at 7 and 14 days after virus inoculation. Plasma and myocardial ET-1 levels were significantly higher in infected than noninfected mice between 5 and 14 days after virus inoculation. Immunohistochemical analyses revealed that not only endothelial cells and myocytes but also infiltrating mononuclear cells produced ET-1 protein at 7 days. Oral bosentan, a mixed ET-1 receptor antagonist, was administered after virus inoculation in doses of 0 (control group), 10, or 100 mg · kg-1 · d-1, and the animals were killed on day 14. Mean heart weight/body weight ratios were 8.3±1.8 versus 11.2±2.4 versus 10.8±2.4 in the bosentan 100 mg · kg-1 · d-1 versus 10 mg · kg-1 · d-1 versus control groups, respectively (P<0.05). Corresponding histological scores for myocardial necrosis were 2.0±0.2 versus 2.9±0.3 versus 3.0±0.4 (P<0.05), and cellular infiltration scores were 2.3±0.3 versus 2.9±0.4 versus 3.3±0.4 (P<0.05). Animals killed on day 5 had significantly smaller necrotic areas after treatment with bosentan 100 mg · kg-1 · d-1 than the group treated with a lower dose or the control group, despite the absence of differences in virus titers.
Conclusions—This study suggests that ET-1 plays an important pathophysiological role in viral myocarditis. Treatment with bosentan had a cardioprotective effect without modifying viral replication.
Key Words: myocarditis • cardiomyopathy • endothelin • viruses
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