Contribution of endothelin-1 to myocardial injury in a murine model of myocarditis - Acute effects of bosentan, an endothelin receptor antagonist

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-I) and prepro-ET-l mRNA were significantly increased at 7 and 14 days after virus inoculation. Plasma and myocardial ET-I 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 bur also infiltrating mononuclear cells produced ET-I protein at 7 days. Oral bosentan, a mixed ET-I 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.