title: Contribution of endothelin-1 to myocardial injury in a murine model of myocarditis: acute effects of bosentan, an endothelin receptor antagonist.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ono
authors.forename: A
authors.initials: A
authors.lastname: Matsumori
authors.forename: T
authors.initials: T
authors.lastname: Shioi
authors.forename: Y
authors.initials: Y
authors.lastname: Furukawa
authors.forename: S
authors.initials: S
authors.lastname: Sasayama
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D000077300:Bosentan; D018188:Cardiovirus Infections / Q000473:pathology; D004195:Disease Models, Animal; D004686:Encephalomyocarditis virus; D019332:Endothelin-1 / Q000502:physiology*; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000096:biosynthesis / Q000235:genetics; D006321:Heart / Q000821:virology; D008297:Male; D008666:Metalloendopeptidases; D051379:Mice; D008811:Mice, Inbred DBA; D009205:Myocarditis / Q000473:pathology* / Q000821:virology; D009206:Myocardium / Q000473:pathology*; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides / Q000627:therapeutic use*
chemical_list: D000959:Antihypertensive Agents; D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D012333:RNA, Messenger; D013449:Sulfonamides; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606925:Ece1 protein, mouse; D000072396:Endothelin-Converting Enzymes; D000077300:Bosentan