title: Role of endogenous endothelin in the development of graft arteriosclerosis in rat cardiac allografts: antiproliferative effects of bosentan, a nonselective endothelin receptor antagonist.
abstract: BACKGROUND
  The purpose of this study was to determine whether endothelin-1 (ET-1) contributes to the development of graft arteriosclerosis and whether the orally active nonpeptide endothelin receptor antagonist bosentan, which blocks both ETA and ETB receptors, can protect against this pathologic damage.
  
  
  RESULTS
  Recipient male Lewis rats were divided into three groups; group 1 received heterotopic heart transplantations from Lewis donors and groups 2 and 3 received transplantations from Brown-Norway donors; group 3 recipients also received bosentan orally at the dose of 20 mg/kg per day for 120 days. All recipients were given cyclosporine and were euthanized at examination 120 days after transplantation. Plasma ET-1 levels were significantly higher in group 2 than in group 1 (6.99+/-0.91 and 4.15+/-.83 pg/mL, respectively). Strong ET-1 immunoreactivity was seen in both the thickened neointima and the media of the coronary arteries in group 2 but not in group 1. The mean ratio of the coronary luminal area to the total vascular area in group 2 (19.0+/-11.7%) was significantly lower than that in group 1 (34.2+/-9.9%) and was significantly increased in group 3 (33.2+/-9.2%).
  
  
  CONCLUSIONS
  These results show that local upregulation of ET-1, mainly in the thickened neointima and the media of the coronary arteries, may play an important role in the pathogenesis of graft arteriosclerosis by stimulating ETA receptors, ETB receptors, or both. Orally active bosentan might be a useful agent for the clinical prevention of graft arteriosclerosis.
authors.affiliation: Department of Physiology, Kagawa Medical University, Japan. kgwphysl@kms.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Okada
authors.forename: Y
authors.initials: Y
authors.lastname: Nishida
authors.forename: H
authors.initials: H
authors.lastname: Murakami
authors.forename: I
authors.initials: I
authors.lastname: Sugimoto
authors.forename: H
authors.initials: H
authors.lastname: Kosaka
authors.forename: H
authors.initials: H
authors.lastname: Morita
authors.forename: C
authors.initials: C
authors.lastname: Yamashita
authors.forename: M
authors.initials: M
authors.lastname: Okada
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000077300:Bosentan; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D019332:Endothelin-1 / Q000032:analysis / Q000097:blood*; D004730:Endothelium, Vascular / Q000737:chemistry / Q000187:drug effects / Q000473:pathology*; D006085:Graft Survival / Q000502:physiology*; D016027:Heart Transplantation; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D013194:Staining and Labeling; D013449:Sulfonamides / Q000494:pharmacology; D014184:Transplantation, Homologous
chemical_list: D000199:Actins; D000959:Antihypertensive Agents; D019332:Endothelin-1; D013449:Sulfonamides; D000077300:Bosentan