A Role for Endogenous Endothelin in Graft Arteriosclerosis in Rat Cardiac Allografts

1996 Fiscal Year Final Research Report Summary

• Project/Area Number: 07671469
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Thoracic surgery
• Research Institution: Kobe University
• Principal Investigator: YAMASHITA Chojiro Kobe University, Surgery, Associated Professor, 医学部・附属病院, 講師 (00144569)
• Co-Investigator(Kenkyū-buntansha): ATAKA Keiji Kobe University, Surgery, Assistant Professor, 医学部・附属病院, 助手 (20252760)
• Project Period (FY): 1995 – 1996
• Keywords: graft arterioscrelosis / endothelin / endothelin receptor / endothelin receptor antagonist / bosentan

Research Abstract

Background The development of graft arteriosclerosis is the most important impediment in long-surviving transplants recipients, but the pathogenesis of graft arteriosclerosis has not yet been elucidated. Endothelin-1 (ET-1) which is known to have powerful mitogenic properties could play an important pathogenic role. The purpose of this study is to determine ET-1 would contribute to the progression of graft arteriosclerosis and nonpeptide orally active nonselective endothelin antagonist (bosentan) suppresses it. Methods and Results Recipients Lewis (LEW) (RT1) rats in group I received heterotopic heart transplants from LEW donors. Recipients Lewis (LEW) (RT1) rats groups II and III received from Brown-Norway (BN) (RTn) donors. All recipients rats were given cyclospoline (CsA : 5mg/kg, 3times/week). Additionally, rats in groups III received bosentan orally 20 mg/kg/day for 120 days, which dose significantly inhibited both the depressor and the pressor response to exogenous ET-1. All rats were put to death after 120 days. plasma ET-1 was significantly higher in group I compared to group II (4.15 (]SY.+-。[) 0.83 and 6.99 (]SY.+-。[) 0.91 pg/mi, respectively). And stronger immunoreactivity of ET was seen both in proliferative neointima and the smooth muscle cells in group II compared to those in group I.The mean %lumen in groups II (18.1 (]SY.+-。[) 3.0%) was aignificantly lower than froups I (36.2 (]SY.+-。[) 3.0%), but it was significantly improved in group III (33.1 (]SY.+-。[) 2.8%). Conclusions There results strongly suggests that increased ET mainly expressed in the coronary smooth muscle cells and proliferative neointima might play an important role in the pathogenesis of graft arteriosclerosis by stimulating ETA or ETB receptors. Orally active bosentan might be potentially useful agents to the prevention of graft arteriosclerosis in clinical case.