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(Circulation. 1998;97:2346-2351.)
© 1998 American Heart Association, Inc.

Basic Science Reports

Role of Endogenous Endothelin in the Development of Graft Arteriosclerosis in Rat Cardiac Allografts

Antiproliferative Effects of Bosentan, a Nonselective Endothelin Receptor Antagonist

Kenji Okada, MD, PhD; Yasuhiro Nishida, MD, PhD; Hiroshi Murakami, MD, PhD; Isao Sugimoto, MD; Hiroaki Kosaka, MD, PhD; Hironobu Morita, MD, PhD; Chojiro Yamashita, MD, PhD; ; Masayoshi Okada, MD, PhD

From the Department of Physiology, Kagawa (Japan) Medical University (K.O., Y.N., H.M., I.S., H.K.); the Department of Physiology, Gifu (Japan) University (H.M.); and the Department of Surgery, Division II, Kobe (Japan) University (C.Y., M.O.).

Correspondence to Dr Kenji Okada, Department of Physiology, Kagawa Medical University, 1750–1, Miki-cho, Kita-gun, Kagawa 761–05, Japan. E-mail kgwphysl{at}kms.ac.jp

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 ET_A and ET_B receptors, can protect against this pathologic damage.

Methods and 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±0.83 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 ET_A receptors, ET_B receptors, or both. Orally active bosentan might be a useful agent for the clinical prevention of graft arteriosclerosis.

Key Words: endothelin • receptors • coronary disease • arteriosclerosis • transplantation

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