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J Thorac Cardiovasc Surg 2004;127:1317-1322
© 2004 The American Association for Thoracic Surgery

Cardiopulmonary support and physiology

The endothelin 1_A receptor antagonist BSF 302146 is a potent inhibitor of neointimal and medial thickening in porcine saphenous vein–carotid artery interposition grafts

^a Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
^b The Bristol Heart Institute, Bristol Royal Infirmary, University of Bristol, Bristol, United Kingdom
^c Department of Surgery, Bristol Royal Infirmary, University of Bristol, Bristol, United Kingdom
^d Department of Clinical Biochemistry, Royal Free Hospital, London, United Kingdom

Received for publication December 31, 2002; revisions received March 24, 2003; revisions received April 22, 2003; accepted for publication June 10, 2003.

^* Address for reprints: Jamie Y. Jeremy, PhD, Bristol Heart Institute, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom
j.y.jeremy{at}bris.ac.uk

OBJECTIVE: Late saphenous vein graft failure after coronary artery bypass graft surgery is initiated by medial thickening and neointima formation, both of which are mediated by the proliferation of vascular smooth muscle cells. Because porcine vein grafts contain high levels of endothelin 1 receptor subtypes and endothelin 1 promotes the proliferation of vascular smooth muscle cells, the effect of administration of the endothelin 1_A receptor antagonist BSF 302146 ([+]-[S]-2-[4,6-dimethyl-pyrimidin-2-yloxy]-3,3-diphenyl-butanoic acid) on porcine vein graft thickening was investigated.

METHODS: Saphenous vein–carotid artery interposition grafting was performed in 4 groups of large white pigs (30-35 kg, n = 10 for each group). BSF 302146 was administered orally (3, 10, and 30 mg · kg^–1 · d^–1) for 4 weeks to one group of pigs, and placebo was administered to the other group (control animals). Pigs were then anesthetized, and the grafts were removed and fixed at 100 mm Hg with 4% paraformaldehyde. Histologic sections were prepared, and graft morphometry was carried out by using computer-aided planimetry.

RESULTS: In vein grafts from animals treated with BSF 302146 compared with grafts from control animals (untreated), there were significant dose-dependent reductions in the increase in medial thickness and neointimal thickness, an increase in luminal area, and a decrease in proliferating cell nuclear antigen–positive cells in the medial-intimal area.

CONCLUSIONS: The administration of BSF 302146 reduces graft thickening and promotes positive remodeling through an endothelin 1_A–mediated effect on vascular smooth muscle cell replication. The administration of this endothelin 1_A receptor antagonist might therefore be therapeutically effective in preventing late vein graft failure in patients undergoing coronary artery bypass grafting.

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