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

Abstract

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.