Probucol reduces the cellularity of aortic intimal thickening at anastomotic regions adjacent to prosthetic grafts in cholesterol-fed rabbits

Intimal hyperplasia is a persistent problem after implantation of prosthetic grafts. Although the mechanisms underlying this hyperplastic response are unknown, it has been proposed that such responses may be due to chronic vascular injury similar to that of atherogenesis. Thus, the role of oxidation was explored using the potent antioxidant drug probucol. Adult New Zealand White rabbits fed a modestly (0.25%) cholesterol-enriched diet had a polytetrafluoroethylene prosthetic graft placed into the lower aorta. After the grafting procedure, a group of 11 rabbits was placed on the cholesterol-enriched diet supplemented with 1% wt/wt probucol while a control group of 10 rabbits was placed on the cholesterol-enriched diet alone. The rabbits were maintained for a further 10 weeks before histological examination of the area surrounding the graft. Although administration of probucol did not significantly alter the dimensions of lesions at the anastomotic sites, the drug promoted striking histological changes in the surrounding tissue. Both groups of rabbits had a similar intimal hyperplastic response of the aortic tissue surrounding the graft. The vascular lesions present in the perigraft region of the control group consisted of a normal-appearing media but a thickened intima. The thickened intima contained numerous smooth muscle cells in a network of extracellular matrix. Regions in the neointima that were rich in smooth muscle cells exhibited modest staining for proliferating cell nuclear antigen. A few macrophages were present in the control group as determined by immunostaining with the monoclonal antibody RAM-11. In contrast, administration of probucol led to a marked reduction in the presence of RAM-11-staining macrophages. There was also a marked reduction in the cellularity of lesions, from 934±135 nuclei/mm² in the control group versus 358±32 nuclei/mm² in probucol-treated rabbits. Thus, administration of probucol did not significantly reduce the size of the intimai thickening at the relatively early interval under study, but the drug did produce cellular changes that may have beneficial effects on the main-tenance of long-term patency of implanted grafts.