Sarpogrelate hydrochloride reduced intimal hyperplasia in experimental rabbit vein graft

ObjectivesThe selective 5-HT2A receptor antagonist sarpogrelate has been clinically used for treatment in atherosclerotic diseases. However, it remains unknown whether administration of sarpogrelate inhibits intimal hyperplasia seen in autologous vein grafts. Therefore, we sought to clarify this question using an experimental rabbit vein graft model.MethodsMale rabbits were divided into two groups: a control group and a sarpogrelate-treated group. The jugular vein was interposed in the carotid artery in reversed fashion for 4 weeks and intimal hyperplasia of the grafted vein was measured (n = 8, in each group). Acetylcholine (ACh)-induced endothelium-dependent relaxation was tested by precontraction with prostaglandin F2α (PGF2α, 5 μM) (n = 5, in each). endothelial nitric oxide synthase (eNOS) protein expression and superoxide production of these veins were also assessed.ResultsThe suppression of intimal hyperplasia was significantly greater in the sarpogrelate-treated group than in the control group. ACh induced an endothelium-dependent relaxation in the sarpogrelate-treated group (but not in the control group). In endothelium-intact strips from the sarpogrelate-treated group, the nitric oxide (NO) synthase inhibitor nitroarginine enhanced the PGF2α-induced contraction and blocked the ACh-induced relaxation. Immunoreactive eNOS protein expression was similar between the two groups but superoxide production (estimated from ethidium fluorescence) in endothelial cells was significantly smaller in the sarpogrelate-treated group.ConclusionThe present results indicate that in vivo blockade of 5-HT2A receptors leads to an inhibition of intimal hyperplasia in rabbit vein graft. It is suggested that an increased function of endothelium-derived NO through a reduction in endothelial superoxide production may be a possible underlying mechanism for this. These novel findings support the clinical usefulness of sarpogrelate for preventing intimal hyperplasia in vein graft after bypass grafting.

Clinical RelevanceIntimal hyperplasia is a major obstacle to patency after vein grafting. Despite a diverse array of trials to prevent it, a satisfactory therapeutic strategy for clinical use has not been established. We report here the inhibitory effect of 5-HT2A receptor antagonist, sarpogrelate hydrochloride on the development of vein graft intimal hyperplasia. In addition, we demonstrate that sarpogrelate showed endothelium-dependent relaxation through a reduction in endothelial superoxide production in vitro. Because the clinical benefits and safety of sarpogrelate have been established to a certain extent through long-term clinical usage, the study provides further evidence to support the clinical investigation of the role of sarpogrelate in prevention of intimal hyperplasia in venous bypass grafting.