Celiprolol reduces the intimal thickening of autogenous vein grafts via an enhancement of nitric oxide function through an inhibition of superoxide production

Backgroundβ-adrenoceptor antagonist celiprolol has been widely used as an effective antihypertensive agent. Some studies reported that celiprolol enhances nitric oxide production. The purpose of the present study is to examine the effects of celiprolol on vein graft intimal hyperplasia and endothelium-dependent nitric oxide (NO)-mediated relaxation.MethodsJapanese white rabbits were randomized to a control group that was fed regular rabbit chow or to a celiprolol group that was fed regular rabbit chow supplemented with 100 mg/body celiprolol sodium. The reversed jugular vein was implanted into the carotid artery. At 2 and 4 weeks after the operation, vein grafts in both groups were harvested, and intimal hyperplasia of the vein grafts was assessed. At 4 weeks after the operation, harvested vein grafts from both the groups were examined on the endothelium-dependent relaxation by application of Ach and were examined to detect for endothelial NO synthase (eNOS) expression and superoxide anion production.ResultsCeliprolol inhibited intimal hyperplasia of carotid interposition-reversed jugular vein grafts 4 weeks after implantation (Intima/media index of celiprolol group, 0.48 ± 0.01 vs control group, 1.07 ± 0.08, P < .05) and suppressed cell proliferation in the neointima 2 weeks after implantation. In addition, celiprolol significantly enhanced endothelium-dependent NO-mediated relaxation in the vein graft with no change in eNOS expression and a reduction in superoxide production.ConclusionsThese novel findings clearly demonstrate that β-adrenoceptor antagonist celiprolol can suppress intimal hyperplasia of the vein graft, which may be due to the enhancement of nitric oxide function through an inhibition of superoxide production. These results strongly support the clinical usefulness of celiprolol administration for preventing intimal hyperplasia of the vein graft after bypass grafting.

Clinical RelevanceLate graft failure caused by neointimal hyperplasia limits the efficacy of vein grafting. Various treatments were examined to reduce neointimal hyperplasia, but a standard clinical treatment has not yet been established. We report here the inhibitory effect of β-adrenoceptor antagonist celiprolol on the development of vein graft intimal hyperplasia. In addition, we demonstrate that celiprolol showed endothelium-dependent NO-mediated relaxation through an inhibition of superoxide production in vein graft. Because the clinical benefits and safety of celiprolol have been established to a certain extent through long-term clinical usage, celiprolol may soon become available treatment after vein bypass grafting.