Chronic treatment of hydroxytryptamine type 2a receptor antagonist sarpogrelate hydrochloride modulates the vasoreactivity of serotonin in experimental rabbit vein grafts

ObjectiveIt has been suggested that 5-hydroxytryptamine (5-HT) plays a role in the pathogenesis of vein graft spasms. It is suggested that smooth muscle 5-HT2A and 5-HT1B receptors contribute to 5-HT-induced contraction, while endothelial 5-HT1B receptors contribute to the 5-HT-induced endothelium-mediated relaxation. We recently found that chronic administration of the selective 5-HT2A receptor antagonist sarpogrelate hydrochloride (SH) enhances the function of endothelium-derived nitric oxide (NO) in rabbit vein grafts. However, it is unknown if such treatment modulates 5-HT-induced vasospasm in vein grafts, and if so, what the underlying mechanisms are.MethodsMale rabbits were divided into two groups: a control group and an SH-treated group. The jugular vein was interposed in the carotid artery in reversed fashion. Isometric tension was examined using vein grafts after 4 weeks. 5-HT (10−8 -10−6 M)-induced contraction was obtained in each group in the absence or presence of the NO synthase inhibitor l-NG-nitroarginine (l-NNA). The expression of 5-HT2A and 5-HT1B receptors was examined immunohistochemically.ResultsThe 5-HT induced a concentration-dependent contractions in both groups. l-NNA did not significantly modify the 5-HT-induced contraction in the control group but enhanced it in the SH group. The 5-HT1B receptor antagonist GR55562 inhibited the 5-HT-induced contraction in the control group, while it increased the sensitivity of contraction to 5-HT in the SH-treated group in the absence (but not in the presence) of l-NNA. Positive immunoreactivities against 5-HT1B and 5-HT2A receptors were identified in endothelial and medial regions of vein grafts in both groups, and the expression of 5-HT2A receptors (but not 5-HT1B receptors) was significantly less in the SH-treated group than in the control group.ConclusionChronically administered SH to rabbits upregulates the autoinhibitory mechanism by 5-HT through a release of NO from endothelium via an activation of endothelial 5-HT1B receptors, thus attenuating its own contraction in vein grafts. Furthermore, such SH treatment downregulates the expression of smooth muscle 5-HT2A receptors, thus further attenuating the 5-HT-induced contraction. These novel findings further support the clinical usefulness of SH in vein graft spasm after bypass grafting.

Clinical RelevanceIt has been suggested that 5-HT plays a role in the pathogenesis of vein graft spasms. It is suggested that smooth muscle 5-HT2A and 5-HT1B receptors contribute to 5-HT-induced contraction, while endothelial 5-HT1B receptors contribute to the 5-HT-induced endothelium-mediated relaxation. However, it is unknown if chronic administration of 5-HT2A receptor antagonist SH modulates 5-HT-induced vasospasm in vein grafts. We report here that such treatment attenuates the 5-HT-induced contraction. In addition, we demonstrate the possible underlying mechanism. 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 vein graft spasm after bypass grafting.