nitroarginine and Graft-Occlusion--Vascular

It 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-HT(2A) and 5-HT(1B) receptors contribute to 5-HT-induced contraction, while endothelial 5-HT(1B) receptors contribute to the 5-HT-induced endothelium-mediated relaxation. We recently found that chronic administration of the selective 5-HT(2A) 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.. Male 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-N(G)-nitroarginine (L-NNA). The expression of 5-HT(2A) and 5-HT(1B) receptors was examined immunohistochemically.. The 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-HT(1B) 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-HT(1B) and 5-HT(2A) receptors were identified in endothelial and medial regions of vein grafts in both groups, and the expression of 5-HT(2A) receptors (but not 5-HT(1B) receptors) was significantly less in the SH-treated group than in the control group.. Chronically administered SH to rabbits upregulates the autoinhibitory mechanism by 5-HT through a release of NO from endothelium via an activation of endothelial 5-HT(1B) receptors, thus attenuating its own contraction in vein grafts. Furthermore, such SH treatment downregulates the expression of smooth muscle 5-HT(2A) 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.

Topics: Animals; Benzamides; Carotid Artery, Common; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Inhibitors; Graft Occlusion, Vascular; Jugular Veins; Male; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Pyridines; Rabbits; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT2A; Serotonin; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Succinates; Vasoconstriction