Kodama A, Komori K, Kajikuri J, Itoh T
Chronic treatment of hydroxytryptamine type 2a receptor antagonist sarpogrelate hydrochloride modulates the vasoreactivity of serotonin in experimental rabbit vein grafts. [Journal Article]
J Vasc Surg 2009 Sep; 50(3):617-25.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.
More from this journalRelated subjects (MeSH)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 Antagonists
Succinates
Vasoconstriction
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