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


CONCLUSIONS
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.
Kodama
Akio
A
Division of Vascular Surgery, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya City, Japan.
Komori
Kimihiro
K
Kajikuri
Junko
J
Itoh
Takeo
T
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D017536:Carotid Artery, Common / Q000601:surgery*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006083:Graft Occlusion, Vascular / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007601:Jugular Veins / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology / Q000637:transplantation*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000008:administration & dosage*; D013386:Succinates / Q000008:administration & dosage*; D014661:Vasoconstriction / Q000187:drug effects*
D001549:Benzamides; D004791:Enzyme Inhibitors; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; D044402:Receptor, Serotonin, 5-HT2A; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D013386:Succinates; C103477:3-(3-(dimethylamino)propyl)-4-hydroxy-N-(4-(4-pyridinyl)phenyl)benzamide; C064294:sarpogrelate; D019335:Nitroarginine; D009569:Nitric Oxide; D012701:Serotonin; D019001:Nitric Oxide Synthase