Inhibition of 5-hydroxytryptamine receptor prevents occlusive thrombus formation on neointima of the rabbit femoral artery.
BACKGROUND
Thrombus propagation on disrupted plaque is a major cause of acute coronary events and serious complication after coronary intervention. 5-Hydroxytryptamine (5-HT) is a potent vasoactive and platelet-aggregating substance that is predominantly mediated by 5-HT2A receptor. However, the roles of 5-HT2A receptor in occlusive thrombus formation on disrupted plaque remain obscure.


OBJECTIVE
We investigated the role of 5-HT2A receptor in thrombus formation using a rabbit model of repeated balloon-injury.


METHODS
Three weeks after a first balloon-injury of the femoral arteries, luminal diameter, neointimal growth, and vasoconstriction by 5-HT in vitro were examined. Thrombus propagation and the role of 5-HT2A receptor after a second balloon-injury were evaluated using sarpogrelate, a selective 5-HT2A receptor antagonist.


RESULTS
Three weeks after the first balloon-injury, luminal stenosis was evident in the femoral arteries, where the neointima expressed tissue factor and 5-HT2A receptor. The hypercontractile response of the stenotic arteries to 5-HT was significantly reduced by sarpogrelate. Balloon-injury of the neointima with substantially reduced blood flow promoted the formation of occlusive thrombus that was immunoreactive against glycoprotein IIb-IIIa, 5-HT2A receptor and fibrin. Intravenous injection of sarpogrelate significantly inhibited ex vivo platelet aggregation induced by adenosine 5'-diphosphate, thrombin and collagen alone as well as with 5-HT, and significantly prevented occlusive thrombus formation in vivo.


CONCLUSIONS
The 5-HT2A receptor appears to play a crucial role in occlusive thrombus formation in diseased arteries via platelet aggregation and vasoconstriction. Inhibition of 5-HT2A receptor might help reduce the onset of acute coronary events and of acute coronary occlusion after the intervention.
Nishihira
K
K
Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Yamashita
A
A
Tanaka
N
N
Kawamoto
R
R
Imamura
T
T
Yamamoto
R
R
Eto
T
T
Asada
Y
Y
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000209:etiology / Q000517:prevention & control; D002404:Catheterization / Q000009:adverse effects; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000293:injuries / Q000473:pathology; D005337:Fibrin / Q000032:analysis; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000032:analysis; D011817:Rabbits; D044402:Receptor, Serotonin, 5-HT2A / Q000032:analysis / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013386:Succinates / Q000008:administration & dosage / Q000494:pharmacology; D013927:Thrombosis / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D017539:Tunica Intima / Q000254:growth & development; D014661:Vasoconstriction / Q000187:drug effects
D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D013386:Succinates; C064294:sarpogrelate; D012701:Serotonin; D005337:Fibrin