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Sarpogrelate Hydrochloride Reduced Intimal Hyperplasia in Experimental Rabbit Vein Graft-Possible Involvement of Enhancement of Nitric Oxide (NO) Production

Akio Kodama¹, Akihito Idetsu¹, Masayuki Sugimoto¹, Tsutomu Ihara¹, Kiyoaki Niimi¹, Hiroshi Narita¹, Masayoshi Kobayashi¹, Kiyohito Yamamoto¹, Takeo Itoh², Kimihiro Komori.^1
1Division of Vascular Surgery, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan;²Department of Cellular and Molecular Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.

OBJECTIVES: 5-hydroxytryptamine (5-HT) induces vascular responses through an activation of various subtypes of its own receptors. 5-HT2A receptors are present in vascular smooth muscle cells and platelet that mediate the 5-HT-induced vascular contraction and platelet aggregation, respectively. Sarpogrelate hydrochloride (SH) is known to be the selective 5-HT2A receptor antagonist and has been used clinically in atherosclerotic diseases. However, little information is available about the effect of SH on the intimal hyperplasia in autologous vein grafts. Therefore, we examined whether chronic administration of SH inhibit the intimal hyperplasia of vein graft and NO activities were also examined by using mechanical tension recordings.

METHODS: Male rabbits were divided into two groups: a control and SH-treated group (SH group). Jugular vein was interposed in carotid artery in reversed fashion. Intimal hyperplasia and proliferative activity were assessed in vein grafts after 4-weeks and 2-weeks implantation. Mechanical tension recordings were studied in the tissue taken from the vein grafts after 4-weeks.

RESULTS: In SH group, both intimal hyperplasia and cell proliferative activity were significantly inhibited compared to the control group. In SH group, acetylcholine (ACh) caused endothelium-dependent relaxation and it was abolished by the NOS inhibitor nitroarginine, although ACh did not in the control. The 5HT1B receptor antagonist GR55562 shifted the concentration -response curve of 5-HT to the left in SH group, but not in control, and it was also abolished by nitroarginine.

CONCLUSIONS: These findings indicate that the 5HT2A receptor antagonist SH suppresses intimal hyperplasia in vein graft, possibly due to an enhancement of endothelium NO function. It is suggested that 5HT1B receptor in endothelium may contribute to this action. These novel findings support the clinical usefulness of SH for preventing intimal hyperplasia in vein graft after bypass grafting.

AUTHOR DISCLOSURES: Kodama, None; A. Idetsu, None; M. Sugimoto, None; T. Ihara, None; K. Niimi, None; H. Narita, None; M. Kobayashi, None; K. Yamamoto, None; T. Itoh, None; K. Komori, None.