Effects of M-1, a Major Metabolite of Sarpogrelate, on 5-HT-Induced Constriction of Isolated Human Internal Thoracic Artery

• Tanaka-Totoribe Naoko

  Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare

• Hidaka Muneaki

  Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare

• Gamoh Shuji

  Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare

• Yokota Atsuko

  Department of Cardiovascular Surgery, Miyazaki City Medical Association Hospital

• Nakamura Eisaku

  Department of Cardiovascular Surgery, Miyazaki Prefectural Miyazaki Hospital

• Kuwabara Masachika

  Kuwabara Clinic

• Tsunezumi Jun

  Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare

• Yamamoto Ryuichi

  Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare

Abstract

Sarpogrelate, a selective 5-hydroxytryptamine (5-HT)_2A receptor antagonist, inhibits 5-HT-induced platelet aggregation and vasoconstriction. It improves ischemic symptoms in patients with arteriosclerosis obliterans. M-1 is a major metabolite of sarpogrelate, and has been reported to show a higher affinity for the 5-HT_2A receptor on platelets than sarpogrelate. However, the effects of M-1 on 5-HT-induced constrictive response in human blood vessels have not been investigated. The internal thoracic artery (ITA) is the key conduit for coronary artery bypass grafting (CABG). 5-HT has been implicated as playing an important role in the pathogenesis of vasospasm. Thus, in the present study, the effects of M-1 on 5-HT-induced vasoconstriction were examined in isolated human endothelium denuded ITA. M-1 inhibited 5-HT-induced vasoconstriction in a concentration-dependent manner. At the highest concentration, M-1 almost completely inhibited the 5-HT-induced vasoconstriction. Expression of 5-HT_2A and 5-HT_1B receptor proteins in the membrane fraction of ITA smooth muscle cells was confirmed by Western blot analysis. Individually, supramaximal concentrations of sarpogrelate and SB224289, a selective 5-HT_1B receptor antagonist, only partially inhibited the 5-HT-induced vasoconstriction. However, simultaneous pretreatment with both these antagonists almost completely inhibited the 5-HT-induced vasoconstriction. The inhibitory effect of M-1 pretreatment mimicked the inhibitory effect of simultaneous pretreatment with sarpogrelate and SB224289. These results suggest that M-1 has antagonistic effects not only on the 5-HT_2A receptor but also on the 5-HT_1B receptor in human ITA smooth muscle cells. M-1 may be useful as a lead compound for the development of drugs for the treatment of 5-HT-induced vasospasms in CABG.

Journal

• Biological and Pharmaceutical Bulletin

  Biological and Pharmaceutical Bulletin 43 (12), 1979-1982, 2020-12-01

  The Pharmaceutical Society of Japan

Keywords

• 5-hydroxytryptamine (5-HT)
• sarpogrelate
• vasoconstriction
• internal thoracic artery
• 5-HT_2A receptor
• 5-HT_1B receptor

Details

• CRID: 1391130851444989056
• NII Article ID: 130007948737
• NII Book ID: AA10885497
• DOI: 10.1248/bpb.b20-00591
• ISSN: 13475215
• ISSN: 09186158
• NDL BIB ID: 030782356
• PubMed: 32999137
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I030782356
• Web Site: https://www.jstage.jst.go.jp/article/bpb/43/12/43_b20-00591/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2021296561
• Text Lang: en
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
• Abstract License Flag: Disallowed