Abstract
Antiproliferative behavior of sarpogrelate (Anplag, MCI-9042, (±)-1-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]-3-(dimethylamino)-2-propyl hydrogen succinate hydrochloride), a serotonin 2A (5-HT2A) receptor antagonist, was established using radioactive incorporation of [3H]thymidine, [3H]uridine, and [3H]phenylalanine in cultured rat aortic smooth muscle cells in response to a 5-HT-induced cytokine trigger. Fluorescence-activated cell sorting was used to confirm these observations. 5-HT-induced DNA, RNA, and protein synthesis were inhibited maximally at a concentration of 1 μM sarpogrelate. Although other cytokines such as platelet-derived growth factor and endothelin also induced DNA, RNA, and protein synthesis in rat aortic smooth muscle cells, cell proliferation was not influenced by sarpogrelate, even at large pharmacological concentrations (10 μM). Sarpogrelate’s antiproliferative actions were found to be more potent than ketanserin. These data indicate that sarpogrelate operates as a specific inhibitor of 5-HT-mediated cell proliferation and is a good candidate for preventing serotonin-induced neointimal hyperplasia.
Footnotes
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Send reprint requests to: Dr. Peter Zahradka, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, 351 Tache Ave., Winnipeg, Manitoba R2H 2A6, Canada. E-mail:peterz{at}sbrc.umanitoba.ca.
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↵1 This work was supported by a grant from the Medical Research Council Group in Experimental Cardiology. N.S.D. holds the Medical Research Council/Pharmaceutical Manufacturers Association of Canada Chair in Cardiovascular Research supported by Merck Frosst, Canada.
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↵2 Present address: Department of Internal Medicine, Aoto Hospital, Jikei University School of Medicine, Tokyo, Japan.
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Received for publication February 19, 1999.
- Abbreviations:
- 5-HT
- 5-hydroxytryptamine (serotonin)
- FACS
- fluorescence-activated cell sorting
- MTT
- 3-(4,5-dimethyl(thiozol-2-yl)-2,5 diphenyltetrazolium bromide
- PDGF
- platelet-derived growth factor
- SMC
- smooth muscle cell
- RASMC
- rat aortic smooth muscle cell
- DMEM
- Dulbecco’s modified Eagle’s medium
- FBS
- fetal bovine serum
- Accepted May 5, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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