Inhibition of serotonin-induced vascular smooth muscle cell proliferation by sarpogrelate.
Antiproliferative behavior of sarpogrelate (Anplag, MCI-9042, (+/-)-1-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]-3-(dimethylamino)-2-pro pyl hydrogen succinate hydrochloride), a serotonin 2A (5-HT2A) receptor antagonist, was established using radioactive incorporation of [(3)H]thymidine, [(3)H]uridine, and [(3)H]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 microM 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 microM). 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.
Sharma
S K
SK
Department of Physiology, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
Zahradka
P
P
Chapman
D
D
Kumamoto
H
H
Takeda
N
N
Dhalla
N S
NS
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D005434:Flow Cytometry; D006131:Growth Inhibitors / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013386:Succinates / Q000494:pharmacology*; D013936:Thymidine; D014316:Tritium
D006131:Growth Inhibitors; D012702:Serotonin Antagonists; D013386:Succinates; D014316:Tritium; C064294:sarpogrelate; D012701:Serotonin; D004247:DNA; D013936:Thymidine