Sarpogrelate HCl, a selective 5-HT2A antagonist, retards the progression of atherosclerosis through a novel mechanism.
Although sarpogrelate HCl is widely used for the prevention of arterial thrombosis, its effect on atherosclerosis is unknown. Accordingly, we here investigated the effects of sarpogrelate HCl on a rabbit model of atherosclerosis. Male rabbits were fed a 0.5% cholesterol diet (HCD) (Gp 1), HCD with vitamin E (Gp 2), HCD with vitamin E and sarpogrelate (Gp 3), or HCD with sarpogrelate alone (Gp 4) for 8 weeks. The atherosclerotic area was decreased by feeding of vitamin E and sarpogrelate (16.9+/-2.0% in Gp 1 vs. 8.2+/-2.0% in Gp 3). Tone-related basal NO release was higher in Gps 3 and 4. Acetylcholine-induced relaxation tended to be improved in Gp 3. The amount of eNOS mRNA was increased in Gp 4, and aortic cyclic GMP concentration showed the same tendency. O(2)(-) release tended to be decreased in Gps 2 and 3. The matrix metalloproteinase-1 (MMP-1)-positive area was decreased, and the percentage ratio of cell numbers of smooth muscle cells/macrophages in the plaque was increased in Gp 3. The results demonstrated that sarpogrelate HCl retards the progression of atherosclerosis in rabbits, and that this effect is enhanced by concomitant administration of vitamin E. Although upregulation of eNOS may play a role as one of the underlying mechanisms, our results suggest that an additional mechanism-possibly involving the antiproliferative effects of sarpogrelate HCl on smooth muscle cells and macrophages-may also play an important role.
Department of Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Japan. hayashi@med.nagoya-u.ac.jp
Toshio
T
Hayashi
Daigo
D
Sumi
Hisako
H
Matsui-Hirai
Akiko
A
Fukatsu
Juliet
J
Arockia Rani P
Hatsuyo
H
Kano
Taku
T
Tsunekawa
Akihisa
A
Iguchi
D000109:Acetylcholine / Q000008:administration & dosage; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D001798:Blood Proteins / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000187:drug effects / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000378:metabolism; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D012702:Serotonin Antagonists / Q000627:therapeutic use*; D013386:Succinates / Q000627:therapeutic use*; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000008:administration & dosage; D014810:Vitamin E / Q000627:therapeutic use
D000975:Antioxidants; D015415:Biomarkers; D001798:Blood Proteins; D008076:Cholesterol, HDL; D012333:RNA, Messenger; D012702:Serotonin Antagonists; D013386:Succinates; D014665:Vasodilator Agents; D014810:Vitamin E; C064294:sarpogrelate; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1; D006152:Cyclic GMP; D000109:Acetylcholine