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. O2 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.



      ACh, acetylcholine chloride (), Ang II, angiotensin II (), AT1, type 1 angiotensin receptor (), eNOS, endothelial nitric oxide synthase (), 5-HT, 5-hydroxytryptamine (serotonin) (), iNOS, inducible nitric oxide synthase (), l-NMA, NG-monomethyl-l-arginine acetate (an inhibitor of NO synthase) (), NO, nitric oxide (), NOS, nitric oxide synthase (), NTG, nitroglycerine (), PGF2α, prostaglandin F2α (), sarpogrelate, sarpogrelate HCl ()
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Shimokawa H.
        • Vanhoute P.M.
        Angiographic demonstration of hyperconstriction induced by serotonin and aggregating platelets in porcine coronary arteries with regenerated endothelium.
        J. Am. Coll. Cardiol. 1992; 17: 1197-1202
        • Vikenes K.
        • Farstad M.
        • Nordrehaug J.E.
        Serotonin is associated with coronary artery disease and cardiac events.
        Circulation. 1999; 100: 483-489
        • Hoyer D.
        • Clarke D.E.
        • Fozard J.R.
        • et al.
        International union of pharmacology classification of receptors for 5-hydroxytryptamine (serotonin).
        Pharmacol. Rev. 1994; 46: 157-201
        • Pakala R.
        • Benedict C.R.
        Synergy between thrombin and serotonin in inducing vascular smooth muscle cell proliferation.
        J. Lab. Clin. Med. 1999; 134: 659-667
        • Keegan A.
        • Morecroft I.
        • Smillie D.
        • Hicks M.N.
        • MacLean M.R.
        Contribution of the 5-HT1B receptor to hypoxia-induced pulmonary hypertension. Converting evidence using 5-HT-receptor knockout mice and the 5-HT1B/1D-receptor antagonist GR.
        Circ. Res. 2001; 89: 1231-1239
        • Dinerman J.L.
        • Lowenstein C.J.
        • Snyder S.H.
        Molecular mechanisms of nitric oxide regulation-potential relevance to cardiovascular disease.
        Circ. Res. 1993; 73: 217-222
        • Kleinvwld H.A.
        • Demacker P.N.M.
        • Stalenhoef A.F.H.
        Comparative study on the effect of low-dose vitamin E and probucol on the susceptibility of low-density lipoprotein to oxidation and the progression of atherosclerosis in Wantanabe heritable hyperlipidemic rabbits.
        Arterioscler. Thromb. 1994; 14: 1386-1391
        • Esterbauer H.
        • Dieber-Rotheneder M.
        • Strigl G.
        Role of vitamin E in preventing the oxidation of low-density lipoprotein.
        Am. J. Clin. Nutr. 1992; 53: 314S-321S
        • Kleinveld H.A.
        • Hak-Lemmers H.L.M.
        • Hectors M.P.C.
        • Fouw N.J.
        • Demacker P.N.M.
        • Stalenhoef A.F.H.
        Vitamin E and fatty acid intervention does not attenuate the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbits.
        Arterioscler. Thromb. Vasc. Biol. 1995; 15: 290-297
      1. Lipid Research Clinics Program Manual of Laboratory Operations: vol. 1, Ed. 2: Lipid and Lipoprotein Analysis. US Department of Health, Education and Welfare, Publ. No. (NIH). Washington, DC, US Government Printing Office, 1982. p. 76–628.

        • Hayashi T.
        • Fukuto J.M.
        • Ignarro L.J.
        • Chaudhuri G.
        Basal release of nitric oxide from aortic rings are greater in female rabbits than in male rabbits: implications for atherosclerosis.
        Proc. Natl. Acad. Sci. USA. 1992; 89: 11259-11263
        • Weiner B.H.
        • Ockene I.S.
        • Hoogasian J.J.
        Inhibition of atherosclerosis by cod-liveroil in a hyperlipidemic swine model.
        New Engl. J. Med. 1986; 315: 841-845
        • Esaki T.
        • Hayashi T.
        • Muto E.
        • Yamada K.
        • Kuzuya M.
        • Iguchi A.
        Expression of inducible nitric oxide synthase in T lymphocytes and macrophages of cholesterol-fed rabbits.
        Atherosclerosis. 1997; 128: 39-46
        • Hayashi T.
        • Esaki T.
        • Muto E.
        • Sumi D.
        • Kano H.
        • Takur N.K.
        • Iguchi A.
        Endothelium-dependent relaxation of rabbit atherosclerotic aorta was not restored by control of hyperlipidemia—the possible role of peroxynitrite.
        Atherosclerosis. 1999; 147: 349-367
        • Chilvers E.R.
        • Giembycz M.A.
        • Challiss R.A.
        • Barnes B.J.
        • Nahorski S.R.
        Lack of effect of zaprinast on methacholine-induced contraction and inositol 1,4,5-trisphosphate accumulation in bovine tracheal smooth muscle.
        Br. J. Pharmacol. 1991; 103: 1119-1125
        • Kano H.
        • Hayashi T.
        • Sumi D.
        • Esaki T.
        • Muto E.
        • Thakur N.K.
        • Iguchi A.
        A HMG-CoA reductase inhibitor improved regression of atherosclerosis without affecting serum lipid levels-relevance of upregulation of eNOS.
        Biochem. Biophys. Res. Commun. 1999; 259: 414-419
        • Kumar N.T.
        • Hayashi T.
        • Sumi D.
        • Kano H.
        • Iguchi A.
        Stabilization of atherosclerosis by a HMG-CoA reductase inhibitor—effects of increasing basal NO and decreasing superoxide.
        Am. J. Physiol. Heart Circ. Physiol. 2001; 281: H75-83
        • Baiy A.V.
        • Gebickki J.M.
        • Sulivan D.R.
        Vitamin E content and low-density lipo-protein oxidizability induced by free radicals.
        Atherosclerosis. 1990; 81: 175-182
        • Miyata K.
        • Shimokawa H.
        • Higo T.
        • et al.
        Sarpogrelate, a selective 5-HT2A serotonergic receptor antagonist, inhibits serotonin-induced coronary artery spasm in a porcine model.
        J. Cardiovasc. Pharmacol. 2000; 35: 294-301
        • Vaziri N.D.
        • Wang X.Q.
        cGMP-mediated negative-feedback regulation of endothelial nitric oxide synthase expression by nitric oxide.
        Hypertension. 1999; 34: 1237-1241
        • Aikawa M.
        • Rabkin E.
        • Okada Y.
        • et al.
        Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma. A potential mechanism of lesion stabilization.
        Circulation. 1998; 97: 2433-2444
        • Galis Z.S.
        • Sukhova G.K.
        • Kranzhofer R.
        • Clark S.
        • Libby P.
        Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases.
        Proc. Natl. Acad. Sci. USA. 1995; 92: 402-406
        • Tamura K.
        • Kanzaki T.
        • Saito Y.
        • Otabe M.
        • Saito Y.
        • Morisaki N.
        Serotonin (5-hydroxytryptamine, 5-HT) enhances migration of rat aortic smooth muscle cells through 5-HT2 receptors.
        Atherosclerosis. 1997; 132: 139-143
        • Hogg N.
        • Darley-Usmar V.M.
        • Graham A.
        • Moncada S.
        Peroxynitrite and atherosclerosis.
        Biochem. Soc. Trans. 1993; 21: 358-362
        • Shah P.K.
        • Falk E.
        • Badimon J.J.
        • et al.
        Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques: potential role of matrix-degrading metalloproteinases and implications for plaque rupture.
        Circulation. 1995; 92: 1585-1589
        • Pakala R.
        • Wilerson J.T.
        • Benedict C.R.
        Effect of serotonin, thromboxne A2, and specific receptor antagonists on vascular smooth muscle cell proliferation.
        Circulation. 1997; 96: 2280-2286
        • Lee S.L.
        • Wang W.W.
        • Moore B.J.
        • Fanburg B.L.
        Dual effect of serotonin on growth of bovine pulmonary artery smooth muscle cells in culture.
        Circ. Res. 1991; 68: 1362-1368
        • Parrot D.P.
        • Lockey P.M.
        • Bright C.P.
        Comparison of the mitogenic activity of angiotensin II and serotonin on porcine arterial smooth muscle cells.
        Atherosclerosis. 1991; 88: 213-218
        • Bobik A.
        • Grinpukel S.
        • Little P.J.
        • Grooms A.
        • Jackman G.
        Angiotensin II and noradrenaline increase PDGF-BB receptors and potentiate PDGF-BB stimulated DNA synthesis in vascular smooth muscle.
        Biochem. Biophys. Res. Commun. 1990; 166: 580-588
        • Watanabe T.
        • Pakala R.
        • Katagiri T.
        • Benedict C.R.
        Serotonin potentiates angiotensin II induced vascular smooth muscle cell proliferation.
        Atherosclerosis. 2001; 159: 269-279