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Naranjan S. Dhalla - One of the best experts on this subject based on the ideXlab platform.
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Blockade of 5-HT2A Receptors by Sarpogrelate Protects the Heart Against Myocardial Infarction in Rats
Journal of cardiovascular pharmacology and therapeutics, 2002Co-Authors: David Brasil, Hideo Kumamoto, Nobuakira Takeda, Rana M. Temsah, Kanwal Kumar, Naranjan S. DhallaAbstract:Background: It has been shown that serotonin (5-hydroxytryptamine, 5-HT) is involved in exacerbating vascular abnormalities; however, its role in mediating changes in cardiac function due to myocardial injury has yet to be established. This study examined the effect of Sarpogrelate, a 5-HT2A receptor blocker, in preventing cardiac dysfunction due to myocardial infarction (MI).Methods and Results: Rats were treated 3 days before surgery with or without 5 mg.kg-1.day-1 Sarpogrelate, and the left coronary artery was ligated for 3 weeks to induce MI. Sarpogrelate reduced the mortality from 40% to 30%, infarct size from 35% to 25%, and left ventricular end diastolic pressure from 15 mm Hg to 10 mm Hg in MI rats. Electrocardiographic (ECG) tracings showed a marked deviation in the ST-segment and prolongation of the QTc interval in MI rats during the 3 weeks; these changes were attenuated by Sarpogrelate pretreatment. In another set of experiments, MI rats were treated with 5 mg.kg-1.day-1 Sarpogrelate 1 hour af...
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Sarpogrelate diminishes changes in energy stores and ultrastructure of the ischemic-reperfused rat heart.
Canadian journal of physiology and pharmacology, 2001Co-Authors: Rana M. Temsah, Hideo Kumamoto, Nobuakira Takeda, Naranjan S. DhallaAbstract:Although the involvement of serotonin in exacerbating vascular abnormalities in ischemic heart disease has been established, its role in mediating changes in cardiac function due to ischemia reperfusion (IR) is poorly understood. The aim of this study was to investigate the effect of a serotonin blocker, Sarpogrelate (5-HT2A antagonist), in preventing cardiac injury due to IR. Isolated rat hearts were subjected to 30 min of global ischemia followed by 1 h of reperfusion. Sarpogrelate (50 nM-0.9 µM) was infused 10 min before ischemia as well as during the reperfusion period. The IR-induced changes in left ventricular developed pressure, left ventricular end diastolic pressure, rate of pressure development, and rate of pressure decay were attenuated (P < 0.05) with Sarpogrelate treatment. Sarpogrelate also decreased the ultrastructural damage and improved the high energy phosphate level in the IR hearts (P < 0.05). This study provides evidence for the attenuation of IR-induced cardiac injury by 5-HT2A recep...
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Sarpogrelate inhibits serotonin-induced proliferation of porcine coronary artery smooth muscle cells: implications for long-term graft patency
The Annals of thoracic surgery, 2001Co-Authors: Sushil K. Sharma, Dario F Del Rizzo, Peter Zahradka, Sukhinder K Bhangu, Jeffrey P Werner, Hideo Kumamoto, Nobuakira Takeda, Naranjan S. DhallaAbstract:Abstract Background . Serotonin can induce proliferation of vascular smooth muscle cells. We assessed the ability of a specific serotonin receptor antagonist, Sarpogrelate, to inhibit proliferation of cultured porcine coronary artery smooth muscle cells. Methods . Cell proliferation and mitotic activity were measured using 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide. To determine the effect of Sarpogrelate on DNA (deoxyribonucleic acid), RNA (ribonucleic acid), and protein synthesis, radioactive incorporation of 3 H-thymidine, 3 H-uridine, and 3 H-phenylalanine, respectively, was used. Synthesis of DNA was also assessed by flow cytometry with propidium iodide as a fluorochrome. Results . Serotonin, platelet-derived growth factor, endothelin, and angiotensin II all induced proliferation of porcine coronary artery smooth muscle cells. Sarpogrelate specifically inhibited the serotonin-induced cytokine trigger but did not influence platelet-derived growth factor–, endothelin–, or angiotensin II–induced cell proliferation. Sarpogrelate inhibited the serotonin-induced increase in intracellular free ionized calcium concentration, prevented mitogen-activated protein kinase activation, and down-regulated expression of the protooncogenes c- fos and c- jun. Sarpogrelate acted at the G 1 phase of the cell cycle. Conclusions . These data suggest that Sarpogrelate could be used as a therapeutic agent to inhibit serotonin-induced neointimal hyperplasia and improve patency of coronary artery bypass grafts.
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Inhibition of serotonin-induced vascular smooth muscle cell proliferation by Sarpogrelate.
The Journal of pharmacology and experimental therapeutics, 1999Co-Authors: Sushil K. Sharma, Peter Zahradka, Hideo Kumamoto, Nobuakira Takeda, Donald Chapman, Naranjan S. DhallaAbstract: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.
Masaaki Kakihana - One of the best experts on this subject based on the ideXlab platform.
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Abstract 11204: Long-term Effects of Sarpogrelate, a Selective Serotonin Receptor Antagonist, in Diabetic Patients with Stable Angina and Chronic Kidney Disease
Circulation, 2011Co-Authors: Hideki Watanabe, Kunio Nakagawa, Masaaki KakihanaAbstract:Background: Diabetes mellitus (DM) and Chronic Kidney Disease (CKD) are known as a major risk factor for cardiovascular disease (CVD). Sarpogrelate, a selective serotonin blocker, is known to have not only the inhibitory effects of platelet aggregation and vasoconstriction, but also the improvement of albuminuria. This study was designed to investigate long-term effects of Sarpogrelate in diabetic patients with stable angina and chronic kidney disease (CKD). Methods: After the standard medical therapy, seventy nine type 2 diabetic patients with stable angina and CKD (stage 3 or 4) were randomized to receive Sarpogrelate (Sarpogrelate group, n=42) or not to receive Sarpogrelate (control group, n=37). We measured flow-mediated dilatation (FMD) of brachial artery and pulse wave velocity (PWV), and assessed exercise tolerance and renal function (estimated glomerular filtration rate, eGFR). Measurements were performed at baseline, and then at every one year after the treatments. The primary outcome was major a...
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Abstract 2452: Long-term Effects of Sarpogrelate HCl, a Selective Serotonin Receptor Antagonist, in Diabetic Patients with Stable Angina
Circulation, 2007Co-Authors: Hideki Watanabe, Kunio Nakagawa, Masaaki KakihanaAbstract:Background: Sarpogrelate HCl, a selective serotonin blocker, is known to have not only the inhibitory effects of platelet aggregation and vasoconstriction, but also the improvement of insulin resistance in type 2 diabetic state. This study was designed to investigate long-term outcome of Sarpogrelate in diabetic patients with stable angina. Methods: After the standard medical therapy, forty two patients with type 2 diabetic mellitus and stable angina were randomized to receive Sarpogrelate HCl ( Sarpogrelate group , 300mg/day, n=21) or not to receive Sarpogrelate HCl ( control group , n=21). The primary outcome was hospitalization for acute coronary syndrome or revascularization during a follow-up period 4.2 to 4.7 years (median, 4.4 years). We measured flow-mediated dilatation (FMD) of brachial artery and pulse wave velocity (PWV), and assessed exercise tolerance and insulin resistance (HOMA-IR). Results: The 4.4-year cumulative primary-event rates were 9.5% in the Sarpogrelate group and 38.1% in the control group (p Conclusion: Sarpogrelate HCl, a serotonin blocker, not only improves vascular function (FMD, PWV), exercise tolerance, and insulin resistance, but also improves long-term outcome in diabetic patients with stable angina.
Takafumi Nagatomo - One of the best experts on this subject based on the ideXlab platform.
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Identification of a Key Amino Acid of the Human 5-HT2B Serotonin Receptor Important for Sarpogrelate Binding
Journal of pharmacological sciences, 2007Co-Authors: Habib Abul Muntasir, Mohiuddin Ahmed Bhuiyan, Masanobu Ozaki, Murad Hossain, Tadazumi Komiyama, Takashi Nakamura, Takafumi NagatomoAbstract:Based on radio-ligand binding and molecular modeling studies, Sarpogrelate shows a moderate selectivity for 5-HT2B versus 5-HT2A receptors. To confirm the modeling data of Sarpogrelate to 5-HT2B receptors predicting interaction of Sarpogrelate towards Asp135 in helix 3 of 5-HT2B receptors, we constructed and characterized the mutation of this residue by site-directed mutagenesis. The Asp135Ala mutant did not exhibit any affinity for [3H]rauwolscine. Therefore, it was not possible to find Sarpogrelate affinity to the mutant using [3H]rauwolscine. The mutation also abolished agonist-stimulated inositol phosphates formation. These results provide evidence that Asp135 is important for the interaction between 5-HT2B receptors and Sarpogrelate.
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Identification of Amino Acid Residues Important for Sarpogrelate Binding to the Human 5-Hydroxytryptamine2A Serotonin Receptor
Journal of pharmacological sciences, 2006Co-Authors: Habib Abul Muntasir, Mamunur Rashid, Tadazumi Komiyama, Jun Kawakami, Takafumi NagatomoAbstract:Abstract The purpose of the present study was to examine 5-hydroxytryptamine (5-HT)2A-receptor Sarpogrelate interactions by site-directed mutagenesis. Based on molecular modeling studies, aspartic acid (Asp)155[3.32] and tryptophan (Trp)151[3.28] in transmembrane helix (TMH) III and Trp336[6.48] in TMH VI of the 5-HT2A receptor were found to interact with Sarpogrelate. All of these residues were mutated to alanine (Ala). The Asp3.32Ala mutant did not exhibit any affinity for [3H]ketanserin, whereas the Trp3.28Ala mutant showed a markedly decrease in the binding affinity for [3H]ketanserin (Kd >10,000 nM). Therefore, it was not possible to find any Sarpogrelate affinity to the mutants using [3H]ketanserin. The mutation also abolished agonist-stimulated formation of [3H]inositol phosphates (IP) in both cases. On the other hand, the Trp6.48Ala mutant showed reduced binding affinity for [3H]ketanserin (Kd 2.0 nM vs 0.8 nM for the wild-type receptor) and had reduced affinity for Sarpogrelate (pKi value of 5.71 vs 9.06 for the wild-type receptor). The Trp6.48Ala mutant also showed the greatest decrease in sensitivity to Sarpogrelate (pKb value 8.81 for wild-type and 5.11 for mutant) in inhibiting agonist-stimulated IP formation. These results provide direct evidence that Asp3.32, Trp3.28, and less importantly, Trp6.48 are responsible for the interaction between the 5-HT2A receptor and Sarpogrelate. In addition, these results support the findings obtained from molecular modeling studies.
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Inverse Agonist Activity of Sarpogrelate, a Selective 5-HT2A-Receptor Antagonist, at the Constitutively Active Human 5-HT2A Receptor
Journal of Pharmacological Sciences, 2006Co-Authors: Habib Abul Muntasir, Mohiuddin Ahmed Bhuiyan, Masaji Ishiguro, Masanobu Ozaki, Takafumi NagatomoAbstract:Abstract Mutations producing constitutively active G-protein coupled receptors have been found in the pathophysiology of several diseases, implying that inverse agonists at the constitutively active receptors may have preferred therapeutic applications. Because of the involvement of 5-HT2A receptors in mediating many cardiovascular diseases, constitutively active mutants of the 5-HT2A receptor may be responsible for the disease states. Thus, the purpose of the present study was to investigate the inverse agonist activity of Sarpogrelate, a selective 5-HT2A-receptor antagonist, and its active metabolite, M-1; and we compared their activities with those of other 5-HT2A-receptor antagonists such as ritanserin, ketanserin, and cyproheptadine. Using a constitutively active mutant (C322K) of the human 5-HT2A receptor, we demonstrated that like other 5-HT2A-receptor antagonists, Sarpogrelate acts as a potent inverse agonist by significantly reducing basal inositol phosphate levels. However, there were no significant differences between Sarpogrelate and other 5-HT2A-receptor antagonists for their inverse agonist activity. Compared with the wild type receptor, mutant receptor displayed significantly higher affinity for 5-HT and lower affinity for Sarpogrelate. These results indicate that stabilization of the inactive conformation of the 5-HT2A receptor may be a key component of the mechanism of action of Sarpogrelate.
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Site-directed mutagenesis of the serotonin 5-Hydroxytryptamine2c receptor: identification of amino acids responsible for Sarpogrelate binding.
Biological & pharmaceutical bulletin, 2006Co-Authors: Habib Abul Muntasir, Mamunur Rashid, Murad Hossain, Tadazumi Komiyama, Jun Kawakami, Jyuniti Takahashi, Maruf Ahmed, Masayuki Nashimoto, Takafumi NagatomoAbstract:Site-directed mutagenesis was used to investigate the molecular interactions involved in Sarpogrelate binding to the human 5-Hydroxytryptamine(5-HT)2C receptor. Based on molecular modeling studies, Aspartic acid (Asp)155[3.32] in transmembrane region III and Serine(Ser)361[7.46] in transmembrane region VII of the 5-HT2C receptor were found to interact with Sarpogrelate. Asp3.32 and Ser7.46 were mutated to alanine (Ala) and expressed in COS-7 cells. The radioligand [3H]mesulergine did not show any binding to Asp3.32Ala mutant of 5-HT2C receptor. Therefore, it was not possible to find any Sarpogrelate affinity to the mutant using [3H]mesulergine. The mutation also abolished agonist-stimulated IP formation of [3H]myo-inositol. Introduction of dual mutation at position Ser7.46 (Asp3.32Ala–Ser7.46Ala) could not restore the function disrupted by the first mutation (Asp3.32Ala). On the other hand, the Ser7.46Ala mutant showed reduced binding affinity for [3H]mesulergine (Kd 3557 pM versus 573 pM for the wild-type receptor) and had reduced affinity for Sarpogrelate. Moreover, the Ser7.46Ala mutant receptor also showed a great loss of potency for Sarpogrelate in inhibiting 5-HT-stimulated IP formation of [3H]myo-inositol. The results provide direct evidence that Asp3.32 and less importantly, Ser7.46 are responsible for the interaction between 5-HT2C receptor and [3H]mesulergine as well as Sarpogrelate. More interestingly, Ser7.46Ala increases the receptor expression (20-fold vs. wild-type) of the mutant receptors and basal [3H]myo-inositol formation (2.5-fold vs. wild-type), which indicates that the 5-HT2C receptor could be rendered constitutively active by mutating the amino acid serine at position 7.46 to alanine.
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identification of the binding sites and selectivity of Sarpogrelate a novel 5 ht2 antagonist to human 5 ht2a 5 ht2b and 5 ht2c receptor subtypes by molecular modeling
Life Sciences, 2003Co-Authors: Mamunur Rashid, Masaji Ishiguro, Philippe Manivet, Hiroaki Nishio, Jaturong Pratuangdejkul, Mazen Rajab, Jeanmarie Launay, Takafumi NagatomoAbstract:The aim of the present study was to investigate the binding sites interactions and the selectivity of Sarpogrelate to human 5-HT(2) receptor family (5-HT(2A), 5-HT(2B) and 5-HT(2C) receptor subtypes) using molecular modeling. Rhodopsin (RH) crystal structures were used as template to build structural models of the human serotonin-2A and -2C receptors (5-HT(2A)R, 5-HT(2C)R), whereas for 5-HT(2B)R, we used our previously published three-dimensional (3D) models based on bacteriorhodopsin (BR). Sarpogrelate, a novel 5-HT(2)R antagonist, was docked to the receptors. Molecular dynamics (MD) simulations produced the strongest interaction for 5-HT(2A)R/Sarpogrelate complex. Upon binding, Sarpogrelate constraints aromatic residues network (Trp(3.28), Phe(5.47), Trp(6.48), Phe(6.51), Phe(6.52) in 5-HT(2A)R; Phe(3.35), Phe(6.51), Trp(7.40) in 5-HT(2B)R; Trp(3.28), Phe(3.35), Phe(5.47), Trp(6.48), Phe(6.51), Phe(6.52) in 5-HT(2C)R) in a stacked configuration, preventing activation of the receptor. The models suggest that the structural origin of the selectivity of Sarpogrelate to 5-HT(2A)R vs both 5-HT(2B)R and 5-HT(2C)R comes from the following results: (1) The tight interaction between the antagonist and the transmembrane domain (TMD) 3. Asp(3.32) neutralizes the cationic head and interacts simultaneously with carboxylic group hydrogen of the antagonist molecule. (2) Due to steric hindrance, Ser(5.46) (vs Ala(5.46) in 5HT(2B) and 5HT(2C)) prevents Sarpogrelate to enter deeply inside the hydrophobic core of the helix bundle and to interact with Pro(5.50). (3) The side chain of Ile(4.56) (vs Ile(4.56) in 5HT(2B)R and Val(4.56) in 5HT(2C)R) constraints Sarpogrelate to adjust its position by translating toward the strongly attractive Asp(3.32). These results are in good agreement with binding affinities (pKi) of Sarpogrelate for 5-HT(2) receptor family expressed in transfected cell.
Hideki Watanabe - One of the best experts on this subject based on the ideXlab platform.
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Abstract 11204: Long-term Effects of Sarpogrelate, a Selective Serotonin Receptor Antagonist, in Diabetic Patients with Stable Angina and Chronic Kidney Disease
Circulation, 2011Co-Authors: Hideki Watanabe, Kunio Nakagawa, Masaaki KakihanaAbstract:Background: Diabetes mellitus (DM) and Chronic Kidney Disease (CKD) are known as a major risk factor for cardiovascular disease (CVD). Sarpogrelate, a selective serotonin blocker, is known to have not only the inhibitory effects of platelet aggregation and vasoconstriction, but also the improvement of albuminuria. This study was designed to investigate long-term effects of Sarpogrelate in diabetic patients with stable angina and chronic kidney disease (CKD). Methods: After the standard medical therapy, seventy nine type 2 diabetic patients with stable angina and CKD (stage 3 or 4) were randomized to receive Sarpogrelate (Sarpogrelate group, n=42) or not to receive Sarpogrelate (control group, n=37). We measured flow-mediated dilatation (FMD) of brachial artery and pulse wave velocity (PWV), and assessed exercise tolerance and renal function (estimated glomerular filtration rate, eGFR). Measurements were performed at baseline, and then at every one year after the treatments. The primary outcome was major a...
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Abstract 2452: Long-term Effects of Sarpogrelate HCl, a Selective Serotonin Receptor Antagonist, in Diabetic Patients with Stable Angina
Circulation, 2007Co-Authors: Hideki Watanabe, Kunio Nakagawa, Masaaki KakihanaAbstract:Background: Sarpogrelate HCl, a selective serotonin blocker, is known to have not only the inhibitory effects of platelet aggregation and vasoconstriction, but also the improvement of insulin resistance in type 2 diabetic state. This study was designed to investigate long-term outcome of Sarpogrelate in diabetic patients with stable angina. Methods: After the standard medical therapy, forty two patients with type 2 diabetic mellitus and stable angina were randomized to receive Sarpogrelate HCl ( Sarpogrelate group , 300mg/day, n=21) or not to receive Sarpogrelate HCl ( control group , n=21). The primary outcome was hospitalization for acute coronary syndrome or revascularization during a follow-up period 4.2 to 4.7 years (median, 4.4 years). We measured flow-mediated dilatation (FMD) of brachial artery and pulse wave velocity (PWV), and assessed exercise tolerance and insulin resistance (HOMA-IR). Results: The 4.4-year cumulative primary-event rates were 9.5% in the Sarpogrelate group and 38.1% in the control group (p Conclusion: Sarpogrelate HCl, a serotonin blocker, not only improves vascular function (FMD, PWV), exercise tolerance, and insulin resistance, but also improves long-term outcome in diabetic patients with stable angina.
Sushil K. Sharma - One of the best experts on this subject based on the ideXlab platform.
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Sarpogrelate inhibits serotonin-induced proliferation of porcine coronary artery smooth muscle cells: implications for long-term graft patency
The Annals of thoracic surgery, 2001Co-Authors: Sushil K. Sharma, Dario F Del Rizzo, Peter Zahradka, Sukhinder K Bhangu, Jeffrey P Werner, Hideo Kumamoto, Nobuakira Takeda, Naranjan S. DhallaAbstract:Abstract Background . Serotonin can induce proliferation of vascular smooth muscle cells. We assessed the ability of a specific serotonin receptor antagonist, Sarpogrelate, to inhibit proliferation of cultured porcine coronary artery smooth muscle cells. Methods . Cell proliferation and mitotic activity were measured using 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide. To determine the effect of Sarpogrelate on DNA (deoxyribonucleic acid), RNA (ribonucleic acid), and protein synthesis, radioactive incorporation of 3 H-thymidine, 3 H-uridine, and 3 H-phenylalanine, respectively, was used. Synthesis of DNA was also assessed by flow cytometry with propidium iodide as a fluorochrome. Results . Serotonin, platelet-derived growth factor, endothelin, and angiotensin II all induced proliferation of porcine coronary artery smooth muscle cells. Sarpogrelate specifically inhibited the serotonin-induced cytokine trigger but did not influence platelet-derived growth factor–, endothelin–, or angiotensin II–induced cell proliferation. Sarpogrelate inhibited the serotonin-induced increase in intracellular free ionized calcium concentration, prevented mitogen-activated protein kinase activation, and down-regulated expression of the protooncogenes c- fos and c- jun. Sarpogrelate acted at the G 1 phase of the cell cycle. Conclusions . These data suggest that Sarpogrelate could be used as a therapeutic agent to inhibit serotonin-induced neointimal hyperplasia and improve patency of coronary artery bypass grafts.
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Inhibition of serotonin-induced vascular smooth muscle cell proliferation by Sarpogrelate.
The Journal of pharmacology and experimental therapeutics, 1999Co-Authors: Sushil K. Sharma, Peter Zahradka, Hideo Kumamoto, Nobuakira Takeda, Donald Chapman, Naranjan S. DhallaAbstract: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.
