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Licensed Unlicensed Requires Authentication Published by De Gruyter September 13, 2005

Effects of arecoline in relaxing human umbilical vessels and inhibiting endothelial cell growth

  • Fu-Chen Kuo , Deng-Chyang Wu , Shyng-Shiou F. Yuan , Kwo-Ming Hsiao , Yuan-Yung Wang , Yuan-Chieh Yang and Yi-Ching Lo
From the journal


This study investigated the effects of arecoline, an active ingredient of the areca nut, on the tone of human umbilical arteries and veins and on the eNOS expression and cell proliferation of human umbilical vein endothelial cells (HUVECs). We found that arecoline relaxes the human umbilical artery and vein rings in a concentration-dependent manner; the higher the concentration of arecoline, the greater the relaxation of the rings. However, the relaxation decreases after the endothelium was removed or pretreated with L-NAME, a nitric oxide synthase inhibitor. Moreover, arecoline increases in a dose-dependent way the cGMP levels of human umbilical arteries and veins. In HUVECs, arecoline also increases the eNOS expression. Therefore, the relaxant effects of arecoline on the umbilical artery and vein rings were endothelium-dependent through the NO-cGMP systems. In addition, arecoline at higher doses (100–1000 μM) inhibits endothelial cell proliferation; the exposure toarecoline (100–1000 μM) for 24 and 48 h induces G2/M cell cycle arrest of HUVECs. Our results indicate that arecoline would decrease vascular tone, in part mediated by NO. Higher doses of arecoline inhibit endothelial cell growth, which suggest that long-term use or high doses of areca nut might induce endothelial dysfunction and associated diseases.


Corresponding author: Graduate Institute and Department of Pharmacology Kaohsiung Medical University No.100, Shih-Chuan 1st road Kaohsiung 807 Taiwan Tel.: 886-7-3121101 ext 2139 Fax: 886-7-3234686


1 Arjungi KN: Areca nut: a review. Arzneimittelforschung26 (1976) 951Search in Google Scholar

2 Asthana S, NH Greig, HW Holloway, et al.: Clinical pharmacokinetics of arecoline in subjects with Alzheimer's disease. Clin Pharmacol Ther60 (1996) 276Search in Google Scholar

3 Bodick NC, WW Offen, AI Levey, et al.: Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch Neurol54 (1997) 465Search in Google Scholar

4 Boura AL, WA Walters, MA Read, et al.: Autacoids and control of human placental blood flow. Clin Exp Pharmacol Physiol21 (1994) 737Search in Google Scholar

5 Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem72 (1976) 24810.1016/0003-2697(76)90527-3Search in Google Scholar

6 Chang MC, YS Ho, PH Lee, et al.: Areca nut extract and arecoline induced the cell cycle arrest but not apoptosis of cultured oral KB epithelial cells: association of glut-athione, reactive oxygen species and mitochondrial membrane potential. Carcinogenesis22 (2001) 1527Search in Google Scholar

7 de Costa C, AR Griew: Effects of betel chewing on pregnancy outcome. Aust N Z J Obstet Gynaecol22 (1982) 22Search in Google Scholar

8 Fox SB, TY Khong: Lack of innervation of human umbilical cord. An immunohistological and histochemical study. Placenta11 (1990) 59Search in Google Scholar

9 Gude NM, RG King, SP Brennecke: Role of endothelium-derived nitric oxide in maintenance of low fetal vascular resistance in placenta. Lancet336 (1990) 1589Search in Google Scholar

10 Gupta PC, S Warnakulasuriya: Global epidemiology of areca nut usage. Addiction Biology7 (2002) 77Search in Google Scholar

11 Ho CS, MJ Gee: The parental influence of betel-chewing behavior among junior high school students in Taiwan. Subst Abus23 (2002) 183Search in Google Scholar

12 Hu FB, MJ Stampfer, JE Manson, et al.: Frequent nut consumption and risk of coronary heart disease in women: prospective cohort study. BMJ317 (1998) 1341Search in Google Scholar

13 Hung DZ, JF Deng: Acute myocardial infarction temporally related to betel nut chewing. Vet Hum Toxicol40 (1998) 25Search in Google Scholar

14 Jeng JH, ML Kuo, LJ Hahn, et al.: Genotoxic and non-genotoxic effects of betel quid ingredients on oral mucosal fibroblasts in vitro. J Dent Res73 (1994) 1043Search in Google Scholar

15 Ko YC, TA Chiang, SJ Chang, et al.: Prevalence of betel quid chewing habit in Taiwan and related sociodemographic factors. J Oral Pathol Med21 (1992) 261Search in Google Scholar

16 Ko YC, YL Huang, CH Lee, et al.: Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. J Oral Pathol Med24 (1995) 450Search in Google Scholar

17 Lees C, E Jauniaux, D Jurkovic, et al.: Placental nitric oxide production and umbilical artery vascular impedance in early pregnancy. Obstet Gynecol91 (1998) 761Search in Google Scholar

18 Lo YC, JR Wu, SN Wu, et al.: Glyceryl nonivamide: a capsaicin derivative with cardiac calcitonin gene-related peptide releasing, K+ channel opening and vasorelaxant properties. J Pharmacol Exp Ther281 (1997) 253Search in Google Scholar

19 Ma RH, CC Tsai, TY Shieh: Increased lysyl oxidase activity in fibroblasts cultured from oral submucous fibrosis associated with betel nut chewing in Taiwan. J Oral Pathol Med24 (1995) 407Search in Google Scholar

20 Merchant A, SS Husain, M Hosain, et al.: Paan without tobacco: an independent risk factor for oral cancer. Int J Cancer86 (2000) 128Search in Google Scholar

21 Remuzzi G, R Misiani, D Muratore, et al.: Prostacyclin and human foetal circulation. Prostaglandins18 (1979) 341Search in Google Scholar

22 Roberts JM, RN Taylor, A Goldfien: Clinical and biochemical evidence of endothelial cell dysfunction in the pregnancy syndrome preeclampsia. Am J Hypertens4 (1991) 700Search in Google Scholar

23 Schonfelder G, Fuhr N, Hadzidiakos D, et al.: Preeclampsia is associated with loss of neuronal nitric oxide synthase expression in vascular smooth muscle cells of the human umbilical cord. Histopathology44 (2004) 116Search in Google Scholar

24 Sinha A, AR Rao: Embryotoxicity of betel nuts in mice. Toxicology37 (1985) 315Search in Google Scholar

25 Sinha A, AR Rao: Transplacental micronucleus inducing ability of arecoline, a betel nut alkaloid, in mice. Mutat Res158 (1985) 193Search in Google Scholar

26 Tandon R: Cholinergic aspects of schizophrenia. Br J Psychiatry Suppl (1999) 710.1192/S0007125000293586Search in Google Scholar

27 Thomas S, J Kearsley: Betel quid and oral cancer: a review. Eur J Cancer B Oral Oncol29B (1993) 25110.1016/0964-1955(93)90044-FSearch in Google Scholar

28 Towbin H, T Staehelin, J Gordon: Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A76 (1979) 4350Search in Google Scholar

29 Trivedy C, S Warnakulasuriya, TJ Peters: Areca nuts can have deleterious effects. BMJ318 (1999) 1287Search in Google Scholar

30 Warnakulasuriya KA, JD Harrison, NW Johnson, et al.: Localised oral histoplasmosis lesions associated with HIV infection. J Oral Pathol Med26 (1997) 294Search in Google Scholar

31 Wohlfart P, J Dedio, K Wirth, et al.: Different B1 kinin receptor expression and pharmacology in endothelial cells of different origins and species. J Pharmacol Exp Ther280 (1997) 1109Search in Google Scholar

32 Yang MS, FT Chang, SS Chen, et al.: Betel quid chewing and risk of adverse pregnancy outcomes among aborigines in southern Taiwan. Public Health113 (1999) 189Search in Google Scholar

33 Yang MJ, TC Chung, TY Hsu, et al.: Betel quid chewing and risk of adverse birth outcomes among aborigines in eastern Taiwan. Journal of Toxicology and Environmental Health Part A64 (2001) 465Search in Google Scholar

34 Yoganathan P: Betel chewing creeps into the New World. N Z Dent J98 (2002) 40Search in Google Scholar

35 Zain RB, N Ikeda, PC Gupta, et al.: Oral mucosal lesions associated with betel quid, areca nut and tobacco chewing habits: consensus from a workshop held in KualaLumpur, Malaysia, November 25–27, 1996. J Oral Pathol Med28 (1999) 1Search in Google Scholar

Published Online: 2005-09-13
Published in Print: 2005-10-01

©2005 by Walter de Gruyter Berlin New York

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