Download PDF
Planta Med 2020; 86(07): 496-504
DOI: 10.1055/a-1123-7852
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Vasorelaxant and Antihypertensive Effects of Neferine in Rats: An In Vitro and In Vivo Study

Piyawadee Wicha
1   Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
,
Amnart Onsa-ard
2   Division of Biochemistry, School of Medical Sciences, University of Phayao, Phayao, Thailand
,
Waraluck Chaichompoo
3   Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
,
Apichart Suksamrarn
3   Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
,
Chainarong Tocharus
1   Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
› Author AffiliationsSupported by: The Thailand Research Fund DBG6180030
Further Information

Publication History

received 02 September 2019
revised 02 February 2020

accepted 14 February 2020

Publication Date:
27 March 2020 (online)

Also available at
    Permissions and Reprints

Abstract

The present study was performed to examine the antihypertensive effect of neferine in hypertensive rats and its relaxant mechanisms in isolated rat thoracic aorta. The antihypertensive effect was evaluated by tail-cuff methods on NG-nitro-L-arginine methyl ester (L-NAME) (40 mg/kg BW) 4-week hypertensive-induced hypertensive rats. The vasorelaxant effect and its mechanisms were studied by the organ bath technique in the thoracic aorta isolated from normotensive rats. The results indicated that the treatment of neferine (1 mg/kg and 10 mg/kg) markedly decreased the systolic blood pressure (SBP) when compared with the hypertension group (137.75 ± 10.14 mmHg and 132.23 ± 9.5 mmHg, respectively, p < 0.001), without affecting the heart rate. Moreover, neferine (10−12 − 10−4 M) exhibited concentration-dependent vasorelaxation in endothelium-intact rings (Emax values = 98.95 ± 0.66% and pD2 = 7.93 ± 0.28) and endothelium-denuded rings (Emax values = 90.61 ± 1.91% and pD2 = 6.85 ± 0.36). The effects of neferine were reduced by pre-incubation with L-NAME and 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ) but not with pre-incubation with indomethacin and K+channel blockers. Neferine attenuated the contractions induced by phenylephrine and caffeine in a Ca2+-free solution and also inhibited in CaCl2- and phenylephrine-induced contracted rings. Our study suggests that neferine exhibited hypertensive potential, induced vasorelaxation through the endothelium nitric oxide synthase (eNOS)/nitric oxide (NO)/soluble guanylyl cyclase (sGC) pathway and involved the modulation of Ca2+ influx through Ca2+ channels and intracellular Ca2+ release from the sarcoplasmic reticulum.

Key words

endothelium-dependent - endothelium-independent - hypertension - neferine - nelumbonaceae - Nelumbo nucifera - rat aorta vasorelaxation
 

  • References

  • 1 Chockalingam A. Impact of world hypertension day. Can J Cardiol 2007; 23: 517-519
    CrossrefPubMedSearch in Google Scholar
  • 2 World Health Organization. A global Brief on Hypertension: silent Killer, global public Health Crisis. Geneva, Switzerland: WHO; 2013
    Search in Google Scholar
  • 3 Dharmashankar K, Widlansky ME. Vascular endothelial function and hypertension: insights and directions. Curr Hypertens Rep 2010; 12: 448-455
    CrossrefPubMedSearch in Google Scholar
  • 4 Noll G, Tschudi M, Nava E, Lüscher TF. Endothelium and high blood pressure. Int J Microcirc Clin Exp 1997; 17: 273-279
    CrossrefPubMedSearch in Google Scholar
  • 5 Ajebli M, Eddouks M. Antihypertensive activity of Petroselinum crispum through inhibition of vascular calcium channels in rats. J Ethnopharmacol 2019; 242: 112039
    CrossrefPubMedSearch in Google Scholar
  • 6 Kianbakht S, Hashem-Dabaghian F. Antihypertensive efficacy and safety of Vaccinium arctostaphylos berry extract in overweight/obese hypertensive patients: a randomized, double-blind and placebo-controlled clinical trial. Complement Ther Med 2019; 44: 296-300
    CrossrefPubMedSearch in Google Scholar
  • 7 Plangar AF, Anaeigoudari A, KhajaviRad A, Shafei MN. Beneficial cardiovascular effects of hydroalcoholic extract from Crocus sativus in hypertension induced by angiotensin II. J Pharmacopuncture 2019; 22: 95-101
    PubMedSearch in Google Scholar
  • 8 Liu S, Wang B, Li XZ, Qi LF, Liang YZ. Preparative separation and purification of liensinine and neferine from seed embryo of Nelumbo nucifera GAERTN using high-speed counter-current chromatography. J Sep Sci 2009; 32: 2476-2481
    CrossrefPubMedSearch in Google Scholar
  • 9 Marthandam Asokan S, Mariappan R, Muthusamy S, Velmurugan BK. Pharmacological benefits of neferine – a comprehensive review. Life Sci 2018; 199: 60-70
    CrossrefPubMedSearch in Google Scholar
  • 10 Khan A, Bai H, Shu M, Chen M, Khan A, Bai Z. Antioxidative and antiphotoaging activities of neferine upon UV-A irradiation in human dermal fibroblasts. Biosci Rep 2018; 38: BSR20181414
    PubMedSearch in Google Scholar
  • 11 Zhao L, Wang X, Chang Q, Xu J, Huang Y, Guo Q, Zhang S, Wang W, Chen X, Wang J. Neferine, a bisbenzylisoquinline alkaloid attenuates bleomycin-induced pulmonary fibrosis. Eur J Pharmacol 2010; 627: 304-312
    CrossrefPubMedSearch in Google Scholar
  • 12 Zhou YJ, Xiang JZ, Yuan H, Liu H, Tang Q, Hao HZ, Yin Z, Wang J, Ming ZY. Neferine exerts its antithrombotic effect by inhibiting platelet aggregation and promoting dissociation of platelet aggregates. Thromb Res 2013; 132: 202-210
    CrossrefPubMedSearch in Google Scholar
  • 13 Kadioglu O, Law BYK, Mok SWF, Xu SW, Efferth T, Wong VKW. Mode of action analyses of neferine, a bisbenzylisoquinoline alkaloid of lotus (Nelumbo nucifera) against multidrug-resistant tumor cells. Front Pharmacol 2017; 8: 238
    CrossrefPubMedSearch in Google Scholar
  • 14 Zhou H, Jiang H, Yao T, Zeng S. Fragmentation study on the phenolic alkaloid neferine and its analogues with anti-HIV activities by electrospray ionization tandem mass spectrometry with hydrogen/deuterium exchange and its application for rapid identification of in vitro microsomal metabolites of neferine. Rapid Commun Mass Spectrom 2007; 21: 120-128
    PubMedSearch in Google Scholar
  • 15 Sugimoto Y, Furutani S, Nishimura K, Itoh A, Tanahashi T, Nakajima H, Oshiro H, Sun S, Yamada J. Antidepressant-like effects of neferine in the forced swimimg test involve the serotonin1A (5-HT1A) receptor in mice. Eur J Pharmacol 2010; 634: 62-67
    CrossrefPubMedSearch in Google Scholar
  • 16 Li G, Xu H, Zhu S, Xu W, Qin S, Liu S, Tu G, Peng H, Qiu S, Yu S, Zhu Q, Fan B, Zheng C, Li G, Liang S. Effects of neferine on CCL5 and CCR5 expression in SCG of type 2 diabetic rats. Brain Res Bull 2013; 90: 79-87
    CrossrefPubMedSearch in Google Scholar
  • 17 Qian JQ. Cardiovascular pharmacological effects of bisbenzylisoquinoline allaloid derivatives. Acta Pharmacol Sin 2002; 23: 1086-1092
    PubMedSearch in Google Scholar
  • 18 Yu J, Hu WS. [Effects of neferine on platelet aggregation in rabbits]. Yao Xue Xue Bao 1997; 32: 1-4
    PubMedSearch in Google Scholar
  • 19 Martinez JL, Russo A, Vinet R, Jaimes L, Russo L, Laurido C. Berberis chilensis gillies ex hook: alkaloids and pharmacological activities. Pharmacologyonline 2018; 1: 58-67
    PubMedSearch in Google Scholar
  • 20 Martinez JL, Torres R, Morales MA. Hypotensive effect of O-methylisothalicberine, a bisbenzylisoquinoline alkaloid isolated from Berberis chilensis on normotensive rats. Phytother Res 1997; 11: 246-248
    CrossrefPubMedSearch in Google Scholar
  • 21 Fang DH, Yao WX, Xia GJ, Qu L, Jiang MX. Studies on the calcium antagonistic action of tetrandrine: I. Effects of tetrandrine on contractility of isolated guinea pig atrium. Acta Acad Med Wuhan 1981; 1: 46-50
    PubMedSearch in Google Scholar
  • 22 Chen J, Qi J, Chen F, Liu JH, Wang T, Yang J, Yin CP. Relaxation mechanisms of neferine on the rabbit corpus cavernosum tissue in vitro . Asian J Androl 2007; 9: 795-800
    CrossrefPubMedSearch in Google Scholar
  • 23 Yang GM, Sun J, Pan Y, Zhang JL, Xiao M, Zhu MS. Isolation and identification of a tribenzylisoquinoline alkaloid from Nelumbo nucifera Gaertn, a novel potential smooth muscle relaxant. Fitoterapia 2018; 124: 58-65
    CrossrefPubMedSearch in Google Scholar
  • 24 Li GR, Lue FH, Qian JQ. [Effects of neferine on physiologic properties and dose-effect response of isoprenaline and Ca2+ in guinea pig atria]. Yao Xue Xue Bao 1988; 23: 241-245
    PubMedSearch in Google Scholar
  • 25 Zhang SD, Peng ZY, Liu S, Pei ZF, Chen F, Yang L. [Neferine protects endothelial cells against damages induced by LPC and relationship with asymmetric dimethylarginine]. Zhongguo Zhong Yao Za Zhi 2008; 33: 2526-2529
    PubMedSearch in Google Scholar
  • 26 Bernátová I, Pechánová O, Babál P, Kyselá S, Stvrtina S, Andriantsitohaina R. Wine polyphenols improve cardiovascular remodeling and vascular function in NO-deficient hypertension. Am J Physiol Heart Circ Physiol 2002; 282: H942-948
    CrossrefPubMedSearch in Google Scholar
  • 27 Sandoo A, van Zanten JJ, Metsios GS, Carroll D, Kitas GD. The endothelium and its role in regulating vascular tone. Open Cardiovasc Med J 2010; 4: 302-312
    CrossrefPubMedSearch in Google Scholar
  • 28 Raghavan SA, Dikshit M. Vascular regulation by the L-arginine metabolites, nitric oxide and agmatine. Pharmacol Res 2004; 49: 397-414
    CrossrefPubMedSearch in Google Scholar
  • 29 Ignarro LJ, Harbison RG, Wood KS, Kadowitz PJ. Activation of purified soluble guanylate cyclase by endothelium-derived relaxing factor from intrapulmonary artery and vein: stimulation by acetylcholine, bradykinin and arachidonic acid. J Pharmacol Exp Ther 1986; 237: 893-900
    PubMedSearch in Google Scholar
  • 30 Jones KA, Wong GY, Jankowski CJ, Akao M, Warner DO. cGMP modulation of Ca2+ sensitivity in airway smooth muscle. Am J Physiol 1999; 276: L35-40
    PubMedSearch in Google Scholar
  • 31 Flavahan NA. Balancing prostanoid activity in the human vascular system. Trends Pharmacol Sci 2007; 28: 106-110
    CrossrefPubMedSearch in Google Scholar
  • 32 Billington CK, Penn RB. Signaling and regulation of G protein-coupled receptors in airway smooth muscle. Respir Res 2003; 4: 2
    PubMedSearch in Google Scholar
  • 33 Ehrlich BE, Watras J. Inositol 1,4,5-trisphosphate activates a channel from smooth muscle sarcoplasmic reticulum. Nature 1988; 336: 583-586
    CrossrefPubMedSearch in Google Scholar
  • 34 Somlyo AV, Somlyo AP. Electromechanical and oharmacomechanical coupling in vascular smooth muscle. J Pharmacol Exp Ther 1968; 159: 129-145
    PubMedSearch in Google Scholar
  • 35 Clapham DE, Runnels LW, Strübing C. The TRP ion channel family. Nat Rev Neurosci 2001; 2: 387-396
    PubMedSearch in Google Scholar
  • 36 Chaichompoo W, Chokchaisiri R, Apiratikul N, Chairoungdua A, Yingyongnarongkul B, Chunglok W, Tocharus C, Suksamrarn A. Cytotoxic alkaloids against human colon adenocarcinoma cell line (HT-29) from the seed embryos of Nelumbo nucifera . Med Chem Res 2018; 27: 939-943
    CrossrefPubMedSearch in Google Scholar
  • 37 Nishimura K, Horii S, Tanahashi T, Sugimoto Y, Yamada J. Synthesis and pharmacological activity of alkaloids from embryo of lotus, Nelumbo nucifera . Chem Pharm Bull 2013; 61: 59-68
    CrossrefPubMedSearch in Google Scholar
  • 38 Zhang XX, Ma SC, Mao P, Wang Y. A new bisbenzylisoquinoline alkaloid from Plumula nelumbinis . Chin Chem Lett 2016; 27: 1755-1758
    CrossrefPubMedSearch in Google Scholar