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Planta Med 2020; 86(02): 121-131
DOI: 10.1055/a-1023-8918
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Centaurium Erythraea Extracts Exert Vascular Effects through Endothelium- and Fibroblast-dependent Pathways

Alae Chda
1   Laboratory Bioactives Molecules, Faculty of Sciences and Techniques, University Sidi Mohamed Ben Abdellah, Fes, Morocco
2   Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
,
Mohamed El Kabbaoui
1   Laboratory Bioactives Molecules, Faculty of Sciences and Techniques, University Sidi Mohamed Ben Abdellah, Fes, Morocco
,
Paula Fresco
2   Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
,
Dany Silva
2   Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
,
Jorge Gonçalves
2   Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
3   I₃ S Institute for Research and Innovation in Health Sciences, University of Porto, Porto, Portugal
,
Andreia P. Oliveira
4   REQUIMTE/LAQV, Laboratory of Pharmacognosy, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
,
Paula B. Andrade
4   REQUIMTE/LAQV, Laboratory of Pharmacognosy, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
,
Patrícia Valentão
4   REQUIMTE/LAQV, Laboratory of Pharmacognosy, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
,
Abdelali Tazi
1   Laboratory Bioactives Molecules, Faculty of Sciences and Techniques, University Sidi Mohamed Ben Abdellah, Fes, Morocco
,
Kaouakib El Abida
1   Laboratory Bioactives Molecules, Faculty of Sciences and Techniques, University Sidi Mohamed Ben Abdellah, Fes, Morocco
,
Rachid Bencheikh
1   Laboratory Bioactives Molecules, Faculty of Sciences and Techniques, University Sidi Mohamed Ben Abdellah, Fes, Morocco
› Author Affiliations Acknowledgements: We are grateful to Professor Amina Bari (Department of Biology, FSDM, University sidi Mohamed Ben Abdellah, Fez, Maroc) for botanical identification, to M. Céu Pereira (Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Portugal) for technical support, and to Professor Paulo Correia-de-Sá (Laboratory of Pharmacology, ICBAS, University of Porto, Portugal) for the generous gift of fibroblast cells. AC received a scholarship from Erasmus+ International Credit Mobility – MARE NOSTRUM Consortium to support his stay, as a visiting Ph.D. student, in Porto, Portugal. This work was supported by UID/QUI/50006/2019 with funding from FCT/MCTES through national funds, by Programa de Cooperación Interreg V-A España – Portugal (POCTEP) 2014 – 2020 (project 0377_IBERPHENOL_6_E), and by REQUIMTE through the APO research contract (DL57/2016/CP1346/CT0015).
Further Information

Publication History

received 28 May 2019
revised 30 September 2019

accepted 03 October 2019

Publication Date:
23 October 2019 (online)

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Abstract

Centaurium erythraea is a plant used in traditional medicine for several cardiovascular disorders, namely hypertension, but there is no scientific evidence able to provide a molecular basis for its claimed antihypertensive effects. After a preliminary screen of extracts obtained from sequential extraction of C. erythraea aerial parts, effects of the methanolic fraction (MFCE) on changes in perfusion pressure of isolated rat mesenteric vascular bed (MVB) and in rat cardiac fibroblasts proliferation were investigated, gathering information on the mechanisms involved in endothelium-dependent effects and their dependence on a pro-proliferative stimulus. The HPLC-DAD determination of the phenolics content of MFCE revealed the presence of 22 phenolic compounds. MFCE reduced (63.3 ± 3.9%; n = 4) perfusion pressure in MVB and almost completely abrogated the Ang II-induced increase in cardiac fibroblasts proliferation. Reduction of the perfusion pressure caused by MFCE was endothelium-dependent and occurred in parallel with an increase in NO release. These effects were inhibited by muscarinic receptor antagonists, by L-NAME (a NO synthase inhibitor), and by ODQ (a soluble guanylate cyclase inhibitor). Experiments revealed that effects required the involvement of K+ channels, being inhibited by tetraethylamonium (TEA; a Ca2+ activated K+ channels inhibitor) and by glibenclamide (an ATP-sensitive K+ channels inhibitor). In conclusion, extracts from C. erythraea, particularly the compounds present in the MFCE, induce endothelium-dependent vasodilation and prevent fibroblast proliferation induced by angiotensin II, which can account for the claimed antihypertensive effects of C. erythraea in traditional medicine.

Key words

Centaurium erythraea - Gentianaceae - hypertension - endothelium-dependent relaxation - cholinomimetic effects - K⁺ channel mediated hyperpolarization - fibroblast proliferation - phenolic composition

Supporting Information

    Additional evidence for involvement of muscarinic receptors and NO release on the effects of MFCE was gathered by investigating the effects of MFCE on isolated rat ileum contractions and on NO release in breast cancer MCF-7 cells, using DAF-FM DA, a highly sensitive and selective fluorescent NO probe.

  • Supporting Information
 

  • References

  • 1 Merzouki A, Ed-derfoufi F, Molero Mesa J. Contribution to the knowledge of Rifian traditional medicine. II: folk medicine in Ksar Lakbir district (NW Morocco). Fitoterapia 2000; 71: 278-307
    CrossrefPubMedSearch in Google Scholar
  • 2 Bouyahya A, Abrini J, Et-Touys A, Bakri Y, Dakka N. Indigenous knowledge of the use of medicinal plants in the north-west of Morocco and their biological activities. Eur J Integr Med 2017; 13: 9-25
    CrossrefPubMedSearch in Google Scholar
  • 3 Bnouham M, Mekhfi H, Legssyer A, Ziyyat A. Medicinal plants used in the treatment of diabetes in Morocco. Int J Diabetes Metab 2002; 10: 33-50
    PubMedSearch in Google Scholar
  • 4 Bellakhdar J, Claisse R, Fleurentin J, Younos C. Repertory of standard herbal drugs in the Moroccan pharmacopoea. J Ethnopharmacol 1991; 35: 123-143
    CrossrefPubMedSearch in Google Scholar
  • 5 Uncini Manganelli RE, Chericoni S, Baragatti B. Ethnopharmacobotany in Tuscany: plants used as antihypertensives. Fitoterapia 2000; 71: S95-S100
    CrossrefPubMedSearch in Google Scholar
  • 6 Calvo MI, Cavero RY. Medicinal plants used for cardiovascular diseases in Navarra and their validation from official sources. J Ethnopharmacol 2014; 157: 268-273
    CrossrefPubMedSearch in Google Scholar
  • 7 Chda A, Kabbaoui M, Chokri A, Abida K, Tazi A, Bencheikh R. Spasmolytic action of Centaurium erythraea on rabbit jejunum is through calcium channel blockade and NO release. European J Med Plants 2016; 11: 1-13
    PubMedSearch in Google Scholar
  • 8 Valentão P, Fernandes E, Carvalho F, Andrade PB, Seabra RM, Bastos ML. Antioxidant activity of Centaurium erythraea infusion evidenced by its superoxide radical scavenging and xanthine oxidase inhibitory activity. J Agric Food Chem 2001; 49: 3476-3479
    CrossrefPubMedSearch in Google Scholar
  • 9 Haloui M, Louedec L, Michel JB, Lyoussi B. Experimental diuretic effects of Rosmarinus officinalis and Centaurium erythraea . J Ethnopharmacol 2000; 71: 465-472
    CrossrefPubMedSearch in Google Scholar
  • 10 Tuluce Y, Ozkol H, Koyuncu I, Ine H. Gastroprotective effect of small centaury (Centaurium erythraea L) on aspirin-induced gastric damage in rats. Toxicol Ind Health 2011; 27: 760-768
    CrossrefPubMedSearch in Google Scholar
  • 11 Sefi M, Fetoui H, Lachkar N, Tahraoui A, Lyoussi B, Boudawara T, Zeghal N. Centaurium erythrea (Gentianaceae) leaf extract alleviates streptozotocin-induced oxidative stress and β-cell damage in rat pancreas. J Ethnopharmacol 2011; 135: 243-250
    CrossrefPubMedSearch in Google Scholar
  • 12 Đorđević M, Mihailović M, Arambašić Jovanović J, Grdović N, Uskoković A, Tolić A, Sinadinović M, Rajić J, Mišić D, Šiler B, Poznanović G, Vidaković M, Dinić S. Centaurium erythraea methanol extract protects red blood cells from oxidative damage in streptozotocin-induced diabetic rats. J Ethnopharmacol 2017; 202: 172-183
    CrossrefPubMedSearch in Google Scholar
  • 13 Varadharaj S, Kelly OJ, Khayat RN, Kumar PS, Webb AJ, Miller MR. Role of dietary antioxidants in the preservation of vascular function and the modulation of health and disease. Front Cardiovasc Med 2017; 4: 1-11
    PubMedSearch in Google Scholar
  • 14 Brocq ML, Leslie SJ, Milliken P, Megson IL. Endothelial dysfunction: from molecular mechanisms to measurement, clinical implications and therapeutic opportunities. Antioxid Redox Signal 2008; 10: 1631-1674
    CrossrefPubMedSearch in Google Scholar
  • 15 Božunović J, Živković S, Gašić U, Glamočlija J, Ćirić A, Matekalo D, Šiler B, Soković M, Tešić Ž, Mišić D. In vitro and in vivo transformations of Centaurium erythraea secoiridoid glucosides alternate their antioxidant and antimicrobial capacity. Ind Crops Prod 2018; 111: 705-721
    CrossrefPubMedSearch in Google Scholar
  • 16 Ghiadoni L, Taddei S, Virdis A. Hypertension and endothelial dysfunction: therapeutic approach. Curr Vasc Pharmacol 2011; 10: 43-60
    PubMedSearch in Google Scholar
  • 17 Goszcz K, Deakin SJ, Duthie GG, Stewart D, Leslie SJ, Megson IL. Antioxidants in cardiovascular therapy: panacea or false hope?. Front Cardiovasc Med 2015; 2: 1-22
    PubMedSearch in Google Scholar
  • 18 Vanhoutte PM, Shimokawa H, Feletou M, Tang EHC. Endothelial dysfunction and vascular disease – a 30th anniversary update. Acta Physiol (Oxf) 2017; 219: 22-96
    CrossrefPubMedSearch in Google Scholar
  • 19 Mombouli JV, Vanhoutte PM. Endothelium-derived hyperpolarizing factor(s): updating the unknown. Trends Pharmacol Sci 1997; 18: 252-256
    PubMedSearch in Google Scholar
  • 20 Nelson MT, Quayle JM. Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol 1995; 4: C799-C822
    PubMedSearch in Google Scholar
  • 21 Furchgott RF. The role of endothelium in the responses of vascular smooth muscle to drugs. Annu Rev Pharmacol Toxicol 1984; 24: 175-197
    CrossrefPubMedSearch in Google Scholar
  • 22 McAnulty RJ. Fibroblasts and myofibroblasts: their source, function and role in disease. Int J Biochem Cell Biol 2007; 39: 666-671
    CrossrefPubMedSearch in Google Scholar
  • 23 Brecher P. Angiotensin II and cardiac fibrosis. Trends Cardiovasc Med 1996; 6: 193-198
    CrossrefPubMedSearch in Google Scholar
  • 24 Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 2000; 52: 11-34
    PubMedSearch in Google Scholar
  • 25 Porter KE, Turner NA. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther 2009; 123: 255-278
    CrossrefPubMedSearch in Google Scholar
  • 26 van Eickels M, Vetter H, Grohe C. Angiotensin-converting enzyme (ACE) inhibition attenuates insulin-like growth factor-I (IGF-I) induced cardiac fibroblast proliferation. Br J Pharmacol 2000; 131: 1592-1596
    CrossrefPubMedSearch in Google Scholar
  • 27 Sadoshima J, Izumo S. Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ Res 1993; 73: 413-423
    CrossrefPubMedSearch in Google Scholar
  • 28 Kachmar MR, Oliveira AP, Valentão P, Gil-Izquierdo A, Domínguez-Perles R, Ouahbi A, Badaoui KE, Andrade PB, Ferreres F. HPLC-DAD-ESI/MSn phenolic profile and in vitro biological potential of Centaurium erythraea Rafn aqueous extract. Food Chem 2019; 278: 424-433
    CrossrefPubMedSearch in Google Scholar
  • 29 Sanchez M, Lodi F, Vera R, Villar IC, Cogolludo A, Jimenez R, Moreno L, Romero M, Tamargo J, Perez-Vizcaino F, Duarte J. Quercetin and isorhamnetin prevent endothelial dysfunction, superoxide production, and overexpression of p47phox induced by angiotensin II in rat aorta. J Nutr 2007; 137: 910-915
    CrossrefPubMedSearch in Google Scholar
  • 30 Penso J, Cordeiro K, da Cunha CR, da Silva Castro PF, Martins DR, Lião LM, Rocha ML, de Oliveira V. Vasorelaxant activity of 7-β-O-glycosides biosynthesized from flavonoids. Eur J Pharmacol 2014; 733: 75-80
    CrossrefPubMedSearch in Google Scholar
  • 31 Hügel HM, Jackson N, May B, Zhang AL, Xue CC. Polyphenol protection and treatment of hypertension. Phytomedicine 2016; 23: 220-231
    CrossrefPubMedSearch in Google Scholar
  • 32 Peluso MR. Flavonoids attenuate cardiovascular disease, inhibit phosphodiesterase, and modulate lipid homeostasis in adipose tissue and liver. Exp Biol Med 2006; 231: 1287-1299
    CrossrefPubMedSearch in Google Scholar
  • 33 Gasparotto Junior A, Dos Reis Piornedo R, Assreuy J, Da Silva-Santos JE. Nitric oxide and Kir6.1 potassium channel mediate isoquercitrin-induced endothelium-dependent and independent vasodilation in the mesenteric arterial bed of rats. Eur J Pharmacol 2016; 788: 328-334
    CrossrefPubMedSearch in Google Scholar
  • 34 Mahobiya A, Singh TU, Rungsung S, Kumar T, Chandrasekaran G, Parida S, Kumar D. Kaempferol-induces vasorelaxation via endothelium-independent pathways in rat isolated pulmonary artery. Pharmacol Rep 2018; 70: 863-874
    CrossrefPubMedSearch in Google Scholar
  • 35 Xiao H, Lu X, Chen X, Sun Z. Protective effects of kaempferol against endothelial damage by an improvement in nitric oxide production and a decrease in asymmetric dimethylarginine level. Eur J Pharmacol 2009; 616: 213-222
    CrossrefPubMedSearch in Google Scholar
  • 36 Teixeira J, Gaspar A, Garrido EM, Garrido J, Borges F. Hydroxycinnamic acid antioxidants: an electrochemical overview. Biomed Res Int 2013; 2013: 251754 doi:10.1155/2013/251754
    PubMedSearch in Google Scholar
  • 37 Mudnic I, Modun D, Rastija V, Vukovic J, Brizic I, Katalinic V, Kozina B, Medic-Saric M, Boban M. Antioxidative and vasodilatory effects of phenolic acids in wine. Food Chem 2010; 119: 1205-1210
    CrossrefPubMedSearch in Google Scholar
  • 38 Brand-Williams W, Cuvelier ME, Berset C. Use of a free radical method to evaluate antioxidant activity. Lebensm Wiss Technol 1995; 28: 25-30
    CrossrefPubMedSearch in Google Scholar
  • 39 Mcgregor DD. The effect of sympathetic nerve stimulation of vasoconstrictor responses in perfused mesenteric blood vessels of the rat. J Physiol 1965; 177: 21-30
    CrossrefPubMedSearch in Google Scholar
  • 40 Bencheikh R, Féray JC, Alaoui A, Crozatier B. Thromboxane A2 in vasomotor effects of phenylephrine, acetylcholine, and bradykinin in rat mesenteric bed. J Cardiovasc Pharmacol 2002; 40: 255-264
    CrossrefPubMedSearch in Google Scholar
  • 41 Adeagbo ASO, Tabrizchi R, Triggle CR. The effects of perfusion rate and NG-nitro-L-arginine methyl ester on cirazoline- and KCl-induced responses in the perfused mesenteric arterial bed of rats. Br J Pharmacol 1994; 111: 13-20
    CrossrefPubMedSearch in Google Scholar
  • 42 Chda A, El Kabbaoui M, Baba BF, Mahfoud A, El Abida K, Bousfiha A, Al Houari G, Abdelali T, Kerbal A, Ben Cheikh R. Endothelium-independent vasorelaxant effect of synthestized 2-hydroxymethylchromone on rat mesenteric arterial bed. Curr Bioact Compd 2018; 14: 289-298
    CrossrefPubMedSearch in Google Scholar
  • 43 Green L, Wagner D, Glogowski J, Skipper P, Wishnok JS, Tannenbaum S. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 1982; 126: 131-138
    CrossrefPubMedSearch in Google Scholar
  • 44 Certal M, Vinhas A, Pinheiro AR, Ferreirinha F, Barros-Barbosa AR, Silva I, Costa MA, Correia-de-Sá P. Calcium signaling and the novel antiproliferative effect of the UTP-sensitive P2Y11 receptor in rat cardiac myofibroblasts. Cell Calcium 2015; 58: 518-533
    CrossrefPubMedSearch in Google Scholar
  • 45 Denizot F, Lang R. Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J Immunol Methods 1986; 89: 271-277
    CrossrefPubMedSearch in Google Scholar