RSS-Feed abonnieren
DOI: 10.1055/a-1023-8918
Centaurium Erythraea Extracts Exert Vascular Effects through Endothelium- and Fibroblast-dependent Pathways
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).Publikationsverlauf
received 28. Mai 2019
revised 30. September 2019
accepted 03. Oktober 2019
Publikationsdatum:
23. Oktober 2019 (online)
![](https://www.thieme-connect.de/media/plantamedica/202002/lookinside/thumbnails/10-1055-a-1023-8918_pmd0448-1.jpg)
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 compositionSupporting Information
- 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.
-
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
- 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
- 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
- 4 Bellakhdar J, Claisse R, Fleurentin J, Younos C. Repertory of standard herbal drugs in the Moroccan pharmacopoea. J Ethnopharmacol 1991; 35: 123-143
- 5 Uncini Manganelli RE, Chericoni S, Baragatti B. Ethnopharmacobotany in Tuscany: plants used as antihypertensives. Fitoterapia 2000; 71: S95-S100
- 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
- 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
- 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
- 9 Haloui M, Louedec L, Michel JB, Lyoussi B. Experimental diuretic effects of Rosmarinus officinalis and Centaurium erythraea . J Ethnopharmacol 2000; 71: 465-472
- 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
- 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
- 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
- 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
- 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
- 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
- 16 Ghiadoni L, Taddei S, Virdis A. Hypertension and endothelial dysfunction: therapeutic approach. Curr Vasc Pharmacol 2011; 10: 43-60
- 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
- 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
- 19 Mombouli JV, Vanhoutte PM. Endothelium-derived hyperpolarizing factor(s): updating the unknown. Trends Pharmacol Sci 1997; 18: 252-256
- 20 Nelson MT, Quayle JM. Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol 1995; 4: C799-C822
- 21 Furchgott RF. The role of endothelium in the responses of vascular smooth muscle to drugs. Annu Rev Pharmacol Toxicol 1984; 24: 175-197
- 22 McAnulty RJ. Fibroblasts and myofibroblasts: their source, function and role in disease. Int J Biochem Cell Biol 2007; 39: 666-671
- 23 Brecher P. Angiotensin II and cardiac fibrosis. Trends Cardiovasc Med 1996; 6: 193-198
- 24 Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 2000; 52: 11-34
- 25 Porter KE, Turner NA. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther 2009; 123: 255-278
- 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
- 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
- 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
- 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
- 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
- 31 Hügel HM, Jackson N, May B, Zhang AL, Xue CC. Polyphenol protection and treatment of hypertension. Phytomedicine 2016; 23: 220-231
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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