Vasorelaxant effects of ellagitannins isolated from Cuphea carthagenensis

Abstract

Cuphea carthagenensis (Jacq.) J. F. Macbr. is a popular plant in Brazilian folk medicine owing to its hypotensive and central nervous system depressant effects. This study aimed to validate the hypotensive effect of the plantʼs aqueous extract (AE) in rats and examine the vascular actions of three hydrolyzable tannins, oenothein B, woodfordin C, and eucalbanin B, isolated from AE. Systolic blood pressure in unanesthetized rats was determined using the non-invasive tail-cuff method. Oral treatment of normotensive rats with 0.5 and 1.0 g/kg/day AE induced a dose-related hypotensive effect after 1 week. In rat aortic rings pre-contracted with noradrenaline, all ellagitannins (20 – 180 µM) induced a concentration-related vasorelaxation. This effect was blocked by either removing the endothelium or pre-incubating with N^G-nitro-l-arginine methyl ester (10 µM), an inhibitor of nitric oxide (NO) synthase. In KCl-depolarized rat portal vein preparations, the investigated compounds did not affect significantly the maximal contractile responses and pD2 values of the concentration-response curves to CaCl₂. Our results demonstrated the hypotensive effect of C. carthagenensis AE in unanesthetized rats. All isolated ellagitannins induced vasorelaxation in vitro via activating NO synthesis/NO release from endothelial cells, without altering the Ca²⁺ influx in vascular smooth muscle preparations. Considering the low oral bioavailability of ellagitannins, the determined in vitro actions of these compounds are unlikely to account for the hypotensive effect of AE in vivo. It remains to be determined the role of the bioactive ellagitannin-derived metabolites in the hypotensive effect observed after oral treatment of unanesthetized rats with the plant extract.

Key words

Cuphea carthagenensis - Lythraceae - hypotension - ellagitannins - vasorelaxation - aortic rings

Publication History

Received: 07 July 2023

Accepted after revision: 27 December 2023

Article published online:
25 January 2024

• References

• 1 Lapa AJ. Bioprospecting in Brazil: Alternative approaches toward producing autochthonic medicines. 2002 Accessed August 21, 2002 at: http://nextwave.sciencemag.org/cgi/content/full/2002/07/30/1
• 2 World Health Organization. The declaration of Alma Ata. Presented at the international conference on primary health care, Alma Ata. WHO Chron 1978; 32: 428-430
• 3 Lorenzi H, Matos FJA. Cuphea carthagenensis (Jacq.) J.F. Macbr. In: Plantas Medicinais no Brasil: Nativas e Exóticas Cultivadas. Nova Odessa, São Paulo: Instituto Plantarum; 2002: 321-322
• 4 Das A, Chaudary SK, Bhat HR, Shakya A. Cuphea Carthagenensis: A review of its ethnobotany, pharmacology and phytochemistry. Bull Arunachal Forest Res 2018; 33: 01-14
• 5 Graham SA. Cuphea: A new plant source of medium-chain fatty acids. Crit Rev Food Sci Nutr 1989; 28: 139-173
• 6 Ramos LCS, Roath MW, Cavalcanti TB, Kirkbride JH. Cuphea (Lythraceae) Descriptors. Staff Report. North Central Regional Plant Introduction Station. Agriculture and Home Experiment Station. Ames, Iowa: Iowa State University of Science and Technology; 1992: 41
• 7 Wang CC, Chen LG, Yang LL. Antitumor activity of four macrocyclic ellagitannins from Cuphea hyssopifolia . Cancer Lett 1999; 140: 195-200
• 8 Schuldt EZ, Ckless K, Simas ME, Farias MR, Ribeiro-do-Valle RM. Butanolic fraction from Cuphea carthagenensis Jacq McBride relaxes rat thoracic aorta through endothelium-dependent and endothelium-independent mechanisms. J Cardiovasc Pharmacol 2000; 35: 234-239
• 9 Schuldt EZ, Farias MR, Ribeiro-do-Valle RM, Ckless K. Comparative study of radical scavenger activities of crude extract and fractions from Cuphea carthagenensis leaves. Phytomedicine 2004; 11: 523-529
• 10 Andrighetti-Frohner CR, Sincero TCM, da Silva AC, Savia LA, Gaido CM, Bettega JMR, Mancini M, de Almeida MTR, Barbosa RA, Farias MR, Barardi CRM, Simões CMO. Antiviral evaluation of plants from Brazilian Atlantic Tropical Forest. Fitoterapia 2005; 76: 374-378
• 11 Fernandes FR, Santos AL, Arruda AMS, Vasques-Pinto LMC, Godinho RO, Torres LMB, Lapa AJ, Souccar C. Antinociceptive and anti-inflammatory activities of the aqueous extract and isolated fraction of Cuphea carthagenensis (Jacq.) J. F. Macbr. Rev Bras Farmacogn 2002; 12: 55-56
• 12 Santos DYAC, Salatino MLF, Salatino A. Flavonoids of species of Cuphea (Lythraceae) from Brazil. Biochem Syst Ecol 1995; 23: 99-103
• 13 Krepsky PB, Isidório RG, de Souza Filho JD, Côrtes SF, Braga FC. Chemical composition and vasodilatation induced by Cuphea carthagenensis preparations. Phytomedicine 2012; 19: 953-957
• 14 Tanae MM, Diaz IEC, Lima-Landman MTR, Souccar C, Lapa AJ. Isolation of tannins and flavonoids from Cuphea carthagenensis (Jacq.) J.F. Macbr. by High Performance Liquid Chromatography. XX Simpósio de Plantas Medicinais do Brasil, X International Congress of Ethnopharmacology, São Paulo, SP, 2008; Abstr. 05.309.
• 15 Knapp SJ, Tagliani LA, Roath WW. Fatty acid and oil diversity of Cuphea viscosissima: A source of medium-chain fatty acids. J Am Oil Chem Soc 1991; 68: 515-517
• 16 Chen LG, Yen KY, Yang LL, Hatano T, Okuda T, Yoshida T. Macrocyclic ellagitannin dimers, cuphiins D₁ and D₂, and accompanying tannins from Cuphea hyssopifolia . Phytochemistry 1999; 50: 307-312
• 17 González AG, Valencia E, Expósito TS, Barrera JB, Gupta MP. Chemical components of Cuphea species. Carthagenol: A new triterpene from C. carthagenensis . Planta Medica 1994; 60: 592-593
• 18 Ericeira VR, Martins MMR, Souccar C, Lapa AJ. Atividade farmacológica do extrato etanólico da “sete-sangrias”, Cuphea balsamona Cham & Schltd. Cad. Pesq. São Luís: Universidade Federal do Maranhão 1985; 1: 44-62
• 19 Lorenzo MA, Lapa AJ, De Lima TCM. Nicotinic mechanism involved in the anxiolytic-like effect produced by Cuphea carthagenensis (Jacq.) J.F. Macbr. XVI Latinamerican Congress of Pharmacology, 2000; Abstr. 10.182.
• 20 Neves SMB, Vieira CB, Parisoto RE, Lima TCM, Souccar C, Lapa AJ, Lima-Landman MTR. Avaliação da Cuphea carthagenensis em modelo de depressão e na captação de monoaminas. 39 °Congresso Brasileiro de Farmacologia e Terapêutica Experimental. Ribeirão Preto, SP 2007; Abstr. 09.150.
• 21 Neves SMB. Actions of flavonoids isolated from Cuphea carthagenensis (Jacq.) J.F. Macbr on the concentration of brain monoamines [Thesis (MS)]. São Paulo: Universidade Federal de São Paulo; 2008: 77
• 22 Beech DJ. Actions of neurotransmitters and other messengers on Ca²⁺ channels and K⁺ channels in smooth muscle cells. Pharmacol Ther 1997; 73: 91-119
• 23 Hallam TJ, Jacob R, Merritt JE. Evidence that agonists stimulate bivalent-cation influx into human endothelial cells. J Biochemistry 1988; 255: 179-184
• 24 Coimbra R. Notas de Fitoterapia. Catálogo dos dados principais sobre Plantas utilizadas em Medicina e Farmácia. 2nd Ed.. Rio de Janeiro – RJ: Laboratorio Clínico Silva Araujo; 1958: 95
• 25 Yoshida T, Amakura Y, Yoshimura M. Structural features and biological properties of ellagitannins in some plant families of the order Myrtales. Int J Mol Sci 2010; 11: 79-106
• 26 Adamczyk B, Simon J, Kitunen V, Adamczyk S, Smolander A. Tannins and their complex interaction with different organic nitrogen compounds and enzymes: Old paradigms versus Recent Advances. ChemistryOpen 2017; 6: 610-614
• 27 Yoshida T, Yoshimura M, Amakura Y. Chemical and biological significance of oenothein B and related ellagitannin oligomers with macrocyclic structure. Molecules 2018; 23: 552
• 28 Akata T. Cellular and molecular mechanisms regulating vascular tone. Part 1: basic mechanisms controlling cytosolic Ca²⁺ concentration and the Ca²⁺-dependent regulation of vascular tone. J Anesth 2007; 21: 220-231
• 29 Triggle CR, Samuel SM, Ravishankar S, Marei I, Ding H. The endothelium: Influencing vascular smooth muscle in many ways. Can J Physiol Pharmacol 2012; 90: 713-738
• 30 Tang F, Yan HL, Wang LX, Xu JF, Peng C, Ao H, Tan YZ. Review of natural resources with vasodilation: Traditional medicinal plants, natural products, and their mechanism and clinical efficacy. Front Pharmacol 2021; 12: 627458
• 31 Okuyama S, Furukawa Y, Yoshimura M, Amakura Y, Nakajima M, Yoshida T. Oenothein B, a bioactive ellagitannin, activates the extracellular signal-regulated kinase 2 signaling pathway in the mouse brain. Plants (Basel) 2021; 10: 1030
• 32 Larrosa M, García-Conesa MT, Espín JC, Tomás-Barberán FA. Ellagitannins, ellagic acid and vascular health. Mol Aspects Med 2010; 31: 513-539
• 33 Landete JM. Ellagitannins, ellagic acid and their derived metabolites: A review about source, metabolism, functions and health. Food Res Int 2011; 44: 1150-1160
• 34 Espín JC, Larrosa M, García-Conesa MT, Tomás-Barberán F. Biological significance of urolithins, the gut microbial ellagic acid-derived metabolites. Evid Based Complement Alternat Med 2013; 2013: 270418
• 35 Ríos JL, Giner RM, Marín M, Recio MC. A pharmacological update of ellagic acid. Planta Med 2018; 84: 1068-1093
• 36 Alfei S, Marengo B, Zuccari G. Oxidative stress, antioxidant capabilities, and bioavailability: Ellagic acid or urolithins?. Antioxidants 2020; 9: 707
• 37 Sharifi-Rad J, Quispe C, Castillo CMS, Caroca R, Lazo-Vélez MA, Antonyak H, Polishchuk A, Lysiuk R, Oliinyk P, De Mais L, Bontempo P, Martorell M, Daştan SD, Rigano D, Wink M, Cho WC. Ellagic Acid: A Review on Its Natural Sources, Chemical Stability, and Therapeutic Potential. Oxid Med Cell Longev 2022; 2022: 3848084
• 38 Yılmaz B, Usta C. Ellagic acid-induced endothelium-dependent and endothelium-independent vasorelaxation in rat thoracic aortic rings and the underlying mechanism. Phytother Res 2013; 27: 285-289
• 39 Berkban T, Boonprom P, Bunbupha S, Welbat JU, Kukongviriyapan U, Kukongviriyapan V, Pakdeechote P, Prachaney P. Ellagic acid prevents l-NAME-induced hypertension via restoration of eNOS and p 47phox expression in rats. Nutrients 2015; 7: 5265-5280
• 40 Jordão JBR, Porto HKP, Lopes FM, Batista AC, Rocha ML. Protective effects of ellagic acid on cardiovascular injuries caused by hypertension in rats. Planta Med 2017; 83: 830-836
• 41 Hasheminezhad SH, Boozari M, Iranshahi M, Yazarlu O, Sahebkar A, Hasanpour M, Iranshahy M. A mechanistic insight into the biological activities of urolithins as gut microbial metabolites of ellagitannins. Phytother Res 2022; 36: 112-146
• 42 Spigoni V, Mena P, Cito M, Fantuzzi F, Bonadonna RC, Brighenti F, Dei Cas A, Del Rio D. Effects on nitric oxide production of urolithins, gut-derived ellagitannin metabolites, in human aortic endothelial cells. Molecules 2016; 21: 1009
• 43 Lima-Landman MT, Borges AC, Cysneiros RM, De Lima TC, Souccar C, Lapa AJ. Antihypertensive effect of a standardized aqueous extract of Cecropia glaziovii Sneth in rats: an in vivo approach to the hypotensive mechanism. Phytomedicine 2007; 14: 314-320
• 44 Garcia FA, Tanae MM, Torres LM, Lapa AJ, Lima-Landman MT, Souccar C. A comparative study of two clerodane diterpenes from Baccharis trimera (Less.) DC on the influx and mobilization of intracellular calcium in rat cardiomyocytes. Phytomedicine 2014; 21: 1021-1025
• 45 Merritt JE, Jacob R, Hallam TJ. Use of manganese to discriminate between calcium influx and mobilization from internal stores in stimulated human neutrophils. J Biol Chem 1989; 264: 1522-1527