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Planta Med 2024; 90(05): 380-387
DOI: 10.1055/a-2244-8855
Biological and Pharmacological Activity
Original Papers

Affinin, Isolated from Heliopsis longipes, Induces an Antihypertensive Effect That Involves CB1 Cannabinoid Receptors and TRPA1 and TRPV1 Channel Activation

Beatriz A. Luz-Martínez
1   Posgrado en Ciencias Químico Biológicas, Facultad de Química, Universidad Autónoma de Querétaro, Querétaro, México
,
Dailenys Marrero-Morfa
1   Posgrado en Ciencias Químico Biológicas, Facultad de Química, Universidad Autónoma de Querétaro, Querétaro, México
,
Francisco J. Luna-Vázquez
2   Laboratorio de Investigación Química y Farmacológica de Productos Naturales, Facultad de Química, Universidad Autónoma de Querétaro, Centro Universitario, Querétaro, México
,
Alejandra Rojas-Molina
2   Laboratorio de Investigación Química y Farmacológica de Productos Naturales, Facultad de Química, Universidad Autónoma de Querétaro, Centro Universitario, Querétaro, México
,
César Ibarra-Alvarado 
2   Laboratorio de Investigación Química y Farmacológica de Productos Naturales, Facultad de Química, Universidad Autónoma de Querétaro, Centro Universitario, Querétaro, México
› Author AffiliationsBeatriz Adriana Luz-Martínez acknowledges Consejo Nacional de Ciencia y Tecnología (CONACYT) for his doctoral grant. The authors are very grateful to the Autonomous University of Querétaro for the funding granted through the project Química Somos Todos 2023 (FQU202312).
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Abstract

In previous studies, we demonstrated that the ethanolic extract of Heliopsis longipes roots and its main alkamide, affinin, elicit a vasorelaxant effect through a mechanism involving activation of the gasotransmitter pathways and stimulation of cannabinoid type 1 receptors and transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1 channels. However, it has not yet been demonstrated whether the EEH and affinin are capable of lowering high blood pressure. Therefore, the aim of the present study was to determine the effect of the oral administration of the EEH and affinin on the systolic blood pressure of NG-nitro-L-arginine methyl ester-induced hypertensive rats and to explore the participation of cannabinoid receptors and transient receptor potential channels in the mechanism of action of this alkamide. Our results showed that the ethanolic extract of H. longipes and affinin significantly lowered systolic blood pressure and induced an improvement in endothelial function, which is associated with increased serum nitric oxide levels. Inhibition of cannabinoid type 1 receptors by rimonabant (3 mg/kg), transient receptor potential ankyrin 1 channels by HC-030031 (8 mg/kg), and transient receptor potential vanilloid 1 channels by capsazepine (5 mg/kg) significantly decreased the antihypertensive effect induced by affinin, suggesting that the blood pressure-lowering effect of this alkamide involves activation of cannabinoid type 1 receptors and transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1 channels.

Keywords

affinin - Asteraceae - CB1 cannabinoid receptor - Heliopsis longipes - hypertension - TRP channels

Supporting Information

    The effects of the oral administration of EEH and AF for 4 days on SBP are available as Supporting Information.

  • Supporting Information


Publication History

Received: 17 October 2023

Accepted after revision: 14 January 2024

Accepted Manuscript online:
14 January 2024

Article published online:
20 February 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
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  • References

  • 1 Mendis S, Graham I, Narula J. Addressing the global burden of cardiovascular diseases; Need for scalable and sustainable frameworks. Glob Heart 2022; 17: 48
    CrossrefPubMedGoogle Scholar
  • 2 NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants. Lancet 2021; 398: 957-980
    CrossrefPubMedGoogle Scholar
  • 3 Chukwuma CI, Matsabisa MG, Ibrahim MA, Erukainure OL, Chabalala MH, Islam MS. Medicinal plants with concomitant anti-diabetic and anti-hypertensive effects as potential sources of dual acting therapies against diabetes and hypertension: A review. J Ethnopharmacol 2019; 235: 329-360
    CrossrefPubMedGoogle Scholar
  • 4 Cilia-López VG, Aguirre-Rivera JR, Espinosa-Reyes G, Flores-Cano JA, Reyes-Agüero JA, Juárez-Flores BI. Distribution of Heliopsis longipes (Heliantheae: Asteraceae), an endemic resource from Central-Mexico. Rev Chapingo Ser Ciencias For y del Ambient 2014; 20: 47-53
    CrossrefPubMedGoogle Scholar
  • 5 Rios Y, Aguilar-Guadarrama AB, Gutiérrez Mdel C. Analgesic activity of affinin, an alkamide from Heliopsis longipes (Compositae). J Ethnopharmacol 2007; 110: 364-367
    CrossrefPubMedGoogle Scholar
  • 6 Hernández I, Márquez L, Martínez I, Dieguez R, Delporte C, Prieto S, Molina-Torres J, Garrido G. Anti-inflammatory effects of ethanolic extract and alkamides-derived from Heliopsis longipes roots. J Ethnopharmacol 2009; 124: 649-652
    CrossrefPubMedGoogle Scholar
  • 7 Déciga-Campos M, Rios MY, Aguilar-Guadarrama AB. Antinociceptive effect of Heliopsis longipes extract and affinin in mice. Planta Med 2010; 76: 665-670
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Castro-Ruiz JE, Rojas-Molina A, Luna-Vázquez FJ, Rivero-Cruz F, García-Gasca T, Ibarra-Alvarado C. Affinin (Spilanthol), isolated from Heliopsis longipes, induces vasodilation via activation of gasotransmitters and prostacyclin signaling pathways. Int J Mol Sci 2017; 18: 218
    CrossrefPubMedGoogle Scholar
  • 9 Valencia-Guzmán CJ, Castro-Ruiz JE, García-Gasca T, Rojas-Molina A, Romo-Mancillas A, Luna-Vázquez FJ, Rojas-Molina JI, Ibarra-Alvarado C. Endothelial TRP channels and cannabinoid receptors are involved in affinin-induced vasodilation. Fitoterapia 2021; 153: 104985
    CrossrefPubMedGoogle Scholar
  • 10 Bratz IN, Dick GM, Tune JD, Edwards JM, Neeb ZP, Dincer UD, Sturek M. Impaired capsaicin-induced relaxation of coronary arteries in a porcine model of the metabolic syndrome. Am J Physiol Heart Circ Physiol 2008; 294: H2489-H2496
    CrossrefPubMedGoogle Scholar
  • 11 Riera CE, Menozzi-Smarrito C, Affolter M, Michlig S, Munari C, Robert F, Vogel H, Simon SA, le Coutre J. Compounds from Sichuan and Melegueta peppers activate, covalently and non-covalently, TRPA1 and TRPV1 channels. Br J Pharmacol 2009; 157: 1398-1409
    CrossrefPubMedGoogle Scholar
  • 12 Stanley CP, Hind WH, Tufarelli C, OʼSullivan SE. The endocannabinoid anandamide causes endothelium-dependent vasorelaxation in human mesenteric arteries. Pharmacol Res 2016; 113: 356-363
    CrossrefPubMedGoogle Scholar
  • 13 Yang D, Luo Z, Ma S, Wong WT, Ma L, Zhong J, He H, Zhao Z, Cao T, Yan Z, Liu D, Arendshorst WJ, Huang Y, Tepel M, Zhu Z. Activation of TRPV1 by dietary capsaicin improves endothelium-dependent vasorelaxation and prevents hypertension. Cell Metab 2010; 12: 130-141
    CrossrefPubMedGoogle Scholar
  • 14 Torres-Narváez JC, Pérez-Torres I, Castrejón-Téllez V, Varela-López E, Oidor-Chan VH, Guarner-Lans V, Vargas-González Á, Martínez-Memije R, Flores-Chávez P, Cervantes-Yañez EZ, Soto-Peredo CA, Pastelín-Hernández G, Del Valle-Mondragón L. The role of the activation of the TRPV1 receptor and of nitric oxide in changes in endothelial and cardiac function and biomarker levels in hypertensive rats. Int J Environ Res Public Health 2019; 16: 3576
    CrossrefPubMedGoogle Scholar
  • 15 Bondarenko AI. Cannabinoids and cardiovascular system. Adv Exp Med Biol 2019; 1162: 63-87
    CrossrefPubMedGoogle Scholar
  • 16 Wongsawatkul O, Prachayasittikul S, Isarankura-Na-Ayudhya C, Satayavivad J, Ruchirawat S, Prachayasittikul V. Vasorelaxant and antioxidant activities of Spilanthes acmella Murr. Int J Mol Sci 2008; 9: 2724-2744
    CrossrefPubMedGoogle Scholar
  • 17 Jama HA, Muralitharan RR, Xu C, OʼDonnell JA, Bertagnolli M, Broughton BRS, Head GA, Marques FZ. Rodent models of hypertension. Br J Pharmacol 2022; 179: 918-937
    CrossrefPubMedGoogle Scholar
  • 18 Zhao X, Ho D, Gao S, Hong C, Vatner DE, Vatner SF. Arterial pressure monitoring in mice. Curr Protoc Mouse Biol 2011; 1: 105-122
    CrossrefPubMedGoogle Scholar
  • 19 Cariño-Cortés R, Gayosso-De-Lucio JA, Ortiz MI, Sánchez-Gutiérrez M, García-Reyna PB, Cilia-López VG, Pérez-Hernández N, Moreno E, Ponce-Monter H. Antinociceptive, genotoxic and histopathological study of Heliopsis longipes S.F. Blake in mice. J Ethnopharmacol 2010; 130: 216-221
    CrossrefPubMedGoogle Scholar
  • 20 Marrero-Morfa D, Ibarra-Alvarado C, Luna-Vázquez FJ, Estévez M, Ledesma-Miranda E, Rojas-Molina A, Quirino-Barreda CT. Self-microemulsifying system of an ethanolic extract of Heliopsis longipes root for enhanced solubility and release of affinin. AAPS Open 2023; 9: 17
    CrossrefPubMedGoogle Scholar
  • 21 López-Martínez S, Aguilar-Guadarrama AB, Rios Y. Minor alkamides from Heliopsis longipes S.F. Blake (Asteraceae) fresh roots. Phytochem Lett 2011; 4: 275-279
    CrossrefPubMedGoogle Scholar
  • 22 Stein R, Berger M, Santana de Cecco B, Mallmann LP, Terraciano PB, Driemeier D, Rodrigues E, Beys-da-Silva WO, Konrath EL. Chymase inhibition: A key factor in the anti-inflammatory activity of ethanolic extracts and spilanthol isolated from Acmella oleracea . J Ethnopharmacol 2021; 270: 113610
    CrossrefPubMedGoogle Scholar
  • 23 Harrison DG, Coffman TM, Wilcox CS. Pathophysiology of hypertension: The mosaic theory and beyond. Circ Res 2021; 128: 847-863
    CrossrefPubMedGoogle Scholar
  • 24 Huang WC, Wu LY, Hu S, Wu SJ. Spilanthol inhibits COX-2 and ICAM-1 expression via suppression of NF-κB and MAPK signaling in interleukin-1β-stimulated human lung epithelial cells. Inflammation 2018; 41: 1934-1944
    CrossrefPubMedGoogle Scholar
  • 25 Gan Z, Huang D, Jiang J, Li Y, Li H, Ke Y. Captopril alleviates hypertension-induced renal damage, inflammation, and NF-κB activation. Braz J Med Biol Res 2018; 51: e7338
    CrossrefPubMedGoogle Scholar
  • 26 Pakdeechote P, Meephat S, Sakonsinsiri C, Phetcharaburanin J, Bunbupha S, Maneesai P. Syzygium gratum extract alleviates vascular alterations in hypertensive rats. Medicina (Kaunas) 2020; 56: 509
    CrossrefPubMedGoogle Scholar
  • 27 Konukoglu D, Uzun H. Endothelial dysfunction and hypertension. Adv Exp Med Biol 2016; 956: 511-540
    CrossrefPubMedGoogle Scholar
  • 28 Bakhle YS. How ACE inhibitors transformed the renin–angiotensin system. Br J Pharmacol 2020; 177: 2657-2665
    CrossrefPubMedGoogle Scholar
  • 29 Hannan RE, Davis EA, Widdop RE. Functional role of angiotensin II AT2 receptor in modulation of AT1 receptor-mediated contraction in rat uterine artery: Involvement of bradykinin and nitric oxide. Br J Pharmacol 2003; 140: 987-995
    CrossrefPubMedGoogle Scholar
  • 30 Stanley C, OʼSullivan SE. Vascular targets for cannabinoids: Animal and human studies. Br J Pharmacol 2014; 171: 1361-1378
    CrossrefPubMedGoogle Scholar
  • 31 Guo Z, Liu YX, Yuan F, Ma HJ, Maslov L, Zhang Y. Enhanced vasorelaxation effect of endogenous anandamide on thoracic aorta in renal vascular hypertension rats. Clin Exp Pharmacol Physiol 2015; 42: 950-955
    CrossrefPubMedGoogle Scholar
  • 32 Yien RMK, Gomes ACC, Goetze Fiorot R, Miranda ALP, Neves GA, Andrade BDS, Costa FN, Tributino JLM, Simas NK. Alkylamides from Acmella oleracea: antinociceptive effect and molecular docking with cannabinoid and TRPV1 receptors. Nat Prod Res 2023; 37: 3136-3144
    CrossrefPubMedGoogle Scholar
  • 33 Lake KD, Martin BR, Kunos G, Varga K. Cardiovascular effects of anandamide in anesthetized and conscious normotensive and hypertensive rats. Hypertension 1997; 29: 1204-1210
    CrossrefPubMedGoogle Scholar
  • 34 Woelkart K, Xu W, Pei Y, Makriyannis A, Picone RP, Bauer R. The endocannabinoid system as a target for alkamides from Echinacea angustifolia roots. Planta Med 2005; 71: 701-705
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Dimmito MP, Stefanucci A, Della Valle A, Scioli G, Cichelli A, Mollica A. An overview on plants cannabinoids endorsed with cardiovascular effects. Biomed Pharmacother 2021; 142: 111963
    CrossrefPubMedGoogle Scholar
  • 36 Li J, Kaminski NE, Wang DH. Anandamide-induced depressor effect in spontaneously hypertensive rats: Role of the vanilloid receptor. Hypertension 2003; 41: 757-762
    CrossrefPubMedGoogle Scholar
  • 37 de la Rosa-Lugo V, Acevedo-Quiroz M, Déciga-Campos M, Rios MY. Antinociceptive effect of natural and synthetic alkamides involves TRPV1 receptors. J Pharm Pharmacol 2017; 69: 884-895
    CrossrefPubMedGoogle Scholar
  • 38 Wang Z, Ye D, Ye J, Wang M, Liu J, Jiang H, Xu Y, Zhang J, Chen J, Wan J. The TRPA1 channel in the cardiovascular system: Promising features and challenges. Front Pharmacol 2019; 10: 1253
    CrossrefPubMedGoogle Scholar
  • 39 Peixoto-Neves D, Soni H, Adebiyi A. CGRPergic nerve TRPA1 channels contribute to epigallocatechin gallate-induced neurogenic vasodilation. ACS Chem Neurosci 2019; 10: 216-220
    CrossrefPubMedGoogle Scholar
  • 40 Eberhardt M, Dux M, Namer B, Miljkovic J, Cordasic N, Will C, Kichko TI, de la Roche J, Fischer M, Suárez SA, Bikiel D, Dorsch K, Leffler A, Babes A, Lampert A, Lennerz JK, Jacobi J, Martí MA, Doctorovich F, Högestätt ED, Zygmunt PM, Ivanovic-Burmazovic I, Messlinger K, Reeh P, Filipovic MR. H2S and NO cooperatively regulate vascular tone by activating a neuroendocrine HNO-TRPA1-CGRP signalling pathway. Nat Commun 2014; 5: 4381
    CrossrefPubMedGoogle Scholar
  • 41 Pozsgai G, Bodkin JV, Graepel R, Bevan S, Andersson DA, Brain SD. Evidence for the pathophysiological relevance of TRPA1 receptors in the cardiovascular system in vivo . Cardiovasc Res 2010; 87: 760-768
    CrossrefPubMedGoogle Scholar
  • 42 Luna-Vázquez FJ, Ibarra-Alvarado C, Rojas-Molina A, Rojas-Molina JI, Yahia EM, Rivera-Pastrana DM, Rojas-Molina A, Zavala-Sánchez MÁ. Nutraceutical value of black cherry Prunus serotina Ehrh. fruits: Antioxidant and antihypertensive properties. Molecules 2013; 18: 14597-14612
    CrossrefPubMedGoogle Scholar
  • 43 Rezq S, Hassan R, Mahmoud MF. Rimonabant ameliorates hepatic ischemia/reperfusion injury in rats: Involvement of autophagy via modulating ERK- and PI3K/AKT-mTOR pathways. Int Immunopharmacol 2021; 100: 108140
    CrossrefPubMedGoogle Scholar
  • 44 Chung CL, Lin YS, Chan NJ, Chen YY, Hsu CC. Hypersensitivity of airway reflexes induced by hydrogen sulfide: Role of TRPA1 receptors. Int J Mol Sci 2020; 21: 3929
    CrossrefPubMedGoogle Scholar
  • 45 Kukula O, Çiçekli MN, Şafak S, Günaydın C. Role of TRPV1 channels on glycogen synthase kinase-3β and oxidative stress in ouabain-induced bipolar disease. J Recept Signal Transduct Res 2021; 42: 338-348
    CrossrefPubMedGoogle Scholar