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Review Article

Alkaloids as Vasodilator Agents: A Review

Author(s): Ayoub Amssayef and Mohamed Eddouks*

Volume 29, Issue 24, 2023

Published on: 16 August, 2023

Page: [1886 - 1895] Pages: 10

DOI: 10.2174/1381612829666230809094313

Price: $65

Abstract

The pathophysiology of hypertension is often associated with endothelial dysfunction and the impairment of endothelium-dependent vasodilation mechanisms, as well as alterations in vascular smooth muscle (VSM) tone. Natural products, particularly alkaloids, have received increased attention in the search for new vasodilator agents. This review aims to summarize the noteworthy results from ex-vivo and in-vitro studies that explored the vasodilatory effects of some selected alkaloids (Berberine, Sinomenine, (S)-Reticuline, Neferine, Nuciferine, Villocarine A, 8-Oxo-9-Dihydromakonakine, Harmaline, Harman, and Capsaicin) and the underlying mechanisms implicated. The results obtained from the literature revealed that these selected alkaloids exhibited vasodilation in various vascular models, including mesenteric, carotid, and coronary arteries, thoracic aorta, and cultured HUCECs and VSMCs. Furthermore, most of these alkaloids induced vasodilation through endothelium- dependent and endothelium-independent mechanisms, which were primarily mediated by activating eNOS/NO/sGC/cGMP pathway, opening various potassium (K+) channels, or modulating calcium (Ca2+) channels. Additionally, several alkaloids exerted vasodilatory effects through multiple mechanism pathways. Moreover, different alkaloids demonstrated the ability to protect endothelial function by reducing oxidative stress, endoplasmic reticulum and inflammation. In conclusion, this class of secondary metabolites holds interesting therapeutic potential in the prevention and treatment of cardiovascular diseases (CVD), particularly hypertension.

Keywords: Vasodilator agents, hypertension, alkaloids, vascular endothelium, vascular smooth muscle, eNOS/NO/sGC/cGMP pathway, potassium (K+) channels, calcium (Ca2+) channels.

« Previous Next »
[1]
Mills KT, Stefanescu A, He J. The global epidemiology of hypertension. Nat Rev Nephrol 2020; 16(4): 223-37.
[http://dx.doi.org/10.1038/s41581-019-0244-2] [PMID: 32024986]
[2]
Fuchs FD, Whelton PK. High blood pressure and cardiovascular disease. Hypertension 2020; 75(2): 285-92.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14240] [PMID: 31865786]
[3]
Méndez-Barbero N, Gutiérrez-Muñoz C, Blanco-Colio L. Cellular crosstalk between endothelial and smooth muscle cells in vascular wall remodeling. Int J Mol Sci 2021; 22(14): 7284.
[http://dx.doi.org/10.3390/ijms22147284] [PMID: 34298897]
[4]
Wilson C, Zhang X, Buckley C, Heathcote HR, Lee MD, McCarron JG. Increased vascular contractility in hypertension results from impaired endothelial calcium signaling. Hypertension 2019; 74(5): 1200-14.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13791] [PMID: 31542964]
[5]
Zsotér TT. Vasodilators. Can Med Assoc J 1983; 129(5): 424-428, 432.
[PMID: 6349763]
[6]
Hariri L, Patel JB. Vasodilators. StatPearls. Treasure Island, FL: StatPearls Publishing 2023.
[7]
Shimokawa H, Godo S. Nitric oxide and endothelium-dependent hyperpolarization mediated by hydrogen peroxide in health and disease. Basic Clin Pharmacol Toxicol 2020; 127(2): 92-101.
[http://dx.doi.org/10.1111/bcpt.13377] [PMID: 31846200]
[8]
Zhao Y, Vanhoutte PM, Leung SWS. Vascular nitric oxide: Beyond eNOS. J Pharmacol Sci 2015; 129(2): 83-94.
[http://dx.doi.org/10.1016/j.jphs.2015.09.002] [PMID: 26499181]
[9]
Krishnan S, Kraehling J, Eitner F, Bénardeau A, Sandner P. The impact of the nitric oxide (NO)/soluble guanylyl cyclase (sGC) signaling cascade on kidney health and disease: A preclinical perspective. Int J Mol Sci 2018; 19(6): 1712.
[http://dx.doi.org/10.3390/ijms19061712] [PMID: 29890734]
[10]
Ameer OZ, Salman IM, Siddiqui MJA, et al. Pharmacological mechanisms underlying the vascular activities of Loranthus ferrugineus Roxb. in rat thoracic aorta. J Ethnopharmacol 2010; 127(1): 19-25.
[http://dx.doi.org/10.1016/j.jep.2009.09.057] [PMID: 19808083]
[11]
Tanaka Y, Yamaki F, Koike K, Toro L. New insights into the intracellular mechanisms by which PGI2 analogues elicit vascular relaxation: Cyclic AMP-independent, Gs-protein mediated-activation of MaxiK channel. Curr Med Chem Cardiovasc Hematol Agents 2004; 2(3): 257-65.
[http://dx.doi.org/10.2174/1568016043356273] [PMID: 15320791]
[12]
Walch L, Gascard JP, Dulmet E, Brink C, Norel X. Evidence for a M1 muscarinic receptor on the endothelium of human pulmonary veins. Br J Pharmacol 2000; 130(1): 73-8.
[http://dx.doi.org/10.1038/sj.bjp.0703301] [PMID: 10781000]
[13]
Kellogg DL Jr, Zhao JL, Coey U, Green JV. Acetylcholine-induced vasodilation is mediated by nitric oxide and prostaglandins in human skin. J Appl Physiol 2005; 98(2): 629-32.
[http://dx.doi.org/10.1152/japplphysiol.00728.2004] [PMID: 15649880]
[14]
Ludmer PL, Selwyn AP, Shook TL, et al. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 1986; 315(17): 1046-51.
[http://dx.doi.org/10.1056/NEJM198610233151702] [PMID: 3093861]
[15]
Rodríguez C, Muñoz M, Contreras C, Prieto D. AMPK, metabolism, and vascular function. FEBS J 2021; 288(12): 3746-71.
[http://dx.doi.org/10.1111/febs.15863] [PMID: 33825330]
[16]
Kee Z, Kodji X, Brain SD. The role of calcitonin gene related peptide (CGRP) in neurogenic vasodilation and its cardioprotective effects. Front Physiol 2018; 9: 1249.
[http://dx.doi.org/10.3389/fphys.2018.01249] [PMID: 30283343]
[17]
Russell FA, King R, Smillie SJ, Kodji X, Brain SD. Calcitonin gene-related peptide: Physiology and pathophysiology. Physiol Rev 2014; 94(4): 1099-142.
[http://dx.doi.org/10.1152/physrev.00034.2013] [PMID: 25287861]
[18]
Guo Y, Zhang Q, Chen H, Jiang Y, Gong P. The protective role of calcitonin gene-related peptide (CGRP) in high-glucose-induced oxidative injury in rat aorta endothelial cells. Peptides 2019; 121: 170121.
[http://dx.doi.org/10.1016/j.peptides.2019.170121] [PMID: 31386894]
[19]
Dobovišek L, Hojnik M, Ferk P. Overlapping molecular pathways between cannabinoid receptors type 1 and 2 and estrogens/androgens on the periphery and their involvement in the pathogenesis of common diseases (review). Int J Mol Med 2016; 38(6): 1642-51.
[http://dx.doi.org/10.3892/ijmm.2016.2779] [PMID: 27779654]
[20]
Liu J, Gao B, Mirshahi F, et al. Functional CB1 cannabinoid receptors in human vascular endothelial cells. Biochem J 2000; 346(3): 835-40.
[http://dx.doi.org/10.1042/bj3460835] [PMID: 10698714]
[21]
López-Dyck E, Andrade-Urzúa F, Elizalde A, et al. ACPA and JWH-133 modulate the vascular tone of superior mesenteric arteries through cannabinoid receptors, BKCa channels, and nitric oxide dependent mechanisms. Pharmacol Rep 2017; 69(6): 1131-9.
[http://dx.doi.org/10.1016/j.pharep.2017.06.011] [PMID: 29128791]
[22]
Sánchez-Pastor E, Andrade F, Sánchez-Pastor JM, et al. Cannabinoid receptor type 1 activation by arachidonylcyclopropylamide in rat aortic rings causes vasorelaxation involving calcium-activated potassium channel subunit alpha-1 and calcium channel, voltage-dependent, L type, alpha 1C subunit. Eur J Pharmacol 2014; 729: 100-6.
[http://dx.doi.org/10.1016/j.ejphar.2014.02.016] [PMID: 24561046]
[23]
Jackson WF. Potassium channels in the peripheral microcirculation. Microcirculation 2005; 12(1): 113-27.
[http://dx.doi.org/10.1080/10739680590896072] [PMID: 15804979]
[24]
Brozovich FV, Nicholson CJ, Degen CV, Gao YZ, Aggarwal M, Morgan KG. Mechanisms of vascular smooth muscle contraction and the basis for pharmacologic treatment of smooth muscle disorders. Pharmacol Rev 2016; 68(2): 476-532.
[http://dx.doi.org/10.1124/pr.115.010652] [PMID: 27037223]
[25]
Martín P, Rebolledo A, Palomo ARR, Moncada M, Piccinini L, Milesi V. Diversity of potassium channels in human umbilical artery smooth muscle cells: A review of their roles in human umbilical artery contraction. Reprod Sci 2014; 21(4): 432-41.
[http://dx.doi.org/10.1177/1933719113504468] [PMID: 24084522]
[26]
Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: Molecular regulation to clinical use. Pharmacol Rev 2006; 58(3): 488-520.
[http://dx.doi.org/10.1124/pr.58.3.5] [PMID: 16968949]
[27]
Graham RM, Lanier SM. Identification and characterization of alpha-adrenergic receptors. The Heart and Cardiovascular System. New York: Raven Press 1986; pp. 1059-96.
[28]
Perez DM. Current developments on the role of α1-adrenergic receptors in cognition, cardioprotection, and metabolism. Front Cell Dev Biol 2021; 9: 652152.
[http://dx.doi.org/10.3389/fcell.2021.652152] [PMID: 34113612]
[29]
Tang F, Yan HL, Wang LX, et al. Review of natural resources with vasodilation: Traditional medicinal plants, natural products, and their mechanism and clinical efficacy. Front Pharmacol 2021; 12: 627458.
[http://dx.doi.org/10.3389/fphar.2021.627458] [PMID: 33867985]
[30]
Enseleit F, Hürlimann D, Lüscher TF. Vascular protective effects of angiotensin converting enzyme inhibitors and their relation to clinical events. J Cardiovasc Pharmacol 2001; 37 (Suppl. 1): S21-30.
[http://dx.doi.org/10.1097/00005344-200109011-00004] [PMID: 11392475]
[31]
Simões SC, Balico-Silva AL, Parreiras-e-Silva LT, Bitencourt ALB, Bouvier M, Costa-Neto CM. Signal transduction profiling of angiotensin II type 1 receptor with mutations associated to atrial fibrillation in humans. Front Pharmacol 2020; 11: 600132.
[http://dx.doi.org/10.3389/fphar.2020.600132] [PMID: 33424609]
[32]
Hanif K, Bid HK, Konwar R. Reinventing the ACE inhibitors: Some old and new implications of ACE inhibition. Hypertens Res 2010; 33(1): 11-21.
[http://dx.doi.org/10.1038/hr.2009.184] [PMID: 19911001]
[33]
Luna-Vázquez F, Ibarra-Alvarado C, Rojas-Molina A, Rojas-Molina I, Zavala-Sánchez M. Vasodilator compounds derived from plants and their mechanisms of action. Molecules 2013; 18(5): 5814-57.
[http://dx.doi.org/10.3390/molecules18055814] [PMID: 23685938]
[34]
Ghosh D, Syed AU, Prada MP, et al. Calcium channels in vascular smooth muscle. Adv Pharmacol 2017; 78: 49-87.
[http://dx.doi.org/10.1016/bs.apha.2016.08.002] [PMID: 28212803]
[35]
Cao YX, Zhang W, He JY, He LC, Xu CB. Ligustilide induces vasodilatation via inhibiting voltage dependent calcium channel and receptor-mediated Ca2+ influx and release. Vascul Pharmacol 2006; 45(3): 171-6.
[http://dx.doi.org/10.1016/j.vph.2006.05.004] [PMID: 16807126]
[36]
Earley S, Brayden JE. Transient receptor potential channels in the vasculature. Physiol Rev 2015; 95(2): 645-90.
[http://dx.doi.org/10.1152/physrev.00026.2014] [PMID: 25834234]
[37]
Randhawa PK, Jaggi AS. TRPV1 and TRPV4 channels: Potential therapeutic targets for ischemic conditioning-induced cardioprotection. Eur J Pharmacol 2015; 746: 180-5.
[http://dx.doi.org/10.1016/j.ejphar.2014.11.010] [PMID: 25449039]
[38]
Liu L, Guo M, Lv X, et al. Role of transient receptor potential vanilloid 4 in vascular function. Front Mol Biosci 2021; 8: 677661.
[http://dx.doi.org/10.3389/fmolb.2021.677661] [PMID: 33981725]
[39]
Knox M, Vinet R, Fuentes L, Morales B, Martínez JL. A review of endothelium-dependent and-independent vasodilation induced by phytochemicals in isolated rat aorta. Animals (Basel) 2019; 9(9): 623.
[http://dx.doi.org/10.3390/ani9090623] [PMID: 31470540]
[40]
Hong KS, Lee MG. Endothelial Ca2+ signaling-dependent vasodilation through transient receptor potential channels. Korean J Physiol Pharmacol 2020; 24(4): 287-98.
[http://dx.doi.org/10.4196/kjpp.2020.24.4.287] [PMID: 32587123]
[41]
Bhambhani S, Kondhare KR, Giri AP. Diversity in chemical structures and biological properties of plant alkaloids. Molecules 2021; 26(11): 3374.
[http://dx.doi.org/10.3390/molecules26113374] [PMID: 34204857]
[42]
Bruce SO. Secondary Metabolites from Natural Products. Secondary Metabolites: Trends and Reviews. London: IntechOpen 2022; p. 51.
[http://dx.doi.org/10.5772/intechopen.102222]
[43]
Matsuura HN, Fett-Neto AG. Plant alkaloids: Main features, toxicity, and mechanisms of action. Plant Toxins. Heidelberg: Springer 2015; pp. 1-15.
[http://dx.doi.org/10.1007/978-94-007-6728-7_2-1]
[44]
Buckingham J, Baggaley KH, Roberts AD, Szabo LF. Dictionary of alkaloids, with CD-ROM. Boca Raton, FL: CRC Press 2010.
[http://dx.doi.org/10.1201/EBK1420077698]
[45]
Gutiérrez-Grijalva EP, López-Martínez LX, Contreras-Angulo LA, Elizalde-Romero CA, Heredia JB. Plant alkaloids: Structures and bioactive properties. Plant-derived Bioactives: Chemistry and Mode of Action. Singapore: Springer 2020; pp. 85-117.
[http://dx.doi.org/10.1007/978-981-15-2361-8_5]
[46]
Hussain G, Rasul A, Anwar H, et al. Role of plant derived alkaloids and their mechanism in neurodegenerative disorders. Int J Biol Sci 2018; 14(3): 341-57.
[http://dx.doi.org/10.7150/ijbs.23247] [PMID: 29559851]
[47]
Aniszewski T. Alkaloids: Chemistry, biology, ecology, and applications. (2nd ed.), Pacific Grove, CA: Elsevier 2015.
[48]
Kumar A, Aswal S, Semwal RB, Chauhan A, Joshi SK, Semwal DK. Role of plant-derived alkaloids against diabetes and diabetes-related complications: A mechanism-based approach. Phytochem Rev 2019; 18(5): 1277-98.
[http://dx.doi.org/10.1007/s11101-019-09648-6]
[49]
Feng X, Sureda A, Jafari S, et al. Berberine in cardiovascular and metabolic diseases: From mechanisms to therapeutics. Theranostics 2019; 9(7): 1923-51.
[http://dx.doi.org/10.7150/thno.30787] [PMID: 31037148]
[50]
Ai X, Yu P, Peng L, et al. Berberine: A review of its pharmacokinetics properties and therapeutic potentials in diverse vascular diseases. Front Pharmacol 2021; 12: 762654.
[http://dx.doi.org/10.3389/fphar.2021.762654] [PMID: 35370628]
[51]
Ko WH, Yao XQ, Lau CW, et al. Vasorelaxant and antiproliferative effects of berberine. Eur J Pharmacol 2000; 399(2-3): 187-96.
[http://dx.doi.org/10.1016/S0014-2999(00)00339-3] [PMID: 10884519]
[52]
Kang DG, Sohn EJ, Kwon EK, Han JH, Oh H, Lee HS. Effects of berberine on angiotensin-converting enzyme and NO/cGMP system in vessels. Vascul Pharmacol 2002; 39(6): 281-6.
[http://dx.doi.org/10.1016/S1537-1891(03)00005-3] [PMID: 14567065]
[53]
Wang J, Guo T, Peng QS, Yue SW, Wang SX. Berberine via suppression of transient receptor potential vanilloid 4 channel improves vascular stiffness in mice. J Cell Mol Med 2015; 19(11): 2607-16.
[http://dx.doi.org/10.1111/jcmm.12645] [PMID: 26177349]
[54]
Liu L, Liu J, Huang Z, et al. Berberine improves endothelial function by inhibiting endoplasmic reticulum stress in the carotid arteries of spontaneously hypertensive rats. Biochem Biophys Res Commun 2015; 458(4): 796-801.
[http://dx.doi.org/10.1016/j.bbrc.2015.02.028] [PMID: 25686503]
[55]
Geng FH, Li GH, Zhang X, et al. Berberine improves mesenteric artery insulin sensitivity through up-regulating insulin receptor- mediated signalling in diabetic rats. Br J Pharmacol 2016; 173(10): 1569-79.
[http://dx.doi.org/10.1111/bph.13466] [PMID: 26914282]
[56]
Wang Y, Huang Y, Lam KSL, et al. Berberine prevents hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase. Cardiovasc Res 2009; 82(3): 484-92.
[http://dx.doi.org/10.1093/cvr/cvp078] [PMID: 19251722]
[57]
Lee PY, Chen W, Liu IM, Cheng JT. Vasodilatation induced by sinomenine lowers blood pressure in spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 2007; 34(10): 979-84.
[http://dx.doi.org/10.1111/j.1440-1681.2007.04668.x] [PMID: 17714082]
[58]
Martin M, Diaz M, Montero M, Prieto P, Roman L, Cortes D. Antispasmodic activity of benzylisoquinoline alkaloids analogous to papaverine. Planta Med 1993; 59(1): 63-7.
[http://dx.doi.org/10.1055/s-2006-959606] [PMID: 8441784]
[59]
Dias KL, Da Silva Dias C, Barbosa-Filho JM, Almeida RN, De Azevedo Correia N, Medeiros IA. Cardiovascular effects induced by reticuline in normotensive rats. Planta Med 2004; 70(4): 328-33.
[http://dx.doi.org/10.1055/s-2004-818944] [PMID: 15095148]
[60]
Medeiros MAA, Nunes XP, Barbosa-Filho JM, et al. (S)-reticuline induces vasorelaxation through the blockade of L-type Ca2+ channels. Naunyn Schmiedebergs Arch Pharmacol 2009; 379(2): 115-25.
[http://dx.doi.org/10.1007/s00210-008-0352-1] [PMID: 18825370]
[61]
Wicha P, Onsa-ard A, Chaichompoo W, Suksamrarn A, Tocharus C. Vasorelaxant and antihypertensive effects of neferine in rats: An in vitro and in vivo study. Planta Med 2020; 86(7): 496-504.
[http://dx.doi.org/10.1055/a-1123-7852] [PMID: 32219782]
[62]
Wang X, Cheang WS, Yang H, et al. Nuciferine relaxes rat mesenteric arteries through endothelium-dependent and -independent mechanisms. Br J Pharmacol 2015; 172(23): 5609-18.
[http://dx.doi.org/10.1111/bph.13021] [PMID: 25409881]
[63]
Deng H, Xu Q, Sang XT, et al. Study on the vasodilatory activity of lotus leaf extract and its representative substance nuciferine on thoracic aorta in rats. Front Pharmacol 2022; 13: 946445.
[http://dx.doi.org/10.3389/fphar.2022.946445] [PMID: 36278191]
[64]
Matsuo H, Okamoto R, Zaima K, et al. New vasorelaxant indole alkaloids, villocarines A-D from Uncaria villosa. Bioorg Med Chem 2011; 19(13): 4075-9.
[http://dx.doi.org/10.1016/j.bmc.2011.05.014] [PMID: 21641808]
[65]
Cifuentes F, Palacios J, Paredes A, Nwokocha C, Paz C. 8-oxo-9-dihydromakomakine isolated from Aristoteliachilensis induces vasodilation in rat aorta: Role of the extracellular calcium influx. Molecules 2018; 23(11): 3050.
[http://dx.doi.org/10.3390/molecules23113050] [PMID: 30469451]
[66]
Berrougui H, Martíncordero C, Khalil A, et al. Vasorelaxant effects of harmine and harmaline extracted from Peganum harmala L. seed’s in isolated rat aorta. Pharmacol Res 2006; 54(2): 150-7.
[http://dx.doi.org/10.1016/j.phrs.2006.04.001] [PMID: 16750635]
[67]
Shi CC, Chen SY, Wang GJ, Liao JF, Chen CF. Vasorelaxant effect of harman. Eur J Pharmacol 2000; 390(3): 319-25.
[http://dx.doi.org/10.1016/S0014-2999(99)00928-0] [PMID: 10708740]
[68]
Panchal S, Bliss E, Brown L. Capsaicin in metabolic syndrome. Nutrients 2018; 10(5): 630.
[http://dx.doi.org/10.3390/nu10050630] [PMID: 29772784]
[69]
Yang D, Luo Z, Ma S, et al. Activation of TRPV1 by dietary capsaicin improves endothelium-dependent vasorelaxation and prevents hypertension. Cell Metab 2010; 12(2): 130-41.
[http://dx.doi.org/10.1016/j.cmet.2010.05.015] [PMID: 20674858]
[70]
Potenza M, De Salvatore G, Montagnani M, Serio M, Mitolo-Chieppa D. Vasodilatation induced by capsaicin in rat mesenteric vessels is probably independent of nitric oxide synthesis. Pharmacol Res 1994; 30(3): 253-61.
[http://dx.doi.org/10.1016/1043-6618(94)80107-X] [PMID: 7532303]
[71]
Gupta S, Lozano-Cuenca J, Villalón CM, et al. Pharmacological characterisation of capsaicin-induced relaxations in human and porcine isolated arteries. Naunyn Schmiedebergs Arch Pharmacol 2007; 375(1): 29-38.
[http://dx.doi.org/10.1007/s00210-007-0137-y] [PMID: 17295025]
[72]
Andrade F, Rangel-Sandoval C, Rodríguez-Hernández A, et al. Capsaicin causes vasorelaxation of rat aorta through blocking of L-type Ca2+ channels and activation of CB1 receptors. Molecules 2020; 25(17): 3957.
[http://dx.doi.org/10.3390/molecules25173957] [PMID: 32872656]
[73]
Hopps JJ, Dunn WR, Randall MD. Vasorelaxation to capsaicin and its effects on calcium influx in arteries. Eur J Pharmacol 2012; 681(1-3): 88-93.
[http://dx.doi.org/10.1016/j.ejphar.2012.02.019] [PMID: 22532967]
[74]
Yeon D, Kwon S, Lee Y, Leem J, Nam T, Ahn D. Capsaicin-induced relaxation in rabbit coronary artery. J Vet Med Sci 2001; 63(5): 499-503.
[http://dx.doi.org/10.1292/jvms.63.499] [PMID: 11411493]

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