Natural vasodilators: mechanisms and therapeutic potential in cardiovascular diseases

Abstract

Natural products with vasodilatory properties are increasingly recognized for treating hypertension, angina, and heart failure owing to their efficacy, accessibility, and favorable safety profiles, rendering them viable therapeutic alternatives. Following a systematic search of the NCBI PubMed and CNKI databases, 227 natural compounds with potent vasodilatory activity were identified. This review delineates the vasodilatory effects of major phytochemical classes—specifically flavonoids, saponins, phenols, and alkaloids—and evaluates preclinical evidence supporting their therapeutic application. Furthermore, potential vasodilatory mechanisms are elucidated, encompassing endothelium-dependent regulation of smooth muscle tone, fluid homeostasis, oxidative stress mitigation, and antagonism of the renin-angiotensin-aldosterone system. These mechanisms clarify the pharmacological basis of natural vasodilators, offering researchers and clinicians enhanced strategies for managing cardiovascular diseases.

Keywords

Natural products / Vasodilation / Vasodilatory factors / Ion Channel / RAAS / Ginsenosides / Berberine / Resveratrol

References

[1] Christodoulou A, Nikolaou PE, Symeonidi L, et al. Cardioprotective potential of oleuropein, hydroxytyrosol, oleocanthal and their combination: unravelling complementary effects on acute myocardial infarction and metabolic syndrome. Redox Biol 2024; 76: 103311.

[2] Ran Q, Li A, Tan Y, et al. Action and therapeutic targets of myosin light chain kinase, an important cardiovascular signaling mechanism. Pharmacol Res 2024; 206: 107276.

[3] Yan Z, Zhong L, Zhu W, et al. Chinese herbal medicine for the treatment of cardiovascular diseases—targeting cardiac ion channels. Pharmacol Res 2023; 192: 106765.

[4] Kleeberg A, Luft T, Golkowski D, et al. Endothelial dysfunction in acute ischemic stroke: a review. J Neurol 2025; 272(2): 143.

[5] Okazaki RA, Rizvi SH, Lyons R, et al. Vascular dysfunction in diabetes and pharmacotherapeutic opportunities: a focus on endothelial cell health. Am J Physiol Heart Circ Physiol 2025; 329(3): H705-H718.

[6] Lukoschewitz JD, Miger KC, Olesen ASO, et al. Vasodilators for acute heart failure—a systematic review with meta—analysis. NEJM Evid 2024; 3(6): EVIDoa2300335.

[7] Zhong C, Deng K, Lang X, et al. Therapeutic potential of natural flavonoids in atherosclerosis through endothelium—protective mechanisms: an update. Pharmacol Ther 2025; 271: 108864.

[8] Huang Y, Ye Q, Tian Y, et al. Choerospondias axillaris: a review of its clinical application, phytochemistry, and an investigation into its potential cardiovascular therapy. Acupunct Herb Med 2025; 5(2): 246-269.

[9] Li Y, Xiang Y, Liang J, et al. The mechanism and treatment strategies of GSDMD—mediated pyroptosis in myocardial infarction. Acupunct Herb Med 2024; 4(3): 295-305.

[10] Luo B, Wang W, Li Y, et al. Tetramethylpyrazine attenuates chronic intermittent hypoxia—exacerbated diabetic atherosclerosis: a mechanistic study of the IRE1α—XBP1 signaling pathway. Acupunct Herb Med 2025; 5(2): 160-172.

[11] Sabando C, Rodríguez—Díaz M, Ide W, et al. Improvement of endothelial function by Gunnera tinctoria extract with antioxidant properties. Biol Res 2020; 53(1): 55.

[12] Li S, Zhan J, Wang Y, et al. Suxiao Jiuxin Pill attenuates acute myocardial ischemia via regulation of coronary artery tone. Front Pharmacol 2023; 14: 1104243.

[13] Arrigo E, Comità S, Pagliaro P, et al. Clinical applications for gasotransmitters in the cardiovascular system: are we there yet? Int J Mol Sci 2023; 24(15): 12480.

[14] Vu GH, Kim CS. Redox regulation of endogenous gasotransmitters in vascular health and disease. Int J Mol Sci 2025; 26(18): 9037.

[15] Behringer EJ. Impact of aging on vascular ion channels: perspectives and knowledge gaps across major organ systems. Am J Physiol Heart Circ Physiol 2023; 325(5): H1012-H1038.

[16] Ning X, Zhu X, Wang Y, et al. Recent advances in carbon monoxide—releasing nanomaterials. Bioact Mater 2024; 37: 30-50.

[17] Siracusa R, Voltarelli VA, Salinaro AT, et al. NO, CO and H₂S: a trinacrium of bioactive gases in the brain . Biochem Pharmacol 2022; 202: 115122.

[18] Cesarini V, Guida E, Campolo F, et al. Type 5 phosphodiesterase (PDE5) and the vascular tree: from embryogenesis to aging and disease. Mech Ageing Dev 2020; 190: 111311.

[19] Liu XY, Qian LL, Wang RX. Hydrogen sulfide—induced vasodilation: the involvement of vascular potassium channels. Front Pharmacol 2022; 13: 911704.

[20] Munteanu C, Popescu C, Vlădulescu—Trandafir AI, et al. Signaling paradigms of H₂S—induced vasodilation: a comprehensive review . Antioxidants (Basel) 2024; 13(10): 1158.

[21] Bootman MD, Bultynck G. Fundamentals of cellular calcium signaling: a primer. Cold Spring Harbor Perspect Biol 2020; 12(1): a038802.

[22] Teng X, Li H, Xue H, et al. GABA_A receptor, K_ATP channel and L—type Ca ²⁺ channel is associated with facilitation effect of H₂S on the baroreceptor reflex in spontaneous hypertensive rats . Pharmacol Rep 2019; 71(5): 968-975.

[23] Wang JJ, Jin S, Zhang H, et al. Molecular recognition and activation of the prostacyclin receptor by anti—pulmonary arterial hypertension drugs. Sci Adv 2024; 10(6): eadk5184.

[24] Liu L, Guo M, Lv X, et al. Role of transient receptor potential vanilloid 4 in vascular function. Front Mol Biosci 2021; 8: 677661.

[25] Rajabian A, Rajabian F, Babaei F, et al. Interaction of medicinal plants and their active constituents with potassium ion channels: a systematic review. Front Pharmacol 2022; 13: 831963.

[26] Jiang S, Han S, Wang DW. The involvement of soluble epoxide hydrolase in the development of cardiovascular diseases through epoxyeicosatrienoic acids. Front Pharmacol 2024; 15: 1358256.

[27] Johnson KA, Jeffery E, Bray JF, et al. Exercise training rescues impaired H₂O₂—mediated vasodilation in porcine collateral—dependent coronary arterioles through enhanced K ⁺ channel activation . Am J Physiol Heart Circ Physiol 2023; 324(5): H637-H653.

[28] Zhang Y, Wernly B, Cao X, et al. Adenosine and adenosine receptor—mediated action in coronary microcirculation. Basic Res Cardiol 2021; 116(1): 22.

[29] Qian Y, Zheng Y, Leng L, et al. Adenosine and adenosine receptors: a “double—edged sword” in cardiovascular system. Front Pharmacol 2025; 16: 1538680.

[30] Solanki N, Dodiya R, Vejpara D, et al. Adenosine receptor subtype modulators: Insight into molecular mechanisms and their therapeutic application. Am J Transl Res 2025; 17(4): 2376-2395.

[31] Chapman FA, Maguire JJ, Newby DE, et al. Targeting the apelin system for the treatment of cardiovascular diseases. Cardiovasc Res 2023; 119(17): 2683-2696.

[32] Gao Z, Zhong X, Tan YX, et al. Apelin—13 alleviates diabetic nephropathy by enhancing nitric oxide production and suppressing kidney tissue fibrosis. Int J Mol Med 2021; 48(3): 175.

[33] Robillard S, Trân K, Lachance MS, et al. Apelin prevents diabetes—induced poor collateral vessel formation and blood flow reperfusion in ischemic limb. Front Cardiovasc Med 2023; 10: 1191891.

[34] Lu J, Piper SJ, Zhao P, et al. Targeting VIP and PACAP receptor signaling: new insights into designing drugs for the PACAP subfamily of receptors. Int J Mol Sci 2022; 23(15): 8069.

[35] Argunhan F, Thapa D, Aubdool AA, et al. Calcitonin gene—related peptide protects against cardiovascular dysfunction independently of nitric oxide in vivo. Hypertension 2021; 77(4): 1178-1190.

[36] Argunhan F, Brain SD. The vascular—dependent and —independent actions of calcitonin gene—related peptide in cardiovascular disease. Front Physiol 2022; 13: 833645.

[37] Russo AF, Hay DL. CGRP physiology, pharmacology, and therapeutic targets: migraine and beyond. Physiol Rev 2023; 103(2): 1565-1644.

[38] de Vries T, Labruijere S, Rivera—Mancilla E, et al. Intracellular pathways of calcitonin gene—related peptide—induced relaxation of human coronary arteries: a key role for Gβγ subunit instead of cAMP. Br J Pharmacol 2024; 181(15): 2478-2491.

[39] Clement A, Christensen SL, Jansen—Olesen I, et al. The ATP sensitive potassium channel (K_ATP) is a novel target for migraine drug development . Front Mol Neurosci 2023; 16: 1182515.

[40] Coskun H, Elbahi FA, Al—Karagholi MAM, et al. The effect of K_ATP channel blocker glibenclamide on CGRP—induced headache and hemodynamic in healthy volunteers . Front Physiol 2021; 12: 652136.

[41] Wang HY, Wang FZ, Chang R, et al. Adrenomedullin improves hypertension and vascular remodeling partly through the receptor—mediated AMPK pathway in rats with obesity—related hypertension. Int J Mol Sci 2023; 24(4): 3943.

[42] Bálint L, Nelson—Maney NP, Tian Y, et al. Clinical potential of adrenomedullin signaling in the cardiovascular system. Circ Res 2023; 132(9): 1185-1202.

[43] Ross GR, Yallampalli C. Endothelium—independent relaxation by adrenomedullin in pregnant rat mesenteric artery: role of cAMP—dependent protein kinase A and calcium—activated potassium channels. J Pharmacol Exp Ther 2006; 317(3): 1269-1275.

[44] Spoto S, Basili S, Cangemi R, et al. A focus on the pathophysiology of adrenomedullin expression: endothelitis and organ damage in severe viral and bacterial infections. Cells 2024; 13(11): 892.

[45] Dai C, Khalil RA. Calcium signaling dynamics in vascular cells and their dysregulation in vascular disease. Biomolecules 2025; 15(6): 892.

[46] Lu T, Zhang Y, Su Y, et al. Role of store—operated Ca ²⁺ entry in cardiovascular disease . Cell Commun Signal 2022; 20(1): 33.

[47] Pereira da Silva EA, Martín—Aragón Baudel M, Navedo MF, et al. Ion channel molecular complexes in vascular smooth muscle. Front Physiol 2022; 13: 999369.

[48] Mironova GY, Haghbin N, Welsh DG. Functional tuning of vascular L—type Ca ²⁺ channels . Front Physiol 2022; 13: 1058744.

[49] Woll KA, Van Petegem F. Calcium—release channels: structure and function of IP₃ receptors and ryanodine receptors . Physiol Rev 2022; 102(1): 209-268.

[50] Sun Z, Li Z, Rodgers M, et al. Myosin light chain phosphorylation exhibits a gradient across the wall of cerebellar arteries under sustained ex vivo vascular tone. Sci Rep 2023; 13(1): 909.

[51] Chen YC, Shih CL, Wu CL, et al. Exploring the impact of BK_Ca channel function in cellular membranes on cardiac electrical activity . Int J Mol Sci 2024; 25(3): 1537.

[52] Sung MW, Yang Z, Driggers CM, et al. Vascular K_ATP channel structural dynamics reveal regulatory mechanism by Mg—nucleotides . Proc Natl Acad Sci USA 2021; 118(44): e2109441118.

[53] Li C, Yang Y. Advancements in the study of inward rectifying potassium channels on vascular cells. Channels (Austin) 2023; 17(1): 2237303.

[54] Maranduca MA, Tanase DM, Cozma CT, et al. The impact of angiotensin—converting enzyme—2/angiotensin 1—7 axis in establishing severe COVID—19 consequences. Pharmaceutics 2022; 14(9): 1906.

[55] Miller AJ, Arnold AC. The renin—angiotensin system and cardiovascular autonomic control in aging. Peptides 2022; 150: 170733.

[56] Johnstone E KM, Ayoub MA, Hertzman RJ, et al. Novel pharmacology following heteromerization of the angiotensin II type 2 receptor and the bradykinin type 2 receptor. Front Endocrinol 2022; 13: 848816.

[57] Steckelings UM, Widdop RE, Sturrock ED, et al. The angiotensin AT₂ receptor: from a binding site to a novel therapeutic target . Pharmacol Rev 2022; 74(4): 1051-1135.

[58] Brunetti V, Berra—Romani R, Conca F, et al. Lysosomal TRPML1 triggers global Ca ²⁺ signals and nitric oxide release in human cerebrovascular endothelial cells . Front Physiol 2024; 15: 1426783.

[59] Lin Q, Zhao L, Jing R, et al. Inositol 1,4,5—trisphosphate receptors in endothelial cells play an essential role in vasodilation and blood pressure regulation. J Am Heart Assoc 2019; 8(4): e011704.

[60] Janaszak—Jasiecka A, Płoska A, Wierońska JM, et al. Endothelial dysfunction due to eNOS uncoupling: molecular mechanisms as potential therapeutic targets. Cell Mol Biol Lett 2023; 28(1): 21.

[61] Penna C, Pagliaro P. Endothelial dysfunction: redox imbalance, NLRP3 inflammasome, and inflammatory responses in cardiovascular diseases. Antioxidants (Basel) 2025; 14(3): 256.

[62] Zhang W, Sun Y, Yang Y, et al. Impaired intracellular calcium homeostasis enhances protein O—GlcNAcylation and promotes vascular calcification and stiffness in diabetes. Redox Biol 2023; 63: 102720.

[63] Huang F, Zhang F, Huang L, et al. Inositol 1,4,5—trisphosphate receptors regulate vascular smooth muscle cell proliferation and neointima formation in mice. J Am Heart Assoc 2024; 13(15): e034203.

[64] Pourová J, Dias P, Pour M, et al. The machinery of healthy vasodilatation: an overview. Pflugers Arch 2025; 477(9): 1135-1162.

[65] Wang H, Li J, Wang Z, et al. Perivascular brown adipocytes—derived kynurenic acid relaxes blood vessel via endothelium PI3K—Akt—eNOS pathway. Biomed Pharmacother 2022; 150: 113040.

[66] Li J, Wang S, Jin E, et al. Norisoboldine induces endothelium—dependent vasorelaxation and attenuates hypertension by modulating Ca ²⁺—eNOS signaling, oxidative stress, and inflammation . Antioxidants (Basel) 2026; 15(1): 131.

[67] Angulo—Urarte A, Casado P, Castillo SD, et al. Endothelial cell rearrangements during vascular patterning require PI3—kinase—mediated inhibition of actomyosin contractility. Nat Commun 2018; 9(1): 4826.

[68] Guan G, Cannon RD, Coates DE, et al. Effect of the rho—kinase/ROCK signaling pathway on cytoskeleton components. Genes 2023; 14(2): 272.

[69] Lorigo M, Oliveira N, Cairrao E. PDE—mediated cyclic nucleotide compartmentation in vascular smooth muscle cells: from basic to a clinical perspective. J Cardiovasc Dev Dis 2021; 9(1): 4.

[70] Niloy SI, Shen Y, Guo L, et al. Loss of IP₃R—BK_Ca coupling is involved in vascular remodeling in spontaneously hypertensive rats . Int J Mol Sci 2023; 24(13): 10903.

[71] Suzuki Y, Giles WR, Zamponi GW, et al. Ca ²⁺ signaling in vascular smooth muscle and endothelial cells in blood vessel remodeling: a review . Inflamm Regen 2024; 44(1): 50.

[72] Chan EC, Pannangpetch P, Woodman OL. Relaxation to flavones and flavonols in rat isolated thoracic aorta: mechanism of action and structure—activity relationships. J Cardiovasc Pharmacol 2000; 35(2): 326-333.

[73] Woodman OL, Chan EC. Vascular and anti—oxidant actions of flavonols and flavones. Clin Exp Pharmacol Physiol 2004; 31(11): 786-790.

[74] Tan CS, Yam MF. Mechanism of vasorelaxation induced by 3’—hydroxy—5,6,7,4’—tetramethoxyflavone in the rats aortic ring assay. Naunyn Schmiedebergs Arch Pharmacol 2018; 391(6): 561-569.

[75] Bertin R, Chen Z, Martínez—Vázquez M, et al. Vasodilation and radical—scavenging activity of imperatorin and selected coumarinic and flavonoid compounds from genus Casimiroa. Phytomedicine 2014; 21(5): 586-594.

[76] Dai R, Wang T, Si X, et al. Vasodilatory effects and underlying mechanisms of the ethyl acetate extracts from Gastrodia elata. Can J Physiol Pharmacol 2017; 95(5): 564-571.

[77] Cheng YW, Li CH, Lee CC, et al. Alpha—naphthoflavone induces vasorelaxation through the induction of extracellular calcium influx and NO formation in endothelium. Naunyn Schmiedebergs Arch Pharmacol 2003; 368(5): 377-385.

[78] Li Y, Dang Q, Li Z, et al. Restoration of mitochondrial function is essential in the endothelium—dependent vasodilation induced by acacetin in hypertensive rats. Int J Mol Sci 2022; 23(19): 11350.

[79] Wang ZT, Lau CW, Chan FL, et al. Vasorelaxant effects of cardamonin and alpinetin from Alpinia henryi K. Schum. J Cardiovasc Pharmacol 2001; 37(5): 596-606.

[80] Kang DG, Yin MH, Oh H, et al. Vasorelaxation by amentoflavone isolated from Selaginella tamariscina. Planta Med 2004; 70(8): 718-722.

[81] Zhang YH, Park YS, Kim TJ, et al. Endothelium—dependent vasorelaxant and antiproliferative effects of apigenin. Gen Pharmacol 2000; 35(6): 341-347.

[82] Ma X, Li YF, Gao Q, et al. Inhibition of superoxide anion—mediated impairment of endothelium by treatment with luteolin and apigenin in rat mesenteric artery. Life Sci 2008; 83(3—4): 110-117.

[83] Calderone V, Chericoni S, Martinelli C, et al. Vasorelaxing effects of flavonoids: investigation on the possible involvement of potassium channels. Naunyn Schmiedebergs Arch Pharmacol 2004; 370(4): 290-298.

[84] Ma X, He D, Ru X, et al. Apigenin, a plant—derived flavone, activates transient receptor potential vanilloid 4 cation channel. Br J Pharmacol 2012; 166(1): 349-358.

[85] Jin BH, Qian LB, Chen S, et al. Apigenin protects endothelium—dependent relaxation of rat aorta against oxidative stress. Eur J Pharmacol 2009; 616(1—3): 200-205.

[86] Guerrero MF, Puebla P, Carrón R, et al. Quercetin 3,7—dimethyl ether: a vasorelaxant flavonoid isolated from Croton schiedeanus Schlecht. J Pharm Pharmacol 2002; 54(10): 1373-1378.

[87] Huang Y, Tsang SY, Yao X, et al. Baicalin—induced vascular response in rat mesenteric artery: role of endothelial nitric oxide. Clin Exp Pharmacol Physiol 2002; 29(8): 721-724.

[88] Kumar T, Sharma M, Rana A, et al. Biochanin—A elicits relaxation in coronary artery of goat through different mechanisms. Res Vet Sci 2020; 131: 206-214.

[89] Wu XL, Wang YY, Cheng J, et al. Calcium channel blocking activity of calycosin, a major active component of Astragali Radix, on rat aorta. Acta Pharmacol Sin 2006; 27(8): 1007-1012.

[90] Duarte J, Jiménez R, Villar IC, et al. Vasorelaxant effects of the bioflavonoid chrysin in isolated rat aorta. Planta Med 2001; 67(6): 567-569.

[91] Tew WY, Tan CS, Yan CS, et al. Evaluation of vasodilatory effect and antihypertensive effect of chrysin through in vitro and sub—chronic in vivo study. Biomed Pharmacother 2023; 157: 114020.

[92] Villar IC, Vera R, Galisteo M, et al. Endothelial nitric oxide production stimulated by the bioflavonoid chrysin in rat isolated aorta. Planta Med 2005; 71(9): 829-834.

[93] Deng Y, Ng ESK, Yeung JHK, et al. Mechanisms of the cerebral vasodilator actions of isoflavonoids of Gegen on rat isolated basilar artery. J Ethnopharmacol 2012; 139(1): 294-304.

[94] Avila—Villarreal G, Hernández—Abreu O, Hidalgo—Figueroa S, et al. Antihypertensive and vasorelaxant effects of dihydrospinochalcone—A isolated from Lonchocarpus xuul Lundell by NO production: computational and ex vivo approaches. Phytomedicine 2013; 20(14): 1241-1246.

[95] Trigueiro F, Cortes SF, Almeida RN, et al. Endothelium—independent vasorelaxant effect of dioclein, a new flavonoid isolated from Dioclea grandiflora, in the rat aorta. J Pharm Pharmacol 2000; 52(11): 1431-1434.

[96] Ahmad T, Shah AJ, Khan T, et al. Mechanism underlying the vasodilation induced by diosmetin in porcine coronary artery. Eur J Pharmacol 2020; 884: 173400.

[97] Yam MF, Tan CS, Ahmad M, et al. Mechanism of vasorelaxation induced by eupatorin in the rats aortic ring. Eur J Pharmacol 2016; 789: 27-36.

[98] Qin X, Hou X, Zhang M, et al. Relaxation of rat aorta by farrerol correlates with potency to reduce intracellular calcium of VSMCs. Int J Mol Sci 2014; 15(4): 6641-6656.

[99] Lemos VS, Côrtes SF, dos Santos MH, et al. Structure and vasorelaxant activity of floranol, a flavonoid isolated from the roots of Dioclea grandiflora. Chem Biodivers 2006; 3(6): 635-645.

[100] Zhao Y, Chen BN, Wang SB, et al. Vasorelaxant effect of formononetin in the rat thoracic aorta and its mechanisms. J Asian Nat Prod Res 2012; 14(1): 46-54.

[101] Xiang Q, Huang Y, Xu J. Effects of phytoestrogen genistein on isolated thoracic aorta function of rats. Chin J Geriatr Heart Brain Vessel Dis 2008; 10(8): 617-619.

[102] Xie YW, Ming DS, Xu HX, et al. Vasorelaxing effects of Caesalpinia sappan involvement of endogenous nitric oxide. Life Sci 2000; 67(15): 1913-1918.

[103] Yu DJ, Jun JH, Kim TJ, et al. The relaxing effect of Poncirus fructus and its flavonoid content on porcine coronary artery. Lab Anim Res 2015; 31(1): 33-39.

[104] Orallo F, Alvarez E, Basaran H, et al. Comparative study of the vasorelaxant activity, superoxide—scavenging ability and cyclic nucleotide phosphodiesterase—inhibitory effects of hesperetin and hesperidin. Naunyn Schmiedebergs Arch Pharmacol 2004; 370(6): 452-463.

[105] Zhou Y, Wang L, Liu Y, et al. Homoplantaginin attenuates high glucose—induced vascular endothelial dysfunction via inhibiting store—operated calcium entry channel and endoplasmic reticulum stress. J Pharm Pharmacol 2023; 75(12): 1530-1543.

[106] Ding L, Chen Z, Guo Y. Vasodilatation and mechanism of hyperin on rat cerebral basilar artery. Acta Univ Med Anhui 2016; 51(11): 1625-1629.

[107] Wang Q, Chen Z. Study on the relaxing effect and mechanism of hyperoside on isolated rat abdominal aorta. Chin Tradit Herb Drugs 2010; 41(5): 766-770.

[108] Xu HB, Huang ZQ. Vasorelaxant effects of icariin on isolated canine coronary artery. J Cardiovasc Pharmacol 2007; 49(4): 207-213.

[109] Demirel S, Sahinturk S, Isbil N, et al. Physiological role of K ⁺ channels in irisin—induced vasodilation in rat thoracic aorta . Peptides 2022; 147: 170685.

[110] Lodi F, Jimenez R, Moreno L, et al. Glucuronidated and sulfated metabolites of the flavonoid quercetin prevent endothelial dysfunction but lack direct vasorelaxant effects in rat aorta. Atherosclerosis 2009; 204(1): 34-39.

[111] Xu YC, Yeung DKY, Man RYK, et al. Kaempferol enhances endothelium—independent and dependent relaxation in the porcine coronary artery. Mol Cell Biochem 2006; 287(1—2): 61-67.

[112] Leeya Y, Mulvany MJ, Queiroz EF, et al. Hypotensive activity of an n—butanol extract and their purified compounds from leaves of Phyllanthus acidus (L.) Skeels in rats. Eur J Pharmacol 2010; 649(1—3):30 1—313.

[113] Jiang H, Xia Q, Wang X, et al. Luteolin induces vasorelaxion in rat thoracic aorta via calcium and potassium channels. Die Pharmazie 2005; 60(6): 444-447.

[114] Sun YH, Zhao J, Jin HT, et al. Vasorelaxant effects of the extracts and some flavonoids from the buds of Coreopsis tinctoria. Pharm Biol 2013; 51(9): 1158-1164.

[115] Si H, Wyeth RP, Liu D. The flavonoid luteolin induces nitric oxide production and arterial relaxation. Eur J Nutr 2014; 53(1): 269-275.

[116] Qian LB, Wang HP, Chen Y, et al. Luteolin reduces high glucose—mediated impairment of endothelium—dependent relaxation in rat aorta by reducing oxidative stress. Pharmacol Res 2010; 61(4): 281-287.

[117] Orallo F, Camiña M, Alvarez E, et al. Implication of cyclic nucleotide phosphodiesterase inhibition in the vasorelaxant activity of the citrus—fruits flavonoid (+/—)—naringenin. Planta Med 2005; 71(2): 99-107.

[118] Wong ESW, Li RWS, Li J, et al. Relaxation effect of narirutin on rat mesenteric arteries via nitric oxide release and activation of voltage—gated potassium channels. Eur J Pharmacol 2021; 905: 174190.

[119] Yang W, Li S, Liao L, et al. Nobiletin relaxes isolated mesenteric arteries by activating the endothelial Ca ²⁺—eNOS pathway in rats . J Vasc Res 2016; 53(5—6): 330-339.

[120] Fu XC, Wang MW, Li SP, et al. Vasodilatation produced by orientin and its mechanism study. Biol Pharm Bull 2005; 28(1): 37-41.

[121] Zhu XM, Fang LH, Li YJ, et al. Endothelium—dependent and —independent relaxation induced by pinocembrin in rat aortic rings. Vascul Pharmacol 2007; 46(3): 160-165.

[122] Novakovic A, Marinko M, Jankovic G, et al. Endothelium—dependent vasorelaxant effect of procyanidin B2 on human internal mammary artery. Eur J Pharmacol 2017; 807: 75-81.

[123] Ibarra M, Moreno L, Vera R, et al. Effects of the flavonoid quercetin and its methylated metabolite isorhamnetin in isolated arteries from spontaneously hypertensive rats. Planta Med 2003; 69(11): 995-1000.

[124] Fusi F, Saponara S, Pessina F, et al. Effects of quercetin and rutin on vascular preparations: a comparison between mechanical and electrophysiological phenomena. Eur J Nutr 2003; 42(1): 10-17.

[125] Zhou XM, Yao H, Xia ML, et al. Comparison of vasodilatation effect between quercetin and rutin in the isolated rat thoracic aorta. Zhejiang Da Xue Xue Bao Yi Xue Ban 2006; 35(1): 29-33.

[126] Xia ML, Zhou XM, Yao H, et al. Rutin—induced endothelium—dependent vasorelaxation in rat aortic rings and the underlying mechanism. Conf Proc IEEE Eng Med Biol Soc 2005; 2005: 5595-5597.

[127] Pan Z, Feng T, Shan L, et al. Scutellarin—induced endothelium—independent relaxation in rat aorta. Phytother Res 2008; 22(11): 1428-1433.

[128] Chen YJ, Chen C, Li MY, et al. Scutellarin reduces cerebral ischemia reperfusion injury involving in vascular endothelium protection and PKG signal. Nat Prod Bioprospect 2021; 11(6): 659-670.

[129] Xu Q, Xia P, Li X, et al. Tetramethylpyrazine ameliorates high glucose—induced endothelial dysfunction by increasing mitochondrial biogenesis. PLoS One 2014; 9(2): e88243.

[130] Zhang L, Ling S, Chen G, et al. Vasodilatory and anti—inflammatory mechanisms of extracts of chrysanthemum indicum. Shanghai J Tradit Chin Med 2009; 43(5): 60-63.

[131] Mendes A, Desgranges C, Chèze C, et al. Vasorelaxant effects of grape polyphenols in rat isolated aorta. Possible involvement of a purinergic pathway. Fundam Clin Pharmacol 2003; 17(6): 673-681.

[132] Unemoto T, Honda H, Kogo H. Differences in the mechanisms for relaxation of aorta induced by 17beta—estradiol or progesterone between normotensive and hypertensive rats. Eur J Pharmacol 2003; 472(1—2): 119-126.

[133] Gan L, Wang ZH, Zhang H, et al. Endothelium—independent vasorelaxant effect of 20(S)—protopanaxadiol on isolated rat thoracic aorta. Acta Pharmacol Sin 2016; 37(12): 1555-1562.

[134] Kim JH, Lee JH, Jeong SM, et al. Stereospecific effects of ginsenoside Rg3 epimers on swine coronary artery contractions. Biol Pharm Bull 2006; 29(2): 365-370.

[135] Lin XP, Cui HJ, Yang AL, et al. Astragaloside IV improves vasodilatation function by regulating the PI3K/Akt/eNOS signaling pathway in rat aorta endothelial cells. J Vasc Res 2018; 55(3): 169-176.

[136] Zhang WD, Zhang C, Wang XH, et al. Astragaloside IV dilates aortic vessels from normal and spontaneously hypertensive rats through endothelium—dependent and endothelium—independent ways. Planta Med 2006; 72(7): 621-626.

[137] Kamkaew N, Paracha TU, Ingkaninan K, et al. Vasodilatory effects and mechanisms of action of bacopa monnieri active compounds on rat mesenteric arteries. Molecules (Basel) 2019; 24(12): 2243.

[138] Liu J, Zhu K, Ma D. Effects of dioscin on the aortic vascular rings isolated from rats. J Tianjin Med Univ 2012; 18(1): 24-26.

[139] Wang Y, Ren Y, Xing L, et al. Endothelium—dependent vasodilation effects of Panax notoginseng and its main components are mediated by nitric oxide and cyclooxygenase pathways. Exp Ther Med 2016; 12(6): 3998-4006.

[140] Ren Y, Liu T, Qi B, et al. Effect and mechanism of ginsenoside Rg2 on isolated rat thoracic aorta smooth muscle. J Yichun Univ 2022; 44(3): 20-25 + 82.

[141] Kim ND, Kang SY, Kim MJ, et al. The ginsenoside Rg3 evokes endothelium—independent relaxation in rat aortic rings: role of K ⁺ channels . Eur J Pharmacol 1999; 367(1): 51-57.

[142] Kang YJ, Sohn JT, Chang KC. Relaxation of canine corporal smooth muscle relaxation by ginsenoside saponin Rg3 is independent from eNOS activation. Life Sci 2005; 77(1): 74-84.

[143] Li Z, Chen X, Niwa Y, et al. Involvement of Ca ²⁺—activated K ⁺ channels in ginsenosides—induced aortic relaxation in rats . J Cardiovasc Pharmacol 2001; 37(1): 41-47.

[144] Ul Haq I, Khan T, Ahmad T, et al. Insight into the cardiovascular mechanisms of blood pressure lowering effect of gitogenin: a steroidal saponin. Clin Exp Hypertens 2021; 43(8): 723-729.

[145] Wong KL, Chan P, Yang HY, et al. Isosteviol acts on potassium channels to relax isolated aortic strips of Wistar rat. Life Sci 2004; 74(19): 2379-2387.

[146] Shen K, Leung SWS, Ji L, et al. Notoginsenoside Ft1 activates both glucocorticoid and estrogen receptors to induce endothelium—dependent, nitric oxide—mediated relaxations in rat mesenteric arteries. Biochem Pharmacol 2014; 88(1): 66-74.

[147] Zhao Y, Zhang X, Li J, et al. Jujuboside B reduces vascular tension by increasing Ca ²⁺ influx and activating endothelial nitric oxide synthase . PLoS One 2016; 11(2): e0149386.

[148] Dias KL, Correia Nde A, Pereira KK, et al. Mechanisms involved in the vasodilator effect induced by diosgenin in rat superior mesenteric artery. Eur J Pharmacol 2007; 574(2—3): 172-178.

[149] Kim ND, Kang SY, Park JH, et al. Ginsenoside Rg3 mediates endothelium—dependent relaxation in response to ginsenosides in rat aorta: role of K ⁺ channels . Eur J Pharmacol 1999; 367(1): 41-49.

[150] Carvalho MTM, Rezende KCS, Evora PRB, et al. The lignan (—)—cubebin inhibits vascular contraction and induces relaxation via nitric oxide activation in isolated rat aorta. Phytother Res 2013; 27(12): 1784-1789.

[151] Raffai G, Kim B, Park S, et al. Cinnamaldehyde and cinnamaldehyde—containing micelles induce relaxation of isolated porcine coronary arteries: role of nitric oxide and calcium. Int J Nanomedicine 2014; 9: 2557-2566.

[152] Xue YL, Shi HX, Murad F, et al. Vasodilatory effects of cinnamaldehyde and its mechanism of action in the rat aorta. Vasc Health Risk Manag 2011; 7: 273-280.

[153] Alvarez—Collazo J, Alonso—Carbajo L, López—Medina AI, et al. Cinnamaldehyde inhibits L—type calcium channels in mouse ventricular cardiomyocytes and vascular smooth muscle cells. Pflugers Arch 2014; 466(11): 2089-2099.

[154] Yanaga A, Goto H, Nakagawa T, et al. Cinnamaldehyde induces endothelium—dependent and —independent vasorelaxant action on isolated rat aorta. Biol Pharm Bull 2006; 29(12): 2415-2418.

[155] Raimundo JM, Trindade APF, Velozo LSM, et al. The lignan eudesmin extracted from Piper truncatum induced vascular relaxation via activation of endothelial histamine H₁ receptors . Eur J Pharmacol 2009; 606(1—3): 150-154.

[156] Seok YM, Choi YW, Kim GD, et al. Effects of gomisin A on vascular contraction in rat aortic rings. Naunyn Schmiedebergs Arch Pharmacol 2011; 383(1): 45-56.

[157] Park JY, Lee SJ, Yun MR, et al. Gomisin A from Schisandra chinensis induces endothelium—dependent and direct relaxation in rat thoracic aorta. Planta Med 2007; 73(15): 1537-1542.

[158] Inchoo M, Chirdchupunseree H, Pramyothin P, et al. Endothelium—independent effects of phyllanthin and hypophyllanthin on vascular tension. Fitoterapia 2011; 82(8): 1231-1236.

[159] Zhang H, Tian G, Yang T, et al. Vasodilatative mechanism of magnolin in isolated rat thoracic aorta and its toxicity in rat renal cells NRK. Chin J Exp Tradit Med Formul 2013; 19(23): 209-212.

[160] Piccinelli AL, Arana S, Caceres A, et al. New lignans from the roots of Valeriana prionophylla with antioxidative and vasorelaxant activities. J Nat Prod 2004; 67(7): 1135-1140.

[161] Demirci B, Dost T, Gokalp F, et al. Silymarin improves vascular function of aged ovariectomized rats. Phytother Res 2014; 28(6): 868-872.

[162] Xu Z, Wang X, Dai Y, et al. (+/—)—Praeruptorin A enantiomers exert distinct relaxant effects on isolated rat aorta rings dependent on endothelium and nitric oxide synthesis. Chem Biol Interact 2010; 186(2): 239-246.

[163] Li X, Lee YJ, Kim YC, et al. Bakuchicin induces vascular relaxation via endothelium—dependent NO—cGMP signaling. Phytother Res 2011; 25(10): 1574-1578.

[164] Lavaud A, Soleti R, Hay AE, et al. Paradoxical effects of polyphenolic compounds from Clusiaceae on angiogenesis. Biochem Pharmacol 2012; 83(4): 514-523.

[165] Zhang S, Zhang J, Liu N, et al. In—vitro vasodilatory effects and mechanism of marmesin on thoracic aorta rings of rats. Tradit Chin Drug Res Clin Pharmacol 2016; 27(5): 637-643.

[166] Khan AU, Ullah R, Khan A, et al. Vasodilator effect of Phlomis bracteosa constituents is mediated through dual endothelium—dependent and endothelium—independent pathways. Clin Exp Hypertens 2012; 34(2): 132-139.

[167] Campos DR, Celotto AC, Albuquerque AAS, et al. The diterpene sclareol vascular effect in normotensive and hypertensive rats. Arq Bras Cardiol 2017; 109(2): 0.

[168] Pinto NV, Assreuy AMS, Coelho—de—Souza AN, et al. Endothelium—dependent vasorelaxant effects of the essential oil from aerial parts of Alpinia zerumbet and its main constituent 1,8—cineole in rats. Phytomedicine 2009; 16(12): 1151-1155.

[169] Tirapelli CR, Ambrosio SR, da Costa FB, et al. Evidence for the mechanisms underlying the effects of pimaradienoic acid isolated from the roots of Viguiera arenaria on rat aorta. Pharmacology 2004; 70(1): 31-38.

[170] Fang J, Li R, Zhang Y, et al. Aristolone in Nardostachys jatamansi DC. induces mesenteric vasodilation and ameliorates hypertension via activation of the K_ATP channel and PDK1—Akt—eNOS pathway . Phytomedicine 2022; 104: 154257.

[171] Fu JY, Xia ML, Lu JF, et al. Betulinic acid ameliorates impairment of endothelium—dependent relaxation induced by oxidative stress in rat aorta. Zhejiang Da Xue Xue Bao Yi Xue Ban 2010; 39(5): 523-529.

[172] Fu JY, Qian LB, Zhu LG, et al. Betulinic acid ameliorates endothelium—dependent relaxation in L—NAME—induced hypertensive rats by reducing oxidative stress. Eur J Pharm Sci 2011; 44(3): 385-391.

[173] Pereira SL, Marques AM, Sudo RT, et al. Vasodilator activity of the essential oil from aerial parts of Pectis brevipedunculata and its main constituent citral in rat aorta. Molecules (Basel) 2013; 18(3): 3072-3085.

[174] Martinsen A, Baccelli C, Navarro I, et al. Vascular activity of a natural diterpene isolated from Croton zambesicus and of a structurally similar synthetic trachylobane. Vascul Pharmacol 2010; 52(1—2): 63-69.

[175] Rodríguez—Rodríguez R, Herrera MD, Perona JS, et al. Potential vasorelaxant effects of oleanolic acid and erythrodiol, two triterpenoids contained in “orujo” olive oil, on rat aorta. Br J Nutr 2004; 92(4): 635-642.

[176] Xing S, Nong F, Qin J, et al. Gentiopicroside produces endothelium—independent vasodilation by deactivating the PI3K/Akt/Rho—kinase pathway in isolated rat thoracic aorta. Biomed Res Int 2021; 2021: 5565748.

[177] El—Bassossy HM, Elberry AA, Ghareib SA. Geraniol improves the impaired vascular reactivity in diabetes and metabolic syndrome through calcium channel blocking effect. J Diabetes Complications 2016; 30(6): 1008-1016.

[178] Tirapelli CR, Ambrosio SR, Coutinho ST, et al. Pharmacological comparison of the vasorelaxant action displayed by kaurenoic acid and pimaradienoic acid. J Pharm Pharmacol 2005; 57(8): 997-1004.

[179] Tirapelli CR, Ambrosio SR, da Costa FB, et al. Analysis of the mechanisms underlying the vasorelaxant action of kaurenoic acid in the isolated rat aorta. Eur J Pharmacol 2004; 492(2—3): 233-241.

[180] Yoo MY, Oh KS, Lee JW, et al. Vasorelaxant effect of stilbenes from rhizome extract of rhubarb (Rheum undulatum) on the contractility of rat aorta. Phytother Res 2007; 21(2): 186-189.

[181] Luna—Vázquez FJ, Ibarra—Alvarado C, Rojas—Molina A, et al. Role of nitric oxide and hydrogen sulfide in the vasodilator effect of ursolic acid and uvaol from black cherry prunus serotina fruits. Molecules (Basel) 2016; 21(1): 78.

[182] Fusi F, Durante M, Sgaragli G, et al. In vitro vasoactivity of zerumbone from Zingiber zerumbet. Planta Med 2015; 81(4): 298-304.

[183] Santos SE, Ribeiro FPRA, Menezes PMN, et al. New insights on relaxant effects of (—)—borneol monoterpene in rat aortic rings. Fundam Clin Pharmacol 2019; 33(2): 148-158.

[184] Wicha P, Onsa—Ard A, Chaichompoo W, et al. Vasorelaxant and antihypertensive effects of neferine in rats: an in vitro and in vivo study. Planta Med 2020; 86(7): 496-504.

[185] Matsumoto T, Kobayashi T, Ishida K, et al. Vasodilator effect of Cassiarin A, a novel antiplasmodial alkaloid from Cassia siamea, in rat isolated mesenteric artery. Biol Pharm Bull 2010; 33(5): 844-848.

[186] Ko WH, Yao XQ, Lau CW, et al. Vasorelaxant and antiproliferative effects of berberine. Eur J Pharmacol 2000; 399(2—3): 187-196.

[187] Panthiya L, Pantan R, Tocharus J, et al. Endothelium—dependent and endothelium—independent vasorelaxant effects of tiliacorinine 12’—O—acetate and mechanisms on isolated rat aorta. Biomed Pharmacother 2019; 109: 2090-2099.

[188] Cifuentes F, Palacios J, Paredes A, et al. 8—Oxo—9—dihydromakomakine isolated from Aristotelia chilensis induces vasodilation in rat aorta: role of the extracellular calcium influx. Molecules (Basel) 2018; 23(11): 3050.

[189] Lee PY, Chen W, Liu IM, et al. Vasodilatation induced by sinomenine lowers blood pressure in spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 2007; 34(10): 979-984.

[190] Ma HY, Song YC, Mao YY, et al. Endophytic fungal metabolite fumigaclavine C causes relaxation of isolated rat aortic rings. Planta Med 2006; 72(5): 387-392.

[191] Mitamura M, Horie S, Sakaguchi M, et al. Mesaconitine—induced relaxation in rat aorta: involvement of Ca ²⁺ influx and nitric—oxide synthase in the endothelium . Eur J Pharmacol 2002; 436(3): 217-225.

[192] Li T, Xu K, Che D, et al. Endothelium—independent vasodilator effect of isocorynoxeine in vitro isolated from the hook of Uncaria rhynchophylla (Miquel). Naunyn Schmiedebergs Arch Pharmacol 2018; 391(11): 1285-1293.

[193] Shen J, Gao J, Gao Z, et al. Comparison of the vasorelaxant effects of cyclovirobuxine D and its derivatives in rat aorta rings. Chin J New Drugs 2012; 21(3): 240-245.

[194] Yuzurihara M, Ikarashi Y, Goto K, et al. Geissoschizine methyl ether, an indole alkaloid extracted from Uncariae Ramulus et Uncus, is a potent vasorelaxant of isolated rat aorta. Eur J Pharmacol 2002; 444(3): 183-189.

[195] Li Y, Tang N, Bian K. Vasodilatory effect of oxymatrine and its mechanisms. Shanghai J Tradit Chin 2009; 43(4): 62-66.

[196] Dongmo AB, Nkeng—Efouet PA, Devkota KP, et al. Tetra—acetylajugasterone a new constituent of Vitex cienkowskii with vasorelaxant activity. Phytomedicine 2014; 21(6): 787-792.

[197] Senejoux F, Girard—Thernier C, Berthelot A, et al. New insights into the mechanisms of the vasorelaxant effects of apocynin in rat thoracic aorta. Fundam Clin Pharmacol 2013; 27(3): 262-270.

[198] Matsui T, Korematsu S, Byun EB, et al. Apple procyanidins induced vascular relaxation in isolated rat aorta through NO/cGMP pathway in combination with hyperpolarization by multiple K ⁺ channel activations . Biosci Biotechnol Biochem 2009; 73(10): 2246-2251.

[199] Zhang H, Liu H, Chen Y, et al. The curcumin—induced vasorelaxation in rat superior mesenteric arteries. Ann Vasc Surg 2018; 48: 233-240.

[200] Jain M, Singh A, Singh V, et al. Gingerol inhibits serum—induced vascular smooth muscle cell proliferation and injury—induced neointimal hyperplasia by suppressing p38 MAPK activation. J Cardiovasc Pharmacol Ther 2016; 21(2): 187-200.

[201] Peixoto—Neves D, Silva—Alves KS, Gomes MDM, et al. Vasorelaxant effects of the monoterpenic phenol isomers, carvacrol and thymol, on rat isolated aorta. Fundam Clin Pharmacol 2010; 24(3): 341-350.

[202] Testai L, Chericoni S, Martelli A, et al. Voltage—operated potassium (Kv) channels contribute to endothelium—dependent vasorelaxation of carvacrol on rat aorta. J Pharm Pharmacol 2016; 68(9): 1177-1183.

[203] Kim JA, Formoso G, Li Y, et al. Epigallocatechin gallate, a green tea polyphenol, mediates NO—dependent vasodilation using signaling pathways in vascular endothelium requiring reactive oxygen species and Fyn. J Biol Chem 2007; 282(18): 13736-13745.

[204] Wang GJ, Lin YL, Chen CH, et al. Cellular calcium regulatory machinery of vasorelaxation elicited by petasin. Clin Exp Pharmacol Physiol 2010; 37(3): 309-315.

[205] Moohammadaree A, Changtam C, Wicha P, et al. Mechanisms of vasorelaxation induced by hexahydrocurcumin in isolated rat thoracic aorta. Phytother Res 2015; 29(11): 1806-1813.

[206] Chen ZY, Yao XQ, Chan FL, et al. (—)epicatechin induces and modulates endothelium—dependent relaxation in isolated rat mesenteric artery rings. Acta Pharmacol Sin 2002; 23(12): 1188-1192.

[207] Novakovic A, Marinko M, Vranic A, et al. Mechanisms underlying the vasorelaxation of human internal mammary artery induced by (—)—epicatechin. Eur J Pharmacol 2015; 762: 306-312.

[208] Matsuura M, Kimura Y, Nakata K, et al. Artery relaxation by chalcones isolated from the roots of Angelica keiskei. Planta Med 2001; 67(3): 230-235.

[209] Tom ENL, Girard—Thernier C, Demougeot C. The Janus face of chlorogenic acid on vascular reactivity: a study on rat isolated vessels. Phytomedicine 2016; 23(10): 1037-1042.

[210] He WJ, Fang TH, Ma X, et al. Echinacoside elicits endothelium—dependent relaxation in rat aortic rings via an NO—cGMP pathway. Planta Med 2009; 75(13): 1400-1404.

[211] Ramón Sánchez de Rojas V, Somoza B, Ortega T, et al. Vasodilatory effect in rat aorta of eriodictyol obtained from Satureja obovata. Planta Med 1999; 65(3): 234-238.

[212] Guo Z, Yang X, Wu M, et al. Gastrodin attenuates angiotensin II—induced vascular contraction and MLCK/p—MLC2 pathway activation. Pharm Biol 2023; 61(1): 858-867.

[213] Zhang J, Zhao L, Yu X. Vasodilatation effect of paeonol on renal artery and coronary artery in healthy and hyperlipidemia rats. Chin J New Drugs 2013; 22(20): 2414-2417.

[214] Wang Y, Peng X, Zhang C. Study on the mechanism of the vasodilation effect of proanthocyanidins on resistance vessels in rats. Chin J Clin Pharmacol Ther 2010; 15(2): 170-174.

[215] Matsui T, Kudo A, Tokuda S, et al. Identification of a new natural vasorelaxatant compound, (+)—osbeckic acid, from rutin—free tartary buckwheat extract. J Agric Food Chem 2010; 58(20): 10876-10879.

[216] Zhang H, Zhang H, Liu Y, et al. The vasodilatory effect of salidroside on the thoracic aortic ring isolated from rats. Pharmacol Clin Chin Materia Medica 2015; 31(1): 37-40.

[217] Raffai G, Khang G, Vanhoutte PM. Vanillin and vanillin analogs relax porcine coronary and basilar arteries by inhibiting L—type Ca ²⁺ channels . J Pharmacol Exp Ther 2015; 352(1): 14-22.

[218] de Oliveira LM, de Oliveira TS, da Costa RM, et al. The vasorelaxant effect of gallic acid involves endothelium—dependent and —independent mechanisms. Vascul Pharmacol 2016; 81: 69-74.

[219] Li YJ, Duan CL, Liu JX. Salvianolic acid A promotes the acceleration of neovascularization in the ischemic rat myocardium and the functions of endothelial progenitor cells. J Ethnopharmacol 2014; 151(1): 218-227.

[220] Yu M, Kim HJ, Heo H, et al. Comparison of the antihypertensive activity of phenolic acids. Molecules 2022; 27(19): 6185.

[221] Safaeian L, Asghari—Varzaneh M, Alavi SS, et al. Cardiovascular protective effects of cinnamic acid as a natural phenolic acid: a review. Arch Physiol Biochem 2025; 131(1): 52-62.

[222] Al Shukor N, Van Camp J, Gonzales GB, et al. Angiotensin—converting enzyme inhibitory effects by plant phenolic compounds: a study of structure activity relationships. J Agric Food Chem 2013; 61(48): 11832-11839.

[223] Ekowati J, Tejo BA, Maulana S, et al. Potential utilization of phenolic acid compounds as anti—inflammatory agents through TNF—α convertase inhibition mechanisms: a network pharmacology, docking, and molecular dynamics approach. ACS Omega 2023; 8(49): 46851-46868.

[224] Arruda—Barbosa L, Rodrigues KM, Souza—Neto FD, et al. Vasorelaxant effects of 1—nitro—2—phenylethene in rat isolated aortic rings. Vascul Pharmacol 2014; 63(2): 55-62.

[225] Wang SP, Zang WJ, Kong SS, et al. Vasorelaxant effect of isopropyl 3—(3, 4—dihydroxyphenyl)—2—hydroxypropanoate, a novel metabolite from Salvia miltiorrhiza, on isolated rat mesenteric artery. Eur J Pharmacol 2008; 579(1—3): 283-288.

[226] Paredes A, Palacios J, Quispe C, et al. Hydroalcoholic extract and pure compounds from Senecio nutans Sch. Bip (Compositae) induce vasodilation in rat aorta through endothelium—dependent and independent mechanisms. J Ethnopharmacol 2016; 192: 99-107.

[227] Grbović L, Radenković M. Analysis of adenosine vascular effect in isolated rat aorta: possible role of Na ⁺/K ⁺—ATPase . Pharmacol Toxicol 2003; 92(6): 265-271.

[228] Gauthier KM, Spitzbarth N, Edwards EM, et al. Apamin—sensitive K ⁺ currents mediate arachidonic acid—induced relaxations of rabbit aorta . Hypertension 2004; 43(2): 413-419.

[229] Ririe DG, Roberts PR, Shouse MN, et al. Vasodilatory actions of the dietary peptide carnosine. Nutrition 2000; 16(3): 168-172.

[230] Rubiolo JA, Lence E, González—Bello C, et al. Crambescin C1 acts as a possible substrate of iNOS and eNOS Increasing nitric oxide production and inducing in vivo hypotensive effect. Front Pharmacol 2021; 12: 694639.

[231] Meng Z, Zhang H. The vasodilator effect and its mechanism of sulfur dioxide—derivatives on isolated aortic rings of rats. Inhal Toxicol 2007; 19(11): 979-986.

[232] Engler MB, Engler MM. Docosahexaenoic acid—induced vasorelaxation in hypertensive rats: mechanisms of action. Biol Res Nurs 2000; 2(2): 85-95.

[233] Wicha P, Tocharus J, Nakaew A, et al. Ethyl rosmarinate relaxes rat aorta by an endothelium—independent pathway. Eur J Pharmacol 2015; 766: 9-15.

[234] Terroni B, de Moraes LHO, Pavan AR, et al. Vascular effects of the fetal hemoglobin inducer agent 3—(1,3—dioxoisoindolin—2—yl) benzyl nitrate. Pharmaceuticals (Basel) 2022; 15(11): 1311.

[235] Paredes—Gamero EJ, Medeiros VP, Farias EHC, et al. Heparin induces rat aorta relaxation via integrin—dependent activation of muscarinic M₃ receptors . Hypertension 2010; 56(4): 713-721.

[236] Mendes LJ, Capettini LS, Lôbo LT, et al. Endothelial nitric oxide—dependent vasorelaxant effect of isotirumalin, a dihydroflavonol from Derris urucu, on the rat aorta. Biol Pharm Bull 2011; 34(9): 1499-1500.

[237] Jiang D, Xu C, Zhu Y, et al. Study on mechanism of endothelium—dependent vasodilating effect of phytoestrogen α—zearalanol. Chin J Geriatric Heart Brain Vessel Dis 2008; 10(9): 699-702.

[238] Cuong NM, Son NT, Nhan NT, et al. Vasorelaxing activity of R—(—)—3’—hydroxy—2,4,5—trimethoxydalbergiquinol from Dalbergia tonkinensis: involvement of smooth muscle Ca_V1.2 channels . Planta Med 2020; 86(4): 284-293.

[239] Hu CM, Cheng YW, Cheng HW, et al. Impairment of vascular function of rat thoracic aorta in an endothelium—dependent manner by shikonin/alkannin and derivatives isolated from roots of Macrotomia euchroma. Planta Med 2004; 70(1): 23-28.

[240] Niu LG, Zhang MS, Liu Y, et al. Vasorelaxant effect of taurine is diminished by tetraethylammonium in rat isolated arteries. Eur J Pharmacol 2008; 580(1—2): 169-174.

[241] Bernardino—Paula R, Carvalho—Galvão A, Cavalcanti ALM, et al. The new organic nitrate 2—nitrate—1,3—diocthanoxypropan (NDOP) induces nitric oxide production and vasorelaxation via activation of inward—rectifier potassium channels (K_IR) . Nitric Oxide 2020; 104—105: 61-69.

[242] Mariano LNB, da Silva RCV, Niero R, et al. Vasodilation and blood pressure—lowering effect of 3—demethyl—2—geranyl—4—prenylbellidifoline, a xanthone obtained from garcinia achachairu, in hypertensive rats. Plants (Basel) 2024; 13(4): 528.

[243] Palacios J, Paredes A, Catalán MA, et al. Novel oxime synthesized from a natural product of senecio nutans SCh. Bip. (Asteraceae) enhances vascular relaxation in rats by an endothelium—independent mechanism. Molecules 2022; 27(10): 3333.

[244] Liu H, Fu S, Hu C, et al. Relaxing effect of an flavonoid WX—02 on isolated vascular rings of rabbits. J Shenyang Pharm Univ 2013; 30(9): 709-712.

[245] Javed A, Khan S, Salma U, et al. Extract of Chenopodium album lowers blood pressure in rats through endothelium—dependent and —independent vasorelaxation. Ann Pharm Fr 2024; 82(1): 84-95.

[246] Lam FFY, Yeung JHK, Chan KM, et al. Dihydrotanshinone, a lipophilic component of Salvia miltiorrhiza (danshen), relaxes rat coronary artery by inhibition of calcium channels. J Ethnopharmacol 2008; 119(2): 318-321.

[247] Di Giulio C, Gonzalez Guzman JM, Dutra Gomes JV, et al. A new Lignan from Annona squamosa L. (Annonaceae) demonstrates vasorelaxant effects in vitro. Molecules 2023; 28(11): 4256.

[248] Xie YL, Zhou M, Ma HH, et al. Vasorelaxation effect of gastrodin on isolated thoracic aorta rings of rats. Chin J Integr Med 2015; 21(12): 944-948.

[249] Jo C, Kim B, Lee S, et al. Vasorelaxant effect of prunus mume (Siebold) Siebold & Zucc. Branch through the endothelium—dependent pathway. Molecules 2019; 24(18): 3340.

[250] Li L, Su XL, Bai TT, et al. New paeonol derivative C302 reduces hypertension in spontaneously hypertensive rats through endothelium—dependent and endothelium—independent vasodilation. Eur J Pharmacol 2022; 927: 175057.

[251] Qamar HMUD, Qayyum R, Salma U, et al. Vascular mechanisms underlying the hypotensive effect of Rumex acetosa. Pharm Biol 2018; 56(1): 225-234.

[252] Mushtaq MN, Ghimire S, Alamgeer, et al. Tambulin is a major active compound of a methanolic extract of fruits of Zanthoxylum armatum DC causing endothelium—independent relaxations in porcine coronary artery rings via the cyclic AMP and cyclic GMP relaxing pathways. Phytomedicine 2019; 53: 163-170.

[253] Domingo—Fernández D, Gadiya Y, Preto AJ, et al. Natural products have increased rates of clinical trial success throughout the drug development process. J Nat Prod 2024; 87(7): 1844-1851.