Blockade of the Renin-Angiotensin System with Delphinidin, Cyanin, and Quercetin

Abstract

Overactivation of the renin-angiotensin system is one of the most important risk factors for the development of hypertension. The use of the crude extracts and/or active compounds, such as anthocyanins and quercetin, of herbal plants that have antihypertensive effects is beneficial for decreasing of blood pressure level. However, the molecular mechanisms by which anthocyanins (delphinidin and cyanin) and quercetin regulate the renin-angiotensin system are not completely understood. In this study, we demonstrate that delphinidin, cyanin, and quercetin interrupt the renin-angiotensin system signaling pathway by inhibiting the angiotensin-converting enzyme activity and decreasing its mRNA production. Furthermore, treatment with either delphinidin or cyanin significantly inhibited renin mRNA production. However, delphinidin, cyanin, and quercetin did not act as the angiotensin II type 1 receptor antagonist and did not play roles in the regulation of its internalization. The direct inhibition of components of the renin-angiotensin system advances our understanding of the antihypertensive effects of these compounds.

Key words

angiotensin-converting enzyme - cyanin - delphinidin - quercetin - renin - renin-angiotensin system

• References

• 1 Zaman MA, Oparil S, Calhoun DA. Drugs targeting the renin-angiotensin-aldosterone system. Nat Rev Drug Discov 2002; 1: 621-636
• 2 Ojeda D, Jimenez-Ferrer E, Zamilpa A, Herrera-Arellano A, Tortoriello J, Alvarez L. Inhibition of angiotensin convertin enzyme (ACE) activity by the anthocyanins delphinidin- and cyanidin-3-O-sambubiosides from Hibiscus sabdariffa . J Ethnopharmacol 2010; 127: 7-10
• 3 Herrera-Arellano A, Flores-Romero S, Chavez-Soto MA, Tortoriello J. Effectiveness and tolerability of a standardized extract from Hibiscus sabdariffa in patients with mild to moderate hypertension: a controlled and randomized clinical trial. Phytomedicine 2004; 11: 375-382
• 4 Tsutsumi Y, Shimada A, Miyano A, Nishida T, Mitsunaga T. In vitro screening of angiotensin I-converting enzyme inhibitors from Japanese cedar (Cryptomeria japonica). J Wood Sci 1998; 44: 463-468
• 5 Larson AJ, Symons JD, Jalili T. Quercetin: A treatment for hypertension?- A review of efficacy and mechanisms. Pharmaceuticals 2010; 3: 237-250
• 6 Hackl LP, Cuttle G, Dovichi SS, Lima-Landman MT, Nicolau M. Inhibition of angiotesin-converting enzyme by quercetin alters the vascular response to brandykinin and angiotensin I. Pharmacology 2002; 65: 182-186
• 7 Caballero-George C, Vanderheyden PM, De Bruyne T, Shahat AA, Van den Heuvel H, Solis PN, Gupta MP, Claeys M, Pieters L, Vauquelin G, Vlietinck AJ. In vitro inhibition of [³ H]-angiotensin II binding on the human AT1 receptor by proanthocyanidins from Guazuma ulmifolia bark. Planta Med 2002; 68: 1066-1071
• 8 Mangmool S, Haga T, Kobayashi H, Kim KM, Nakata H, Nishida M, Kurose H. Clathrin required for phosphorylation and internalization of beta2-adrenergic receptor by G protein-coupled receptor kinase 2 (GRK2). J Biol Chem 2006; 281: 31940-31949
• 9 Luhtala S, Vaajanen A, Oksala O, Valjakka J, Vapaatalo H. Activities of angiotensin-converting enzymes ACE1 and ACE2 and inhibition by bioactive peptides in porcine ocular tissues. J Ocul Pharmacol Ther 2009; 25: 23-28
• 10 Mendelsohn FA, Lloyd CJ, Kachel C, Funder JW. Induction by glucocorticoids of angiotensin converting enzyme production from bovine endothelial cells in culture and rat lung in vivo . J Clin Invest 1982; 70: 684-692
• 11 Dalakos TG, Elias AN, Anderson Jr. GH, Streeten DH, Schroeder ET. Evidence for an angiotensinogenic mechanism of the hypertension of Cushingʼs syndrome. J Clin Endocrinol Metab 1978; 46: 114-118
• 12 Cheng HF, Wang SW, Zhang MZ, McKanna JA, Breyer R, Harris RC. Prostaglandins that increase renin production in response to ACE inhibition are not derived from cyclooxygenase-1. Am J Physiol Regul Integr Comp Physiol 2002; 283: R638-R646
• 13 Menard J, Campbell DJ, Azizi M, Gonzales MF. Synergistic effects of ACE inhibition and Ang II antagonism on blood pressure, cardiac weight, and renin in spontaneously hypertensive rats. Circulation 1997; 96: 3072-3078
• 14 Fortin JP, Bouthillier J, Bastien L, Bachvarov DR, Marceau F. Characterization of a fluorescent conjugate of the rabbit angiotensin AT(1) receptor. Br J Pharmacol 2003; 138: 1495-1504
• 15 Hall JE. Historical perspective of the renin-angiotensin system. Mol Biotechnol 2003; 24: 27-39
• 16 Baker KM, Booz GW, Dostal DE. Cardiac actions of angiotensin II: Role of an intracardiac renin-angiotensin system. Annu Rev Physiol 1992; 54: 227-241
• 17 Phillips MI, Speakman EA, Kimura B. Levels of angiotensin and molecular biology of the tissue renin angiotensin systems. Regul Pept 1993; 43: 1-20
• 18 Warner FJ, Lew RA, Smith AI, Lambert DW, Hooper NM, Turner AJ. Angiotensin-converting enzyme 2 (ACE2), but not ACE, is preferentially localized to the apical surface of polarized kidney cells. J Biol Chem 2005; 280: 39353-39362
• 19 Steege A, Fähling M, Paliege A, Bondke A, Kirschner KM, Martinka P, Kaps C, Patzak A, Persson PB, Thiele BJ, Scholz H, Mrowka R. Wilmsʼ tumor protein (-KTS) modulates renin gene transcription. Kidney Int 2008; 74: 458-466
• 20 Dzau VJ. Renin-angiotensin system and renal circulation in clinical congestive heart failure. Kidney Int Suppl 1987; 20: S203-S209
• 21 Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res 2000; 87: E1-E9
• 22 Rice GI, Thomas DA, Grant PJ, Turner AJ, Hooper NM. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J 2004; 383: 45-51
• 23 Da Silva Pinto M, Kwon YI, Apostolidis E, Lajolo FM, Genovese MI, Shetty K. Potential of Ginkgo biloba L. leaves in the management of hyperglycemia and hypertension using in vitro models. Bioresour Technol 2009; 100: 6599-6609
• 24 Carretero OA. Novel mechanism of action of ACE and its inhibitors. Am J Physiol Heart Circ Physiol 2005; 289: H1796-H1797
• 25 Wyld PJ, Grant J, Lippi A, Criscuoli M, Del Re G, Subissi A. Pharmacokinetics and biochemical efficacy of idrapril calcium, a novel ACE inhibitor, after multiple oral administration in humans. Br J Clin Pharmacol 1994; 38: 421-425
• 26 Chen CK, Pace-Asciak CR. Vasorelaxing activity of resveratrol and quercetin in isolated rat aorta. Gen Pharmacol 1996; 27: 363-366
• 27 Loizzo MR, Said A, Tundis R, Rashed K, Statti GA, Hufner A, Menichini F. Inhibition of angiotensin converting enzyme (ACE) by flavonoids isolated from Ailanthus excelsa (Roxb) (Simaroubaceae). Phytother Res 2007; 21: 32-36
• 28 Johns DW, Peach MJ, Gomez RA, Inagami T, Carey RM. Angiotensin II regulates renin gene expression. Am J Physiol 1990; 259: F882-F887
• 29 Schricker K, Hegyi I, Hamann M, Kaissling B, Kurtz A. Tonic stimulation of renin gene expression by nitric oxide is counteracted by tonic inhibition through angiotensin II. Proc Natl Acad Sci USA 1995; 92: 8006-8010
• 30 Balasuriya BWN, Rupasinghe HPV. Plant flavonoids as angiotensin converting enzyme inhibitors in regulation of hypertension. Funct Foods Health Dis 2011; 5: 172-188
• 31 Kwon EK, Lee DY, Lee H, Kim DO, Baek NI, Kim YE, Kim HY. Flavonoids from the buds of Rosa damascena inhibit the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and angiotensin I-converting enzyme. J Agric Food Chem 2010; 58: 882-886
• 32 Persson IA, Persson K, Andersson RG. Effect of Vaccinium myrtillus and its polyphenols on angiotensin-converting enzyme activity in human endothelial cells. J Agric Food Chem 2009; 57: 4626-4629
• 33 Campbell DJ, Lawrence AC, Towrie A, Kladis A, Valentijn AJ. Differential regulation of angiotensin peptide levels in plasma and kidney of the rat. Hypertension 1991; 18: 763-773
• 34 Gomez RA, Chevalier RL, Everett AD, Elwood JP, Peach MJ, Lynch KR, Carey RM. Recruitment of renin gene-expressing cells in adult rat kidneys. Am J Physiol 1990; 259: F660-F665
• 35 Dasarathy Y, Lanzillo JJ, Fanburg BL. Stimulation of bovine pulmonary artery endothelial cell ACE by dexamethasone: involvement of steroid receptors. Am J Physiol 1992; 263: L645-L649
• 36 Ferguson SS. Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev 2001; 53: 1-24
• 37 Hunyady L, Catt KJ, Clark AJ, Gaborik Z. Mechanisms and functions of AT(1) angiotensin receptor internalization. Regul Pept 2000; 91: 29-44
• 38 Le MT, De Backer JP, Hunyady L, Vanderheyden PM, Vauquelin G. Ligand binding and functional properties of human angiotensin AT1 receptors in transiently and stably expressed CHO-K1 cells. Eur J Pharmacol 2005; 513: 35-45