Dihydrogoniothalamin, an Endothelium and NO-Dependent Vasodilator Drug Isolated from Aniba panurensis

Abstract

Dihydrogoniothalamin is a styrylpyrone isolated from the leaves of Aniba panurensis. The present work aimed at investigating the vasorelaxant activity of dihydrogoniothalamin and its underlying mechanism of action in the rat aorta. Dihydrogoniothalamin (0.01–100 µM) induced a concentration-dependent vasodilatation of aortas precontracted with phenylephrine. Endothelium removal or pretreatment of the preparation with N_G nitro-L-arginine-methyl-ester abolished the vasodilator response for dihydrogoniothalamin. Pretreatment with calmidazolium did not affect the vasodilator response of dihydrogoniothalamin. On the other hand, wortmannin, a nonselective inhibitor of phosphatidylinositol 3-kinases, and protein kinase B inhibitor IV significantly shifted the concentration-response curve of dihydrogoniothalamin to the right and reduced its maximal effect. A nonselective antagonist of estrogen receptors, ICI 182,780, and a selective antagonist of estrogen receptor α, methyl-piperidino-pyrazole, were able to reduce the relaxation induced by dihydrogoniothalamin, but no effect was observed in the presence of the selective antagonists of estrogen receptor β and G protein-coupled receptor 30, 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP), and G-15, respectively. Dihydrogoniothalamin also increased the phosphorylation of the activation sites of endothelial nitric oxide synthase and protein kinase B. The present results led us to conclude that dihydrogoniothalamin is a vasodilator drug acting in an endothelium- and nitric oxide-dependent manner through a mechanism involving the activation of nitric oxide synthase via the phosphatidylinositol 3-kinase/protein kinase B pathway, partially by stimulation of estrogen receptor α.

Key words

Aniba panurensis - Lauraceae - dihydrogoniothalamin - 6-styryl-2-pyrone - vasodilation - rat aorta

• References

• 1 Riemersma RA, Rice-Evans CA, Tyrrell RM, Clifford MN, Lean ME. Tea flavonoids and cardiovascular health. QJM 2001; 94: 277-282
• 2 Rezende BA, Cortes SF, De Sousa FB, Lula IS, Schmitt M, Sinisterra RD, Lemos VS. Complexation with beta-cyclodextrin confers oral activity on the flavonoid dioclein. Int J Pharm 2009; 367: 133-139
• 3 Schini-Kerth VB, Etienne-Selloum N, Chataigneau T, Auger C. Vascular protection by natural product-derived polyphenols: in vitro and in vivo evidence. Planta Med 2011; 77: 1161-1167
• 4 Kay CD, Hooper L, Kroon PA, Rimm EB, Cassidy A. Relative impact of flavonoid composition, dose and structure on vascular function: a systematic review of randomised controlled trials of flavonoid-rich food products. Mol Nutr Food Res 2012; 56: 1605-1616
• 5 Godse S, Mohan M, Kasture V, Kasture S. Effect of myricetin on blood pressure and metabolic alterations in fructose hypertensive rats. Pharm Biol 2010; 48: 494-498
• 6 Wiart C. Goniothalamus species: a source of drugs for the treatment of cancers and bacterial infections?. Evid Based Complement Alternat Med 2007; 4: 299-311
• 7 Guabiraba R, Campanha-Rodrigues AL, Souza AL, Santiago HC, Lugnier C, Alvarez-Leite J, Lemos VS, Teixeira MM. The flavonoid dioclein reduces the production of pro-inflammatory mediators in vitro by inhibiting PDE4 activity and scavenging reactive oxygen species. Eur J Pharmacol 2010; 633: 85-92
• 8 Di Stasi LC, Hiruma-Lima CA. Plantas medicinais na Amazônia e na mata Atlântica. 2nd. edition. São Paulo: Unesp; 2003: 139-143
• 9 Correa MP. Dicionário das plantas úteis do Brasil e das exóticas cultivadas. 2nd. edition. Brasília: Ministério da Agricultura; 1984: 705-706
• 10 Bittencourt AM, Gottlieb OR, Mageswaram S, Mors WB, Ollis WD, Sutherland IO, Magalhaes MT. The natural occurrence of 6-styryl-2-pyrones and their synthesis. Tetrahedron 1971; 27: 5
• 11 Motidome M, Gottlieb OR, Kubitzki K. The chemistry of Brazilian Lauraceae – LXXI. Styrylpyrones of Aniba panurensis and A. permollis . Acta Amazon 1982; 12: 667-668
• 12 Barbosa-Filho JM, Yoshida M, Gottlieb OR, Barbosa RC, Giesbrecht AM, Young MCM. The chemistry of Brazilian Lauraceae. Part LXXXV. Benzoyl esters and amides, styrylpyrones and neolignans from the fruits of Aniba riparia . Phytochemistry 1987; 26: 2615-2617
• 13 Seyed MA, Jantan I, Bukhari SN. Emerging anticancer potentials of goniothalamin and its molecular mechanisms. Biomed Res Int advance online publication 28 August 2014
• 14 Petsophonsakul P, Pompimon W, Banjerdpongchai R. Apoptosis induction in human leukemic promyelocytic HL-60 and monocytic U937 cell lines by goniothalamin. Asian Pac J Cancer Prev 2013; 14: 2885-2889
• 15 Endemann DH, Schiffrin EL. Endothelial dysfunction. J Am Soc Nephrol 2004; 15: 1983-1992
• 16 Levy AS, Chung JC, Kroetsch JT, Rush JW. Nitric oxide and coronary vascular endothelium adaptations in hypertension. Vasc Health Risk Manag 2009; 5: 1075-1087
• 17 Dora KA. Coordination of vasomotor responses by the endothelium. Circ J 2010; 74: 226-232
• 18 Chawengsub Y, Gauthier KM, Campbell WB. Role of arachidonic acid lipoxygenase metabolites in the regulation of vascular tone. Am J Physiol Heart Circ Physiol 2009; 297: H495-H507
• 19 Berenyiova A, Grman M, Mijuskovic A, Stasko A, Misak A, Nagy P, Ondriasova E, Cacanyiova S, Brezova V, Feelisch M, Ondrias K. The reaction products of sulfide and S-nitrosoglutathione are potent vasorelaxants. Nitric Oxide 2015; 46: 123-130
• 20 Donald JA, Forgan LG, Cameron MS. The evolution of nitric oxide signalling in vertebrate blood vessels. J Comp Physiol B 2015; 185: 153-171
• 21 Cau SB, Carneiro FS, Tostes RC. Differential modulation of nitric oxide synthases in aging: therapeutic opportunities. Front Physiol 2012; 3: 218
• 22 Capettini LS, Cortes SF, Silva JF, Alvarez-Leite JI, Lemos VS. Decreased production of neuronal NOS-derived hydrogen peroxide contributes to endothelial dysfunction in atherosclerosis. Br J Pharmacol 2011; 164: 1738-1748
• 23 Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991; 43: 109-142
• 24 Wyatt AW, Steinert JR, Mann GE. Modulation of the L-arginine/nitric oxide signalling pathway in vascular endothelial cells. Biochem Soc Symp 2004; 71: 143-156
• 25 Martin S, Andriambeloson E, Takeda K, Andriantsitohaina R. Red wine polyphenols increase calcium in bovine aortic endothelial cells: a basis to elucidate signalling pathways leading to nitric oxide production. Br J Pharmacol 2002; 135: 1579-1587
• 26 Stoclet JC, Kleschyov A, Andriambeloson E, Diebolt M, Andriantsitohaina R. Endothelial NO release caused by red wine polyphenols. J Physiol Pharmacol 1999; 50: 535-540
• 27 Moritoki H, Miyano H, Takeuchi S, Yamaguchi H, Hisayama T, Kondoh W. Endothelin-3-induced relaxation of rat thoracic aorta: a role for nitric oxide formation. Br J Pharmacol 1993; 108: 1125-1130
• 28 Matsubara M, Hayashi N, Jing T, Titani K. Regulation of endothelial nitric oxide synthase by protein kinase C. J Biochem 2003; 133: 773-781
• 29 Bauer PM, Fulton D, Boo YC, Sorescu GP, Kemp BE, Jo H, Sessa WC. Compensatory phosphorylation and protein-protein interactions revealed by loss of function and gain of function mutants of multiple serine phosphorylation sites in endothelial nitric-oxide synthase. J Biol Chem 2003; 278: 14841-14849
• 30 Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 1999; 399: 597-601
• 31 Michell BJ, Griffiths JE, Mitchelhill KI, Rodriguez-Crespo I, Tiganis T, Bozinovski S, de Montellano PR, Kemp BE, Pearson RB. The Akt kinase signals directly to endothelial nitric oxide synthase. Curr Biol 1999; 9: 845-848
• 32 Caulin-Glaser T, García-Cardeña G, Sarrel P, Sessa WC, Bender JR. 17 beta-estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca²⁺ mobilization. Circ Res 1997; 81: 885-892
• 33 Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 1999; 399: 601-605
• 34 Ndiaye M, Chataigneau M, Lobysheva I, Chataigneau T, Schini-Kerth VB. Red wine polyphenol-induced, endothelium-dependent NO-mediated relaxation is due to the redox-sensitive PI3-kinase/Akt-dependent phosphorylation of endothelial NO-synthase in the isolated porcine coronary artery. FASEB J 2005; 19: 455-457
• 35 Anselm E, Chataigneau M, Ndiaye M, Chataigneau T, Schini-Kerth VB. Grape juice causes endothelium-dependent relaxation via a redox-sensitive Src- and Akt-dependent activation of eNOS. Cardiovasc Res 2007; 73: 404-413
• 36 Siow RC, Mann GE. Dietary isoflavones and vascular protection: activation of cellular antioxidant defenses by SERMs or hormesis?. Mol Aspects Med 2010; 31: 468-477
• 37 Yano H, Nakanishi S, Kimura K, Hanai N, Saitoh Y, Fukui Y, Nonomura Y, Matsuda Y. Inhibition of histamine secretion by wortmannin through the blockade of phosphatidylinositol 3-kinase in RBL-2H3 cells. J Biol Chem 1993; 268: 25846-25856
• 38 Kau TR, Schroeder F, Ramaswamy S, Wojciechowski CL, Zhao JJ, Roberts TM, Clardy J, Sellers WR, Silver PA. A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells. Cancer Cell 2003; 4: 463-476
• 39 Smiley DA, Khalil RA. Estrogenic compounds, estrogen receptors and vascular cell signaling in the aging blood vessels. Curr Med Chem 2009; 16: 1863-1887
• 40 Cairrão E, Alvarez E, Carvas JM, Santos-Silva AJ, Verde I. Non-genomic vasorelaxant effects of 17β-estradiol and progesterone in rat aorta are mediated by L-type Ca²⁺ current inhibition. Acta Pharmacol Sin 2012; 33: 615-624
• 41 Lin AH, Leung GP, Leung SW, Vanhoutte PM, Man RY. Genistein enhances relaxation of the spontaneously hypertensive rat aorta by transactivation of epidermal growth factor receptor following binding to membrane estrogen receptors-α and activation of a G protein-coupled, endothelial nitric oxide synthase-dependent pathway. Pharmacol Res 2011; 63: 181-189
• 42 Li QY, Chen L, Zhu YH, Zhang M, Wang YP, Wang MW. Involvement of estrogen receptor-β in farrerol inhibition of rat thoracic aorta vascular smooth muscle cell proliferation. Acta Pharmacol Sin 2011; 32: 433-440
• 43 Dennis MK, Burai R, Ramesh C, Petrie WK, Alcon SN, Nayak TK, Bologa CG, Leitao A, Brailoiu E, Deliu E, Dun NJ, Sklar LA, Hathaway HJ, Arterburn JB, Oprea TI, Prossnitz ER. In vivo effects of a GPR30 antagonist. Nat Chem Biol 2009; 5: 421-427
• 44 Horta CC, Rezende BA, Oliveira-Mendes BB, Carmo AO, Capettini LS, Silva JF, Gomes MT, Chávez-Olórtegui C, Bravo CE, Lemos VS, Kalapothakis E. ADP is a vasodilator component from Lasiodora sp. mygalomorph spider venom. Toxicon 2013; 72: 102-112
• 45 Walther S, Pluteanu F, Renz S, Nikonova Y, Maxwell JT, Yang LZ, Schmidt K, Edwards JN, Wakula P, Groschner K, Maier LS, Spiess J, Blatter LA, Pieske B, Kockskämper J. Urocortin 2 stimulates nitric oxide production in ventricular myocytes via Akt- and PKA-mediated phosphorylation of eNOS at serine 1177. Am J Physiol Heart Circ Physiol 2014; 307: H689-H700
• 46 Zhang QJ, McMillin SL, Tanner JM, Palionyte M, Abel ED, Symons JD. Endothelial nitric oxide synthase phosphorylation in treadmill-running mice: role of vascular signalling kinases. J Physiol 2009; 587: 3911-3920
• 47 Kajta M, Rzemieniec J, Litwa E, Lason W, Lenartowicz M, Krzeptowski W, Wojtowicz AK. The key involvement of estrogen receptor β and G-protein-coupled receptor 30 in the neuroprotective action of daidzein. Neuroscience 2013; 238: 345-360
• 48 Barbosa-Filho JM. Constituintes químicos dos gêneros: Aniba, Licaria e Nectandra (Lauraceae). Aspectos quimiotaxonômicos, analíticos, sintéticos e biológicos [dissertation]. São Paulo: Universidade de São Paulo; 1986