Abstract
Inhibition of nitric oxide synthesis with N ω-nitro-l-arginine methyl ester (l-NAME) induces marked hypertension and oxidative stress. Curcumin (CUR) has been shown strong antioxidant property. Tetrahydrocurcumin (THU), a major metabolite of CUR, possesses several pharmacological effects similar to CUR; however, it is less studied than CUR. We investigated whether CUR and THU could prevent vascular dysfunction and inhibit development of hypertension in l-NAME-treated rats. Male Sprague–Dawley rats were administered with l-NAME (50 mg/kg/day) in drinking water for 3 weeks. CUR or THU (50 and 100 mg/kg/day) was fed to animals simultaneously with l-NAME. l-NAME administration induced increased arterial blood pressure and elevated peripheral vascular resistance accompanied with impaired vascular responses to angiotensin II and acetylcholine. CUR and THU significantly suppressed the blood pressure elevation, decreased vascular resistance, and restored vascular responsiveness. The improvement of vascular dysfunction was associated with reinstating the marked suppression of eNOS protein expression in the aortic tissue and plasma nitrate/nitrite. Moreover, CUR and THU reduced vascular superoxide production, decreased oxidative stress, and increased the previously depressed blood glutathione (GSH) and the redox ratios of GSH in l-NAME hypertensive rats. The antihypertensive and some antioxidant effects of THU are apparently more potent than those of CUR. This study suggests that CUR and THU prevented the development of vascular dysfunction induced by l-NAME and that the effects are associated with alleviation of oxidative stress.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aggarwal BB, Sung B (2009) Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends Pharmacol Sci 30:85–94
Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB (2007) Bioavailability of curcumin: problems and promises. Mol Pharm 4:807–818
Arnal JF, Warin L, Michel JB (1992) Determinants of aortic cyclic guanosine monophosphate in hypertension induced by chronic inhibition of nitric oxide synthase. J Clin Invest 90:647–652
Baylis C, Mitruka B, Deng A (1992) Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest 90:278–281
Bengmark S (2006) Curcumin, an atoxic antioxidant and natural NFkappaB, cyclooxygenase-2, lipooxygenase, and inducible nitric oxide synthase inhibitor: a shield against acute and chronic diseases. JPEN J Parenter Enteral Nutr 30:45–51
Bredt DS, Snyder SH (1994) Nitric oxide: a physiologic messenger molecule. Annu Rev Biochem 63:175–195
Cai H, Harrison DG (2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 87:840–844
De Gennaro CV, Rossoni G, Rigamonti A, Bonomo S, Manfredi B, Berti F, Muller E (2002) Enalapril and quinapril improve endothelial vasodilator function and aortic eNOS gene expression in l-NAME-treated rats. Eur J Pharmacol 450:61–66
De Gennaro CV, Rigamonti A, Fioretti S, Bonomo S, Manfredi B, Ferrario P, Bianchi M, Berti F, Muller EE, Rossoni G (2005) Angiotensin-converting enzyme inhibition and angiotensin AT1-receptor antagonism equally improve endothelial vasodilator function in l-NAME-induced hypertensive rats. Eur J Pharmacol 516:253–259
Dinkova-Kostova AT, Talalay P (2008) Direct and indirect antioxidant properties of inducers of cytoprotective proteins. Mol Nutr Food Res 52(Suppl 1):S128–S138
Farombi EO, Shrotriya S, Na HK, Kim SH, Surh YJ (2008) Curcumin attenuates dimethylnitrosamine-induced liver injury in rats through Nrf2-mediated induction of heme oxygenase-1. Food Chem Toxicol 46:1279–1287
Ferroni P, Basili S, Paoletti V, Davi G (2006) Endothelial dysfunction and oxidative stress in arterial hypertension. Nutr Metab Cardiovasc Dis 16:222–233
Heiss EH, Schachner D, Werner ER, Dirsch VM (2009) Active NF-E2-related factor (Nrf2) contributes to keep endothelial NO synthase (eNOS) in the coupled state: role of reactive oxygen species (ROS), eNOS, and heme oxygenase (HO-1) levels. J Biol Chem 284:31579–31586
Henrion D, Dowell FJ, Levy BI, Michel JB (1996) In vitro alteration of aortic vascular reactivity in hypertension induced by chronic NG-nitro-l-arginine methyl ester. Hypertension 28:361–366
Ireson CR, Jones DJ, Orr S, Coughtrie MW, Boocock DJ, Williams ML, Farmer PB, Steward WP, Gescher AJ (2002) Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine. Cancer Epidemiol Biomark Prev 11:105–111
Kawazoe T, Kosaka H, Yoneyama H, Hata Y (2000) Acute production of vascular superoxide by angiotensin II but not by catecholamines. J Hypertens 18:179–185
Kitamoto S, Egashira K, Kataoka C, Usui M, Koyanagi M, Takemoto M, Takeshita A (2000) Chronic inhibition of nitric oxide synthesis in rats increases aortic superoxide anion production via the action of angiotensin II. J Hypertens 18:1795–1800
Kukongviriyapan V, Somparn N, Senggunprai L, Prawan A, Kukongviriyapan U, Jetsrisuparb A (2008) Endothelial dysfunction and oxidant status in pediatric patients with hemoglobin E-beta thalassemia. Pediatr Cardiol 29:130–135
Luangaram S, Kukongviriyapan U, Pakdeechote P, Kukongviriyapan V, Pannangpetch P (2007) Protective effects of quercetin against phenylhydrazine-induced vascular dysfunction and oxidative stress in rats. Food Chem Toxicol 45:448–455
Manning RD Jr, Hu L, Mizelle HL, Montani JP, Norton MW (1993) Cardiovascular responses to long-term blockade of nitric oxide synthesis. Hypertension 22:40–48
Moncada S, Higgs EA (1991) Endogenous nitric oxide: physiology, pathology and clinical relevance. Eur J Clin Investig 21:361–374
Motterlini R, Foresti R, Bassi R, Green CJ (2000) Curcumin, an antioxidant and anti-inflammatory agent, induces heme oxygenase-1 and protects endothelial cells against oxidative stress. Free Radic Biol Med 28:1303–1312
Mukai Y, Sato S (2009) Polyphenol-containing azuki bean (Vigna angularis) extract attenuates blood pressure elevation and modulates nitric oxide synthase and caveolin-1 expressions in rats with hypertension. Nutr Metab Cardiovasc Dis 19:491–497
Murakami Y, Ishii H, Takada N, Tanaka S, Machino M, Ito S, Fujisawa S (2008) Comparative anti-inflammatory activities of curcumin and tetrahydrocurcumin based on the phenolic O–H bond dissociation enthalpy, ionization potential and quantum chemical descriptor. Anticancer Res 28:699–707
Murugan P, Pari L (2007) Influence of tetrahydrocurcumin on erythrocyte membrane bound enzymes and antioxidant status in experimental type 2 diabetic rats. J Ethnopharmacol 113:479–486
Okada K, Wangpoengtrakul C, Tanaka T, Toyokuni S, Uchida K, Osawa T (2001) Curcumin and especially tetrahydrocurcumin ameliorate oxidative stress-induced renal injury in mice. J Nutr 131:2090–2095
Pae HO, Jeong GS, Jeong SO, Kim HS, Kim SA, Kim YC, Yoo SJ, Kim HD, Chung HT (2007) Roles of heme oxygenase-1 in curcumin-induced growth inhibition in rat smooth muscle cells. Exp Mol Med 39:267–277
Pari L, Amali DR (2005) Protective role of tetrahydrocurcumin (THC) an active principle of turmeric on chloroquine induced hepatotoxicity in rats. J Pharm Pharm Sci 8:115–123
Pechanova O, Bernatova I, Babal P, Martinez MC, Kysela S, Stvrtina S, Andriantsitohaina R (2004) Red wine polyphenols prevent cardiovascular alterations in l-NAME-induced hypertension. J Hypertens 22:1551–1559
Priviero FB, Teixeira CE, Claudino MA, De Nucci G, Zanesco A, Antunes E (2007) Vascular effects of long-term propranolol administration after chronic nitric oxide blockade. Eur J Pharmacol 571:189–196
Ramaswami G, Chai H, Yao Q, Lin PH, Lumsden AB, Chen C (2004) Curcumin blocks homocysteine-induced endothelial dysfunction in porcine coronary arteries. J Vasc Surg 40:1216–1222
Ravindranath V, Chandrasekhara N (1981) Metabolism of curcumin–studies with [3H]curcumin. Toxicology 22:337–344
Rinwa P, Kaur B, Jaggi AS, Singh N (2010) Involvement of PPAR-gamma in curcumin-mediated beneficial effects in experimental dementia. Naunyn Schmiedebergs Arch Pharmacol 381:529–539
Rungseesantivanon S, Thenchaisri N, Ruangvejvorachai P, Patumraj S (2010) Curcumin supplementation could improve diabetes-induced endothelial dysfunction associated with decreased vascular superoxide production and PKC inhibition. BMC Complement Altern Med 10:1–9
Sharma RA, Gescher AJ, Steward WP (2005) Curcumin: the story so far. Eur J Cancer 41:1955–1968
Simko F, Pechanova O, Pelouch V, Krajcirovicova K, Celec P, Palffy R, Bednarova K, Vrankova S, Adamcova M, Paulis L (2010) Continuous light and l-NAME-induced left ventricular remodelling: different protection with melatonin and captopril. J Hypertens 28(Suppl 1):S13–S18
Sompamit K, Kukongviriyapan U, Nakmareong S, Pannangpetch P, Kukongviriyapan V (2009) Curcumin improves vascular function and alleviates oxidative stress in non-lethal lipopolysaccharide-induced endotoxaemia in mice. Eur J Pharmacol 616:192–199
Somparn P, Phisalaphong C, Nakornchai S, Unchern S, Morales NP (2007) Comparative antioxidant activities of curcumin and its demethoxy and hydrogenated derivatives. Biol Pharm Bull 30:74–78
Sugiyama Y, Kawakishi S, Osawa T (1996) Involvement of the beta-diketone moiety in the antioxidative mechanism of tetrahydrocurcumin. Biochem Pharmacol 52:519–525
Suphim B, Prawan A, Kukongviriyapan U, Kongpetch S, Buranrat B, Kukongviriyapan V (2010) Redox modulation and human bile duct cancer inhibition by curcumin. Food Chem Toxicol 48:2265–2272
Tanwar V, Sachdeva J, Golechha M, Kumari S, Arya DS (2010) Curcumin protects rat myocardium against isoproterenol-induced ischemic injury: attenuation of ventricular dysfunction through increased expression of Hsp27 along with strengthening antioxidant defense system. J Cardiovasc Pharmacol 55:377–384
Tietze F (1969) Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem 27:502–522
Tsukahara H, Hiraoka M, Kobata R, Hata I, Ohshima Y, Jiang MZ, Noiri E, Mayumi M (2000) Increased oxidative stress in rats with chronic nitric oxide depletion: measurement of urinary 8-hydroxy-2′-deoxyguanosine excretion. Redox Rep 5:23–28
Usui M, Egashira K, Kitamoto S, Koyanagi M, Katoh M, Kataoka C, Shimokawa H, Takeshita A (1999) Pathogenic role of oxidative stress in vascular angiotensin-converting enzyme activation in long-term blockade of nitric oxide synthesis in rats. Hypertension 34:546–551
Xu PH, Long Y, Dai F, Liu ZL (2007) The relaxant effect of curcumin on porcine coronary arterial ring segments. Vascul Pharmacol 47:25–30
Zalba G, San Jose G, Moreno MU, Fortuno MA, Fortuno A, Beaumont FJ, Diez J (2001) Oxidative stress in arterial hypertension: role of NAD(P)H oxidase. Hypertension 38:1395–1399
Acknowledgements
This study was supported by Thailand Research Fund (Grant No. DBG 5380045) and a grant from National Research University of Thailand, Khon Kaen University. Saowanee Nakmareong was supported by a CHE-PhD Scholarship, Commission on Higher Education, Ministry of Education, Thailand. The authors thank Professor Stephen E. Greenwald, Queen Mary University of London, for language editing of the manuscript and valuable suggestions.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Nakmareong, S., Kukongviriyapan, U., Pakdeechote, P. et al. Antioxidant and vascular protective effects of curcumin and tetrahydrocurcumin in rats with l-NAME-induced hypertension. Naunyn-Schmiedeberg's Arch Pharmacol 383, 519–529 (2011). https://doi.org/10.1007/s00210-011-0624-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-011-0624-z