Protective Effects of Ellagic Acid on Cardiovascular Injuries Caused by Hypertension in Rats

Abstract

Ellagic acid is described as having antioxidant and antiproliferative properties. Hence, it was hypothesized that ellagic acid could improve cardiovascular damage caused by hypertension. In this work, hypertension was induced in rats with N_ω-Nitro-L-arginine methyl ester hydrochloride (60 mg/kg/day in drinking water) for 6 weeks. Ellagic acid was coadministered (10 or 30 mg/kg/day by gavage) between the second and sixth week. Blood pressure was recorded every week by tail-cuff plethysmography. After 6 weeks, the rats were sacrificed, the hearts and kidneys were weighed, and blood was collected. Aortas were isolated and set up to isometric recordings in an organ bath for histological assay and measuring of calcium content. Hypertension (233.6 ± 9.5 mmHg) was reduced (p < 0.01) by treatment with ellagic acid 10 or 30 mg/kg. The blood levels of nitrate/nitrite were reduced in hypertensive rats and the ellagic acid restored these levels. While the vascular relaxations to acetylcholine and sodium nitoprusside and the contraction to phenylephrine were impaired in the hypertensive group, they were improved after ellagic acid treatment. The alkaline phosphatase activity was increased by hypertension and returned to control levels after ellagic acid treatment. In the aorta, the administration of ellagic acid resulted in less aortic wall thickening and less calcification. In conclusion, ellagic acid attenuates hypertension, possibly improving nitric oxide bioavailability. The vascular response to acetylcholine, sodium nitroprusside, and phenylephrine was impaired by hypertension and improved after treatment with ellagic acid. Moreover, plasmatic alkaline phosphatase activity, calcium content, and hypertrophy in vascular tissues during hypertension were attenuated by treatment with ellagic acid.

Key words

ellagic acid - alkaline phosphatase - aortas - vascular relaxation - hypertension

• References

• 1 Gupta AK, McGlone M, Greenway FL, Jhonson WD. Prehypertension in disease-free adults: a marker for an adverse cardiometabolic risk profile. Hypertens Res 2010; 33: 905-910
• 2 Rapeport N, Middlemost S. Expert report on the 22nd European meeting on hypertension and cardiovascular protection. Cardiovasc J Afr 2012; 23: 232-234
• 3 Kanemaru K, Seya K, Miki I, Motomura S, Furukawa K. Calcification of aortic smooth muscle cells isolated from spontaneously hypertensive rats. J Pharmacol Sci 2008; 106: 280-286
• 4 Rodrigues GJ, Lunardi CN, Lima RG, Santos CX, Laurindo FR, da Silva RS, Bendhack LM. Vitamin C improves the effect of a new nitric oxide donor on the vascular smooth muscle from renal hypertensive rats. Nitric Oxide 2008; 18: 176-183
• 5 Castro MM, Rizzi E, Rodrigues GJ, Ceron CS, Bendhack LM, Gerlach RF, Tanus-Santos JE. Antioxidant treatment reduces matrix metalloproteinase-2-induced vascular changes in renovascular hypertension. Free Radic Biol Med 2009; 46: 1298-1307
• 6 Jensky NE, Criqui MG, Wright MC, Wassel CL, Brody SA, Allison MA. Blood pressure and vascular calcification. Hypertension 2010; 55: 990-997
• 7 Castro MM, Rizzi E, Figueiredo-Lopes L, Fernandes K, Bendhack LM, Pitol DL, Gerlach RF, Tanus-Santos JE. Metalloproteinase inhibition ameliorates hypertension and prevents vascular dysfunction and remodeling in renovascular hypertensive rats. Atherosclerosis 2008; 198: 320-331
• 8 Bhatt SR, Lokhandwala MF, Banday AA. Resveratrol prevents endothelial nitric oxide synthase uncoupling and attenuates development of hypertension in spontaneously hypertensive rats. Eur J Pharmacol 2011; 667: 258-264
• 9 Furchgott RF. Endothelium-derived relaxing factor: discovery, early studies and identifications as nitric oxide. Biosci Rep 1999; 19: 235-251
• 10 Ribeiro MO, Antunes E, de Nucci G, Lovisolo SM, Zatz R. Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension. Hypertension 1992; 20: 298-303
• 11 Clifford MN, Scalbert A. Ellagitannins – nature, occurrence and dietary burden. J Sci Food Agric 2000; 80: 1118-1125
• 12 Kähkönen MP, Hopia AI, Heinonen M. Berry phenolics and their antioxidant activity. J Agric Food Chem 2001; 49: 4076-4082
• 13 Priyadarsini KI, Khopde SM, Kumar SS, Mohan H. Free radical studies of ellagic acid, natural phenolic antioxidants. J Agric Food Chem 2002; 50: 2200-2206
• 14 Atessahín A, Ceribasi AO, Yuce A. Role of ellagic acid against cisplatin-induced nephrotoxicity and oxidative stress in rats. Basic Clin Pharmacol Toxicol 2006; 100: 121-126
• 15 Kannan MM, Quine SD. Ellagic acid ameliorates isoproterenol induced oxidative stress: Evidence from electrocardiological, biochemical and histological study. Eur J Pharmacol 2011; 659: 45-52
• 16 Ding Y, Zhang B, Zhou K. Dietary ellagic acid improves oxidant-induced endothelial dysfunction and atherosclerosis: role of Nrf2 activation. Int J Cardiol 2014; 175: 508-514
• 17 Berkban T, Boonprom P, Bunbupha S, Welbat JU, Kukongviriyapan U, Kukongviriyapan V, Pakdeechote P, Prachaney P. Ellagic acid prevents L-NAME-induced hypertension via restoration of eNOS and p47phox expression in rats. Nutrients 2015; 7: 5265-5280
• 18 Reule S, Drawz PE. Heart rate and blood pressure: any possible implications for management of hypertension?. Curr Hypertens Rep 2012; 14: 478-484
• 19 Ma Y, Huang H, Jiang J, Wu L, Lin C, Tang A, Dai G, He J, Chen Y. AVE0991 attenuates cardiac hypertrophy through reducing oxidative stress. Biochem Biophys Res Commun 2015; 291: 30567-30572
• 20 Panchal SK, Ward L, Brown L. Ellagic acid attenuates high-carbohydrate, high-fat diet-induced metabolic syndrome in rats. Eur J Nutr 2013; 52: 559-568
• 21 Nabha L, Garbern JC, Buller CL, Charpie JR. Vascular oxidative stress precedes high blood pressure in spontaneously hypertensive rats. Clin Exp Hypertens 2005; 27: 71-82
• 22 Han DH, Lee MJ, Kim JH. Antioxidant and apoptosis-inducing activities of ellagic acid. Anticancer Res 2006; 26: 3601-3606
• 23 Wang Y, Qiu Z, Zhou B, Liu C, Ruan J, Yan Q, Liao J, Zhu F. In vitro antiproliferative and antioxidant effects of urolithin A, the colonic metabolite of ellagic acid, on hepatocellular carcinomas HepG2 cells. Toxicol In Vitro 2015; 29: 1107-1115
• 24 Yilmaz B, Usta C. Ellagic acid-anduced endothelium-dependent and endothelium-independent vasorelaxation in rat thoracic aortic rings and the underlying mechanism. Phytother Res 2013; 27: 285-289
• 25 Sekiguchi F, Miyake Y, Hirakawa A, Nakahira T, Yamaoka M, Shimamura K, Yamamoto K, Sunano S. Hypertension and impairment of endothelium-dependent relaxation of arteries from spontaneously hypertensive and L-NAME-treated Wistar rats. J Smooth Muscle Res 2001; 37: 67-79
• 26 Alp Yildirim FI, Eker Kizilay D, Ergin B, Balci Ekmekçi Ö, Topal G, Kucur M, Demirci Tansel C, Uydeş Doğan BS. Barnidipine ameliorates the vascular and renal injury in L-NAME-induced hypertensive rats. Eur J Pharmacol 2015; 764: 433-442
• 27 Perticone F, Perticone M, Maio R, Sciacqua A, Andreucci M, Tripepi G, Corrao S, Mallamaci F, Sesti G, Zoccali C. Serum alkaline phosphatase negatively affects endothelium-dependent vasodilation in naïve hypertensive patients. Hypertension 2015; 66: 874-880
• 28 Bonaventura D, Oliveira FS, da Silva RS, Bendhack LM. Decreased vasodilation induced by a new nitric oxide donor in two kidney, one clip hypertensive rats is due to impaired K+ channel activation. Clin Exp Pharmacol Physiol 2005; 32: 478-481
• 29 Rodrigues GJ, Restini CB, Lunardi CN, Moreira JE, Lima RG, da Silva RS, Bendhack LM. Caveolae dysfunction contributes to impaired relaxation induced by nitric oxide donor in aorta from renal hypertensive rats. J Pharmacol Exp Ther 2007; 323: 831-837
• 30 Chen X, Touyz RM, Park JB, Schiffrin EL. Antioxidant effects of vitamins C and E are associated with altered activation of vascular NADPH oxidase and superoxide dismutase in stroke-prone SHR. Hypertension 2001; 38: 606-611
• 31 Dowell FJ, Henrion D, Duriez M, Michel JB. Vascular reactivity in mesenteric resistance arteries following chronic nitric oxide synthase inhibition in wistar rats. Br J Pharmacol 1996; 117: 341-346
• 32 Küng CF, Moreau P, Takase H, Lüscher TF. L-NAME hypertension alters endothelial and smooth muscle function in rat aorta. Prevention by trandolapril and verapamil. Hypertension 1995; 26: 744-751
• 33 Shimizu Y, Nakazato M, Sekita T, Kadota K, Yamasaki H, Takamura N, Aoyagi K, Kusano Y, Maeda T. Association between alkaline phosphatase and hypertension in a rural Japanese population: the Nagasaki Islands study. J Physiol Anthropol 2013; 32: 10
• 34 Sahin I, Karabulut A, Gungor B, Avci II, Okuyan E, Kizkapan F, Yildiz SS, Can MM, Dinckal M. Correlation between the serum alkaline phosphatase level and the severity of coronary artery disease. Coron Artery Dis 2014; 25: 349-352
• 35 Tölle M, Reshetnik A, Schuchardt M. Arteriosclerosis and vascular calcification: causes, clinical assessment and therapy. Eur J Clin Invest 2015; 45: 976-985
• 36 Ketteler M, Giachelli C. Novel insights into vascular calcification. Kidney Int Suppl 2006; 70: 5-9
• 37 Schutte R, Huisman HW, Malan I, van Rooyen JM, Smith W, Glyn MC, Mels CM, Fourie CM, Malan NT, Schutte AE. Alkaline phosphatase and arterial structure and function in hypertensive African men: the SABPA study. Int J Cardiol 2013; 167: 1995-2001
• 38 Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide 2001; 5: 62-71
• 39 Sui YB, Chang JR, Chen WJ, Zhao L, Zhang BH, Yu YR, Tang CS, Yin XH, Qi YF. Angiotensin-(1–7) inhibits vascular calcification in rats. Peptides 2013; 42: 25-34