|Year : 2015 | Volume
| Issue : 1 | Page : 20-27
Chrysin enhances antioxidants and oxidative stress in L-NAME-induced hypertensive rats
Ramanathan Veerappan1, Rajagopal Senthilkumar2
1 Department of Biochemistry, Rajah Serfoji Government College, Thanjavur, Tamil Nadu, India
2 Department of Zoology, Nizam College, Hyderabad, Telangana, India
|Date of Submission||22-Sep-2014|
|Date of Acceptance||28-Oct-2014|
|Date of Web Publication||27-Jan-2015|
Department of Zoology, Nizam College, Hyderabad - 500 001, Telangana
Source of Support: This work was supported by Department of
Biotechnology, Ministry of Science and Technology, Govt. of India to
R.S. The content is solely the responsibility of the authors and doesn’t
necessarily represent the views of the Department of Biotechnology,
Govt. of India., Conflict of Interest: None
| Abstract|| |
Objectives: The study seeks to evaluate the effect of chrysin; a natural, biologically active compound extracted from plants, honey or propolis, on the tissues and circulatory antioxidant status and lipid peroxidation in Nω-nitro-l-arginine methyl ester (L-NAME) induced hypertensive rats. Materials and Methods: Male albino rats were divided into four groups. Control (Group I) and chrysin supplementation of the control (Group II) received normal diet. Groups III and IV received L-NAME (40 mg/kg B.W). Groups II and IV received chrysin (25 mg/kg B.W) dissolved in 0.2% dimethylsulfoxide solution after the 4 th week. Results and Discussion: The results showed significantly elevated levels of tissue and circulatory thiobarbituric acid reactive substances, conjugated dienes and lipid hydroperoxides, and significantly lowered enzymic and non-enzymic antioxidant activity of superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, vitamin C and vitamin E in L-NAME-induced hypertensive rats compared with those in control group. From chrysin administration to rats with L-NAME-induced hypertension leads to tissue damage which significantly decreases the levels of thiobarbituric acid reactive substances, lipid hydroperoxides and conjugated dienes, and significantly elevates the activity of superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, vitamin C and vitamin E in the tissues and circulation compared with those on the unsupplemented L-NAME induced hypertensive group. Conclusions: Chrysin offers protection against free radical-mediated oxidative stress in rats with L-NAME-induced hypertension.
Keywords: Catalase, glutathione, glutathione reductase, hypertension, nitric oxide, superoxide dismutase, thiobarbituric acid reactive substances
|How to cite this article:|
Veerappan R, Senthilkumar R. Chrysin enhances antioxidants and oxidative stress in L-NAME-induced hypertensive rats. Int J Nutr Pharmacol Neurol Dis 2015;5:20-7
|How to cite this URL:|
Veerappan R, Senthilkumar R. Chrysin enhances antioxidants and oxidative stress in L-NAME-induced hypertensive rats. Int J Nutr Pharmacol Neurol Dis [serial online] 2015 [cited 2020 Jan 19];5:20-7. Available from: http://www.ijnpnd.com/text.asp?2015/5/1/20/150069
| Introduction|| |
Hypertension is an important public health problem across the world because of its high prevalence and concomitant risks of cardiovascular and renal diseases.  Hypertension has affected more than 600 million people and results in 13% of total deaths globally, and it is estimated that 29% of the world's adult will have hypertension by 2025.  Nitric oxide (NO) synthesis and release by endothelial cells have a vascular relaxation effect, contributing to the modulation of vascular tone. Chronic NO inhibition with Nω-nitro-L-arginine methyl ester (L-NAME) can increase regional vascular resistance, raise the blood pressure, and oxidative stress accompanied with renal damage. L-NAME-induced animal models are well standardized and common experimental models for studies on hypertension also investigation of the therapeutic role of various animals on arterial walls.  Reactive Oxygen Species (ROS) also have been shown to be critical determinants in hypertension.  The increased generation or decreased scavenging or metabolism of ROS is defined as oxidative stress. ROS and free radicals are mediators of several forms of tissue damage, such as ischemic injuries to different organs, inflammatory response and injury resulting from intracellular metabolism of drugs and chemicals. 
The principal free radicals are superoxide (O 2•), hydroxyl (•OH) and peroxyl (LOO•) radicals, all of which may play a role in renal damage due to hypertension.  Certain enzymes also play an important role in antioxidant defence, converting free radicals or reactive oxygen intermediates to non-radical products. The best known of these enzymes are superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT). Some defects have been noted in the antioxidant system of hypertensives.  The contribution of oxidative stress to the pathogenesis of hypertension is supported to rely upon inactivation of the NO.
Flavonoids are plant polyphenolic compounds that consist of a number of classes, as flavanols, flavones and flavans. Chrysin (5,7-dihydroxy flavones structure shown in [Figure 1]) is a naturally occurring flavone contained in flowers such as the blue passion flower (Passiflora caerulea) and the Indian trumpet flower, as well as in edible items such as mushroom,  honey and propolis.  Chrysin has been found to possess antioxidant,  anti-allergic,  anti-inflammatory,  anti-cancer,  antiestrogenic,  anxiolytic  and antihypertensive  properties.
Chrysin has also been found to have tyrosinase inhibitory activity  and moderate aromatase inhibitory activity.  It can also inhibit estradiol-induced DNA synthesis.  In order to improve the biological activity of chrysin, a number of its derivatives have been prepared.  C-iso-prenylated hydrophobic derivatives of chrysin are potential P-glycoprotein modulators in tumour cells.  The previous study shows that chrysin has antihypertensive effects, and reduces hepatic, renal damages and endothelial dysfunction in L-NAME-induced hypertensive rats.  The present study aimed to evaluate the effect of chrysin on tissue lipid peroxidation and the antioxidant status in L-NAME-induced hypertensive rats. The findings were compared with those control and un-supplemented groups.
| Materials and methods|| |
Chrysin and L-NAME was purchased from Sigma Chemical Co. (St. Louis, MO, USA). All other chemicals used in this study were of analytical grade and obtained from E-Merck or HIMEDIA, Mumbai, India.
All the animal handling and experimental procedures were approved by the Institutional Animal Ethics Committee of Bharathidasan University (Registration no: 418/01/a/date 04.06.2001) and animals were cared for in accordance with the Indian National Law on Animal Care and Use. Male Wistar rats (180-220 g) were purchased from the Indian Institute of Science, Bangalore, India. Rats were housed in plastic cages with filter tops under controlled conditions of a 12 h light-dark cycle, 50% humidity and temperature of 28°C. All rats received a standard pellet diet (Lipton Lever Mumbai, India) and water ad libitum (BDU/IAEC63/2013).
Induction of L-NAME - induced hypertension
L-NAME (40 mg/kg B.W) was dissolved in 0.2% dimethyl sulfoxide (DMS) and given to rats at an interval of 24 h for 8 weeks. Mean arterial blood pressure (MAP) was measured using tail cuff method. MAP measurements were performed at the time of 1-8 weeks.
Blood pressure measurements
Systolic and diastolic blood pressures were determined by the tail-cuff method (IITC, model 31, Woodland Hills, CA, USA). The animals were placed in a heated chamber at an ambient temperature of 30-34°C for 15 minutes and from each animal one to nine blood pressure values were recorded. The lowest three readings were averaged to obtain a mean blood pressure. All recordings and data analyses were done using a computerized data acquisition system and software.
The rats were divided into four groups of six each, and fed with the standard pellet diet.
- Group I: Control
- Group II: Control+chrysin (25 mg/kg B.W) after 4 th week
- Group III: L-NAME induced hypertension (40 mg/kg B.W)
- Group IV: L-NAME induced hypertension+chrysin (25 mg/kg B.W) after 4 th week.
Chrysin were administered orally once in a day in the morning for 4 weeks. The compound was suspended in 0.2% DMSO solution and fed by intubation. Group 1 received 0.2% DMSO. After 8 th week morning the animals were sacrificed by cervical dislocation. The blood was collected in clean dry test tubes and allowed to coagulate at ambient temperature for 30 minutes. Serum was separated by centrifugation at 175 × g for 10 minutes. The blood, collected in a heparinised centrifuge tube, was centrifuged at 175 × g for 10 minutes and the plasma was separated by aspiration. After the separation of plasma, the buffy coat, enriched in white cells, was removed and the remaining erythrocytes were washed three times with physiological saline. A known volume of erythrocyte was lysed with hypotonic phosphate buffer at pH 7.4. The hemolysate was separated by centrifugation at 290 × g for 10 minutes and the supernatant was used for various estimations. The Liver, heart, kidney and aorta were immediately removed and washed in ice-cold saline to remove the blood. The tissues were sliced and homogenized in 0.1 M Tris-HCl buffer (pH 7.0). The homogenates were centrifuged at 48 × g for 10 minutes at 4°C in a cold centrifuge. The supernatants were separated and used for the determination of various parameters.
Biochemical parameters and free radical markers
The various concentrations of Thiobarbituric acid reactive substances (TBARS) were estimated by the method of Ohkawa et al. The concentration of Lipid hydroperoxides (LOOH) were estimated by the method of Jiang et al. Conjugated Dienes (CD) were estimated by the method of Rao and Recknagel.  The activities of enzymatic antioxidants SOD, CAT and GPx were assayed by the methods of Kakkar et al.;  Sinha  and Rotruck et al. respectively. The non-enzymatic antioxidants reduced glutathione (GSH), vitamin-C and vitamin-E were estimated by the methods of Ellman,  Roe and Kuether  and Baker et al. respectively.
Data were analyzed by Two-way analysis of variance followed by a Duncan's multiple range tests using a commercially available statistics software package (SPSS for Windows, version 11.0; SPSS Inc., Chicago, IL, USA). Results were presented as mean ± standard deviation (SD) values of P < 0.05 were regarded as statistically significant.
| Results|| |
[Table 1] shows the effect of chrysin on body weight and water intake of control rats and L-NAME-induced hypertensive rats. L-NAME-induced hypertensive rats (group III) had significantly (P < 0.05) decreased bodyweight and increased the water intake. Treatment with chrysin (Group IV) (25 mg/kg) significantly (P < 0.05) increased the body weight and reduced the level of water intake in L-NAME-induced hypertensive rats (group III).
|Table 1: Effect of chrysin on bodyweight and water intake of control rats and L-NAME-induced hypertensive rats |
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[Table 2] and [Table 3] shows the effect of chrysin on systolic and diastolic blood pressures in control and experimental rats for 4 weeks. The systolic and diastolic blood pressures were found significantly higher (P < 0.05) in L-NAME induced hypertensive rats (group III). Treatment with chrysin significantly (P < 0.05) reduced the systolic and diastolic blood pressure in L-NAME -induced hypertensive group (group IV). There are no significant variations between groups I and II.
|Table 2: Effect of chrysin on systolic blood pressure in control and L-NAME-induced hypertensive rats |
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|Table 3: Effect of chrysin on diastolic blood pressure in control and L-NAME-induced hypertensive rats |
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The levels of TBARS, LOOH and CD in the tissues and circulation of control and experimental animals are given in [Table 4]. TBARS, LOOH and conjugated diene levels in the liver, kidney, heart, aorta and circulation of rats treated with L-NAME-induced hypertension (group III) were significantly higher compared with those the control rats (group I) (P < 0.05). Chrysin supplementation to rats with L-NAME-induced hypertension (group IV) lowered the TBARS, LOOH and CD levels significantly compared with such L-NAME induced hypertension (group III). Treatment with chrysin did not significant alter the TBARS, LOOH and CD levels in (group II) control.
|Table 4: Effect of chrysin on TBARS, LOOH and CD in plasma and tissues of control and L-NAME-induced hypertensive rats |
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The activities of SOD, CAT and GPx in erythrocytes and tissues (liver, kidney, heart and aorta) of control and Experimental groups are presented in [Table 5]. The activities of these enzymatic antioxidants significantly (P < 0.05) decreased in L-NAME induced hypertensive rats (group III). Treatment with chrysin significantly (P < 0.05) restored the activity of these enzymatic antioxidants in erythrocyte and in other tissues in group IV. SOD, CAT and GPx values did not alter significantly on treatment with chrysin in control rats (group II) compared with the normal control rats (group I).
|Table 5: Effect of chrysin on SOD in erythrocytes and tissues of control and L-NAME-induced hypertensive rats |
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[Table 6] shows the decrease in tissue and circulatory nonenzymic antioxidants such as GSH, vitamins C and E in L-NAME-induced hypertensive rats (group III) compared with the control rats (group I). Administering chrysin to L-NAME-induced hypertensive rats (group IV) significantly elevated levels of GSH, vitamins C and E compared with rats with untreated rats (group III). GSH, Vitamin C and E levels did not alter significantly on treatment with chrysin among the rats (group II) compared with the normal control rats (group I).
|Table 6: Effect of chrysin on non-enzymatic antioxidants (vitamin C, vitamin E, and GSH) in plasma and tissues of control and L-NAME-induced hypertensive rats |
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| Discussion|| |
The purpose of this study is to investigate the protective effects of chrysin against L-NAME-induced hypertension. The present experiments provide evidence that chronic inhibition of NO synthesis in rats leads to marked elevations of systemic blood pressure and peripheral vascular resistance with alteration of vascular responsiveness. These vascular alterations were associated with marked oxidative stress. Six weeks of L-NAME administration causes a chronic increase in blood pressure in rats as previously described by other authors after shorter duration experiments.  Many studies have reported chronic blockade of NO synthesis by NOS inhibitors like L-NAME leading to endothelial dysfunction, a significant increase in blood pressure and further pathological injuries to the cardiovascular system and kidneys, which may lead to aggravation of hypertension.  A mechanism responsible for the increase of BP during L-NAME-treatment is associated with NO deficiency and alterations in various blood pressure regulating systems. Several authors have observed elevation of vasoconstriction and attenuation of vasorelaxation in different parts of the vascular tree and increased sympathetic activity and alterations in renin-angiotensin system in L-NAME treated rats. 
In our previous work demonstrated that a daily oral dose (25 mg/kg) of chrysin for 8 weeks reduced the elevated blood pressure and hepatoprotective effect in L-NAME induced hypertensive rats. , The vasodilator effect of chrysin on resistance vessels might contribute to its antihypertensive effect. The mechanisms involved in the endothelium-dependent vasorelaxant effect induced by chrysin were previously analyzed in the rat aorta.  The administration of chrysin to animals with L-NAME-induced hypertension leads to a decrease of blood pressure also improved NOx in a concentration dependent manner. Chrysin causes a significant drop in blood pressure.
The results show for the first time that chrysin ameliorates L-NAME-induced hypertension by reducing blood pressure, oxidative stress, and improving the levels of plasma NO metabolites. Chronic inhibition of NO synthase by administration of L-NAME is associated with induction of hypertension, hypertrophy, cardiac remodeling  and renal functional alterations.  Bioavailability of NO can be maintained by inhibition of oxidative stress, and therefore the agents with antioxidant properties inactivate free radicals and increase NO bioavailability and thus improve regulation of the vascular tone. Lipid peroxidation is an important pathogenic event in hypertension, and accumulation of lipid hydroperoxides reflects the various stages of the disease and its complications. 
Oxidative stress initiates and facilitates damage to membrane lipids, resulting in a decrease of renal cell membrane fluidity. Oxidative stress, characterized by increased bioavailability of ROS plays an important role in the development and progression of cardiovascular dysfunction associated with hypertensive disease. The increased levels of ROS such as superoxide anion, hydrogen peroxide and lipid peroxides are reported in hypertensive patients.  The increase in lipid peroxidation products in L-NAME-induced hypertensive rats might be a reflection of the decrease in enzymatic and nonenzymatic antioxidants defence system.  The present study shows increased levels of lipid peroxidation products such as TBARS, LOOH, and CD as a consequence of oxidative stress-induced lipid membrane damage. Chrysin significantly inhibits the lipid membrane damage as evidenced from the decreased levels of lipid peroxidation products in L-NAME-induced hypertensive rats treated with chrysin. The decrease in lipid peroxidation on chrysin treatment can be correlated with elevated levels of antioxidants. This may be due to the free radical scavenging properties of the hydroxyl groups in the 5 th and 7 th position of chrysin. The ability of chrysin to enhance the levels of antioxidants along with its antilipid-peroxidative activity suggests that this compound might be potentially useful in counteracting the free radical mediated injury involved in the development of liver damage caused in L-NAME-induced hypertension.
SOD is a ubiquitous chain-breaking antioxidant found in all aerobic organisms. It is a metalloprotein widely distributed in all cells and plays an important protective role against oxidative damage induced by reactive oxygen species. SOD, CAT, and GPx balance act together to eliminate ROS, and even small deviations in physiological concentrations may have a dramatic effect on the resistance of cellular lipids, proteins, and DNA to oxidative damage.  SOD converts superoxide ion (O2 - ) to hydrogen peroxide (H 2 O 2 ) and the hydrogen peroxide thus formed is degraded by CAT and GPx. CAT is present in all major body organs of animals and humans and is especially concentrated in the liver and erythrocytes. In addition, GPx can reduce lipid peroxides and other organic hydroperoxides that are highly cytotoxic products. Accordingly, SOD, CAT and GPx constitute the principal components of the antioxidant defence system and their deficiencies can cause oxidative stress. In the present study, decreased SOD CAT and GPx activities in tissues and erythrocytes in L-NAME-induced hypertensive rats suggests an over consumption of these enzymes, as enzymes of related to increased oxidative stress due to presence hydrogen peroxide in vivo. Reduced activity of SOD and CAT will result in the accumulation of these highly reactive free radicals, leading to deleterious effects such as loss of cell membrane integrity and function.  Administration of chrysin, improved the activities of SOD, CAT, and GPx in L-NAME-induced hypertensive rats. These data clearly suggest a reduction in production of ROS. The protective role of chrysin in preventing overproduction of ROS triggered by ultraviolet A and ultraviolet B in epidermal keratinocytes has also been reported. 
Chrysin supplementation to the L-NAME-induced hypertensive group elevated the SOD and CAT activity in the liver, kidney, heart, aorta and the erythrocytes, emphasizing the antioxidant and hepatoprotective activities of chrysin. The second line of defense consists of nonenzymatic antioxidants namely, vitamin C, vitamin E, and reduced glutathione which scavenge the residual free radicals escaping from decomposition by the antioxidant enzymes.  Reduced glutathione is an important reducing agent in the cell, where it protects against the toxic effects of free radicals, peroxides and other toxic components. It maintains the normal structure and function of the cells, probably by its redox and detoxification reactions. Vitamin C is a primary antioxidant, water-soluble vitamin that can directly scavenge singlet oxygen, superoxide and hydroxyl radicals. Vitamin E reacts with lipid peroxy radicals, acting as a chain terminator of lipid peroxidation, and protects the cellular structures from attack by free radicals. It inhibits lipid peroxidation and regenerates reduced vitamin C and GSH. In the prsent study, was observed a significant decrease in the levels of the nonenzymic antioxidants vitamins C and E, which may be due to the enhanced oxidative stress in L-NAME-induced hypertension. Vitamin E terminates lipid peroxidation by trapping free radicals, thereby getting itself converted to α-tocopheroxyl radicals, while vitamin C may have an important role in the regeneration of α-tocopherol from α-tocopheroxyl radicals. 
Flavonoid antioxidants function as scavengers of free radicals by rapid donation of hydrogen atoms to radicals.  A study on the anti-oxidant potency of various flavonoids has confirmed the importance of the distribution and number of hydroxyl groups in the compounds. Treatment with chrysin significantly elevated the levels of these nonenzymatic antioxidants and this suggests that this compound might be potentially useful in counteracting free radical mediated oxidative stress caused by lipid peroxidation. This anti-oxidant property of flavonoids is believed to mediate the protective action of chrysin against oxidative stress by enhancing the activities of enzymatic and non-enzymatic anti-oxidants and by reducing the intensity of lipid peroxidation. The ability of chrysin to enhance the levels of antioxidants along with its antilipid peroxidative activity suggests that this compound might be potentially useful in counteracting free-radical-mediated tissue damage caused by hypertensivity.
| Conclusion|| |
In conclusion, the present biochemical findings show that chrysin possesses an antihypertensive effect which is evidenced by lowered blood pressure, lipid peroxides, and improved antioxidant status. Scavenging of superoxide anions by chrysin is attributed to its antioxidant effect and leads to relaxation of the vessel wall and controls blood pressure.
| Acknowledgements|| |
This work was supported by Department of Biotechnology, Ministry of Science and Technology, Govt. of India to R.S (BT/RLF/Re-entry/42/2012).
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
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