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Copyright © by the authors. This article has been cited by other articles in PMC. Abstract Hesperidin is a major flavonoid isolated from citrus fruits that exhibits several biological activities. This study aims to evaluate the effect of hesperidin on cardiovascular remodeling induced by n-nitro l-arginine methyl ester l-NAME in rats.

Hesperidin or captopril significantly prevented the development of hypertension in l-NAME rats.

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These data suggested that hesperidin had cardioprotective effects in l-NAME hypertensive rats. The possible mechanism may involve antioxidant and anti-inflammatory effects. Keywords: hesperidin, l-NAME, cardiovascular remodeling, oxidative stress, inflammation 1. Introduction Nitric oxide NO is a crucial vasodilator derived from vascular endothelium to regulate vascular tone [ 1 ].

A reduction of NO production results in increased vascular resistance and high blood pressure. It has been reported that l-NAME-induced hypertension in rats is characterized by insufficient NO production, increased systemic oxidative stress, inflammation, and endothelial dysfunction [ 2 ].

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Furthermore, l-NAME-induced hypertension and cardiovascular remodeling have also been reported in rats. It is generally known that the main sequel of cardiovascular remodeling is heart failure, which is the major cause of death worldwide [ 6 ].

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The initial stage of cardiac remodeling is myocardial hypertrophy because of the adaptive response to a high-pressure load to preserve cardiac function and obtain normal cardiac work. In addition, the cardiac remodeling process in l-NAME-treated rats is involved who high blood pressure control the production of myocardial fibrosis [ 7 ].

There are substantial data to show the molecular mechanism of extensive areas of cardiac fibrosis which is associated with the activation of various downstream inflammatory [ 8 ] and oxidative stress initiatives [ 910 ]. For example, a high level of tumor necrosis factor TNF-αa pro-inflammatory cytokine, developed in response to oxidative stress in l-NAME-induced hypertension has been reported [ 411 ].

These inflammatory responses subsequently activate the profibrotic mediator of the transforming growth factor β1 TGF-β1 [ 11 ].

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It is well-established that TGF-β1 plays a key role in fibrogenesis by activating apoptosis, collagen, and matrix protein synthesis [ 121314 ]. For vascular structural changes in hypertension, it is known to be an adaptive response to an increase in wall tension [ 15 ].

This response is also related to the extracellular matrix degradation of elastic fibers since the up-regulation of matrix metalloproteinase-2 MMP-2 and matrix metalloproteinase-9 MMP-9 expression in vessel tissue has been confirmed in animal models of hypertension.

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Thus, it is noteworthy that natural products with high antioxidant and anti-inflammatory activities might be useful for alleviating cardiovascular alterations induced by nitric oxide deficiency. Captopril is an angiotensin-converting enzyme ACE inhibitor and is commonly used as an anti-hypertensive drug [ 19 ].

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Its mechanism of action has been well-documented to reduce angiotensin II production, which subsequently suppresses the renin-angiotensin-aldosterone system RAAS [ 19 ]. Other possible anti-hypertensive mechanisms include increased bradykinin and prostaglandins levels [ 20 ], the inhibition of superoxide production [ 21 ], and the free radical scavenging effect [ 22 ].

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Many studies have already reported on the cardiovascular effects of captopril in nitric oxide-deficient hypertensive rats, i. Hesperidin is a flavanone glycoside, a subclass of flavonoids, abundantly found in citrus fruits such as lemon or orange peels or juices [ 24 ].

Numerous beneficial effects of hesperidin have been published. For example, the antioxidant effect of hesperidin has been reported to be able to sequester 1,1-diphenylpicrylhydrazyl DPPH and protect cell injury-induced by paraquat and hydrogen peroxide [ 25 ], reduce plasma levels of lipid peroxidation markers, and increase antioxidant enzyme activities in heart tissue in experimentally ischemic myocardial rats [ 26 ].

Hesperidin has also exhibited an anti-inflammatory effect by reducing circulating inflammatory markers, i.

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Subsequently, a clinical study revealed that a combination of hesperidin, diosmin, and troxerutin was effective in relieving the symptoms of acute hemorrhoidal disease [ 29 ]. Recently, the current authors have demonstrated an anti-hypertensive effect of hesperidin in renovascular hypertensive rats that involved the suppression of the renin-angiotensin system [ 30 ].

This study was intended to further explore whether hesperidin could prevent l-NAME-induced hypertension and cardiovascular remodeling in rats. Materials and Methods 2. All the other chemicals used in this study were obtained from standard companies and were of analytical grade quality.

The control group animals received tap water and were orally administrated propylene glycol PG, 1. Hesperidin and captopril were dissolved in vehicle and intragastrically administered once daily for five weeks.

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The doses of hesperidin and captopril used in this study were influenced by previous studies who high blood pressure control this laboratory [ 1030 ]. Collection of Blood and Organs After the blood pressure measurement, the rats were sacrificed by exsanguination and blood samples were collected from abdominal aortas into Ethylenediaminetetraacetic acid EDTA or heparin tubes for assays of oxidative stress and inflammatory markers.

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The thoracic aortas and heart tissues were collected for western blotting and morphometric analysis. Plasma NOx was assayed using an enzymatic conversion method [ 33 ], with some modifications [ 32 ]. The proteins were then electrophoresed on a sodium dodecylsulfate polyacrylamide gel electrophoresis system and transferred to a polyvinylidene fluoride membrane Millipore Corporation, Bedford, MA, USA.

Thereafter, the membranes were washed three times with TBS and then incubated for 2 h at room temperature with a horseradish peroxidase conjugated secondary antibody.

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The intensity of each band was normalized to that of β-actin, and data were expressed as a percentage of the values determined in the control group from the same gel.

Statistical Analysis Data are expressed as mean ± S. A p-value of less than 0. Results 3. Effects of Hesperidin and Captopril on Blood Pressure in Conscious Rats There were no significant differences in the systolic blood pressure of all the rats at the beginning of the study.

Captopril also partially alleviated l-NAME-induced hypertension