Cardiovascular Effects Induced by Fruit Peels from Passiflora edulis in Hypertensive Rats and Fingerprint Analysis by HPLC-ESI-MSⁿ spectrometry

• Abstract
• Introduction
• Results and Discussion
• Materials and Methods
• Chemicals and Reagents
• Plant material and extraction
• HPLC and ion-trap MS analysis
• Animals
• Antihypertensive activity study
• Measurement of Interleukin-10 (IL-10)
• Measurement of MDA and GSH
• Morphometric analysis of the renal artery
• Statistical analysis
• Contributorsʼ Statement
• References

Abstract

Hypertension is a chronic disease and a global health problem. Due to its high prevalence, it constitutes the most important risk factor for cardiovascular disease. Fruit peels from Passiflora edulis fo. flavicarpa are rich in bioactive natural compounds that may have action in hypertension. This study aimed to perform a fingerprinting analysis of Passiflora edulis fruit peel extract and evaluate its actions on the cardiovascular system in an in vivo model. The extract was obtained from the dried and powdered fruit peels of Passiflora edulis. Glycoside flavonoids were identified in the extract by HPLC-ESI-MSⁿ. The extract showed a significant hypotensive effect after 28 days of treatment and improved vascular function in the mesenteric artery. This effect was verified by decreased vascular hypercontractility and increased vasorelaxant in response to sodium nitroprusside and acetylcholine. There was also a decrease in endothelial dysfunction, which can be attributed to nitric oxideʼs increased bioavailability. Thus, we hypothesize that all these effects contributed to a reduction in peripheral vascular resistance, leading to a significant hypotensive effect. These results are novel for fruit peels from P. edulis. Also, there was a decrease in plasma and cardiac malondialdehyde levels and an increase in glutathione, suggesting a reduction in oxidative stress, as well as an increase of anti-inflammatory cytokines such as IL-10 in the plasma. This study demonstrated that the extract can be a new source of raw material to be applied as food or medicine adjuvant for treating hypertension.

Introduction

Hypertension is a condition that accounts for 9.4 million deaths around the world every year, thereby constituting a public health challenge [1]. Data reveal that hypertension is present in 69% of patients in the first episode of acute myocardial infarction, 77% of cerebrovascular accidents, 75% with heart failure, and 60% with peripheral arterial disease [2]. It is also responsible for 45% of cardiac deaths and 51% of deaths due to cerebrovascular accident [1].

There is a change in endothelial function in hypertension, with a consequent imbalance in the production of vasoactive mediators, leading to a deficiency in endothelium-dependent vasodilation [3].

Various antihypertensive drugs have been clinically used to manage hypertension and to alleviate symptoms. However, some hypertensive patients may be resistant to traditional treatment, and 2 or more antihypertensive drugs from different categories must be combined to achieve the optimal results [4]. These problems associated with the therapy justify research into new medications to treat hypertension.

The use of medicinal plants in treating hypertension is common [5]. The Passiflora edulis fo. flavicarpa O. Deg. (Passifloraceae) species is known as yellow passion fruit [6]. Its fruit peel, which is currently considered a by-product in the food industry, could be reused as raw material for developing new products [7]. The P. edulis species is rich in polyphenolic compounds [8]. Several flavonoids have already specifically been described for the P. edulis peel [9]. Modulation of the vascular redox state and vasodilation stand out among the benefits of polyphenolic compounds in hypertension. These effects may increase vasodilation dependent on the endothelial layer and decrease muscular hypercontractility and inhibition of platelet aggregation [10], [11].

In light of this, this study sought to perform a fingerprint analysis of P. edulis fruit peel extract (PFHE) by HPLC-ESI-MSⁿ and evaluate its effects on hypertension and vascular function. In addition, to better understand these effects, the extract action on inflammation and oxidative stress was evaluated.

Results and Discussion

We conducted fingerprint analysis of PFHE using HPLC-ESI-MSⁿ in both negative and positive ionization modes. The negative mode was chosen for data analysis. Metabolite assignments were determined by comparing UV-Vis spectra and MS data (fragmentation pattern in negative ionization), with subsequent confirmation by comparison with literature data. The chromatographic and spectroscopic data are summarized in [Fig. 1] and [Table 1]. A total of 22 compounds were identified, including 19 glycosylated O/C flavonoids (compounds 2, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, and 22), 1 phenolic acid (compound 1) and 2 cyanogenic glycosides (compounds 3 and 4). Photodiode array detection (200 – 600 nm) provided an overview of the main flavonoid constituents, with maximum UV absorbance near 270 nm (band II) and a second absorbance between 335 and 350 nm (band I). It was subsequently possible to differentiate the C-glycoside and O-glycoside flavonoids from the MS/MS profile.

O-glycoside flavonoids are attached to a sugar forming and easily acid-cleavable O-glycosidic bond. Fragmentation of these flavonoids involves cleavage of the O-glycosidic bond, which can be verified by removing the residue of a sugar [M – 162-H]⁻ (hexose), [M – 146 – H]⁻ (deoxyhexose), [M – 132 – H]⁻ (pentose), or [M – 130 – H]⁻ (dideoxyhexose) [12]. Fragmentation of the C-glycoside flavonoids requires higher collision energies than the O-glycosides, and major fragmentations occur in sugar, which has weaker chemical links. Thus, the major fragments in the C-glycosides are related to the [(O-C1 and C2 – C3)] or [(O-C1 and C3 – C4)] cross-ring cleavages of the sugar units. The most extensive fragmentation is in the residue of C-6 sugar, forming ions [M – 120/90 – H]⁻ for C-hexosides, [M – 90/60 – H]⁻ for C-pentosides, and [M – 104/74 – H]⁻ for C-deoxyhexosides [13], [14]. Most flavonoid peaks showed intense molecular ionic signals with [M – 90 – H]⁻ and [M – 120 – H]⁻ fragments in the MSⁿ spectrum, indicative of the sugar cleavage of a C-glycoside found in most peaks of the identified flavones.

It is also possible to identify ions [aglycone + 41/71]⁻ in mono-C and [aglycone + 83/113]⁻ for di-C-glycosides in the C-glycoside flavonoids, in which they represent aglycone plus sugar residues that have remained bound to them. The main ions found for mono-C-glycosides and di-C-glycosides are (mono-C [295, 325]⁻, di-C [337, 367]⁻) for chrysin nucleus, (mono-C [327/357]⁻, di-C [369/399]⁻) for luteolin nucleus, and (mono-C [311/341]⁻, di-C [353/383]⁻) for apigenin nucleus [15]. The flavonoids identified in the extract presented ions corresponding to the nucleus of chrysin, luteolin, apigenin, quercetin, and kaempferol.

In the fingerprint analysis, we observed that C-glycosylated flavonoids are the most common compounds identified in the extract, in which it was possible to identify 19 flavonoids, of which 6 (isoorientin, orientin, chrysin-6,8-C-dihexoside, vicenin-2, lucenin-2, and isovitexin) have already been described in the literature for the P. edulis peel [8], [9], [16]. Other identified flavonoids such as orientin-7-O-glucoside, 2″-O-deoxyhexose-C-hexose-luteolin, luteolin-C-deoxyhexoside-2″-O-hexoside, vitexin-2-O-glycoside, luteolin-7-O-(6-O-ramnosylhexoside), myricetin-3-O-(6″ galloyl) galactoside, chrysin-6-C-hexoside, luteolin-8-C-deoxyhexoside, 2″-O-Deoxyhex-C-deoxyhexoside-luteolin, chrysin-C-hexoside-O-deoxyhexoside, luteolin-6-C-quinomoside/fucoside, X-O-deoxyhexoside-144-luteolin, and kaempferol-3-O-(6-O-ramnosylglucoside) were also identified but have not yet been described for PFHE. Two cyanogenic glycosides were further identified, prunasin and mandelonitrile-O-rutinoside, constituting previously described compounds for P. edulis fruit peels, while chlorogenic acid is considered novel [17], [18].

In summary, the hydroethanolic extract from P. edulis fruit peels is an important source of bioactive compounds, especially flavonoids. Studies indicate that several flavonoids provide beneficial action in the cardiovascular system, reducing the risk of coronary mortality and having cardioprotective properties, in addition to improving vascular tone [19], [20]. Therefore, the presence of these compounds in the extract may contribute to the observed pharmacological effects.

Next, a spontaneously hypertensive rat (SHR) model was used to assess the chronic effect of PFHE on the cardiovascular system. This in vivo model is considered similar to the essential pathophysiology of hypertension [21].

The main pharmacological finding of this article was that oral administration of PFHE at doses of 200 and 400 mg/kg caused a significant reduction in mean, diastolic, and systolic blood pressure and did not change the heart rate in hypertensive rats when compared with the SHR control group (p < 0.05) ([Table 2]). Vascular function was evaluated by obtaining concentration-response curves with phenylephrine (Phe), sodium nitroprusside (SNP), and acetylcholine (Ach) in the presence and absence of inhibitors.

There is an increased contractile response to contracting agents in hypertension, such as the alpha-adrenergic agonists, which may increase peripheral vascular resistance and consequently increase blood pressure [22]. Thus, we evaluated whether treatment with PFHE would decrease this vascular hypercontractility in hypertensive rats by obtaining concentration-response curves with Phe, an alpha-adrenergic agonist.

The results showed that contractile response after cumulative addition of Phe in arterial segments with and without endothelium was reduced in the SHR group treated with PFHE 400 mg/kg when compared to the SHR control group (p < 0.05) ([Fig. 2 a]). Furthermore, a significant decrease of hypercontractility was observed with Phe in arteries with functional endothelium at all tested doses ([Fig. 2 b]). These results indicate that the extract was able to decrease vascular hypercontractility in hypertensive rats.

We also observed that treatment with PFHE at doses of 200 and 400 mg/kg was able to improve the vasorelaxant response of vascular smooth muscle cells to sodium nitroprusside ([Fig. 3]), which is a spontaneous donor of nitric oxide when compared with the SHR control group (p < 0.05).

In addition to vascular smooth muscle cells, vascular endothelium also plays an important role in controlling peripheral vascular resistance by being involved in producing potent vasoactive mediators [23]. The 3 main endothelial-derived relaxing factors are nitric oxide, prostacyclin, and hyperpolarizing factor derived from the endothelium [24]. The release of these factors is essential for regulating vascular tone and maintaining normal blood pressure [25].

ACh is a muscarinic agonist that promotes receptor-mediated vasodilation of nitric oxide production in endothelial cells. There is a decrease in this response in the presence of endothelial dysfunction mediated by vascular endothelium [26].

The results showed that treatment with PFHE at doses of 200 and 400 mg/kg was able to restore the vasorelaxant effect promoted by ACh when compared to the SHR control group (p < 0.05) ([Fig. 4]). Thus, the increase in the vasorelaxant response of ACh in arteries treated with PFHE suggests that the treatment succeeded in reversing the endothelial dysfunction.

The results also indicated that improvement in endothelial dysfunction involved the increased availability of nitric oxide. This effect may be explained by the significant decrease in the vasorelaxant response of acetylcholine in the presence of Nw-nitro-L-arginina (L-NAME), an endothelial nitric oxide synthase inhibitor (eNOS), in the PFHE treated group at a dose of 400 mg/kg when compared to the SHR control group ([Fig. 5 a]).

The cyclooxygenase (COX) pathway was also investigated, and the results showed that PFHE treatment did not interfere with the production of COX derivatives such as prostacyclin. The incubation with indomethacin was not able to decrease the vasorelaxant effect promoted by ACh in the SHR groups treated with doses of 200 and 400 mg/kg when compared to the SHR control group ([Fig. 5 b]).

Thus, it can be concluded that PFHE had a significant hypotensive effect and that vascular function improvement may be contributing to this effect. It is necessary to highlight that these results are unheard of for the PFHE because, thus far, studies have shown that the species had hypotensive action [27], [28]. Still, the pharmacological mechanisms involved in this effect had not yet been elucidated.

Another finding of our study was that treatment with PFHE at doses of 200 and 400 mg/kg was able to attenuate plasma ([Fig. 6 a]) and heart ([Fig. 6 b]) malondialdehyde (MDA) levels in hypertensive rats but with no statistical difference for the WKY control group. The treatment was also able to increase glutathione (GSH) levels in the heart, with no statistical difference for the WKY control group ([Fig. 6 c]). MDA and GSH are important oxidative stress markers [29], [30]. The decreased MDA and increased GSH may indicate that PFHE treatment may have reduced oxidative stress in hypertensive rats.

Next, we evaluated the levels of IL-10 in the plasma of hypertensive rats to assess the anti-inflammatory effect of PFHE. IL-10 is a potent anti-inflammatory cytokine that plays a crucial role in regulating immune and inflammatory responses, including NF-κB inhibition and reduction of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α [31]. Evidence indicates that IL-10 has a protective effect on endothelial function in hypertension by reducing NADPH oxidase activity, increasing endothelial nitric oxide synthase activity, and improving endothelial microvascular relaxation [32], [33]. The study results showed that the SHR group treated with PFHE in doses at 200 and 400 mg/kg had a higher plasma IL-10 level than the SHR-control group (p < 0,05; [Fig. 7]), preliminarily suggesting that the extract may be modulating the inflammatory process.

In the morphometric analysis of the renal artery, a reduction related to the wall/lumen was observed in SHR groups treated with PFHE in doses at 200 and 400 mg/kg when compared to the SHR control group (p < 0.05) ([Fig. 8]). The renal artery plays an important role in controlling blood pressure because its narrowing can lead to hypertensive conditions or worsen this condition [34]. The results showed that treatment with PFHE in the SHR group decreased vascular remodeling, so this effect may increase renal blood perfusion and contribute to lower blood pressure.

In summary, PFHE showed a significant hypotensive effect, in addition to improving vascular function verified by decreased vascular hypercontractility and increasing vasorelaxant response to nitroprusside and ACh. There was also a decrease in endothelial dysfunction that can be attributed to increased bioavailability of nitric oxide, probably due to increased endothelial nitric oxide synthase. Thus, overall improvement of endothelial function may be involved in decreased peripheral vascular resistance and, consequently, systemic blood pressure. An increase in anti-inflammatory mediators and a decrease in oxidative stress were also observed, suggesting that the extract may also be acting by reducing inflammation and oxidative stress in hypertensive rats. A reduction in the renal arteryʼs wall/lumen ratio indicates that the extract was able to reduce vascular remodeling caused by hypertension. Flavonoids identified in the extract can be at least partly responsible for the pharmacological activity. Therefore, this extract is a low-cost alternative to obtain a raw material rich in bioactive compounds with clinical potential for developing a herbal medicine antihypertensive medication.

Materials and Methods

Chemicals and Reagents

All reagents and solvents used were of analytical grade. The water used was purified by reverse osmosis. The drugs used were: L-(−)-phenylephrine, ACh hydrochloride, SNP, L-NAME, and indomethacin from Sigma-Aldrich.

Plant material and extraction

P. edulis fruits were collected in Coronel Ezequiel city, Rio Grande do Norte State, Brazil, in June of 2016 (6°23′44.2″ S 36°10′ 23.7″ W). Access to genetic heritage and traditional knowledge associated with scientific research purposes was registered in SISGEN (A618873). The samples were identified and deposited in the UFERSA Herbarium (ICN13751.6).

The seeds and pulp were removed, and the peels were dried in a circulating air heater (55 °C) and triturated mechanically to obtain the raw material (flour). The flour prepared from the fruit peels was extracted with 50% ethanol (1 : 20, p/v) by maceration for 7 days. The PFHE was filtered and concentrated by rotaevaporator (model V-700, Buchi) and later lyophilized.

HPLC and ion-trap MS analysis

An HPLC system coupled with an Amazon X with an electrospray ion (ESI) source was used to perform the HPLC-ESI-MSⁿ. The LC system consisted of an LC-20AD solvent pump unit (flow rate of 600 µL/min⁻¹), a DGU-20A₅ online degasser, a CBM-20A system controller, and an SPD-M20A (190 – 800 nm) diode array detector. The LC separation was performed on a Kromasil C-18 5 mm 100 Å, 250 × 4.6 mm (Kromasil) analytical column. Injections (20 µL) were performed using an autosampler (SIL-20A). The mobile phase consisted of 0.1% formic acid in water (solvent A) and methanol (solvent B). The exploratory gradient was performed to elution in 60 min. The analysis parameters were as follows: capillary 4.5 kV, ESI in positive and negative mode, final plate offset 500 V, 40 psi nebulizer, dry gas (N₂) with a flow rate of 8 mL/min, and a temperature of 300 °C. CID fragmentation was achieved in auto MS/MS mode using enhanced resolution mode for MS and MS/MS mode. The spectra (m/z 50 – 1000) were recorded every 2 seconds.

Animals

SHRs and Wistar-Kyoto male rats (WKYs) with initial ages of 12 wk with weighing 250 ± 20 g were used for the experiment, all coming from the “Prof. George Thomas” animal house of the Health Sciences Center at the Federal University of Paraíba (UFPB). The use of the animals for the experiments was approved by the Committee of Ethics in Animal Use of the UFPB (March 10, 2017) with certificate 015/2017. These animals were kept under controlled temperature conditions (21 ± 1 °C) under a light-dark cycle of 12 h with free access to water and feed.

Antihypertensive activity study

The animals were divided into 4 groups with 7 animals in each group (n = 7) to evaluate the antihypertensive activity: (i) hypertensive control (SHR-Control); (ii) hypertensive treated with AFM at the dose of 200 mg/kg (SHR-200 mg/Kg); (iii) hypertensive treated with AFM at the dose of 400 mg/kg (SHR-400 mg/Kg); and (iv) normotensive control-Wistar Kioto (WKY-Control). The groups were treated by an intragastric oral probe in a single dose per day for 28 days. The control groups were treated with the same volume of 0.9% physiological solution.

The animals were anesthetized with xylazine and ketamine (10 and 75 mg/kg, respectively, i. p.) after 28 days of treatment for the implantation of a polyethylene catheter in the left femoral artery to record intra-aortic pressure [35]. Mean arterial pressure, systolic pressure, diastolic pressure, and heart rate were measured for 24 h in the non-anesthetized rats by connecting the arterial catheter to a precalibrated pressure transducer (MLT0380/D, ADInstruments) and connected to a data acquisition system ADInstruments PowerLab in Australia. The mesenteric bed was identified and removed in treated and control animals to isolate the superior mesenteric artery for vascular reactivity studies [36].

After the stabilization procedure, the rings were contracted with increasing and cumulative concentrations of Phe (10⁻⁹ − 3 × 10⁻⁵ M), and concentration-response curves were obtained to evaluate contractile responses caused by the incremental addition of Phe. The endothelium was removed in some preparations. Maximum contraction corresponded to the maximum response (MR) for the highest concentration used. Results were normalized by WKY-control.

The vasorelaxant response caused by sodium nitroprusside and ACh were also analyzed. Increasing and cumulative concentrations of sodium nitroprusside (10⁻¹² – 3 × 10⁻⁷ M) or ACh (10⁻¹⁰ – 3 × 10⁻⁵ M) were added in the contraction tonus induced by the addition of Phe (1 µM). The responses obtained were used to obtain a concentration-response curve. The results were normalized by WKY-control.

The ACh response was also evaluated in the presence of various inhibitors to investigate the involvement of 2 endothelium-derived vasorelaxing factors: nitric oxide and prostacyclins. The mesenteric rings were incubated with nitric oxide synthase inhibitor L-NAME (100 µM) [37] to evaluate the participation of the nitric oxide pathway. Furthermore, a nonselective COX inhibitor (indomethacin; 10 µM) was used to inhibit the synthesis of the prostaglandins derived from the endothelium (PGI₂) [38] to evaluate the participation of the prostacyclins (PGI₂).

The arteries were then contracted with Phe (1 µM) after incubation of 30 min with the inhibitors, and concentration-response curves were constructed using increasing and cumulative ACh concentrations (10⁻¹⁰ – 3 × 10⁻⁵ M). Maximum relaxation corresponded to MR for the highest concentration used.

Measurement of Interleukin-10 (IL-10)

The IL-10 cytokine was determined in the plasma of rats (n = 6) (DNBS experiment) using commercial ELISA kits (R & D Systems). The absorbance of each sample was measured at 450 nm.

Measurement of MDA and GSH

MDA content was measured in the plasma and hearts of rats (n = 6) by the methodology described by Esterbauer and Cheeseman (1990) [39]. The results were expressed as nanomoles of MDA per gram of tissue and nanomoles of MDA per mL of plasma. Total GSH content was measured in the hearts of rats (n = 6) by the methodology described by Anderson (1985) [40]. The results were reported as units of GSH per gram of tissue.

Morphometric analysis of the renal artery

Renal tissue (n = 6) was fixed in 10% buffered formalin (pH 7.4), followed by dehydration in a graduated series of ethanol (70 to 100%), clarified in xylene, and included in paraffin. Next, 5 µm thin sections were prepared and stained with hematoxylin and eosin (H&E). Morphometric analysis was performed in the renal artery according to the methodology described by Baumbach and Heistad (1989) [41].

Statistical analysis

The results were expressed as means ± standard error of the mean. Statistical analysis was conducted by 1-way analysis of variance (ANOVA) followed by the Dunnettʼs post hoc using the GraphPad Prism 7 software. Statistical significance was considered as 95% (p < 0.05).

Contributorsʼ Statement

Data collection: B. Cabral, A. F. Gonçalves, L. S. Abreu, A. W. L. Andrade, F. L. A. A. Azevedo, F. D. Castro; analysis and interpretation of the data: B. Cabral, A. F. Gonçalves, L. S. Abreu, A. W. L. Andrade, F. L. A. A. Azevedo, F. D. Castro, J. F. Tavares, G. C. B. Guerra, A. A. Rezende, I. A. Medeiros, S. M. Zucolotto; critical revision of the manuscript: B. Cabral, J. F. Tavares, G. C. B. Guerra, A. A. Rezende, I. A. Medeiros, S. M. Zucolotto.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgements

The authors acknowledge all participants for their valuable time and commitment to the study. SMZ is a research productivity fellow of the CNPq (Grant number 313727/2020-1). The authors are grateful to the CAPES-Finance Code 1 for the PhD scholarship (88882.375434/2019-01).

• References

• 1 Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, Amann M, Anderson HR, Andrews KG, Aryee M, Atkinson C, Bacchus LJ, Bahalim AN, Balakrishnan K, Balmes J, Barker-Collo S, Baxter A, Bell ML, Blore JD, Blyth F, Bonner C, Borges G, Bourne R, Boussinesq M, Brauer M, Brooks P, Bruce NG, Brunekreef B, Bryan-Hancock C, Bucello C, Buchbinder R, Bull F, Burnett RT, Byers TE, Calabria B, Carapetis J, Carnahan E, Chafe Z, Charlson F, Chen H, Chen JS, Cheng AT, Child JC, Cohen A, Colson KE, Cowie BC, Darby S, Darling S, Davis A, Degenhardt L, Dentener F, Des Jarlais DC, Devries K, Dherani M, Ding EL, Dorsey ER, Driscoll T, Edmond K, Ali SE, Engell RE, Erwin PJ, Fahimi S, Falder G, Farzadfar F, Ferrari A, Finucane MM, Flaxman S, Fowkes FG, Freedman G, Freeman MK, Gakidou E, Ghosh S, Giovannucci E, Gmel G, Graham K, Grainger R, Grant B, Gunnell D, Gutierrez HR, Hall W, Hoek HW, Hogan A, Hosgood 3rd HD, Hoy D, Hu H, Hubbell BJ, Hutchings SJ, Ibeanusi SE, Jacklyn GL, Jasrasaria R, Jonas JB, Kan H, Kanis JA, Kassebaum N, Kawakami N, Khang YH, Khatibzadeh S, Khoo JP, Kok C, Laden F, Lalloo R, Lan Q, Lathlean T, Leasher JL, Leigh J, Li Y, Lin JK, Lipshultz SE, London S, Lozano R, Lu Y, Mak J, Malekzadeh R, Mallinger L, Marcenes W, March L, Marks R, Martin R, McGale P, McGrath J, Mehta S, Mensah GA, Merriman TR, Micha R, Michaud C, Mishra V, Mohd Hanafiah K, Mokdad AA, Morawska L, Mozaffarian D, Murphy T, Naghavi M, Neal B, Nelson PK, Nolla JM, Norman R, Olives C, Omer SB, Orchard J, Osborne R, Ostro B, Page A, Pandey KD, Parry CD, Passmore E, Patra J, Pearce N, Pelizzari PM, Petzold M, Phillips MR, Pope D, Pope 3rd CA, Powles J, Rao M, Razavi H, Rehfuess EA, Rehm JT, Ritz B, Rivara FP, Roberts T, Robinson C, Rodriguez-Portales JA, Romieu I, Room R, Rosenfeld LC, Roy A, Rushton L, Salomon JA, Sampson U, Sanchez-Riera L, Sanman E, Sapkota A, Seedat S, Shi P, Shield K, Shivakoti R, Singh GM, Sleet DA, Smith E, Smith KR, Stapelberg NJ, Steenland K, Stöckl H, Stovner LJ, Straif K, Straney L, Thurston GD, Tran JH, Van Dingenen R, van Donkelaar A, Veerman JL, Vijayakumar L, Weintraub R, Weissman MM, White RA, Whiteford H, Wiersma ST, Wilkinson JD, Williams HC, Williams W, Wilson N, Woolf AD, Yip P, Zielinski JM, Lopez AD, Murray CJ, Ezzati M, AlMazroa MA, Memish ZA. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2224-2260
  CrossrefPubMedSearch in Google Scholar
• 2 Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Ferranti S, Després J, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth RD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2015: update a report from the American Heart Association. Circulation 2015; 131: e29-e322
  CrossrefPubMedSearch in Google Scholar
• 3 Brandes RP. Endothelial dysfunction and hypertension. Hypertension 2014; 64: 924-928
  CrossrefPubMedSearch in Google Scholar
• 4 Campbell NRC, Mcalister FA, Duong-Hua M, Tu K. Polytherapy with two or more antihypertensive drugs to lower blood pressure in elderly Ontarians. Room for improvement. Can J Cardiol 2007; 23: 783-787
  CrossrefPubMedSearch in Google Scholar
• 5 Rawat P, Singh PK, Kumar V. Anti-hypertensive medicinal plants and their mode of action. J Herb Med 2016; 6: 107-118
  CrossrefPubMedSearch in Google Scholar
• 6 Yapo BM, Koffi KL. Yellow passion fruit rinds. A potential source of low-methoxyl pectin. J Agric Food Chem 2006; 54: 2738-2744
  CrossrefPubMedSearch in Google Scholar
• 7 Pinheiro ER, Silva IMDA, Gonzaga LV, Amante ER, Teófilo RF, Ferreira MMC, Amboni RDMC. Optimization of extraction of high-ester pectin from passion fruit peel (Passiflora edulis flavicarpa) with citric acid by using response surface methodology. Bioresour Technol 2008; 99: 5561-5566
  CrossrefPubMedSearch in Google Scholar
• 8 Zucolotto SM, Fagundes C, Reginatto FH, Ramos FA, Castellanos L, Duque C, Schenkel EP. Analysis of C-glycosyl flavonoids from South American Passiflora species by HPLC-DAD and HPLC-MS. Phytochem Anal 2012; 23: 232-239
  CrossrefPubMedSearch in Google Scholar
• 9 Cazarin CBB, Rodriguez-Nogales A, Francesca A, Utrilla MP, Rodríguez-Cabezas ME, Garrido-Mesa J, Guerra-Hernández E, Braga PAC, Reyes FGR, Maróstica MR, Gálvez J. Intestinal anti-inflammatory effects of Passiflora edulis peel in the dextran sodium sulphate model of mouse colitis. J Funct Foods 2016; 26: 565-576
  CrossrefPubMedSearch in Google Scholar
• 10 Alhosin M, Anselm E, Rashid S, Kim JH, Madeira SVF, Bronner C, Schini-Kerth VB. Redox-sensitive up-regulation of eNOS by purple grape juice in endothelial cells: role of PI3-kinase/Akt, p38 MAPK, JNK, FoxO1 and FoxO3a. PLoS One 2013; 8: 1-11
  Search in Google Scholar
• 11 Pignatelli P, Di Santo S, Buchetti B, Sanguigni V, Brunelli A, Violi F. Polyphenols enhance platelet nitric oxide by inhibiting protein kinase C dependent NADPH oxidase activation: effect on platelet recruitment. FASEB J 2006; 20: 1082-1089
  CrossrefPubMedSearch in Google Scholar
• 12 Simirgiotis M, Schmeda-Hirschmann G, Bórquez J, Kennelly EJ. The Passiflora tripartita (banana passion) fruit: a source of bioactive flavonoid C-glycosides isolated by HSCCC and characterized by HPLC-DAD-ESI/MS/MS. Molecules 2013; 18: 1672-1692
  CrossrefPubMedSearch in Google Scholar
• 13 Sakalem ME, Negri G, Tabach R. Chemical composition of hydroethanolic extracts from five species of the Passiflora genus. Rev bras farmacogn 2012; 22: 1219-1232
  CrossrefPubMedSearch in Google Scholar
• 14 Otify A, George C, Elsayed A, Farag MA. Mechanistic evidence of Passiflora edulis (Passifloraceae) anxiolytic activity in relation to its metabolite fingerprint as revealed via LC-MS and chemometrics. Food Funct 2015; 12: 1-11
  CrossrefPubMedSearch in Google Scholar
• 15 Farag MA, Otify A, Porzel A, Michel CG, Elsayed A, Wessjohann LA. Comparative metabolite profiling and fingerprinting of genus fractions from Passiflora leaves using a multiplex approach of UPLC-MS and NMR analyzed by chemometric tools. Anal Bioanal Chem 2016; 408: 3125-3143
  CrossrefPubMedSearch in Google Scholar
• 16 Viganó J, Brumer IZ, Braga PAC, Silva JK, Maróstica jr. MR, Reyes FGR, Martínez J. Pressurized liquids extraction as an alternative process to readily obtain bioactive compounds from passion fruit rinds. Food Bioprod Process 2016; 100: 382-390
  CrossrefPubMedSearch in Google Scholar
• 17 Chassagne D, Crouzet JC, Baumes CLBRL. Identification and quantification of passion fruit cyanogenic glycosides. J Agric Food Chem 1996; 44: 3817-3820
  CrossrefPubMedSearch in Google Scholar
• 18 Chassagne D, Crouzet J. A cyanogenic glycoside from Passiflora edulis fruits. Phytochemistry 1998; 49: 757-759
  CrossrefPubMedSearch in Google Scholar
• 19 Ajay M, Gilani AH, Mustafa MR. Effects of flavonoids on vascular smooth muscle of the isolated rat thoracic aorta. Life Sci 2003; 74: 603-612
  CrossrefPubMedSearch in Google Scholar
• 20 Luna-Vazquez F, Ibarra-Alvarado C, Rojas-Molina A, Rojas-Molina I, Zavala-Sanchez M. Vasodilator compounds derived from plants and their mechanisms of action. Molecules 2013; 18: 5814-5857
  CrossrefPubMedSearch in Google Scholar
• 21 Yu J, Zhang B, Su XL, Tie R, Chang P, Zhang XC, Wang JB, Zhao G, Miao-Zhang Z, Zhang HF. Natriuretic peptide resistance of mesenteric arteries in spontaneous hypertensive rat is alleviated by exercise. Physiol Res 2015; 65: 209-217
  PubMedSearch in Google Scholar
• 22 Eichler HG, Ford GA, Blaschke TF, Swislocki A, Hoffman BB. Responsiveness of superficial hand veins to phenylephrine in essential hypertension. Alpha-adrenergic blockade during prazosin therapy. J Clin Invest 1989; 83: 108-112
  CrossrefPubMedSearch in Google Scholar
• 23 Serban DN, Nilius B, Vanhoutte PM. The endothelial saga: the past, the present, the future. Pflugers Arch 2010; 459: 787-792
  CrossrefPubMedSearch in Google Scholar
• 24 Furchgott RF, Vanhoutte PM. Endothelium-derived relaxing and contracting factors. FASEB J 1989; 3: 1989
  CrossrefPubMedSearch in Google Scholar
• 25 Giles TD, Sander GE, Nossaman BD, Kadowitz PJ. Impaired vasodilation in the pathogenesis of hypertension: focus on nitric oxide, endothelialderived hyperpolarizing factors, and prostaglandins. J Clin Hypertens 2012; 14: 198-205
  CrossrefPubMedSearch in Google Scholar
• 26 Jarrett C, Lekic M, Smith CL, Pusec CM, Sweazea KL. Mechanisms of acetylcholine-mediated vasodilation in systemic arteries from mourning doves (Zenaida macroura). J Comp Physiol B 2013; 183: 959-967
  CrossrefPubMedSearch in Google Scholar
• 27 Ichimura T, Yamanaka A, Ichiba T, Toyokawa T, Kamada Y, Tamamura T, Maruyama S. Antihypertensive effect of an extract of Passiflora edulis rind in spontaneously hypertensive rats. Biosci Biotechnol Biochem 2006; 70: 718-721
  CrossrefPubMedSearch in Google Scholar
• 28 Lewis BJ, Herrlingera KA, Craig TA, Mehring-Franklin CE, De Freitas Z, Hinojosa-Laborde C. Antihypertensive effect of passion fruit peel extract and its major bioactive components following acute supplementation in spontaneously hypertensive rats. J Nutr Biochem 2013; 24: 1359-1366
  CrossrefPubMedSearch in Google Scholar
• 29 Davey MW, Stals E, Panis B, Keulemans J, Swennen RL. High-throughput determination of malondialdehyde in plant tissues. Anal Biochem 2005; 347: 201-207
  CrossrefPubMedSearch in Google Scholar
• 30 Sevin G, Ozsarlak-Sozer G, Keles D, Gokce G, Reel B, Ozgur HH, Oktay G, Kerry Z. Taurine inhibits increased MMP-2 expression in a model of oxidative stress induced by glutathione depletion in rabbit heart. Eur J Pharmacol 2013; 706: 98-106
  CrossrefPubMedSearch in Google Scholar
• 31 Andrade DO, Santos SPO, Vilela-Martin JF. Inflamação, disfunção endotelial e eventos agudos na hipertensão arterial. Rev Bras Hipertens 2014; 21: 129-133
  PubMedSearch in Google Scholar
• 32 Tinsley JH, South S, Chiasson VL, Mitchell BM. Interleukin-10 reduces inflammation, endothelial dysfunction, and blood pressure in hypertensive pregnant rats. Am J Physiol Regul Integr Comp Physiol 2010; 298: 713-719
  CrossrefPubMedSearch in Google Scholar
• 33 Kassan M, Galan M, Partyka M, Trebak M, Matrougui K. Interleukin-10 released by CD4(+)CD25(+) natural regulatory T cells improves microvascular endothelial function through inhibition of NADPH oxidase activity in hypertensive mice. Arterioscler Thromb Vasc Biol 2011; 31: 2534-2542
  CrossrefPubMedSearch in Google Scholar
• 34 Laurent S, Boutouyrie P. The structural factor of hypertension large and small artery alterations. Circ Res 2015; 116: 1007-1021
  CrossrefPubMedSearch in Google Scholar
• 35 Dantas BPV, Alves QL, Assis KS, Ribeiro TP, Almeida MM, Vasconcelos AP, Araújo DAM, Braga VA, Medeiros IA, Alencar JL, Silva DF. Participation of the TRP channel in the cardiovascular effects induced by carvacrolin normotensive rat. Vascul Pharmacol 2015; 67 – 69: 48-58
  CrossrefPubMedSearch in Google Scholar
• 36 Assis KS, Araújo IGA, Azevedo FLAA, Maciel PMP, Machado-Calzerra NT, Silva TAF, Assis VL, Vasconcelos AP, Santos CAG, Meireles BRLA, Cordeiro AMTM, Araújo DAM, Ribeiro TP, Medeiros IA. Potassium channel activation is involved in the cardiovascular effects induced by freeze dried Syzygium jambolanum (Lam.) DC fruit Juice. Biomed Res Int 2018; 2018: 1-12
  Search in Google Scholar
• 37 Allami N, Javadi-Paydar M, Rayatnia F, Sehhat K, Dehpour AR. Suppression of nitric oxide synthesis by L-NAME reverses the beneficial effects of pioglitazone on scopolamine-induced memory impairment in mice. Eur J Pharmacol 2011; 650: 240-248
  CrossrefPubMedSearch in Google Scholar
• 38 Rodriguez-Rodriguez R, Herrera MD, Sotomayor MA, Ruiz-Gutierrez V. Effects of pomace olive oil-enriched diets on endothelial function of small mesenteric arteries from spontaneously hypertensive rats. Br J Nutr 2009; 102: 1435-1444
  CrossrefPubMedSearch in Google Scholar
• 39 Esterbauer H, Cheeseman KH. Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. Meth. Enzymol 1990; 186: 407-421
  CrossrefPubMedSearch in Google Scholar
• 40 Anderson ME. Determination of glutathione and glutathione disulfide in biological samples. Meth Enzymol 1985; 113: 548-555
  CrossrefPubMedSearch in Google Scholar
• 41 Baumbach GL, Heistad DD. Remodeling of cerebral arterioles in chronic hypertension. Hypertension 1989; 13: 968-972
  CrossrefPubMedSearch in Google Scholar
• 42 Jaiswal R, Muller H, Muller A, Karar MGE, Kuhnert N. Identification and characterization of chlorogenic acids, chlorogenic acids glycosides and flavonoids from Lonicera henryi L. (Caprifoliaceae) leaves by LC-MSⁿ . Phytochemistry 2014; 108: 252-263
  CrossrefPubMedSearch in Google Scholar
• 43 Wang S, Liu L, Wang L, Hu Y, Zhang W, Liu R. Structural characterization and identification of major constituents in jitai tablets by high-performance liquid chromatography/diode-array detection coupled with electrospray ionization tandem mass spectrometry. Molecules 2012; 17: 10470-10493
  CrossrefPubMedSearch in Google Scholar
• 44 Waridel P, Wolfender J, Ndjoko K, Hobby KR, Major HJ, Hostettman K. Evaluation of quadrupole time-of-flight tandem mass spectrometry and ion-trap multiple-stage mass spectrometry for the differentiation of C-glycosidic flavonoid isomers. J Chromatogr A 2001; 926: 29-41
  CrossrefPubMedSearch in Google Scholar
• 45 Ferreres F, Sousa C, Valentão P, Andrade PB, Seabra RM, Gil-Izquierdo Á. New C-Deoxyhexosyl flavones and antioxidant properties of Passiflora edulis leaf extract. J Agric Food Chem 2007; 55: 10187-10193
  CrossrefPubMedSearch in Google Scholar

Correspondence

Publication History

Received: 08 December 2019

Accepted after revision: 06 February 2021

Article published online:
03 August 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1 Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, Amann M, Anderson HR, Andrews KG, Aryee M, Atkinson C, Bacchus LJ, Bahalim AN, Balakrishnan K, Balmes J, Barker-Collo S, Baxter A, Bell ML, Blore JD, Blyth F, Bonner C, Borges G, Bourne R, Boussinesq M, Brauer M, Brooks P, Bruce NG, Brunekreef B, Bryan-Hancock C, Bucello C, Buchbinder R, Bull F, Burnett RT, Byers TE, Calabria B, Carapetis J, Carnahan E, Chafe Z, Charlson F, Chen H, Chen JS, Cheng AT, Child JC, Cohen A, Colson KE, Cowie BC, Darby S, Darling S, Davis A, Degenhardt L, Dentener F, Des Jarlais DC, Devries K, Dherani M, Ding EL, Dorsey ER, Driscoll T, Edmond K, Ali SE, Engell RE, Erwin PJ, Fahimi S, Falder G, Farzadfar F, Ferrari A, Finucane MM, Flaxman S, Fowkes FG, Freedman G, Freeman MK, Gakidou E, Ghosh S, Giovannucci E, Gmel G, Graham K, Grainger R, Grant B, Gunnell D, Gutierrez HR, Hall W, Hoek HW, Hogan A, Hosgood 3rd HD, Hoy D, Hu H, Hubbell BJ, Hutchings SJ, Ibeanusi SE, Jacklyn GL, Jasrasaria R, Jonas JB, Kan H, Kanis JA, Kassebaum N, Kawakami N, Khang YH, Khatibzadeh S, Khoo JP, Kok C, Laden F, Lalloo R, Lan Q, Lathlean T, Leasher JL, Leigh J, Li Y, Lin JK, Lipshultz SE, London S, Lozano R, Lu Y, Mak J, Malekzadeh R, Mallinger L, Marcenes W, March L, Marks R, Martin R, McGale P, McGrath J, Mehta S, Mensah GA, Merriman TR, Micha R, Michaud C, Mishra V, Mohd Hanafiah K, Mokdad AA, Morawska L, Mozaffarian D, Murphy T, Naghavi M, Neal B, Nelson PK, Nolla JM, Norman R, Olives C, Omer SB, Orchard J, Osborne R, Ostro B, Page A, Pandey KD, Parry CD, Passmore E, Patra J, Pearce N, Pelizzari PM, Petzold M, Phillips MR, Pope D, Pope 3rd CA, Powles J, Rao M, Razavi H, Rehfuess EA, Rehm JT, Ritz B, Rivara FP, Roberts T, Robinson C, Rodriguez-Portales JA, Romieu I, Room R, Rosenfeld LC, Roy A, Rushton L, Salomon JA, Sampson U, Sanchez-Riera L, Sanman E, Sapkota A, Seedat S, Shi P, Shield K, Shivakoti R, Singh GM, Sleet DA, Smith E, Smith KR, Stapelberg NJ, Steenland K, Stöckl H, Stovner LJ, Straif K, Straney L, Thurston GD, Tran JH, Van Dingenen R, van Donkelaar A, Veerman JL, Vijayakumar L, Weintraub R, Weissman MM, White RA, Whiteford H, Wiersma ST, Wilkinson JD, Williams HC, Williams W, Wilson N, Woolf AD, Yip P, Zielinski JM, Lopez AD, Murray CJ, Ezzati M, AlMazroa MA, Memish ZA. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2224-2260
  CrossrefPubMedSearch in Google Scholar
• 2 Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Ferranti S, Després J, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth RD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2015: update a report from the American Heart Association. Circulation 2015; 131: e29-e322
  CrossrefPubMedSearch in Google Scholar
• 3 Brandes RP. Endothelial dysfunction and hypertension. Hypertension 2014; 64: 924-928
  CrossrefPubMedSearch in Google Scholar
• 4 Campbell NRC, Mcalister FA, Duong-Hua M, Tu K. Polytherapy with two or more antihypertensive drugs to lower blood pressure in elderly Ontarians. Room for improvement. Can J Cardiol 2007; 23: 783-787
  CrossrefPubMedSearch in Google Scholar
• 5 Rawat P, Singh PK, Kumar V. Anti-hypertensive medicinal plants and their mode of action. J Herb Med 2016; 6: 107-118
  CrossrefPubMedSearch in Google Scholar
• 6 Yapo BM, Koffi KL. Yellow passion fruit rinds. A potential source of low-methoxyl pectin. J Agric Food Chem 2006; 54: 2738-2744
  CrossrefPubMedSearch in Google Scholar
• 7 Pinheiro ER, Silva IMDA, Gonzaga LV, Amante ER, Teófilo RF, Ferreira MMC, Amboni RDMC. Optimization of extraction of high-ester pectin from passion fruit peel (Passiflora edulis flavicarpa) with citric acid by using response surface methodology. Bioresour Technol 2008; 99: 5561-5566
  CrossrefPubMedSearch in Google Scholar
• 8 Zucolotto SM, Fagundes C, Reginatto FH, Ramos FA, Castellanos L, Duque C, Schenkel EP. Analysis of C-glycosyl flavonoids from South American Passiflora species by HPLC-DAD and HPLC-MS. Phytochem Anal 2012; 23: 232-239
  CrossrefPubMedSearch in Google Scholar
• 9 Cazarin CBB, Rodriguez-Nogales A, Francesca A, Utrilla MP, Rodríguez-Cabezas ME, Garrido-Mesa J, Guerra-Hernández E, Braga PAC, Reyes FGR, Maróstica MR, Gálvez J. Intestinal anti-inflammatory effects of Passiflora edulis peel in the dextran sodium sulphate model of mouse colitis. J Funct Foods 2016; 26: 565-576
  CrossrefPubMedSearch in Google Scholar
• 10 Alhosin M, Anselm E, Rashid S, Kim JH, Madeira SVF, Bronner C, Schini-Kerth VB. Redox-sensitive up-regulation of eNOS by purple grape juice in endothelial cells: role of PI3-kinase/Akt, p38 MAPK, JNK, FoxO1 and FoxO3a. PLoS One 2013; 8: 1-11
  Search in Google Scholar
• 11 Pignatelli P, Di Santo S, Buchetti B, Sanguigni V, Brunelli A, Violi F. Polyphenols enhance platelet nitric oxide by inhibiting protein kinase C dependent NADPH oxidase activation: effect on platelet recruitment. FASEB J 2006; 20: 1082-1089
  CrossrefPubMedSearch in Google Scholar
• 12 Simirgiotis M, Schmeda-Hirschmann G, Bórquez J, Kennelly EJ. The Passiflora tripartita (banana passion) fruit: a source of bioactive flavonoid C-glycosides isolated by HSCCC and characterized by HPLC-DAD-ESI/MS/MS. Molecules 2013; 18: 1672-1692
  CrossrefPubMedSearch in Google Scholar
• 13 Sakalem ME, Negri G, Tabach R. Chemical composition of hydroethanolic extracts from five species of the Passiflora genus. Rev bras farmacogn 2012; 22: 1219-1232
  CrossrefPubMedSearch in Google Scholar
• 14 Otify A, George C, Elsayed A, Farag MA. Mechanistic evidence of Passiflora edulis (Passifloraceae) anxiolytic activity in relation to its metabolite fingerprint as revealed via LC-MS and chemometrics. Food Funct 2015; 12: 1-11
  CrossrefPubMedSearch in Google Scholar
• 15 Farag MA, Otify A, Porzel A, Michel CG, Elsayed A, Wessjohann LA. Comparative metabolite profiling and fingerprinting of genus fractions from Passiflora leaves using a multiplex approach of UPLC-MS and NMR analyzed by chemometric tools. Anal Bioanal Chem 2016; 408: 3125-3143
  CrossrefPubMedSearch in Google Scholar
• 16 Viganó J, Brumer IZ, Braga PAC, Silva JK, Maróstica jr. MR, Reyes FGR, Martínez J. Pressurized liquids extraction as an alternative process to readily obtain bioactive compounds from passion fruit rinds. Food Bioprod Process 2016; 100: 382-390
  CrossrefPubMedSearch in Google Scholar
• 17 Chassagne D, Crouzet JC, Baumes CLBRL. Identification and quantification of passion fruit cyanogenic glycosides. J Agric Food Chem 1996; 44: 3817-3820
  CrossrefPubMedSearch in Google Scholar
• 18 Chassagne D, Crouzet J. A cyanogenic glycoside from Passiflora edulis fruits. Phytochemistry 1998; 49: 757-759
  CrossrefPubMedSearch in Google Scholar
• 19 Ajay M, Gilani AH, Mustafa MR. Effects of flavonoids on vascular smooth muscle of the isolated rat thoracic aorta. Life Sci 2003; 74: 603-612
  CrossrefPubMedSearch in Google Scholar
• 20 Luna-Vazquez F, Ibarra-Alvarado C, Rojas-Molina A, Rojas-Molina I, Zavala-Sanchez M. Vasodilator compounds derived from plants and their mechanisms of action. Molecules 2013; 18: 5814-5857
  CrossrefPubMedSearch in Google Scholar
• 21 Yu J, Zhang B, Su XL, Tie R, Chang P, Zhang XC, Wang JB, Zhao G, Miao-Zhang Z, Zhang HF. Natriuretic peptide resistance of mesenteric arteries in spontaneous hypertensive rat is alleviated by exercise. Physiol Res 2015; 65: 209-217
  PubMedSearch in Google Scholar
• 22 Eichler HG, Ford GA, Blaschke TF, Swislocki A, Hoffman BB. Responsiveness of superficial hand veins to phenylephrine in essential hypertension. Alpha-adrenergic blockade during prazosin therapy. J Clin Invest 1989; 83: 108-112
  CrossrefPubMedSearch in Google Scholar
• 23 Serban DN, Nilius B, Vanhoutte PM. The endothelial saga: the past, the present, the future. Pflugers Arch 2010; 459: 787-792
  CrossrefPubMedSearch in Google Scholar
• 24 Furchgott RF, Vanhoutte PM. Endothelium-derived relaxing and contracting factors. FASEB J 1989; 3: 1989
  CrossrefPubMedSearch in Google Scholar
• 25 Giles TD, Sander GE, Nossaman BD, Kadowitz PJ. Impaired vasodilation in the pathogenesis of hypertension: focus on nitric oxide, endothelialderived hyperpolarizing factors, and prostaglandins. J Clin Hypertens 2012; 14: 198-205
  CrossrefPubMedSearch in Google Scholar
• 26 Jarrett C, Lekic M, Smith CL, Pusec CM, Sweazea KL. Mechanisms of acetylcholine-mediated vasodilation in systemic arteries from mourning doves (Zenaida macroura). J Comp Physiol B 2013; 183: 959-967
  CrossrefPubMedSearch in Google Scholar
• 27 Ichimura T, Yamanaka A, Ichiba T, Toyokawa T, Kamada Y, Tamamura T, Maruyama S. Antihypertensive effect of an extract of Passiflora edulis rind in spontaneously hypertensive rats. Biosci Biotechnol Biochem 2006; 70: 718-721
  CrossrefPubMedSearch in Google Scholar
• 28 Lewis BJ, Herrlingera KA, Craig TA, Mehring-Franklin CE, De Freitas Z, Hinojosa-Laborde C. Antihypertensive effect of passion fruit peel extract and its major bioactive components following acute supplementation in spontaneously hypertensive rats. J Nutr Biochem 2013; 24: 1359-1366
  CrossrefPubMedSearch in Google Scholar
• 29 Davey MW, Stals E, Panis B, Keulemans J, Swennen RL. High-throughput determination of malondialdehyde in plant tissues. Anal Biochem 2005; 347: 201-207
  CrossrefPubMedSearch in Google Scholar
• 30 Sevin G, Ozsarlak-Sozer G, Keles D, Gokce G, Reel B, Ozgur HH, Oktay G, Kerry Z. Taurine inhibits increased MMP-2 expression in a model of oxidative stress induced by glutathione depletion in rabbit heart. Eur J Pharmacol 2013; 706: 98-106
  CrossrefPubMedSearch in Google Scholar
• 31 Andrade DO, Santos SPO, Vilela-Martin JF. Inflamação, disfunção endotelial e eventos agudos na hipertensão arterial. Rev Bras Hipertens 2014; 21: 129-133
  PubMedSearch in Google Scholar
• 32 Tinsley JH, South S, Chiasson VL, Mitchell BM. Interleukin-10 reduces inflammation, endothelial dysfunction, and blood pressure in hypertensive pregnant rats. Am J Physiol Regul Integr Comp Physiol 2010; 298: 713-719
  CrossrefPubMedSearch in Google Scholar
• 33 Kassan M, Galan M, Partyka M, Trebak M, Matrougui K. Interleukin-10 released by CD4(+)CD25(+) natural regulatory T cells improves microvascular endothelial function through inhibition of NADPH oxidase activity in hypertensive mice. Arterioscler Thromb Vasc Biol 2011; 31: 2534-2542
  CrossrefPubMedSearch in Google Scholar
• 34 Laurent S, Boutouyrie P. The structural factor of hypertension large and small artery alterations. Circ Res 2015; 116: 1007-1021
  CrossrefPubMedSearch in Google Scholar
• 35 Dantas BPV, Alves QL, Assis KS, Ribeiro TP, Almeida MM, Vasconcelos AP, Araújo DAM, Braga VA, Medeiros IA, Alencar JL, Silva DF. Participation of the TRP channel in the cardiovascular effects induced by carvacrolin normotensive rat. Vascul Pharmacol 2015; 67 – 69: 48-58
  CrossrefPubMedSearch in Google Scholar
• 36 Assis KS, Araújo IGA, Azevedo FLAA, Maciel PMP, Machado-Calzerra NT, Silva TAF, Assis VL, Vasconcelos AP, Santos CAG, Meireles BRLA, Cordeiro AMTM, Araújo DAM, Ribeiro TP, Medeiros IA. Potassium channel activation is involved in the cardiovascular effects induced by freeze dried Syzygium jambolanum (Lam.) DC fruit Juice. Biomed Res Int 2018; 2018: 1-12
  Search in Google Scholar
• 37 Allami N, Javadi-Paydar M, Rayatnia F, Sehhat K, Dehpour AR. Suppression of nitric oxide synthesis by L-NAME reverses the beneficial effects of pioglitazone on scopolamine-induced memory impairment in mice. Eur J Pharmacol 2011; 650: 240-248
  CrossrefPubMedSearch in Google Scholar
• 38 Rodriguez-Rodriguez R, Herrera MD, Sotomayor MA, Ruiz-Gutierrez V. Effects of pomace olive oil-enriched diets on endothelial function of small mesenteric arteries from spontaneously hypertensive rats. Br J Nutr 2009; 102: 1435-1444
  CrossrefPubMedSearch in Google Scholar
• 39 Esterbauer H, Cheeseman KH. Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. Meth. Enzymol 1990; 186: 407-421
  CrossrefPubMedSearch in Google Scholar
• 40 Anderson ME. Determination of glutathione and glutathione disulfide in biological samples. Meth Enzymol 1985; 113: 548-555
  CrossrefPubMedSearch in Google Scholar
• 41 Baumbach GL, Heistad DD. Remodeling of cerebral arterioles in chronic hypertension. Hypertension 1989; 13: 968-972
  CrossrefPubMedSearch in Google Scholar
• 42 Jaiswal R, Muller H, Muller A, Karar MGE, Kuhnert N. Identification and characterization of chlorogenic acids, chlorogenic acids glycosides and flavonoids from Lonicera henryi L. (Caprifoliaceae) leaves by LC-MSⁿ . Phytochemistry 2014; 108: 252-263
  CrossrefPubMedSearch in Google Scholar
• 43 Wang S, Liu L, Wang L, Hu Y, Zhang W, Liu R. Structural characterization and identification of major constituents in jitai tablets by high-performance liquid chromatography/diode-array detection coupled with electrospray ionization tandem mass spectrometry. Molecules 2012; 17: 10470-10493
  CrossrefPubMedSearch in Google Scholar
• 44 Waridel P, Wolfender J, Ndjoko K, Hobby KR, Major HJ, Hostettman K. Evaluation of quadrupole time-of-flight tandem mass spectrometry and ion-trap multiple-stage mass spectrometry for the differentiation of C-glycosidic flavonoid isomers. J Chromatogr A 2001; 926: 29-41
  CrossrefPubMedSearch in Google Scholar
• 45 Ferreres F, Sousa C, Valentão P, Andrade PB, Seabra RM, Gil-Izquierdo Á. New C-Deoxyhexosyl flavones and antioxidant properties of Passiflora edulis leaf extract. J Agric Food Chem 2007; 55: 10187-10193
  CrossrefPubMedSearch in Google Scholar