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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 57  |  Page : 335-339  

Angiotensin-converting enzyme inhibitory activity of Senna garrettiana active compounds: Potential markers for standardized herbal medicines


1 Sino-Thai Traditional Medicine Research Center, Faculty of Pharmacy, Rangsit University, Lak-Hok, Muang, Pathum Thani, Thailand
2 Department of Pharmacognosy, Faculty of Pharmacy, Rangsit University, Lak-Hok, Muang, Pathum Thani, Thailand

Date of Submission24-Jul-2017
Date of Acceptance13-Sep-2017
Date of Web Publication10-Sep-2018

Correspondence Address:
Tossaton Charoonratana
Department of Pharmacognosy, Faculty of Pharmacy, Rangsit University, Lak-Hok, Muang, Pathum Thani 12000
Thailand
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/pm.pm_325_17

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   Abstract 


Background: Fifteen medicinal plants used in traditional Thai herbal medicine (HM) for hypertension treatment were previously tested for their inhibitory activity against an angiotensin-converting enzyme (ACE). The ethyl acetate extract from one of these medicinal plants, Senna garrettiana, possessed satisfactory ACE inhibitory (ACEi) activity. Objective: For this study, S. garrettiana extract was further subjected to an isolation process to uncover the active compounds with ACEi activity. Materials and Methods: The ethyl acetate fraction was subjected to isolate and purify by column chromatography accompany with the ACEi assay. The structures of all compounds were elucidated using nuclear magnetic resonance spectroscopy. Results: It was found that S. garrettiana extract possessed two active compounds, piceatannol and betulinic acid, which both had good ACEi activity displaying IC50values of 8.44 μM and 26.77 μM, respectively. Conclusions: These findings show that both compounds can be used as markers for quality control of any standardized HM for hypertension treatment and not just for traditional Thai herbal remedies. Moreover, to the best of our knowledge, this is the first report investigating both compounds for their ACEi activity.
Abbreviations used: ACE: Angiotensin-converting enzyme; ACEi: Angiotensin-converting enzyme inhibitory; CH2Cl2: Dichloromethane; DMSO: Dimethyl sulfoxide; HA: Hippuric acid; HCl: Hydrochloric acid; HHL: Hippuryl-L-histidyl-L-leucine; HM: Herbal medicine; HMs: Herbal medicines; HPLC: High-performance liquid chromatography; IC50: The half maximal inhibitory concentration; L-NAME: N (ω)-nitro-L-arginine methyl ester; MeOH: Methanol; NaCl: Sodium chloride; NADPH: Nicotinamide adenine dinucleotide phosphate; NMR: Nuclear magnetic resonance spectroscopy; NO: Nitric oxide; TDR: The Special Programme for Research and Training in Tropical Disease; μL: Microliter; μM: Micromolar.

Keywords: Angiotensin-converting enzyme inhibitory activity, betulinic acid, hypertension, piceatannol, Senna garrettiana


How to cite this article:
Madaka F, Charoonratana T. Angiotensin-converting enzyme inhibitory activity of Senna garrettiana active compounds: Potential markers for standardized herbal medicines. Phcog Mag 2018;14:335-9

How to cite this URL:
Madaka F, Charoonratana T. Angiotensin-converting enzyme inhibitory activity of Senna garrettiana active compounds: Potential markers for standardized herbal medicines. Phcog Mag [serial online] 2018 [cited 2019 Jan 20];14:335-9. Available from: http://www.phcog.com/text.asp?2018/14/57/335/240758





SUMMARY

  • In Thailand, there is one of the renowned traditional Thai herbal medicines (HMs) for hypertension treatment, which contains Senna garrettiana as its major constituents. According to the World Health Organization, since the analysis of marker compounds is required for evaluating the quality of standardized HMs, regrettably, there is no report of marker compounds from S. garrettiana for antihypertensive activity. Thus, the main purpose of this article is to find potential marker compounds from S. garrettiana for a standardized HM for hypertension treatment using an in vitro ACE inhibitor model. Bioassay-guided fractionation of S. garrettiana fractions led to isolation of piceatannol and betulinic acid which possessed satisfactory ACE inhibitory activity. These compounds can be used as markers for a standardized HM aimed at controlling blood pressure. Moreover, both compounds can be used as candidates for finding new ACE inhibitors with fewer undesirable side effects.



   Introduction Top


Although herbal medicines (HMs) have been used for hundreds of years around the world, their practice has not been officially recognized in many countries. This is because the safety, efficacy, and quality control data of HMs are insufficient to meet the standards needed to support their use globally. The main characteristic of a HM is that it, either presenting as single herb or as mixture of herbs, contains many chemical constituents. This may be the reason why quality control of HMs is more problematic than that of conventional medicine. Therefore, a standardized HM is needed.[1],[2] In general, according to the Special Programme for Research and Training in Tropical Disease, analysis of marker compounds coupling with chemical fingerprint is required for evaluating the quality of standardized HMs.[3] For marker compounds, it is indicated that using related pharmacologically active compounds as markers is more favorable than the other compounds with unknown pharmacological activity. For example, one standardized HM which shows promising results is Ginkgo biloba leaf extract: its markers, flavone glycosides, have neuromodulatory effects relevant to Alzheimer's disease treatment.[4]

A recent survey has revealed a high prevalence of hypertension in Thai people.[5] Since current health-care service is inadequate, the use of HMs has attained a reputable status in rural areas of Thailand. One of the renowned traditional Thai HMs, recorded in the official classic medical book by the former Department of Health Service Support, is recommended for hypertension treatment. This HM is comprised several medicinal plants, including Senna garrettiana as one of its main constituents.[6] The heartwood of S. garrettiana has also been reported as a traditional medicine for diseases involving blood circulation.[7] In addition, among the screening of 15 medicinal plants, the extract of S. garrettiana was reported to have high angiotensin-converting enzyme inhibitory activity (ACEi).[8] This evidence guided us to observe the possibility of investigating the existing marker compounds in this plant which could possess antihypertensive activity.

To find the related pharmacological marker compounds, appropriate experiment models for lowering blood pressure were reviewed. According to an Act for the Prevention of Cruelty to Animals, which was formed in the UK, the minimal use of animals in experiments must be considered.[9] While the diuretic, calcium channel, beta-adrenergic, and alpha-adrenergic blocker models all require the use of animals, an ACE inhibitor provides an in vitro assay.[10],[11] Moreover, the in vitro ACEi model advantages include lower costs and less time consumption, compared to those for animal experiments. In this study, the main purpose is to find potential marker compounds from S. garrettiana for a standardized HM for hypertension treatment using an in vitro ACEi model. Moreover, these marker compounds could be considered for developing an ACE inhibitor from a natural source.


   Materials and Methods Top


Plant material and chemicals

S. garrettiana heartwood was purchased from Charoensuk herbal drugstore and authenticated by the Department of Pharmacognosy at the Faculty of Pharmacy, Rangsit University (voucher specimen # 10101). Contaminants were removed, and the heartwood was ground using a blender. The heartwood powder was stored at room temperature and protected from light. Hippuric acid (HA), ACE from rabbit lung, hippuryl-L-histidyl-L-leucine (HHL), betulinic acid, chrysophanol, and piceatannol were purchased from Sigma-Aldrich (USA). High-performance liquid chromatography (HPLC) grade acetonitrile, analytical grade acetic acid, dichloromethane (CH2Cl2), ethyl acetate, ethanol, hexane, and methanol (MeOH) were all purchased from B and J (Korea). Analytical grade formic acid and dimethyl sulfoxide (DMSO) were purchased from Merck (Germany). Distilled water was purchased from Puris, Expe-CB Ele10 Water System (South Korea).

Preparation of plant extract

The air-dried heartwood of S. garrettiana powder (1.58 kg) was extracted with ethyl acetate (11 L four times) by sonication for 1 h, and the residue was dissolved in 2 L of 95% ethanol. Each fraction was evaporated to dryness to give 35.8 g of ethyl acetate and 56.8 g of 95% ethanolic fractions.

Isolation of compounds from the extract

The ethyl acetate fraction (30.0 g) which possessed high ACEi was chromatographed on silica gel (800 g), using hexane/ethyl acetate (90:10 to ethyl acetate 100%) and ethyl acetate/methanol (100:0 to methanol 20%), to afford six fractions (F1-F6). Fraction F4 (8.5 g) was subjected to column chromatography on 150 g of silica gel eluted with CH2Cl2/MeOH (90:10 to methanol 40%) to give six subfractions (F4.1–F4.6). Subfraction F4.4 (100.0 mg) was purified by column chromatography (Sephadex LH-20) using 100% MeOH to give chrysophanol (1) (golden yellow plates, 33 mg). The purity of 1 was detected by spraying with potassium hydroxide solution, followed by heating at 120°C. Subfraction F4.5 (2.5 g) was subjected to column chromatography on 100 g of silica gel eluted with hexane/ethyl acetate (70:30), which finally afforded betulinic acid (2) (white crystals, 20 mg). The purity of 2 was detected by spraying with anisaldehyde/vanillin followed by heating at 120°C. Subfraction F4.6 (2.5 g) was purified by column chromatography on 100 g of silica gel using hexane/CH2Cl2 (50:50 to CH2Cl2 100%) and CH2Cl2/MeOH (100:0 to MeOH 40%) to give seven subfractions (F1b-F8b). Further column chromatography of the subfraction F4b was on 50 g of Sephadex LH-20 using MeOH to obtain piceatannol (3) (white powder, 20 mg).

Identification of compounds

The structures of compounds 1–3 were elucidated using spectroscopic techniques and compared with reported spectral data. The nuclear magnetic resonance (NMR) spectroscopy (1H and 13C NMR) spectra were recorded at AVANCE III 500 MHz Digital NMR Spectrometer 1 (Bruker Biospin; AV-500). The δ values were reported as ppm relative to TMS in DMSO-d6 and MeOH-d4, respectively.

Angiotensin-converting enzyme inhibitory assay

The assay was performed according to a previously reported method with some modification.[12] The buffer, 50 mM Tris buffer pH 8.3 containing 300 mM NaCl, was used to dilute the enzyme and substrate HHL, while 10% DMSO in buffer was used to dilute the extract. An antihypertensive agent, captopril, was used as a positive control, and 10% DMSO was used as a negative control. The total reaction volume was 70 μL. The solution (10 μL) of extract fractions or isolated compounds was added to the substrate solution (50 μL) and incubated at 37°C for 30 min. Then, 2 mU ACE solution (10 μL) in 50 mM Tris buffer pH 8.3 containing 300 mM NaCl was added, and the mixture was incubated at 37°C for 30 min. The enzyme reaction was stopped by addition of 1 M HCl (85 μL). The samples were prepared in duplicate.

Determination of hippuric acid

HA was yielded by HHL hydrolysis catalyzed by purified rabbit ACE. HA from the reaction was analyzed by analytical reverse-phase HPLC. All solutions were filtered through 0.45 μm nylon filter before analysis. The column was Agilent 5 TC-C18 (2), 150 mm × 4.6 mm, 5 μm. The mobile phase comprised 0.05 M aqueous acetic acid and acetonitrile using a step gradient mode at a ratio of 87.5:12.5 (0–8 min) and 40:60 (9–14 min). The system was equilibrated at 87.5:12.5 for 5 min. The injection volume was 10 μL; flow rate was 1 mL/min. HA was detected at 228 nm. The samples were injected in triplicate. The values of percentage inhibition were calculated using the equation (×100 [peak area of HA in negative control-peak area of HA in sample]/[peak area of HA in negative control]). Finally, the IC50 value, the concentration of inhibitor required to inhibit 50% of the ACE activity, was determined by regression analysis of the percentage inhibition versus the log of the inhibitor concentration.


   Results and Discussion Top


ACE is a zinc-containing metalloenzyme which, in the body, regulates blood pressure by catalyzing the conversion of angiotensin I into angiotensin II.[13] In the in vitro ACEi assay, ACE catalyzed the degradation of HHL to form HA so that ACEi was detected from the decrease in the peak area of HA using HPLC. In this study, an appropriate HPLC condition was achieved with good linearity (correlation coefficients of 0.9996) and selectivity. The retention time of HA was 7.45 min which separated from the other peaks in the reaction.

Since the ethyl acetate extract of S. garrettiana showed high ACE percentage inhibition, with 90.64 at the screened concentration of 1 mg/mL, it was selected for the purification of the active compounds by chromatography using ACEi-guided fractionation. The most active fraction (fraction 4) that gave the highest ACE percentage inhibition at 80.72 was further subjected to column chromatography to give six subfractions. These subfractions were used to determine their percentage inhibition. The result indicated that fractions 4.5 and 4.6 showed high ACE percentage inhibition with 94.69 and 97.08, respectively. Since the screened concentration of 1 mg/mL was a high concentration, a false-positive result can be occurred. Before further purification step, the IC50 values were observed by diluting the fractions 4.5 and 4.6 into many concentrations. Satisfactory IC50 values ensured us to continue the experiment. The ACE percentage inhibition and the IC50 of S. garrettiana are shown in [Table 1].
Table 1: Angiotensin-converting enzyme percentage inhibition of Senna garrettiana fractions

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Bioassay-guided investigation of S. garrettiana subfractions 4.4 and 4.6 led to isolation of three pure known compounds: one anthraquinone, one triterpenoid, and one stilbene, identified as chrysophanol (1), betulinic acid (2), and piceatannol (3), respectively [Figure 1]. All the structures were confirmed from NMR spectral data in [Table 2], [Table 3], [Table 4]. The isolated compounds 1–3 were investigated for their ACEi. Although the ACEi effects of all active compounds were significantly less than the captopril (IC50 = 0.02 μM), a well-known ACE inhibitor, the IC50 values of compounds 2 and 3 in [Table 5] suggested that they still had satisfactory ACEi activity.[14] Only compound 1 showed weak inhibitory activity.
Figure 1: Structures of isolated compounds 1–3 from the heartwood of Senna garrettiana

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Table 2: 1H nuclear magnetic resonance spectroscopy spectral data of compound 1 (CDCl3; 500 MHz) and reference

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Table 3: 1H nuclear magnetic resonance spectroscopy spectral data of compound 2 (dimethyl sulfoxide-d6; 500 MHz) and reference

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Table 4: 1H nuclear magnetic resonance spectroscopy spectral data of compound 3 (methanol-d4; 500 MHz) and reference

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Table 5: Angiotensin-converting enzyme inhibitory of compounds from Senna garrettiana

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Betulinic acid, a naturally occurrence pentacyclic triterpenoid, is presented in many plant species, including Betula pubescens, Melaleuca leucadendron, and Ziziphus joazeiro.[15],[16],[17] It is well known for its anticancer activity.[18],[19] However, in this study, it was shown that this compound may also have a benefit as an antihypertensive agent, through ACEi. The evidence from other publications showed that betulinic acid has a potential in cardiovascular disease treatment. For example, first, it can reduce nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression in human endothelial cells through the protein kinase C-independent mechanism.[20] Since NADPH oxidase expression can produce reactive oxygen species which lead to endothelial dysfunction, reducing its expression means reducing cardiovascular risk factors. Second, it was found that betulinic acid can attenuate endothelial dysfunction in diabetic apolipoprotein-E gene knockout mice and may, therefore, be useful for atherosclerosis treatment.[21] Third, Zizyphi Spinosi Semen, a traditional Chinese herb containing betulinic acid as a main component, can decrease blood pressure in L-NAME-induced hypertensive rats.[22] Moreover, ursolic acid, which is also pentacyclic triterpenoid, has been reported to possess some ACEi, but the activity is weaker than that of betulinic acid in this study.[23] Ursolic acid and oleanolic acid were reported to contribute to the antihypertensive effect of genetic hypertension in rats.[24] Investigation on ACEi of ursolic and oleanolic acids using an in silico model suggested that both compounds may possess this activity.[25] This evidence suggests that pentacyclic triterpenoid possesses some ACEi in which the differences in carbon number in ring-E may affect its potency.

Piceatannol is a stilbene naturally available from fruits such as grapes and from medicinal plants such as Euphorbia lagascae and Mezoneuron cucullatum.[26],[27],[28] It possesses anti-HIV-1 integrase activity.[29] Moreover, it has been reported to have a beneficial effect on cardiovascular disease, acting as an antiarrhythmic agent, and preventing endothelial dysfunction.[30],[31] Piceatannol also exhibits vasorelaxation effects, in which can decrease blood pressure. Research shows that piceatannol is a potent vascular relaxant in rat-isolated aorta, and the mechanism may be mediated through the endothelium-dependent nitric oxide signaling pathway.[32],[33] Although there have been no reports about the ACEi of piceatannol, resveratrol was reported to possess this activity with a IC50 reading of 0.97 mM.[34] Resveratrol, a well-known stilbene in grapes, has been suggested as an intermediate in piceatannol biosynthesis.[35] From a study of structure–activity relationships, it was found that resveratrol created hydrogen bonds through its hydroxyl groups with amino acids in the active site of ACE, leading to a blockage of catalytic activity of ACE.[34] This evidence can be used to support the ACEi of piceatannol. Moreover, considering the IC50 value of piceatannol from this study, the inhibition activity was much more than that of resveratrol even if both are stilbenes. This may be because of the presence of a catechol group in piceatannol structure, which is reported to be the important catechol group in some phenolic compounds for ACEi.[36]

The use of pharmacological-related compounds as markers for quality control of standardized HMs is predicted to be widespread in the upcoming years, according to the World Health Organization Traditional Medicine Strategy 2014–2023.[37] Moreover, betulinic acid and piceatannol are promising candidates in therapeutic development due to their IC50 value, which was not too strong or too weak. The side effects of synthetic ACE inhibitors, such as coughing and skin rashes, are suggested to be caused by the increase of bradykinin.[38] ACE activates the degradation of bradykinin; thus, the bradykinin is elevated because ACE activity is completely blocked by synthetic ACE inhibitors, which normally have IC50 values in nM units. Since both piceatannol and betulinic acid have IC50 of 8.44 μM and 26.77 μM, respectively, they may cause fewer secondary effects.


   Conclusions Top


From ethnobotany through bioassay-guided investigations of S. garrettiana, piceatannol and betulinic acid were found to possess ACEi. These compounds can be used as markers for a standardized HM aimed at controlling blood pressure. Moreover, both compounds can be used as candidates for finding new ACE inhibitors with fewer undesirable side effects.

Acknowledgements

The authors are grateful to the Thailand Research Fund (grant number TRG5880033) and the Research Institute of Rangsit University (grant number 32/2558) for financial support. We also thank the Sino-Thai Traditional Medicine Research Center at Rangsit University, Thailand, for providing laboratory facilities. In addition, we give our appreciation to KI Tull in the United Kingdom for providing language assistance and proofreading the article.

Financial support and sponsorship

This study was financially supported by the Research Institute of Rangsit University (grant number 32/2558) and the Thailand Research Fund (grant number TRG5880033).

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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