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A mass of evidence has identified a promoting of nitric oxide (NO) production in endothelial cells using natural products as a potential strategy to prevent and treat hypertension. This study investigated whether the aqueous extract of Moringa oleifera leaves (MOE) could lower mean arterial pressure (MAP) and relax mesenteric arterial beds in rats via stimulating endothelium-derived NO production. Intravenous administration of MOE (1-30 mg/kg) caused a dose-dependent reduction in MAP in anesthetized rats. In rats pretreated with the NO-synthase inhibitor, N ω -nitro-L-arginine methyl ester (L-NAME, 30 mg/kg, i.v.), the effect of MOE on MAP was significantly reduced. MOE (0.001-3 mg) induced relaxation in methoxamine (10 μM) pre-contracted mesenteric arterial beds, which was abolished by endothelium denudation. This endothelium-dependent vasorelaxation was reduced by L-NAME (100 μM) or the NO-sensitive guanylyl cyclase inhibitor, 1H- [1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (10 μM). In primary human pulmonary artery endothelial cells, MOE (3-30 μg/mL) induced NO production, which was inhibited by L-NAME (100 μM) pretreatment. These findings show that MOE stimulates the endothelium-derived NO release for driving its vasorelaxation to lower arterial blood pressure. These suggest the development of MOE as a natural antihypertensive supplement., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: An aqueous extract of Moringa oleifera leaves (MOE) is known to cause relaxation of mesenteric resistance arteries of rats in which hypertension has been induced by the administration of L-NAME, but the mechanism(s) of action of MOE remains unclear. The purpose of this study was to investigate these mechanisms in mesenteric arterial beds isolated from L-NAME induced hypertensive rats. Methods: An investigation of vascular reactivity was conducted on isolated mesenteric arterial beds by measuring the changes in perfusion pressure using an in vitro system., Results: MOE (0.001-3 mg in 0.1 ml injection volume) caused a dose-dependent relaxation in methoxamine (5 µM) pre-contracted arterial beds, which was partially abolished by endothelium removal. The endothelium-dependent component of vasorelaxation was insensitive to both L-NAME (100 µM) and indomethacin (10 µM), while completely inhibited in high KCl (45 mM)-induced contraction. MOE (1 and 3 mg/ml) showed a dose-dependent inhibitory effect on CaCl 2 -induced contractions of denuded preparations in Ca 2+ -free medium containing a high KCl (60 mM) or methoxamine (10 µM). In Ca 2+ -free medium, MOE (3 mg/ml) also inhibited phenylephrine-induced contractions of denuded preparations. Conclusion: These findings suggest that MOE relaxes mesenteric arterial beds of L-NAME hypertensive rats via both endothelium-dependent and endothelium-independent mechanisms. The endothelium-dependent action occurred via endothelium-derived hyperpolarizing factor-mediated hyperpolarization. The endothelium-independent action was related to blocking the entry of extracellular Ca 2+ via voltage-operated and receptor-operated Ca 2+ channels, and inhibiting mobilization of sarcolemmal Ca 2+ via inositol trisphosphate receptor Ca 2+ channels. MOE may be potentially useful as a natural vasodilator against hypertension.

Background: Enhancing relaxation of resistance arteries and decreasing oxidative stress by using natural products are potential strategies for prevention and treatment of hypertension., Purpose: This study investigated whether aqueous extract of Moringa oleifera leaves (MOE) could alleviate N ω -nitro-L-arginine-methyl ester (L-NAME)-induced high blood pressure via modulation of vascular function and antioxidant properties., Methods: An experimental hypertensive model was established by administration of L-NAME (50 mg/kg/day) in drinking water to male Wistar rats for 3 weeks. Arterial pressure was measured indirectly by tail-cuff plethysmography and directly via femoral artery catheterization. Vasoreactivity of isolated rat mesenteric arterial bed was determined by the changes in perfusion pressure detected by a pressure transducer. Vascular superoxide anion (O 2 •- ) production was determined by lucigenin-enhanced chemiluminescence. Other biochemical measurements including malondialdehyde (MDA) level, superoxide dismutase (SOD), and catalase (CAT) activities were measured by colorimetric assay., Results: L-NAME-treated rats developed significantly increased blood pressure and heart rate. Concurrent oral treatment with MOE (30 and 60 mg/kg/day) could decrease the high blood pressure and tachycardia in a dose-dependent manner. MOE reduced the impairment of acetylcholine-induced relaxation and decreased the hyperreactivity of adrenergic-mediated contraction in response to periarterial nerve stimulation and phenylephrine in isolated mesenteric arterial beds. In addition, MOE exhibited antioxidant effects in the hypertensive rats, as indicated by suppression of vascular O 2 •- production, decrease of plasma and thoracic aorta MDA levels, and increase of antioxidant activities of SOD and CAT. Moreover, MOE (0.001-0.3 mg) produced a dose-dependent relaxation in methoxamine pre-contracted arterial beds isolated from L-NAME hypertensive rats, which was abolished by endothelium denudation., Conclusion: These findings suggest that the antihypertensive effect of MOE in L-NAME-hypertensive rats may be mediated by alleviating vascular dysfunction and oxidative stress and promoting endothelium-dependent vasorelaxation. MOE may be potentially useful as a natural product against hypertension., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

N ω -Nitro-l-arginine methyl ester (l-NAME)-induced hypertension and cardiovascular remodeling are associated with oxidative stress and inflammation. Garcinia mangostana Linn., has been reported to have antioxidant and anti-inflammatory properties. This study investigated whether G. mangostana pericarp extract (GME) could prevent l-NAME-induced hemodynamic alterations, cardiovascular remodeling, oxidative stress and inflammation in rats. Male Sprague-Dawley rats were given 40mg/kg/day of l-NAME in drinking water to induce hypertension, and were simultaneously treated with GME at a dose of 200mg/kg/day. Rats that received l-NAME for five weeks had high blood pressure, left ventricular hypertrophy and thickening of aortic wall. Vascular superoxide production, plasma malondialdehyde (MDA), and plasma tumor necrosis factor alpha (TNF-α) were significantly increased in l-NAME-hypertensive rats (p<0.05). This was consistent with up-regulation of the p47 phox NADPH oxidase subunit and iNOS protein expression in aortic tissues (p<0.05). Low levels of plasma nitric oxide metabolites were observed in l-NAME hypertension. GME prevented the development of hypertension and cardiovascular remodeling induced by l-NAME with reduced oxidative stress and inflammation. These data suggest that GME had a protective effect against l-NAME-induced hypertension and cardiovascular remodeling via suppressing p47 phox NADPH oxidase subunit and iNOS protein expression resulting in enhancing NO bioavailability., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Reactive oxygen species (ROS)-induced oxidative stress plays a major role in pathogenesis of hypertension. Antidesma thwaitesianum (local name: Mamao) is a tropical plant distributed in the tropical/subtropical areas of the world, including Thailand. Mamao pomace (MP), a by-product generated from Mamao fruits, contains large amounts of antioxidant polyphenolic compounds. The aim of this study was to investigate the antihypertensive and antioxidative effects of MP using hypertensive rats. For this purpose, male Sprague-Dawley rats were given Nω-nitro-L-arginine methyl ester (L-NAME), an inhibitor of endothelial nitric oxide synthase (eNOS), in drinking water (50 mg/kg) for three weeks. MP extract was orally administered daily at doses of 100 and 300 mg/kg. L-NAME administration induced marked increase in blood pressure, peripheral vascular resistance, and oxidative stress. MP treatment significantly prevented the increase in blood pressure, hindlimb blood flow and hindlimb vascular resistance of L-NAME treated hypertensive rats (p < 0.05). The antihypertensive effect of MP treatment was associated with suppression of superoxide production from carotid strips and also with an increase in eNOS protein expression and nitric oxide bioavailability. The present results provide evidence for the antihypertensive effect of MP and suggest that MP might be useful as a dietary supplement against hypertension.

Morus alba Linn. (MA), mulberry leaves have been used as a beverage for prevention of various diseases including hyperlipidemia and hyperglycemia. Recently, the antioxidant activities of the MA leaf extract have been reported. The objective of this study was to investigate the effect of the MA leaf extract on free radical-induced cellular injury. In the in vitro models, the extract scavenged stable free radical (1, 1-diphenyl-2-picrylhydrazyl; DPPH) in a concentration-dependent manner with an IC(50) of 20.10 ± 0.78 μ g/ml. The extract protected the erythrocytes from free radical (2, 2'-azobis (2-amidinopropane) dihydrochloride; AAPH)-induced hemolysis with an IC(50) of 74.22 ± 9.87 μg/ml. Additionally, the extract significantly prevented the gastric mucosal injury induced by ischemia-reperfusion (I/R) in rats when given orally at doses of 0.25 and 0.50 g/kg/day for 3 consecutive days (p < 0.05; n=7). However, this effect was not found when the higher doses (1 and 2 g/kg/day) of the extract were tested. In conclusion, these results indicate that the MA leaf extract possesses the cytoprotective activity against free radical-induced cell injury. Therefore, when given at the appropriate dose range, the mulberry leaf may potentially be used as a food supplement in patients with certain diseases in which the oxidative stress-induced cellular injury is pathologically involved.

We have previously shown that mulberry leaf extract (MA) causes blood glucose levels to decrease in rats with streptozotocin-induced diabetes while enhancing glucose uptake by isolated fat cells. We hypothesized that the antidiabetic activity of MA is mediated via enhancement of adiponectin secretion and adipogenesis, which consequently decreases blood glucose. In the present study, we aimed to elucidate the molecular basis for the observed antidiabetic activity using murine 3T3-L1 preadipocyte cultures. We found that treatment of differentiating 3T3-L1 cells with MA at concentrations of 5, 15, and 45 μg/mL increased expression of adiponectin messenger RNA from 1.4-fold (control) to 1.5-, 1.95-, and 2.2-fold above basal values, respectively, while causing adiponectin secretion to increase from 70 ± 7.4 ng/mL to 100 ± 1.4, 138 ± 2.0, and 176 ± 21.4 ng/mL, respectively. Furthermore, we observed an increase in both lipid accumulation and messenger RNA expression of transcription factors, such as CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor γ; and of the fatty acid-binding protein aP2 in differentiated 3T3-L1 cells pretreated with MA. Our findings indicate that the stimulatory effects of mulberry leaf extract on adipocyte proliferation and differentiation likely occur through up-regulation of adipogenic transcription factors and downstream gene expression. Such effects of mulberry leaf extract on adiponectin secretion and adipocyte activity may account for, at least in part, the antidiabetic effects of consumption of beverages containing mulberry leaves., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Free radical-induced vascular dysfunction plays a key role in the pathogenesis of vascular disease found in chronic diabetic patients. Morus alba (MA) leaf extract is promoted for good health especially in diabetic patients. Interestingly, antidiabetic and antioxidant activities of MA have been reported in experimental animals. Thus, the hypothesis of this study was that the long-term treatment with MA could improve vascular reactivity of chronic diabetic rats. To test this hypothesis, we examined the effect of long-term treatment with MA on the vascular responses to vasoactive agents in streptozotocin-induced chronic diabetic rats. The diabetic rats were either orally administered with distilled water, MA (0.25, 0.5 and 1 g/kg per day) or subcutaneously injected with insulin (4 U/kg per day) for 8 weeks. After each treatment, the fasting blood glucose, blood pressure, vascular responses to vasoactive agents and tissue malondialdehyde were examined. Morus alba at the doses of 0.5 and 1 g/kg, which significantly reduced blood glucose level, also significantly decreased the high blood pressure in diabetic rats. Vascular responses of the chronic diabetic rats to vasodilators, acetylcholine (3-30 nmol/kg) and sodium nitroprusside (1-10 nmol/kg) were significantly suppressed by 26% to 44% and 45% to 77% respectively, whereas those to vasoconstrictor, phenylephrine (0.01-0.1 micromol/kg) were significantly increased by 23% to 38% as compared to normal rats. Interestingly, the administration of 0.5 and 1 g/kg MA or 4 U/kg insulin significantly restored the vascular reactivities of diabetic rats. Moreover, 8 weeks of diabetes resulted in the elevation of malondialdehyde content in tissues (liver, kidney, heart, and aorta), and MA treatment significantly lessened this increase. These results provide the first evidence for the efficacy of MA in restoring the vascular reactivity of diabetic rats, the mechanism of which may associate with the alleviation of oxidative stress.

In Thailand, beverages containing mulberry leaf (Morus alba L.) are believed to promote good health, especially in people with diabetes. We examined the effects of long-term administration of an ethanolic extract of mulberry leaf (MA) on blood glucose, oxidative damage, and glycation in streptozotocin-induced diabetic rats. Daily administration of 1 g/kg MA for six weeks decreased blood glucose by 22%, which was comparable to the effect of 4 U/kg insulin. Lipid peroxidation, measured as malondialdehyde and lipid hydroperoxide concentrations (3.50 +/- 0.33 and 3.76 +/- 0.18 muM, respectively) decreased significantly (P < 0.05) compared to nontreated control diabetic rats (8.19 +/- 0.45 and 7.50 +/- 0.46 muM, respectively). Hemoglobin A(1C), a biomarker for chronic exposure to high concentration of glucose, was also significantly decreased in the MA-treated group (6.78 +/- 0.30%) in comparison to untreated group (9.02 +/- 0.30%). The IC(50) of in vitro antiglycation and free radical scavenging activities of MA were 16.4 +/- 5.6 microg/ml and 61.7 +/- 2.1 microg/ml, respectively. These findings support that long-term administration of MA has antihyperglycemic, antioxidant and antiglycation effects in chronic diabetic rats, which may be beneficial as food supplement for diabetics.

Aqueous extract of Moringa oleifera leaves (MOE) is a potent inducer of endothelium-dependent relaxation of mesenteric resistance arteries of rats induced to be hypertensive using Nω-nitro-L-arginine methyl ester (L-NAME). Hydrogen sulfide (H2S) has been shown to participate in endothelium-dependent relaxation of small resistance arteries. Therefore, this study aimed to investigate whether endothelial H2S-dependent signaling plays a role in the vasorelaxation in response to MOE. Mesenteric arterial beds isolated from L-NAME hypertensive rats were set up in an ex vivo perfusion system for measurement of vasoreactivity. All experiments were performed in the presence of the nitric oxide synthase inhibitor, L-NAME (100 µM) and the cyclooxygenase inhibitor, indomethacin (10 µM) to prevent the formation of nitric oxide and prostanoids, respectively. In the presence of the nitric oxide synthase inhibitor, L-NAME and the cyclooxygenase inhibitor, indomethacin, the endothelium-dependent vasorelaxation induced by MOE (0.001–3 mg) was completely inhibited by DL-propargylglycine (100 µM), which inhibits the H2Sgenerating enzyme, cystathionine γ-lyase. This H2Sdependent response was reduced by the KATP channel blocker; glibenclamide (10 µM), the KCa channel blocker; tetraethylammonium (1 µM), and the myo-endothelial gap-junctional uncoupler; 18α-glycyrrhetinic acid (10 µM). In contrast, the muscarinic receptor antagonist, atropine (100 µM), did not affect the response to MOE. The results may suggest that H2S is the likely mediator of endothelium-dependent relaxation in response to MOE in mesenteric arterial beds of L-NAME-induced hypertensive rats. MOE-induced H2S-dependent vasorelaxation involves activation of KATP and KCa channels and requires myo-endothelial gap-junctional communication. [ABSTRACT FROM AUTHOR]

Mulberry (Morus alba L.) leaf tea is promoted for its health benefits and the control of diabetes in Asian nations. The blood glucose lowering activity of mulberry leaf extract (MA) has been proven; however, the molecular basis underlying this effect remains unclear. The aim of the present work is to elucidate its mechanism of the antihyperglycemic action, by examining the effect of MA on glucose uptake and the translocation of glucose transporter 4 protein (GLUT4) to the plasma membrane of adipocytes isolated from diabetic rats. The incubation of adipocytes with 5-45 μg/ml MA resulted in 31-54% increase of glucose uptake in a dose-dependent manner. This glucose uptake enhancing effect was inhibited by the phosphoinositol 3-kinase (PI3-K) inhibitor, wortmannin (100 nM). The GLUT4 protein on the plasma membrane fraction of adipocytes was markedly increased after treatment with 15 μg/ml MA extract. Interestingly, gallic acid, one of the phenolic compounds found in MA extract, increased glucose uptake and enhanced the translocation of GLUT4 at concentrations comparable to the amount of gallic acid in the effective concentration ranges of MA. Thus, it is likely that gallic acid contributes, at least in part, to its antihyperglycemic activity. The present results suggest that the antihyperglycemic action of MA is mediated by increasing glucose uptake via the activation of PI3-K signaling pathway and translocation of GLUT4 to the plasma membrane. These findings are the first molecular evidence supporting the mulberry tea as herbal medicine for diabetic patients. [ABSTRACT FROM AUTHOR]

Agarwood leaf extract was found to possess antipyretic, laxative and antimicrobial activities. A trial of one diabetic patient taking long term agarwood leaf tea was found to have blood glucose returned to normal. In this work, the effects of methanol, water and hexane crude extracts of agarwood leaf on hyperglycemia in streptozotocin-induced diabetic rats were investigated. Only methanol and water extracts at the dose of 1 g/kg body weight lowered the fasting blood glucose levels, 54 and 40%, respectively. The results were comparable to 4 U/kg body weight of insulin (73%). In in vitro experiment, the effect of the methanol and water extracts at the concentration of 10 µg/mL enhanced glucose uptake activity on rat adipocytes by 172±10 and 176±21% of the control, respectively. The glucose uptake enhancement activity is comparable to 1.5 nM insulin (166±16%). The thin-layer chromatographic characteristics of all extracts were documented. The findings suggest that agarwood leaf is a promising potential antidiabetic agent. [ABSTRACT FROM AUTHOR]