Relaxant and vasoprotective effects of ginger extracts on porcine coronary arteries
- Authors:
- Published online on: January 11, 2018 https://doi.org/10.3892/ijmm.2018.3380
- Pages: 2420-2428
Abstract
Introduction
Cardiovascular disease is the second leading cause of death among the ten leading chronic diseases in Taiwan according to the 2017 annual report of the Ministry of Health and Welfare, Taiwan, R.O.C. (1). A total of 20,812 people died, and the death rate was 88.5 per 100,000 population, increased by 8.1% from 2015 to 2016 (1). Cardiovascular disease includes coronary heart disease (CHD), peripheral arterial disease, aortic disease and stroke, and many risk factors are associated with the lesions (2,3). The drug treatments can greatly improve cardio-vascular disease (4). Importantly, traditional Chinese medicine, dietary foods and supplements may prevent or help in fighting heart disease (5,6).
Ginger (Zingiber officinale Roscoe) is a natural herb that is widely used for medicinal and culinary purposes (7,8). Ginger exerts many health benefits and may be used to treat ailments, including cramps, arthritis and disorders of the gastrointestinal tract, such as constipation, dyspepsia, diarrhea, nausea and vomiting (8). In addition, ginger is recommended by traditional healers to treat cardiomyopathy, high blood pressure and palpitations (7,9,10). The main bioactive constituents of ginger are gingerol, shogaol, zingerone and paradol (11,12). Furthermore, the main aromatic components of ginger are zingiberol, gingediol, monoacyldigalactosyl-glycerol, iarylheptanoids and phytosterols (13). 6-Gingerol has numerous biological activities, including antioxidant, antitumor and anti-inflammatory effects (14–16). The pharmacological effects of 6-gingerol ameliorate hyperlipidemia by decreasing serum cholesterol and serum triglyceride levels (17). 6-shogaol is a dehydrated form of 6-gingerol, which is isolated from the dried or cooked rhizomes of ginger (18,19). In a previous study, ginger crude extract (GCE) was reported to exhibit hypotensive, endothelium-independent vasodilatory and cardiosuppressive properties, via its specific inhibitory action at voltage-dependent calcium channels (20). The present study aimed to investigate the relaxant effects of GCE on porcine coronary arteries in vivo.
Materials and methods
Reagents and chemicals
DL-homocysteine (Hcy), 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), bradykinin, 1,1-diphenyl-2-picrylhydrazyl (DPPH), dimethyl sulfoxide, propranolol, n-butanol and other chemicals were high-grade products purchased from Sigma-Aldrich (Merck KGaA, Darmstadt, Germany). NG-nitro-L-arginine (L-NNA) and glibenclamide (Glib) were obtained from MP Biomedicals, LLC (Santa Ana, CA, USA). KH solution was composed of 70.2 mM NaCl, 4.2 mM KCl, 2.8 mM CaCl2, 2.7 mM MgSO4, 21.0 mM NaHCO3, 0.2 mM KH2PO4 and 9.8 mM glucose, and the pH was adjusted to 7.4.
Ginger extraction
A total of 600 g fresh ginger rhizome was soaked in 2.5 l ethanol. The extracts were refluxed at 78°C for 2 h; this was repeated three times. Subsequently, the filtrate was concentrated in a rotary evaporator. The weight of extracts was ~34.2 g (yield, 5.7%). The residue was then suspended in 50 ml water and extracted with 50 ml chloroform twice, after which the chloroform partition was evaporated to obtain 8.4 g residue (GCE). The aqueous phase was partitioned with n-butanol. The n-butanol partition was evaporated to obtain 6.3 g residue (ginger n-butanol extract, GNE). The water extract underwent reverse osmosis to obtain 19.5 g residue (ginger water extract, GWE); this process is summarized in Fig. 1. The stock solution of ginger extraction was prepared by dimethyl sulfoxide to dilute for further experiments.
Coronary artery ring preparation
Porcine hearts were freshly obtained from the local abattoir, immersed in cold 0.9% NaCl at 4°C and were transported to the research laboratory. Excess connective tissue was removed and the arteries were cut into 5-mm rings. Endothelium-intact and -denuded porcine coronary artery rings were prepared, and the rings were then mounted with two stainless steel hooks in 10 ml KH solution-filled organ baths. KH solution was kept in oxygenated conditions (95% O2 and 5% CO2) at 37°C and was replaced every 15 min to maintain continuous equilibration. The rings were perfused with 30 mM KCl in the organ bath until tonic phase contraction was achieved, as previously described (21) before pretreatment with 100 µM L-NNA, 10 µM ODQ, 10 µg/ml indomethacin, 20 µM propranolol, 1 µM Glib, 100 µM Hcy, 30 mM bradykinin and 77.5 mM H2O2, respectively, for indicated period of time.
Isometric tension of porcine coronary arteries
The porcine coronary arteries were harvested, cut into numerous 5-mm rings, and were maintained in 5 ml organ baths containing 95% O2 and 5% CO2 at 37°C. Ginger extracts were individually added to the 5-mm rings for 30 min and relaxation was observed. Alterations in tension were recorded using a Grass Force displacement transducer (model FT03; Grass; Natus Medical Incorporated, Pleasanton, CA, USA).
DPPH radical scavenging assay
The DPPH radical scavenging assay was performed according to the method described by Sakanashi et al (21). Briefly, in each well of a 96-well plate, 50 µl sample extract was added to 150 µl 0.25 mM DPPH methanolic solution. After mixing thoroughly, the reactants were incubated in the dark for 30 min at room temperature. The control was prepared by mixing 50 µl methanol with 150 µl DPPH. The absorbance was detected at 517 nm using a spectrophotometer. Samples were measured in triplicate.
Lucigenin-enhanced chemiluminescence assay
The levels of superoxide anion produced by endothelial cells of the porcine arteries were detected using the lucigenin-enhanced chemiluminescence method, as previously described by Sun et al (22). Briefly, the samples of GCE, GNE and GWE were mixed with 5 µM lucigenin for 6 min. Time-based reading was recorded in a 5 min period using a luminometer. The area of each vessel segment was measured using a caliper and was used to normalize the data for each sample.
Protein preparation
Following treatment with or without GCE, GWE and GNE, porcine coronary artery endothelial cells were collected as previously described (23) and mixed with protein lysis buffer [50 mM Tris-HCl (pH 7.4), 1 mM NaF, 150 mM NaCl, 1 mM EGTA, 1 mM phenylmethane-sulfonyl fluoride, 1% NP-40 and 10 µg/ml leupeptin] on ice. The samples were homogenized for 20 sec, incubated for 20 min on ice and centrifuged at 15,000 × g for 30 min at room temperature. The supernatants were then transferred into new tubes for protein quantification, as previously described (24,25).
Western blot analysis
A total of 50 µg protein was loaded and separated by 10% SDS-PAGE. The samples in the gels were then transferred onto polyvinylidene difluoride membranes. The membranes were incubated with 0.1% PBS-Tween containing 5% non-fat milk for 30 min at room temperature, and were then hybridized with cyclooxygenase-2 (COX-2; cat. no. GTX100656; 1:1,000 dilution; GenTex, Hsinchu, Taiwan), inducible nitric oxide synthase (iNOS; cat. no. GTX130246; 1:1,000 dilution; GenTex), endothelial nitric oxide synthase (eNOS; cat. no. 3GTX129843; 1:1,000 dilution; GenTex) and β-actin (cat. no. GTX109639; 1:5,000 dilution; GenTex) primary antibodies. Subsequently, membranes were incubated with horseradish peroxidase-conjugated rabbit IgG antibody (cat. no. GTX213110-01; 1:10,000 dilution; GenTex) at room temperature for 1 h and were then visualized using Immobilon Western HRP substrate kit (EMD Millipore, Billerica, MA, USA). Densitometric analysis of each band was performed utilizing National Institutes of Health (NIH) ImageJ 1.47 software (NIH, Bethesda, MD, USA).
Statistical analysis
Data are presented as the means ± standard deviation from at least three separate experiments. Statistical data were analyzed using one-way ANOVA with post hoc Dunnett's test for comparing groups to the control by SPSS version 13.0 for Windows (SPSS Inc., Chicago, IL, USA). P<0.05 was considered to indicate a statistically significantly difference.
Results
Ginger extracts (GCE, GNE and GWE) preparation
The three varieties of ginger extract (GCE, GNE and GWE) were prepared according to the diagram presented in Fig. 1. These three ginger extracts were used in the present study to explore their effects on the vasorelaxation of porcine coronary artery rings.
GCE relaxes porcine coronary arteries
Porcine coronary arteries were suspended in an organ bath. Various amounts of GCE (1, 3, 10, 30 and 100 µg/ml) were added to the porcine coronary arteries; water was used as a vehicle control. A dose-dependent increase in relaxation was observed in response to GCE (Fig. 2).
GCE induces endothelium-dependent relaxation of porcine coronary arteries
The results of the present study indicated that GCE induced endothelium-dependent vasorelaxation. Endothelium-intact and -denuded porcine coronary artery rings were incubated with various amounts of GCE (1, 3, 10, 30 and 100 µg/ml). GCE was able to reduce KCl-induced contraction and increase vasorelaxation from 27 to 99% in the endothelium-intact porcine coronary artery rings, whereas GCE exerted mild effects on the vasorelaxation of denuded porcine coronary artery rings (from 15 to 93%) (Fig. 3). Based on these data, it was suggested that endothelium-dependent relaxation was increased in porcine coronary arteries following GCE exposure.
The NOS signaling pathway is involved in GCE-induced relaxation
Numerous in vitro and in vivo studies have reported that endothelium-dependent relaxation and vasodilatation persist in the presence of NOS inhibitors, including L-arginine analogues, such as L-NNA (23,26). Porcine coronary artery rings were pretreated in the absence (control) or presence of 100 µM L-NNA for 20 min, and were then incubated with 30 mM KCl to induce contraction until the tonic phase (27). Relaxation was examined in the presence of various concentrations of GCE (1, 3, 10, 30 and 100 µg/ml) in an organ bath. GCE induced relaxation of porcine coronary artery rings from 13 to 86% without L-NNA pretreatment. Conversely, GCE (100 µg/ml) induced relaxation of porcine coronary artery rings to 66%, in the presence of L-NNA (Fig. 4). These results revealed that GCE-induced relaxation of porcine coronary arteries may be mediated by the NOS signaling pathway.
GCE improves relaxation via NO-activated soluble guanylate cyclase (sGC)
The present study determined the effects of GCE on sGC-induced relaxation. Porcine coronary artery rings were pretreated in the absence (control) or presence of 10 µM ODQ for 20 min, and were then incubated with 30 mM KCl to induce contraction until the tonic phase. Relaxation was examined in the presence of various concentrations of GCE (1, 3, 10, 30 and 100 µg/ml) in an organ bath. GCE induced an increase in relaxation from 8 to 87% in porcine coronary artery rings following pretreatment without 10 µM ODQ. Conversely, relaxation of porcine coronary artery rings was significantly reduced following pretreatment with 10 µM ODQ and treatment with GCE at 30 and 100 µg/ml (Fig. 5). These results indicated that NO is a vital factor in GCE-induced relaxation of porcine coronary arteries.
GCE improves relaxation via COX
The present study further examined the effects of GCE on relaxation following treatment with indomethacin, which is an inhibitor of COX. Porcine coronary artery rings were pretreated in the absence (control) or presence of 1 µg/ml indomethacin for 20 min, and were then incubated with 30 mM KCl to induce contraction until the tonic phase. Relaxation was examined in the presence of various concentrations of GCE (1, 3, 10, 30 and 100 µg/ml) in an organ bath. GCE induced an increase in relaxation from 15 to 100% in porcine coronary artery rings without 1 µg/ml indomethacin treatment. Conversely, following pretreatment with 1 µg/ml indomethacin and treatment with low concentrations of GCE (3–30 µg/ml), relaxation of porcine coronary artery rings was significantly attenuated (Fig. 6). These results suggested that GCE attenuated relaxation induced by arachidonic acid. GCE-induced relaxation of porcine coronary arteries may be through COX pathway.
GCE has no effect on relaxation induced by β1-adrenergic receptor blocker
β-blockers have been widely used in the treatment of numerous cardiovascular diseases, particularly hypertension and atherosclerosis (28). Some β1-adrenergic receptor blockers cause vasodilation by increasing NO (29). The present study examined the effects of GCE on relaxation induced by propranolol, which is a β-blocker. Porcine coronary artery rings were pretreated in the absence (control) or presence of 20 µM propranolol for 20 min, and were then incubated with 30 mM KCl to induce contraction until the tonic phase. Relaxation was examined in the presence of various amounts of GCE (1, 3, 10, 30 and 100 µg/ml) in an organ bath. GCE at 3–30 µg/ml induced an increase in relaxation from 11 to 91% in porcine coronary artery rings without pretreatment with 20 µM propranolol (Fig. 7). These results indicated that GCE exhibited no apparent effect on propranolol-induced relaxation.
ATP-sensitive potassium (KATP) channel blocker exerts no effects on GCE-induced relaxation
KATP channels are activated and opened by declining intracellular ATP levels and elevated cAMP concentration, which leads to hyperpolarization of endothelial cells and the promotion of NO formation in vitro (30,31). It has been suggested that endothelial cell hyperpolarization may contribute to vascular relaxation. KATP channels are inhibited by sulfonylurea agents, including Glib (31,32). The present study examined the effects of Glib, a KATP channel blocker, on GCE-induced relaxation. Porcine coronary artery rings were pretreated in the absence (control) or presence of 1 µM Glib for 60 min, and were then incubated with 30 mM KCl to induce contraction until the tonic phase. Relaxation was examined in the presence of various amounts of GCE (1, 3, 10, 30 and 100 µg/ml) in an organ bath. GCE induced an increase in relaxation from 15 to 76% in the porcine coronary artery rings without 1 µM Glib pretreatment (Fig. 8). These results suggested that Glib had no effect on GCE-induced relaxation.
GCE prevents Hcy-induced endothelial vasomotor dysfunction
The present study investigated the effects of GCE on Hcy-induced endothelial cell damage. Porcine coronary artery rings were incubated with 30 µg/ml GCE for 15 min, and were then treated with 100 µM Hcy for 30 min. Porcine coronary artery rings were placed in an organ bath containing 30 mM KCl to induce contraction until the tonic phase. Relaxation was examined following the addition of 30 mM bradykinin into the organ bath. Hcy reduced relaxation, whereas GCE significantly prevented Hcy-induced endothelial dysfunction (Fig. 9). These results indicated that GCE may improve Hcy-induced endothelial cell damage.
GCE prevents hydrogen peroxide (H2O2)-induced endothelial cell damage
The present study clarified the effects of GCE on H2O2-induced endothelial cell damage. Porcine coronary artery rings were incubated with 30 µg/ml GCE for 15 min, and were then placed in an organ bath containing 30 mM KCl to induce contraction until the tonic phase. Rings were treated with 77.5 mM H2O2 for 15 min and contraction was examined. H2O2 induced endothelial contraction, whereas GCE significantly prevented H2O2-induced endothelial dysfunction (Fig. 10). These data revealed that GCE may attenuate H2O2-induced endothelial cell injury.
Ginger extracts possess antioxidant abilities
Reactive oxygen species (ROS) are produced under oxidative stress and adverse cellular environments (33). Vitamins E and C, β-carotene, flavonoids and polyphenols have previously been demonstrated to possess free radical-scavenging abilities (34). In the present study, the antioxidant properties of ginger extracts were individually determined according to DPPH and lucigenin-enhanced chemiluminescence assays. DPPH absorbance decreased from 0.70 to 0.24, as GCE concentration increased from 62.5 to 1,000 µg/ml (Fig. 11A). The rate of inhibition was increased from 40 to 85% in a dose-dependent manner. DPPH absorbance decreased from 0.79 to 0.39, as GNE concentration increased from 62.5 to 1,000 µg/ml. The rate of inhibition was increased from 37 to 78% in a dose-dependent manner (Fig. 11B). DPPH absorbance decreased from 0.73 to 0.66, as GWE concentration increased from 62.5 to 1,000 µg/ml. The rate of inhibition was increased from 42 to 48% (Fig. 11C). These findings indicated that GCE possesses a stronger ability to reduce free radical levels. To determine whether ginger extracts possess H2O2-scavenging abilities, a lucigenin-enhanced chemiluminescence assay was conducted. Various concentrations of GCE, GNE and GWE were used to evaluate their ability to remove H2O2. The H2O2-scavenging ability was increased from 10 to 52% in response to GCE (Fig. 12A). The H2O2-scavenging ability was increased from 68 to 94% in response to GNE (Fig. 12B) and from 63 to 90% in response to GWE (Fig. 12C). These findings indicated that GCE may possess a stronger antioxidant ability to scavenge free radicals.
GCE exerts strong vasoprotective effects
The present study investigated the effects of ginger extracts on Hcy-induced endothelial cell damage by analyzing the protein expression levels of endothelial NOS (eNOS), iNOS and COX-2. Hcy increased eNOS, iNOS and COX-2 expression. In the absence of Hcy, GWE induced eNOS, maintained iNOS and reduced COX-2 expression (Fig. 13A). Conversely, low concentration (10 µg/ml) of GWE slightly reduced eNOS, slightly induced iNOS and reduced COX-2 expression in the presence of Hcy. A high concentration (30 µg/ml) of GWE markedly reduced the expression levels of eNOS, iNOS and COX-2 in the presence of Hcy. GCE markedly reduced eNOS, iNOS and COX-2 expression in the presence of Hcy, whereas GNE markedly induced eNOS, iNOS and COX-2 expression in the presence of Hcy. These findings indicated that GCE exerts stronger vasoprotective effects. In addition, eNOS expression was quantified from western blot analysis (Fig. 13B). These data suggested that GCE, not GWE or GNE, possesses a strong vasoprotective effect.
Discussion
Numerous phytochemicals used in traditional Chinese medicine have beneficial health effects on blood pressure and endothelial function (19,35). Ginger, which is a spice used to enhance the flavor of foods, has been used for centuries in the Taiwanese, Chinese, Indian, Arabic, Tibetan, Unani and Siddha systems of traditional medicine (7–9). It has previously been reported that ginger possesses various beneficial pharmacological effects, including hypoglycemic, insulinotropic and hypolipidemic activities, in humans and animals (13–16). Ginger, and its extracts, have also been reported to possess anticancer, analgesic and antioxidant pharmacological activities (11–13). The present study demonstrated that GCE exerts strong vasoprotective effects and exhibits free radical-scavenging abilities in porcine coronary arteries in vivo.
Ginger has been used to treat cardiovascular diseases for a long time, and it is known to exert diuretic and blood pressure-lowering functions (7,9,10). In the present study, GCE relaxed porcine coronary arteries in a dose-dependent manner (Fig. 2). In rats, ginger has been reported to exhibit hypotensive, endothelium-dependent and -independent vasodilatory effects (36). Distinct receptors on the surface of the aorta and coronary arteries result in varying responses to stimulants. For example, epinephrine induces vasoconstriction of the aorta, but vasodilation of the coronary arteries (37). The present results indicated that GCE may relax KCl-induced contraction of endothelium-intact porcine coronary artery rings, whereas GCE only exerted a mild effect on relaxation of endothelium-denuded porcine coronary artery rings (Fig. 3). These data suggested that GCE may induce endothelium-dependent relaxation of porcine coronary arteries. NO is a major mediator of endothelium-dependent arterial relaxation.
Vasodilators, including NO, prostaglandin I2 and endothelium-derived hyperpolarizing factor, contribute to endothelium-dependent relaxation (38). The present results indicated that GCE-induced endothelium-dependent relaxation was markedly inhibited by L-NNA, an endothelial NOS inhibitor (Fig. 4). NO activates sGC, which is responsible for the enzymatic conversion of GTP to cyclic GMP (cGMP). An increase in cGMP has been reported to mediate relaxation of coronary arteries. ODQ, which is a potent inhibitor of NO-activated sGC, inhibits NO-stimulated activity (39). In the present study, GCE-induced relaxation was significantly attenuated in the porcine coronary artery rings in response to pretreatment with ODQ (Fig. 5). These results indicated that the NO signaling pathway may be involved in GCE-induced relaxation of porcine coronary arteries. Arachidonic acid causes endothelium-dependent relaxation of coronary arteries (40). COX converts arachidonic acid into prostaglandin G2 (41). The present results indicated that GCE -induced relaxation was significantly attenuated in porcine coronary artery rings in response to pretreatment with indomethacin (Fig. 6). These data suggested that COX may be involved in GCE-induced relaxation of porcine coronary arteries.
Elevated Hcy levels in the blood (hyperhomocysteinemia) induce endothelial cell injury and are correlated with the occurrence of blood clots, which in turn may lead to atherogenesis. Hcy is a possible risk factor for coronary artery disease (42). Ilkhanizadeh et al (43) demonstrated that ginger extract may significantly reduce cardiac structural abnormalities in diabetic rats, and these effects were associated with improvements in serum apolipoprotein, leptin, cathepsin G and Hcy levels. The present results suggested that Hcy reduced relaxation, whereas GCE significantly prevented Hcy-induced endothelial dysfunction.
ROS are well-known mediators of vascular damage. H2O2 induces contraction in isolated canine basilar arteries (44). The present study revealed that GCE improved H2O2-induced endothelial cell injury, and possessed a stronger antioxidant ability to scavenge free radicals, compared with GNE and GWE. Dugasani et al (14) demonstrated that [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol exhibited substantial scavenging activities with half maximal inhibitory concentration (IC50) values of 26.3, 19.47, 10.47 and 8.05 µM against DPPH radical, IC50 values of 4.05, 2.5, 1.68 and 0.85 µM against super-oxide radical and IC50 values of 4.62, 1.97, 1.35 and 0.72 µM against hydroxyl radical, respectively. 6-Shogaol exhibited the most potent antioxidant and anti-inflammatory properties. In addition, elevated Hcy levels in the blood are associated with atherogenesis. It has been reported that Hcy increases the mRNA expression levels of eNOS and upregulates iNOS expression, thus resulting in COX-2 production, which eventually leads to the inflammatory response (45,46). The present study examined the effects of ginger extracts on Hcy-induced endothelial cell damage and on the protein expression levels of eNOS, iNOS and COX-2. Hcy increased eNOS, iNOS and COX-2 expression, whereas GCE markedly reduced eNOS, iNOS and COX-2 expression in the presence of Hcy (Fig. 13). These results indicated that GCE may exert a strong vasoprotective effect.
In conclusion, the present study is the first, to the best of our knowledge, to demonstrate that GCE may induce relaxant and vasoprotective effects on porcine coronary arteries, and may possess free radical-scavenging activities. Therefore, GCE may be considered a potential cardioprotective factor in the context of human diseases.
Notes
[1] Competing interests
The authors declare that they have no competing interests.
References
|
Ministry of Health and Welfare, Republic of China (Taiwan). https://www.mohw.gov.tw/cp-3425-33347-2.html. 2017 | |
|
Li H, Sun K, Zhao R, Hu J, Hao Z, Wang F, Lu Y, Liu F and Zhang Y: Inflammatory biomarkers of coronary heart disease. Front Biosci (Schol Ed). 10:185–196. 2018. View Article : Google Scholar | |
|
Antonopoulos AS, Papanikolaou E, Vogiatzi G, Oikonomou E and Tousoulis D: Anti-inflammatory agents in peripheral arterial disease. Curr Opin Pharmacol. 39:1–8. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Salvo F, Bezin J, Bosco-Levy P, Letinier L, Blin P, Pariente A and Moore N: Pharmacological treatments of cardiovascular diseases: Evidence from real-life studies. Pharmacol Res. 118:43–52. 2017. View Article : Google Scholar | |
|
Brown AC: An overview of herb and dietary supplement efficacy, safety and government regulations in the United States with suggested improvements. Part 1 of 5 series. Food Chem Toxicol. 107:449–471. 2017. View Article : Google Scholar | |
|
Aggarwal M, Aggarwal B and Rao J: Integrative medicine for cardiovascular disease and prevention. Med Clin North Am. 101:895–923. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Shukla Y and Singh M: Cancer preventive properties of ginger: a brief review. Food Chem Toxicol. 45:683–690. 2007. View Article : Google Scholar | |
|
Baliga MS, Haniadka R, Pereira MM, Thilakchand KR, Rao S and Arora R: Radioprotective effects of Zingiber officinale Roscoe (ginger): past, present and future. Food Funct. 3:714–723. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Borrelli F, Capasso R, Aviello G, Pittler MH and Izzo AA: Effectiveness and safety of ginger in the treatment of pregnancy-induced nausea and vomiting. Obstet Gynecol. 105:849–856. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Ghayur MN, Gilani AH, Afridi MB and Houghton PJ: Cardio-vascular effects of ginger aqueous extract and its phenolic constituents are mediated through multiple pathways. Vascul Pharmacol. 43:234–241. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Connell DW and McLachla R: Natural pungent compounds: IV. Examination of the gingerols, shogaols, paradols and related compounds by thin-layer and gas chromatography. J Chromatogr A. 67:29–35. 1972. View Article : Google Scholar | |
|
Jolad SD, Lantz RC, Chen GJ, Bates RB and Timmermann BN: Commercially processed dry ginger (Zingiber officinale): composition and effects on LPS-stimulated PGE2 production. Phytochemistry. 66:1614–1635. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Macleod AJ and Pieris NM: Volatile aroma constituents of Sri Lankan ginger. Phytochemistry. 23:353–359. 1984. View Article : Google Scholar | |
|
Dugasani S, Pichika MR, Nadarajah VD, Balijepalli MK, Tandra S and Korlakunta JN: Comparative antioxidant and anti-inflammatory effects of [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol. J Ethnopharmacol. 127:515–520. 2010. View Article : Google Scholar | |
|
Mashhadi NS, Ghiasvand R, Askari G, Hariri M, Darvishi L and Mofid MR: Anti-oxidative and anti-inflammatory effects of ginger in health and physical activity: review of current evidence. Int J Prev Med. 4(Suppl 1): S36–S42. 2013.PubMed/NCBI | |
|
Weng CJ, Chou CP, Ho CT and Yen GC: Molecular mechanism inhibiting human hepatocarcinoma cell invasion by 6-shogaol and 6-gingerol. Mol Nutr Food Res. 56:1304–1314. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Shao Y, Yu Y, Li C, Yu J, Zong RR and Pei CG: Synergistic effect of quercetin and 6-gingerol treatment in streptozotocin induced type 2 diabetic rats and poloxamer P-407 induced hyperlipidemia. Rsc Adv. 6:12235–12242. 2016. View Article : Google Scholar | |
|
Ok S and Jeong WS: Optimization of extraction conditions for the 6-shogaol-rich extract from ginger (Zingiber officinale Roscoe). Prev Nutr Food Sci. 17:166–171. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Chang LC and Yu YL: Dietary components as epigenetic-regulating agents against cancer. Biomedicine (Taipei). 6:22016. View Article : Google Scholar | |
|
Gilani AH, Mandukhail SU, Iqbal J, Yasinzai M, Aziz N, Khan A and Najeeb-ur-Rehman: Antispasmodic and vasodilator activities of Morinda citrifolia root extract are mediated through blockade of voltage dependent calcium channels. BMC Complement Altern Med. 10:22010. View Article : Google Scholar : PubMed/NCBI | |
|
Sakanashi M, Matsuzaki T and Aniya Y: Nitroglycerin relaxes coronary artery of the pig with no change in glutathione content or glutathione S-transferase activity. Br J Pharmacol. 103:1905–1908. 1991. View Article : Google Scholar : PubMed/NCBI | |
|
Sun B, Wang W and Salvaterra PM: Functional analysis and tissue-specific expression of Drosophila Na+, K+-ATPase subunits. J Neurochem. 71:142–151. 1998. View Article : Google Scholar : PubMed/NCBI | |
|
Cohen RA, Plane F, Najibi S, Huk I, Malinski T and Garland CJ: Nitric oxide is the mediator of both endothelium-dependent relaxation and hyperpolarization of the rabbit carotid artery. Proc Natl Acad Sci USA. 94:4193–4198. 1997. View Article : Google Scholar : PubMed/NCBI | |
|
Lu CC, Yang SH, Hsia SM, Wu CH and Yen GC: Inhibitory effects of Phyllanthus emblica L. on hepatic steatosis and liver fibrosis in vitro. J Funct Foods. 20:20–30. 2016. View Article : Google Scholar | |
|
Lee CF, Yang JS, Tsai FJ, Chiang NN, Lu CC, Huang YS, Chen C and Chen FA: Kaempferol induces ATM/p53-mediated death receptor and mitochondrial apoptosis in human umbilical vein endothelial cells. Int J Oncol. 48:2007–2014. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Randriamboavonjy V, Busse R and Fleming I: 20-HETE-induced contraction of small coronary arteries depends on the activation of Rho-kinase. Hypertension. 41:801–806. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Randriamboavonjy V, Kiss L, Falck JR, Busse R and Fleming I: The synthesis of 20-HETE in small porcine coronary arteries antagonizes EDHF-mediated relaxation. Cardiovasc Res. 65:487–494. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Tomiyama H and Yamashina A: Beta-blockers in the management of hypertension and/or chronic kidney disease. Int J Hypertens. 2014:9192562014. View Article : Google Scholar : PubMed/NCBI | |
|
Gupta S and Wright HM: Nebivolol: a highly selective beta1-adrenergic receptor blocker that causes vasodilation by increasing nitric oxide. Cardiovasc Ther. 26:189–202. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Flagg TP, Enkvetchakul D, Koster JC and Nichols CG: Muscle KATP channels: recent insights to energy sensing and myoprotection. Physiol Rev. 90:799–829. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Quast U, Stephan D, Bieger S and Russ U: The impact of ATP-sensitive K+ channel subtype selectivity of insulin secretagogues for the coronary vasculature and the myocardium. Diabetes. 53(Suppl 3): S156–S164. 2004. View Article : Google Scholar | |
|
Drain P, Li L and Wang J: KATP channel inhibition by ATP requires distinct functional domains of the cytoplasmic C terminus of the pore-forming subunit. Proc Natl Acad Sci USA. 95:13953–13958. 1998. View Article : Google Scholar | |
|
Valavanidis A, Vlahogianni T, Dassenakis M and Scoullos M: Molecular biomarkers of oxidative stress in aquatic organisms in relation to toxic environmental pollutants. Ecotoxicol Environ Saf. 64:178–189. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Wang F, Zhao S, Li F, Zhang B, Qu Y, Sun T, Luo T and Li D: Investigation of antioxidant interactions between Radix Astragali and Cimicifuga foetida and identification of synergistic antioxidant compounds. PLoS One. 9:e872212014. View Article : Google Scholar : PubMed/NCBI | |
|
Padma VV: An overview of targeted cancer therapy. Biomedicine (Taipei). 5:192015. View Article : Google Scholar | |
|
Tesfamariam B and Halpern W: Endothelium-dependent and endothelium-independent vasodilation in resistance arteries from hypertensive rats. Hypertension. 11:440–444. 1988. View Article : Google Scholar : PubMed/NCBI | |
|
Nabel EG, Ganz P, Gordon JB, Alexander RW and Selwyn AP: Dilation of normal and constriction of atherosclerotic coronary arteries caused by the cold pressor test. Circulation. 77:43–52. 1988. View Article : Google Scholar : PubMed/NCBI | |
|
Jiang J, Zheng JP, Li Y, Gan Z, Jiang Y, Huang D, Li H, Liu Z and Ke Y: Differential contribution of endothelium-derived relaxing factors to vascular reactivity in conduit and resistance arteries from normotensive and hypertensive rats. Clin Exp Hypertens. 38:393–398. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Ghalayini IF: Nitric oxide-cyclic GMP pathway with some emphasis on cavernosal contractility. Int J Impot Res. 16:459–469. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Pratt PF, Rosolowsky M and Campbell WB: Mediators of arachidonic acid-induced relaxation of bovine coronary artery. Hypertension. 28:76–82. 1996. View Article : Google Scholar : PubMed/NCBI | |
|
Liu J, Seibold SA, Rieke CJ, Song I, Cukier RI and Smith WL: Prostaglandin endoperoxide H synthases: peroxidase hydro-peroxide specificity and cyclooxygenase activation. J Biol Chem. 282:18233–18244. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Steed MM and Tyagi SC: Mechanisms of cardiovascular remodeling in hyperhomocysteinemia. Antioxid Redox Signal. 15:1927–1943. 2011. View Article : Google Scholar : | |
|
Ilkhanizadeh B, Shirpoor A, Khadem Ansari MH, Nemati S and Rasmi Y: Protective Effects of ginger (Zingiber officinale) extract against diabetes-induced heart abnormality in rats. Diabetes Metab J. 40:46–53. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Mittal M, Siddiqui MR, Tran K, Reddy SP and Malik AB: Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal. 20:1126–1167. 2014. View Article : Google Scholar : | |
|
Förstermann U and Li H: Therapeutic effect of enhancing endothelial nitric oxide synthase (eNOS) expression and preventing eNOS uncoupling. Br J Pharmacol. 164:213–223. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Matsumoto T, Goulopoulou S, Taguchi K, Tostes RC and Kobayashi T: Constrictor prostanoids and uridine adenosine tetraphosphate: vascular mediators and therapeutic targets in hypertension and diabetes. Br J Pharmacol. 172:3980–4001. 2015. View Article : Google Scholar : PubMed/NCBI |
