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Effects of GABA supplementation on blood pressure and safety in adults with mild hypertension
Abstract
The purpose of this study is to evaluate the effects of γ-amino butyric acid (GABA) supplementation on blood pressure (BP) and safety in adults with mild hypertension. The optimal amount of daily GABA supplementation for reducing BP was first investigated in adults with systolic blood pressure (SBP) between 130 and 180mmHg. In the dose of 0, 20, 40 and 80mg of GABA per day, the significant BP reduction was observed with 80 mg. To study long-term effects of GABA on BP along with safety issues by oral treatment, an eight-week double-blind cross-over clinical trial was conducted. Fifty men and women were assigned at random by either GABA treatment or control group. The subjects took either four tablets of GABA (80mg) or placebo per day during the study period. Using home blood pressure (HBP) monitoring, SBP and diastolic blood pressure (DBP) were measured twice per day (morning and night). Clinic blood pressure (CBP) was also measured every two weeks. The major result of this study was that SBP and DBP measured in the morning were significantly reduced by 10 and 5mmHg (p < 0.05) compared to baseline BP in the GABA treatment group, and that of delta SBP and DBP between groups was significantly different (p < 0.05). SBP and DBP of CBP also reduced progressively with time. The physical examination revealed negative and there was no report on physical discomfort or laboratory data. The results of this study confirmed that daily supplementation of 80 mg of GABA reduces BP in adults with mild hypertension.
... Numerous studies have examined the effect of supplementation with GABA in dietary supplements or in functional foods (e.g., studies on GABA powder in capsules, added to rice, or produced naturally in fermented milk or fermented soy). Most of these studies examined the effect of GABA on mild hypertension [50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65]. In total, 16 studies were identified that investigated the effect of orally administered GABA as a supplement or in complex matrices (such as fermented milk and soy sauce) on high blood pressure, for relieving stress, or for enhancing sleep. ...
... Another study investigated tolerability of GABA supplementation in mildly hypertensive but otherwise healthy adults [61]. The authors first established an optimum dose in mildly hypertensive subjects (SBP between 130 and 180 mm Hg) who were randomized to receive oral doses of GABA at 0 (placebo), 20, 40, or 80 mg/day for 4 weeks. ...
... A subsequent study evaluated long-term effects of GABA at 80 mg daily versus placebo in mildly hypertensive subjects for 8 weeks. At the end of the 8-week study, SBP and DBP were on average 5% lower (p < 0.05) in all the subjects who received 80 mg/day of GABA compared to participants in the placebo group whose BP levels remained above normal [61]. ...
Gamma-amino butyric acid (GABA) is marketed in the U.S. as a dietary supplement. USP conducted a comprehensive safety evaluation of GABA by assessing clinical studies, adverse event information, and toxicology data. Clinical studies investigated the effect of pure GABA as a dietary supplement or as a natural constituent of fermented milk or soy matrices. Data showed no serious adverse events associated with GABA at intakes up to 18 g/d for 4 days and in longer studies at intakes of 120 mg/d for 12 weeks. Some studies showed that GABA was associated with a transient and moderate drop in blood pressure (<10% change). No studies were available on effects of GABA during pregnancy and lactation, and no case reports or spontaneous adverse events associated with GABA were found. Chronic administration of GABA to rats and dogs at doses up to 1 g/kg/day showed no signs of toxicity. Because some studies showed that GABA was associated with decreases in blood pressure, it is conceivable that concurrent use of GABA with anti-hypertensive medications could increase risk of hypotension. Caution is advised for pregnant and lactating women since GABA can affect neurotransmitters and the endocrine system, i.e., increases in growth hormone and prolactin levels.
... The eggplant powder used in the clinical trial contained GABA in addition to ACh. The daily GABA intake in this clinical trial was 7.65 mg [15], which is lower than the previously reported effective dose of 10 mg [7], although GABA may have been regarded to be a common antihypertensive compound in lower effective dosages [7,16,17]. On the basis of these findings, we assume ACh to be the major antihypertensive factor in eggplant powder. However, we have yet to sufficiently establish the role of GABA in the antihypertensive effect of eggplant consumption, i.e., whether GABA acts synergistically with ACh or whether the GABA content in eggplant is unassociated with the hypotensive effect. ...
... In clinical trials, the effective doses of GABA for lowering blood pressure have been found to range from 10 to 80 mg/day [7,16,17], whereas tranquilizer-like effects have been observed at concentrations between 26.4 and 70 mg/day [31][32][33]. Furthermore, the recommended daily intake of GABA in several dietary supplements worldwide is 100 mg, consumed in divided doses [34]. ...
Daily consumption of eggplant powder containing 2.3 mg acetylcholine (ACh) is known to alleviate hypertension and improve mental status. However, eggplant powder used in clinical trials also contains the antihypertensive compound γ-aminobutyric acid (GABA). Although our previous study indicated that the main antihypertensive compound in eggplant is ACh, given that GABA amounts in eggplant do not reach the effective dosage, the effects of GABA on the antihypertensive effect of eggplant remain unclear. It is necessary to establish whether there is a synergistic effect between GABA and ACh and whether GABA in eggplant exerts antihypertensive effects. Consequently, here we sought to evaluate the effects of GABA on the antihypertensive effects of eggplant. We used a probability sum (q) test to investigate the combined effects of ACh and GABA and prepared eggplant powder with very low ACh content for oral administration in animals. ACh and GABA exhibited additive effects but the GABA content in eggplants was not sufficient to promote a hypotensive effect. In conclusion, ACh is the main component associated with the antihypertensive effects of eggplant but GABA within eggplants has a minimal effect in this regard. Thus, compared with GABA, ACh could be a more effective functional food constituent for lowering blood pressure.
... Although in Europe, GABA does not have any authorized nutrition or health claims by EFSA, evidence of beneficial physiological effects of GABA, are present in the literature (Inoue et al., 2003;Matsubara et al., 2002). Its oral administration elevates GABA levels in blood but is believed to metabolize quickly and it is still unclear if it can cross the blood-brain barrier (Boonstra et al., 2015). ...
... Hypothetically, this means that 100 g of the GABA-enriched bread obtained in this study, equaling circa 14 mg of GABA intake, could have similar effects. Analogous results to those obtained by Inoue et al. (2003) were also shown by Matsubara et al. (2002) but with higher GABA doses (80 mg). In our study, although even higher GABA content in bread could have been obtained by increasing the percentage of slurry added, the supplementation was kept relatively low at 10% to avoid strong repercussions on bread quality. ...
Aims:
The aim of this study was to investigate the effectiveness of bread as substrate for γ-aminobutyric acid (GABA) biosynthesis, establishing a valorization strategy for surplus bread, repurposing it within the food chain.
Methods and results:
Surplus bread was fermented by lactic acid bacteria (LAB) to produce GABA. Pediococcus pentosaceus F01, Levilactobacillus brevis MRS4, Lactiplantibacillus plantarum H64 and C48 were selected among 33 LAB strains for the ability to synthesize GABA. Four fermentation experiments were set-up using surplus bread as such, added of amylolytic and proteolytic enzymes, modifying the pH or mixed with wheat bran. Enzyme treated slurries led to the release of glucose (up to 20 mg g-1 ) and free amino acid, whereas the addition of wheat bran (30% of bread weight) yielded the highest GABA content (circa 800 mg kg-1 of dry weight) and was the most suitable substrate for LAB growth. The selected slurry was ultimately used as ingredient in bread making causing an increase of free amino acids.
Conclusions:
Besides the high GABA concentration (148 mg kg-1 dough), the experimental bread developed in this study was characterized by good nutritional properties, highlighting the efficacy of tailored bioprocessing technologies as means to mitigate food wastage.
Significance and impact of study:
Our results represent a proof of concept of effective strategies to repurpose food industry side streams.
... Neurotransmission Inhibitory neurotransmitter Battaglioli et al., 2003;DeFeudis,1981 Blood pressure regulator Potent hypotensive agent Abe et al., 1995;Aoki et al., 2003;Hayakawa et al., 2004;Inoue et al., 2003;Joye et al., 2011;Kajimoto et al., 2004;Matsubara et al., 2002;Noguchi et al., 2007;Pouliot-Mathieu et al., 2013;Sasaki et al., 1996;Shimada et al., 2009;Tsai et al., 2013;Yamakoshi et al., 2007;Yang et al., 2012;Yoshimura et al., 2010;Wang et al., 2010;Watanabe et al., 2003 Brain diseases Action on neurological disorders Okada et al., 2000;Seidl et al., 2001;Wong et al., 2003;Streeter et and a red algae extract (Porphyra) significantly lowered BP in the same kind of rats (Umekawa et al., 2008). A single administration of GABA-enriched potato snack (1.7 mg/kg BW) reduced blood pressure in a dose-dependent way in rats with normal blood pressure (Noguchi, Nakamura, Nagai, Katsuda, & Koga, 2007), and a recent article reported that a dose of purple sweet potato fermented milk had an antihypertensive effect in SHR (Tsai, Chiu, Ho, Lin, & Wu, 2013). ...
... Moreover, a mushroom species (Agaricus blazei) with enhanced levels of GABA had an antihypertensive effect on mild hypertensive human subjects (Watanabe et al., 2003). Dietary supplementation of 80 mg of GABA also reduced BP in adults with mild hypertension (Matsubara et al., 2002). Other authors suggested that the daily consumption of one portion (30 g) of GABA-enriched breakfast cereals lowered BP (ca. 10 mg) (Joye, Lamberts, Brijs, & Delcour, 2011). ...
Gamma-aminobutyric acid (GABA) is a non-protein amino acid, considered a potent bioactive compound. GABA has been widely studied because of its numerous physiological functions and positive effects on many metabolic disorders. One the most important of these is the hypotensive effect that has been demonstrated in animals and in human intervention trials. The biosynthesis of GABA and its optimization, without affecting sensory characteristics, are the key in obtaining GABA-enriched food products that have health benefits. Lactic acid bacteria (LAB) are the main GABA-producers and therefore there are a wide range of GABA-enriched fermented food products, in which GABA is natural, safe and eco-friendly. Increasing knowledge of bioactive components in food has opened avenues for the development of new, naturally occurring functional food with added value for health.
... It was previously reported that 80 mg of GABA is necessary for an adult person per day. 22) About 40 g pickles are enough to obtain such amounts of GABA. ...
... Based on the assumption that an adult person (60 kg) needs 80 mg of GABA per day, 22) the uptake of GABA for SHR-rats and DIS-rats was 83-fold and 80-fold higher than the calculated values, respectively (GABA content in the sample: 10 mg/g). In addition, based on the assumption that an adult needs 37.5 mg of Captopril per day (http://www.nihon-generic.co.jp/), the uptakes of ACE-inhibitory peptide for SHR-rats and DIS-rats were 9.9 and 9.4% of the calculated values, respectively (ACE-inhibitory peptide content in the sample: 5.83 μg/g). ...
Addition of γ-aminobutyric acid (GABA) and angiotensin converting enzyme (ACE)-inhibitory peptides to the pickles was studied in order to develop a new type of pickles that reduce blood pressure. Based on the outcome of these studies, a new type of fermentation bed composed of rice bran and white miso has been successfully developed. The advantage of such pickles is that they not only contain both GABA and ACE-inhibitory peptides, but also that their taste and flavor are excellent, with colors close to the original ones. The new type of pickles could temporarily reduce blood pressure in two types of rats, spontaneously hypertensive rats and NaCl-sensitive model rats. Thus, the newly developed pickles appear to be beneficial for pickle business.
... It has been proposed that impaired liver GABA clearance may suppress normal neuronal activity and cause hypotension (Minuk 1993 ). This hypothesis may be true because studies have shown that the oral intake of GABA or GABA foods significantly decreases blood pressure in individuals with hypertension (Matsubara et al. 2002 ;Aoki et al. 2003 ;Inoue et al. 2003 ;Shimada et al. 2009 ). Stud-ies have demonstrated that peripheral GABA can transmit signals to the brain and interfere with neuronal activity. ...
Aminobutyric acid (GABA) transaminase (GABA-T) is a GABA-degrading enzyme that plays an essential role in regulating GABA levels and maintaining supplies of GABA. Although GABA in the mammalian brain was discovered 70 years ago, research on GABA and GABA-T has predominantly focused on the brain. Notwithstanding the high activity and expression of GABA-T in the liver, the exact functions of GABA-T in the liver remain unknown. This article reviews the up-to-date information on GABA-T in the liver. It presents recent findings on the role of liver GABA-T in food intake suppression and appetite regulation. Finally, the potential functions of liver GABA-T in other neurological diseases, natural GABA-T inhibitors, and future perspectives in this research area are discussed.
... Higher blood arginine levels resulted in higher NO and lower BP [103]. In addition, the antihypertensive effects of GABA-rich Chlorella may be related to vasodilatory action, inhibitory effects on peripheral sympathetic nerve by reducing noradrenaline release and total vascular resistance and maybe inhibitory effects on angiotensin-I converting enzyme (ACE) of GABA [112][113][114][115]. The CV contains magnesium, vitamin C, vitamin E, dietary fiber, alpha and beta carotene, selenium, some peptides with particular sequences and BCAAs, which have antihypertensive effects separately or together [103,107]. ...
High incidence rate of cardiovascular disease (CVD) make this condition as an important public health concern. The use of natural products in treating this chronic condition has increased in recent years one of which is the single-celled green alga Chlorella. Chlorella vulgaris (CV) has been studied for its potential benefits to human health due to its biological and pharmacological features. CV contains a variety of macro and micronutrients, including proteins, omega-3, polysaccharides, vitamins, and minerals. Some studies have indicated that taking CV as a dietary supplement can help reduce inflammation and oxidative stress. In some studies, cardiovascular risk factors that are based on hematological indices did not show these benefits, and no molecular mechanisms have been identified. This comprehensive review summarized the research on the cardio-protective benefits of chlorella supplementation and the underlying molecular processes.
... GABA has been reported to lower the blood pressure of hypertensive patients but not of normotensive individuals [168]. Daily supplementation of 80 mg of GABA has been found to reduce blood pressure in adults with mild hypertension [215]. A study carried out in 2008 analysed tomato varieties and found that they had an average GABA content of 50.3 mg/100 g fresh weight [216]. ...
This review outlines the health benefits associated with the regular consumption of tomatoes and tomato products. The first section provides a detailed account of the horticultural techniques that can impact the quality of the fruit and its nutritional properties, including water availability, light intensity, temperature, and growing media. The next section provides information on the components of tomato that are likely to contribute to its health effects. The review then details some of the health benefits associated with tomato consumption, including anticancer properties, cardiovascular and neurodegenerative diseases and skin health. This review also discusses the impact tomatoes can have on the gut microbiome and associated health benefits, including reducing the risk of inflammatory bowel diseases. Other health benefits of eating tomatoes are also discussed in relation to effects on diabetes, the immune response, exercise recovery, and fertility. Finally, this review also addresses the negative effects that can occur as a result of overconsumption of tomato products and lycopene supplements.
... In another study of blood pressure (BP) control with GABA, subjects took 80 mg of GABA daily and saw that systolic BP and diastolic BP measured in the morning were significantly reduced by 10 and 5 mmHg (p < 0.05) compared to baseline BP in the GABA treatment group [68]. GABA is also diuretic [69]. ...
Aging is associated with a decline in hormones and an associated decline in GABAergic function and calcium and ion current dysregulation. Neurosteroid hormones act as direct calcium channel blockers, or they can act indirectly on calcium channels through their interaction with GABA receptors. The calcium channel dysfunction associated with hormone loss further leads to an excitatory cell state, which can ultimately lead to cell death. The calcium theory of aging posits that cellular mechanisms, which maintain the homeostasis of cytosol Ca2+ concentration, play a key role in brain aging and that sustained changes in Ca2+ homeostasis provide the final common pathway for age-associated brain changes. There is a link between hormone loss and calcium dysregulation. Loss of calcium regulation associated with aging can lead to an excitatory cell state, primarily in the mitochondria and nerve cells, which can ultimately lead to cell death if not kept in check. A decline in GABAergic function can also be specifically tied to declines in progesterone, allopregnanolone, and DHEA levels associated with aging. This decline in GABAergic function associated with hormone loss ultimately affects GABAergic inhibition or excitement and calcium regulation throughout the body. In addition, declines in GABAergic function can also be tied to vitamin status and to toxic chemicals in the food supply. The decline in GABAergic function associated with aging has an effect on just about every body organ system. Nutritional support of the GABAergic system with supportive foods, vitamins, and GABA or similar GABA receptor ligands may address some of the GABAergic dysfunction associated with aging.
... Indeed, a single oral administration (0.5 mg/kg) significantly lowered the systolic blood pressure in spontaneously hypertensive rats, suggesting that GABA has an antihypertensive effect due to its inhibition of noradrenaline release from sympathetic nerves in the mesenteric arterial bed via presynaptic GABA B receptors [142]. A human study revealed that a daily supplementation of 80 mg of GABA reduces blood pressure in adults with mild hypertension [143]. The content of GABA in cereal vinegar is relatively low in order to fulfill the demand for such high supplementation. ...
Vinegar has been used for its health promoting properties since antiquity. Nowadays, these properties are investigated, scientifically documented, and highlighted. The health benefits of vinegar have been associated with the presence of a variety of bioactive components such as acetic acid and other organic acids, phenolic compounds, amino acids, carotenoids, phytosterols, vitamins, minerals, and alkaloids, etc. These components are known to induce responses in the human body, such as antioxidant, antidiabetic, antimicrobial, antitumor, antiobesity, antihypertensive, and anti-inflammatory effects. The diversity and levels of bioactive components in vinegars depend on the raw material and the production method used. Cereal vinegars, which are more common in the Asia-Pacific region, are usually made from rice, although other cereals, such as millet, sorghum, barley, malt, wheat, corn, rye, oats, bran and chaff, are also used. A variety of bioactive components, such as organic acids, polyphenols, amino acids, vitamins, minerals, alkaloids, melanoidins, butenolides, and specific compounds such as γ-oryzanol, tetramethylpyrazine, γ-aminobutyric acid, etc., have been associated with the health properties of cereal vinegars. In this work, the bioactive components and the related health effects of cereal vinegars are reviewed, and the most recent scientific literature is presented and discussed.
... Интрадуоденальное введение от 0,3 до 300 мг/кг ГАМК вызывало дозозависимое снижение АД через 30-50 мин [26]. В клиническом исследовании ежедневное потребление 80 мг ГАМК эффективно снижало АД у взрослых с легкой степенью артериальной гипертензии [27]. В рандомизированном двойном слепом плацебо-контролируемом исследовании употребление обогащенного ГАМК риса стабилизировало утреннее АД по сравнению с плацебо уже через 1 нед и в последующие 6-8 нед [28]. ...
The review sets out modern ideas about the mechanisms of action of gamma-aminobutyric acid (GABA) in the central nervous system and other organs and systems. Current experimental and clinical studies have shown that GABA has numerous effects: neuroprotective, antihypertensive, antidiabetic, antitumor, anti-inflammatory, antimicrobial, anti-allergic, hepatoprotective, nephroprotective and enteroprotective, and others, which are currently the subject for study by biologists, physiologists, and physicians. Synthetic GABA analogues are widely used in clinical practice. One of these drugs is aminophenylbutyric acid hydrochloride (Anvifen®) that has demonstrated high efficiency and safety in clinical practice.
... Moreover, the lowering effect of Gaba-enriched dairy product on the blood pressure of spontaneously hypertensive and normotensive Wistar-Kyoto rats was also determined [36]. Notably, the clinical trial has confirmed that daily supplementation of 80 mg of Gaba was effective in the reduction of blood pressure in adults with mild hypertension [37]. Therefore, the consumption of Gaba-enriched dairy product would be beneficial for the down-regulation of hypertension. ...
Gamma-aminobutyric acid (Gaba) is a non-proteinogenic amino acid that is widely present in microorganisms, plants, and vertebrates. So far, Gaba is well known as a main inhibitory neurotransmitter in the central nervous system. Its physiological roles are related to the modulation of synaptic transmission, the promotion of neuronal development and relaxation, and the prevention of sleeplessness and depression. Besides, various pharmaceutical properties of Gaba on non-neuronal peripheral tissues and organs were also reported due to anti-hypertension, anti-diabetes, anti-cancer, antioxidant, anti-inflammation, anti-microbial, anti-allergy, hepato-protection, reno-protection, and intestinal protection. Therefore, Gaba may be considered as potential alternative therapeutics for prevention and treatment of various diseases. Accordingly, this updated review was mainly focused to describe the pharmaceutical properties of Gaba as well as emphasize its important role regarding human health.
... This is the first demonstration that orally administrated GABA can lower serum IgE levels. Recently, GABA has been attracting attention as a food ingredient with functions such as improvement of memory and study capability, blood pressure-lowering action (Hayakawa et al. 2002, Matsubara et al. 2002), renoprotective effect and relaxation (Lyou and Yokogoshi 2004). Besides these biological functions, GABA may have anti-allergic activities. ...
γ-aminobutyric acid (GABA) is a kind of amino acid and has been received much attention for their biological activities. In the present study, we examined the influence of GABA on immunomodulatory activities and serum IgE levels, employing ovalbumin (OVA)-immunized BALB/c mice. In cytokine production assay in vitro, GABA showed increased IFN-γ production concomitant with decreased IL-4 production by splenocytes from OVA-immunized BALB/c mice. When administrated orally, GABA was effective for decreasing both total and OVA-specific IgE levels in serum. In addition, these decreased IgE levels by administrated GABA were paralleled with increased IFN-γ production and decreased IL-4 production in splenocytes ex vivo. It seems that GABA can potentially suppress Th2 responses including IL-4 production via promoting Th1-skewed response in vivo, leading to down-regulation of IgE synthesis. These results suggest that GABA might be useful for preventing IgE-mediated allergic diseases. γ-アミノ酪酸（GABA）は，食品に含まれる機能性成分として注目されている。本研究では，オバルブミン（OVA）感作したBALB/cマウスに対するGABAの免疫制御活性について調べ，経口投与による血清IgEレベルの抑制作用について検討した。in vitro培養試験において，GABAはマウス脾細胞のインターフェロン-γ（IFN-γ）の産生を促進すると同時にインターロイキン-4（IL-4）の産生を抑制した。GABAを経口投与した結果，OVA感作BALB/cマウスにおける総IgE及びOVA特異的IgEの血清レベルが有意に低下した。さらに，ex vivo培養試験において，GABAを経口投与したマウスの脾細胞ではOVA誘導性のIFN-γ産生促進とIL-4産生抑制が認められた。GABAは，Th1の誘導を介してIL-4産生を始めとしたTh2応答を抑制し，IgE産生を抑制する可能性がある。以上の結果から，GABAはIgEが関与するアレルギー疾患の予防に有用であることが示唆される。
γ-Aminobutyric acid (GABA) was widely present in many legumes. Soybean GABA was present in fully mature stages, but productions also occurred during both the germinating and the grain embryo stages. Soybean GABA was produced in both immature legumes pod shells and seeds. Soybean GABA and glutamate may be produced in pod shells in early embryo stage and accumulated in seed during the late embryo stage. Soybean GABA was produced in immature legumes pod shells, possibly because of germination and / or reductive enzymatic conditions. Comparisons of chemical properties of the GABA contents between germinated and immature soybean reveled an optimum temperature difference for GABA production of 20℃. The optimum pH for the germinated soybean slurry was similarly pH 6, but the immature soybean slurry was stable at a wider pH range. These results may indicate that two different GAD isomers existed during soybean growth.
Excessive salt intake induces hypertension, but several gamma-aminobutyric acid (GABA) supplements have been shown to reduce blood pressure. GABAsalt, a fermented salt by L. brevis BJ20 containing GABA was prepared through the post-fermentation with refined salt and the fermented GABA extract. We evaluated the effect of GABA-salt on hypertension in a high salt, high cholesterol diet induced mouse model. We analyzed type 1 macrophage (M1) polarization, the expression of M1 related cytokines, GABA receptor expression, endothelial cell (EC) dysfunction, vascular smooth muscle cell (VSMC) proliferation, and medial thicknesses in mice model. GABA-salt attenuated diet-induced blood pressure increases, M1 polarization, and TNF-α and inducible nitric oxide synthase (NOS) levels in mouse aortas, and in salt treated macrophages in vitro. Furthermore, GABA-salt induced higher GABAB receptor and endothelial NOS (eNOS) and eNOS phosphorylation levels than those observed in salt treated ECs. In addition, GABA-salt attenuated EC dysfunction by decreasing the levels of adhesion molecules (E-selectin, Intercellular Adhesion Molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]) and of von Willebrand Factor and reduced EC death. GABA-salt also reduced diet-induced reductions in the levels of eNOS, phosphorylated eNOS, VSMC proliferation and medial thickening in mouse aortic tissues, and attenuated Endothelin-1 levels in salt treated VSMCs. In summary, GABA-salt reduced high salt, high cholesterol diet induced hypertension in our mouse model by reducing M1 polarization, EC dysfunction, and VSMC proliferation.
An automated sequential injection (SI) with second order light scattering (SOS) detection for determination of gamma-aminobutyric acid (GABA) was developed. Quantitation is based on electrostatic interaction between GABA and citrate-capped silver nanoparticles (AgNPs). In acetate buffer at pH 3.8, the positively charged GABA induces the nanoparticles to aggregate. This results in a change of light scattering monitored using a spectrofluorometer. In this work, working standard solutions of GABA were prepared in-line by the SI system pumping appropriate volumes of a stock solution of GABA and acetate buffer into a holding coil. Solution of AgNPs was subsequently drawn into the coil. The reaction zone was then transferred to the spectrofluorometer, set with excitation and detection wavelengths at 300 and 600 nm, respectively. Under optimised condition, the SOS intensity was proportional to the concentration of GABA. As a result, a linear curve was obtained in the range of 100–400 mg L−1 GABA, with a lower limit of detection of 39.6 mg L‐1. Good precision of analysis was achieved, with 0.6 and 3.3% relative standard deviation (RSD) for external calibration (n = 5) and standard addition (n = 3), respectively. The developed method was successfully applied for quantification of GABA in dietary supplements (2 samples) and samples of instant green tea (2 samples).
Hypotensive effects and safety of γ-amino butyric acid (GABA) supplementation were examined in a randomized, double-blind, placebo-controlled, parallel group study. The subjects were adult males and females with high normal blood pressure and mild hypertension, who were not taking hypotensive medicine. Test food or placebo was given one time a day for 12 weeks. The results revealed that the systolic blood pressure (SBP) and diastolic blood pressure (DBF) were significantly reduced after 8 weeks of feeding in the test group, although no changes in blood pressure were observed during the trial in the placebo group. Between the two groups, there were significant difference in SBP at 10 and 12 weeks and DBP at 8, 10 and 12 weeks during the trial. And in case of stratified analysis on high normal blood pressure and mild hypertensive subjects, those results were at the same level as all subjects. No significant abnormal changes were observed in results of blood examination, urinalysis and physical examination. Adverse reactions, such as digestive tract symptoms, and dry coughing were not observed, but cold, anthema, pruritus, diarrhea, loose passage was observed by the intake of the test food. However, we estimated no correlation between the test food and symptoms because these findings were similarly observed by placebo group and also resolved in the course of a few days. Thus, these results demonstrated the benefits and safety of GABA supplementation in subjects with high normal blood pressure and mild hypertension.
We studied a method for producing high concentrations of γ-aminobutyric acid(GABA) in pumpkin tissue using freeze-thaw infusion. We introduced L-glutamic acid monosodium salt (MSG) into pumpkins by freeze thaw infusion, and observed that high concentrations of GABA were produced due to the action of the glutamate decarboxylase present in the pumpkins. For an enzyme reaction at 3°C, the amount of GABA peaked when the MSG concentration was 1% (w/w) and enzyme reaction time was about 48 h. When a softening enzyme (Macerozyme 2A) was added together with MSG and infusion was performed, a soft pumpkin that contained GABA at high concentrations was obtained. By freeze-thawing with MSG, it is now possible to manufacture functional foods that have two added values, i.e., in addition to enrichment of GABA, their hardness can also be adjusted.
We previously reported that gamma aminobutyric acid (GABA) was contained in potato and potato snacks. In addition, it is well known that potato contains abundant amounts of potassium. It is therefore expected that potato containing GABA and potassium will have a reductive effect on blood pressure. In this study, the effects of a single oral administration of potato snacks on blood pressure (BP) in spontaneously hypertensive rats (SHR) and normal-blood-pressure rats (WIST) were investigated. The concentrations of plasma GABA and GABA contained in potato snacks were measured by HPLC, and blood pressure was measured by the tail-cuff method. After 30 minutes, plasma GABA concentration was transiently increased in GABA-enriched potato snacks as well as GABA standard solution. Moreover, 4-8 hours after administration of certain types of snack product made mainly from potato (placed on the market), a significant lowering of SBP and DBP was observed in SHR, but no effects were observed in WIST. In contrast, a product made mainly from wheat flour (not containing GABA) had no influence on BP. Furthermore, ingestion of GABA-enriched potato snacks (1.7 mg/kg b.w.) resulted in a reduction in SBP to about 35mmHg. These results show that GABA from potato snacks is absorbed and may be detected in plasma, and has a dose-related reductive effect on BP.
Previously, we reported that potato tubers and common potato snack products contain GABA, and oral administration of certain types of potato snack products currently on the market reduced blood pressure in spontaneously hypertensive rats. In this study, we examined methods to increase the GABA content of "TOYOSHIRO" potato tubers, as measured by HPLC. Treatments used to increase GABA levels were sprouting, anoxic conditions (nitrogen displacement, soaking in various solutions), freezing and GABA substrate coenzyme addition. Sprouting treatment increased GABA levels by approximately 1.3 times. In the anoxic conditions, GABA increased over three times after three days exposure to a nitrogen atmosphere, during which time glutamic acid in the tubers was converted into GABA, but only about two times after soaking in various solutions (water, salt solution, citrate solution, ethanol) for two days. GABA levels increased 3 times after freezing treatment, 2 times by trituration treatment at 35°C, and over 3 times by co-treatment with glutamic acid, a substrate of GABA, and coenzyme pyridoxal 5′-phosphoric acid. These results indicate that GABA content of potato tubers was increased 2-3 times by several anoxic conditions, freezing, and trituration treatment.
The purposes of this research were to use fig protease for texture tenderizing, and to inhibit angiotensin I-converting enzyme (ACE) action and gamma-aminobutyric acid (GABA) formation of meat. Liberated peptides by the enzymatic action of fig protease in processing meat and free amino acids were determined and ACE inhibitory activity was assayed. Meat treated with fig protease became tender as indicated by shear force value (SFV) which was half of those of non-fig treated meat during storage even at 5 degrees C. Liberated peptides, free amino acids and GABA increased while extremely low levels of Glu were detected after storage. The optimal temperature of fig protease against meat was 80 degrees C. However, the activity of fig protease decreased after pre-heating more than 40 degrees C. High ACE inhibitory activity of a mixture of fig and meat was found around 80 degrees C, and the value corresponded to the amount of liberated peptide. A lot of liberated peptides were found at 60-80 degrees C and pasterization of meat product becomes convenient to produce peptides. Production of ACE inhibitory peptides and GABA can be expected as the healthy functional meat product such as antihypertensive activity and improve brain function.
The anti-hypertensive effect of GABA-rich Chlorella was studied after oral administration for 12 weeks in the subjects with high-normal blood pressure and borderline hypertension in the placebo-controlled, double-blind manner in order to investigate if GABA-rich Chlorella, a dietary supplement, is useful in control of blood pressure. Eighty subjects with Systolic blood pressure (SBP) 130-159 mmHg or diastolic blood pressure (DBP) 85-99 mmHg (40 subjects/group) took the blinded substance of GABA-rich Chlorella (20 mg as gamma-aminobutyric acid) or placebo twice daily for 12 weeks, and had follow-up observation for an additional 4 weeks. Systolic blood pressure in the subjects given GABA-rich Chlorella significantly decreased compared with placebo (p < 0.01). Diastolic blood pressure had the tendency to decrease after intake of GABA-rich Chlorella. Neither adverse events nor abnormal laboratory findings were reported throughout the study period. Reduction of SBP in the subjects with borderline hypertension was higher than those in the subjects with high-normal blood pressure. These results suggest that GABA-rich Chlorella significantly decreased high-normal blood pressure and borderline hypertension, and is a beneficial dietary supplement for prevention of the development of hypertension.
The purpose of this study was to examine the effects of gamma-aminobutyric acid (GABA) in fermented drinking water prepared from sodium glutamate, vinegar, and dried bonito (FDWG) compared with placebo [vinegar and dried bonito without GABA (FDW)] and its safety in normotensive and mildly or moderately hypertensive volunteers. A double-blind, placebo-controlled, randomized study was conducted involving volunteers with normal (group-N) and mildly or moderately high (group-H) blood pressure (BP). After a pretreatment period of 2 weeks (weeks -2), the subjects received FDWG or FDW for 12 weeks followed by 4 weeks of no intake (weeks 16). In group-H, both FDWG and FDW significantly decreased systolic (SBP, -7.6 +/- 4.0 and -5.5 +/- 1.5 mmHg, p<0.05, respectively) and diastolic (DBP, -10.6 +/- 4.0 and -7.6 +/- 1.7 mmHg, p<0.01, respectively) BP compared to the baseline (0-week) value at 12 weeks, respectively. There were no abnormal changes in hematological or blood chemistry variables, urinalysis, heart rate, or body weight in the study groups. These findings indicated that vinegar and dried bonito with or without GABA might have an effect on BP in mildly or moderately hypertensive patients.
The effect of the GABA-agonist muscimol on ADH release induced in rats by administration of hypertonic sodium chloride solutions was studied by means of intracerebroventricular and intraperitoneal injections of the drug. Injected by the intracerebroventricular route, muscimol produced a significant reduction of plasma ADH concentration not only in animals treated with hypertonic sodium chloride, but also in unstimulated animals. Following intraperitoneal administration larger doses were required to produce such an effect, thus suggesting a central site of action for the effect of muscimol on ADH release. Bicuculline, given intraperitoneally before muscimol injection, completely blocked ADH inhibition induced by muscimol, thus suggesting a specific involvement of GABAergic receptors. These findings indicate that GABAergic mechanisms may be involved in the regulation of body fluids in the rat by affecting ADH release.
Intravenous administration of gamma aminobutyric acid (GABA) caused a dose-related (10–1000 βg/kg) hypotension and bradycardia in enflurane (Ethrane) anesthetized dogs. GABA also caused significant decreases in cardiac output, carotid artery blood flow, and in left and right ventricular stroke work indices. Pulmonary arterial and pulmonary wedge pressures were not affected. However, pulmonary vascular resistance was significantly increased after high doses of GABA. Muscimol (20 βg/kg, IV) produced effects similar to those caused by GABA. Blockade of GABA receptors with picrotoxin (1.5 mg/kg, IV) antagonized all effects of GABA and muscimol. Picrotoxin itself, as opposed to GABA, caused significant increases in mean arterial pressure, pulmonary arterial pressure, systemic vascular resistance, and pulmonary vascular resistance. Thus, it is suggested that blood-borne GABA or peripheral GABA-containing neurons may play a role in the control of blood pressure and other cardiopulmonary variables.
Although hypothyroidism (with concomitant increased levels of thyroid-stimulating hormone) has been associated with elevated
plasma vasopressin, the role that vasopressin plays in controlling thyroid-stimulating hormone secretion from the adenohypophysis
is not understood. In two in vitro pituitary cell systems, vasopressin caused a specific and dose-related release of thyroid-stimulating
hormone from cells that was equal in potency to that elicited by thyrotropin-releasing hormone, the primary acknowledged regulator
of thyroid-stimulating hormone release. When injected into the hypothalamus, however, vasopressin specifically inhibited the
release of thyroid-stimulating hormone. Thus, vasopressin may exert differential regulatory effects on thyroid-stimulating
hormone secretion in the hypothalamus and pituitary gland.
To determine the central effects of 4-Amino-n-butyric acid (GABA), pressor and sympathetic nerve responses to electrical stimulation of the ventromedial hypothalamus were recorded following the intracerebroventricular (ICV) injection of GABA. In normotensive Wistar rats, anesthetized with urethane, ICV injections of GABA (50-200 micrograms) reduced sympathetic nerve activity, arterial blood pressure, and heart rate in a dose-dependent manner. Graded electrical stimulation of the ventromedial hypothalamus (50, 100, 150 microA) increased not only mean blood pressure but also the rate of sympathetic nerve firing, and both responses were attenuated by GABA pretreatment (100, 200 micrograms, ICV). In spontaneously hypertensive rats (SHR), ICV-injected GABA also reduced sympathetic and cardiovascular activity, but the magnitude of depressor responses was significantly larger in SHR than in normotensive Wister Kyoto controls (WKY). Pressor and sympathetic nerve responses elicited by ventromedial hypothalamic stimulation were initially larger in SHR than in WKY, but upon subsequent ICV injection of GABA, hypothalamic responsiveness in SHR was inhibited more prominently and became comparable to that in WKY. These results suggest that by depressing hypothalamic function, centrally injected GABA decreases sympathetic nerve activity to thereby lower blood pressure and heart rate, and in SHR, ICV-injected GABA reversed hypothalamo-sympathetic hyperactivity and thus attenuated hypertension.
We investigated factors underlying discrepancy between screening blood pressure and daytime ambulatory blood pressure (the difference) in a community-based population in northeastern Japan. Screening and ambulatory pressures were measured in 706 untreated subjects aged 20 yr or older. We analyzed the effects of age and blood pressure on the difference and then performed multivariate stepwise linear regression analysis using the difference as the dependent variable. The systolic difference positively correlated with age in men. Women in their 40s exhibited a large difference, disturbing the linear relationship between the difference and age. The difference positively correlated with the screening pressure in men and women. A positive difference (screening pressure > ambulatory pressure) was observed at screening pressures above 130/75 mmHg. The difference inversely correlated with the ambulatory pressure. Multivariate analysis demonstrated that body mass index and male sex were positively associated with the systolic and diastolic blood pressure differences. The daytime pulse rate was negatively associated with the systolic difference, and the standard deviation of daytime diastolic ambulatory blood pressure was positively associated with the diastolic difference. The diastolic difference in subjects with isolated systolic hypertension based on the screening pressure was significantly smaller than that in subjects with systolic/diastolic hypertension. The difference in subjects with isolated systolic hypertension based on ambulatory pressure was significantly higher than that in systolic/diastolic hypertension. When white-coal (isolated screening) hypertension was defined as a screening systolic pressure > or = 140 mmHg, a diastolic pressure > or = 90 mmHg, or both, and a 24-h ambulatory pressure < 136/87 mmHg in men and < 131/86 mmHg in women, white-coat (isolated screening) hypertension was present in 79 (56.8%) of 139 subjects with screening hypertension. The results confirm that the discrepancy between screening and ambulatory blood pressure is due to a variety of factors, including age, sex, blood pressure levels, and baroreflex function. Our results indicate that screening blood pressure in elderly hypertensive patients should be evaluated carefully.
A reduction in gamma-aminobutyric (GABA)-mediated inhibition of pressor sites in the caudal hypothalamus of spontaneously hypertensive rats compared with that of normotensive Wistar-Kyoto rats has recently been demonstrated.
To determine whether the reduction in GABA-mediated inhibition of the caudal hypothalamus of the spontaneously hypertensive rats results from reductions both in the number of GABA-synthesizing neurons and in the amount of the GABA-synthesizing enzyme, glutamic acid decarboxylase messenger RNA (mRNA).
A polyclonal antibody (Chemicon) for the 67 kDa isoform of glutamic acid decarboxylase (GAD67) was used to immunocytochemically label GABAergic neurons in the caudal hypothalamus of spontaneously hypertensive and Wistar-Kyoto rats that had been treated beforehand with colchicine. The labeled cells were counted for both strains by a blinded analysis and compared. Caudal hypothalamic tissues from spontaneously hypertensive and Wistar-Kyoto rats were analysed for GAD67 mRNA by Northern blotting. The signal intensities of the radioactive probe specific for GAD67 for the two strains were analyzed by using a phosphorimager and compared. Control areas for the immunocytochemical (zona incerta) and Northern blotting (cortex, midbrain, cerebellum, and brain stem) experiments were used to determine regional differences in expression of GAD67.
Both the hypothalamus and cerebellum of spontaneously hypertensive and Wistar-Kyoto rats contained GAD67-immunoreactive neurons; however, there were 42% fewer GAD67 neurons in the caudal hypothalamus of spontaneously hypertensive rats than there were in that of Wistar-Kyoto rats. Furthermore, a 33% reduction in the amount of GAD67 messenger RNA in the caudal hypothalamus of spontaneously hypertensive rats compared with that for Wistar-Kyoto rats was demonstrated. Analysis of the expression of GAD67 in the cortex, midbrain, cerebellum, brain stem, and total brain revealed no difference between spontaneously hypertensive and Wistar-Kyoto rats.
Our findings demonstrate that the spontaneously hypertensive rat has fewer neurons synthesizing GABA and less GAD67 mRNA in the caudal hypothalamus than do Wistar-Kyoto rats. This deficit in the GABAergic system in the caudal hypothalamus, a well-known cardiovascular regulatory site, could contribute to the essential hypertension in this animal model.
We examined effects of γ-aminobutyric acid (GABA) on vasoconstriction and noradrenaline (NA) release induced by electrical renal nerve stimulation (RNS) in the isolated pump-perfused rat kidney.
RNS (1 and 2 Hz for 2.5 min each, 0.5-ms duration, supramaximal voltage) increased renal perfusion pressure (PP) and renal NA efflux. GABA (3, 10 and 100 μM) attenuated the RNS-induced increases in PP by 10–40% (P<0.01) and NA efflux by 10–30% (P<0.01). GABA did not affect exogenous NA (40 and 60 nM)-induced increases in PP.
The selective GABAB agonist baclofen (3, 10 and 100 μM) also attenuated the RNS-induced increases in PP and NA efflux, whereas the RNS-induced responses were relatively resistant to the selective GABAA agonist muscimol (3, 10 and 100 μM).
The selective GABAB antagonist 2-hydroxysaclofen (50 μM), but not the selective GABAA antagonist bicuculline (50 μM), abolished the inhibitory effects of GABA (10 μM) on the RNS-induced responses.
The selective α2-adrenoceptor antagonist rauwolscine (10 nM) enhanced the RNS-induced responses. GABA (3, 10 and 100 μM) potently attenuated the RNS-induced increases in PP by 40–60% (P<0.01) and NA efflux by 20–50% (P<0.01) in the presence of rauwolscine.
Prazosin (10 and 30 nM) suppressed the RNS-induced increases in PP by about 70–80%. Neither rauwolscine (10 nM) nor GABA (10 μM) suppressed the residual prazosin-resistant PP response.
These results suggest that GABA suppresses sympathetic neurotransmitter release via presynaptic GABAB receptors, and thereby attenuates adrenergically induced vasoconstriction in the rat kidney.
British Journal of Pharmacology (1999) 127, 109–114; doi:10.1038/sj.bjp.0702524
1. The effect of GABA on blood pressure of normotensive and hypertensive rats or men was investigated.
2. GABA, when administered orally one g per day for a month, did not cause any appreciable changes in body weight, blood pressure and other side effects in normotensive rats. No histological changes were found in their organs.
3. On the contrary, GABA reduced the elevated blood pressure of experimental renal hypertensive rats at the doses of more than thirty mg per day. Its effect was maintained during the application, and disappeared within one week after the interruption of treatment.
4. When glutamate or aspartic acid of 50 mg per day was orally applied for three weeks, no change was observed in blood pressure of hypertensive rats.
5. GABA, administered subcutaneously was also more effective in hypertensive rats than in normotensive ones.
6. Subcutaneous injections of GABA (1-3 mg per kg) on normotensive subjects produced slight uncomfortable side effects.
7. GABA, if administered orally three g per day, did not cause any appreciable effects on normotensive persons, but it lowered remarkably the elevated blood pressure of patients.