Re: 황함유 아미노산 타우린 --＞ NO 생성촉진 : 고혈압 치료 RCT 논문 2016년

[문형철]

Taurine Supplementation Lowers Blood Pressure and Improves Vascular Function in Prehypertension: Randomized, Double-Blind, Placebo-Controlled Study

Qianqian Sun, Bin Wang, Yingsha Li, Fang Sun, Peng Li, Weijie Xia, Xunmei Zhou, … Show All … , and Zhiming ZhuAuthor Info & Affiliations

Hypertension

Volume 67, Number 3

https://doi.org/10.1161/HYPERTENSIONAHA.115.06624

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Abstract

Taurine, the most abundant, semiessential, sulfur-containing amino acid, is well known to lower blood pressure (BP) in hypertensive animal models. However, no rigorous clinical trial has validated whether this beneficial effect of taurine occurs in human hypertension or prehypertension, a key stage in the development of hypertension. In this randomized, double-blind, placebo-controlled study, we assessed the effects of taurine intervention on BP and vascular function in prehypertension. We randomly assigned 120 eligible prehypertensive individuals to receive either taurine supplementation (1.6 g per day) or a placebo for 12 weeks. Taurine supplementation significantly decreased the clinic and 24-hour ambulatory BPs, especially in those with high-normal BP. Mean clinic systolic BP reduction for taurine/placebo was 7.2/2.6 mm Hg, and diastolic BP was 4.7/1.3 mm Hg. Mean ambulatory systolic BP reduction for taurine/placebo was 3.8/0.3 mm Hg, and diastolic BP was 3.5/0.6 mm Hg. In addition, taurine supplementation significantly improved endothelium-dependent and endothelium-independent vasodilation and increased plasma H2S and taurine concentrations. Furthermore, changes in BP were negatively correlated with both the plasma H2S and taurine levels in taurine-treated prehypertensive individuals. To further elucidate the hypotensive mechanism, experimental studies were performed both in vivo and in vitro. The results showed that taurine treatment upregulated the expression‎ of hydrogen sulfide–synthesizing enzymes and reduced agonist-induced vascular reactivity through the inhibition of transient receptor potential channel subtype 3–mediated calcium influx in human and mouse mesenteric arteries. In conclusion, the antihypertensive effect of chronic taurine supplementation shows promise in the treatment of prehypertension through improvement of vascular function.

초록
타우린은 가장 풍부하고 반필수적인 황 함유 아미노산으로, 고혈압 동물 모델에서 혈압(BP)을 낮추는 것으로 잘 알려져 있습니다. 그러나 타우린의 이러한 유익한 효과가 고혈압이나 고혈압 전단계인 고혈압의 주요 단계에서 발생하는지 여부를 검증한 엄격한 임상 시험은 없습니다. 이 무작위, 이중맹검, 위약대조군 연구에서 우리는 고혈압 전단계의 혈압과 혈관 기능에 대한 타우린의 효과를 평가했습니다. 

우리는 120명의 고혈압 전단계 대상자를 무작위로 선정하여 

12주 동안 타우린 보충제(하루 1.6g) 

또는 위약을 투여했습니다. 

타우린 보충제는 

특히 고혈압 전단계의 혈압을 현저하게 감소시켰습니다. 

타우린/위약의 평균 클리닉 수축기 혈압 감소는 7.2/2.6mmHg였고, 이완기 혈압은 4.7/1.3mmHg였다. 타우린/위약의 평균 외래 수축기 혈압 감소는 3.8/0.3mmHg였고, 이완기 혈압은 3.5/0.6mmHg였다. 

또한, 타우린 보충은 

내피 의존성 및 내피 비의존성 혈관 확장을 현저하게 개선하고 

혈장 H2S 및 타우린 농도를 증가시켰습니다. 

또한, 

타우린을 투여한 고혈압 전단계 환자의 혈압 변화는 

혈장 H2S 및 타우린 수치와 음의 상관관계가 있었습니다. 

저혈압 메커니즘을 더 자세히 밝히기 위해 

생체 내 및 생체 외 실험 연구가 수행되었습니다. 

그 결과, 

타우린 치료는 

인간과 생쥐의 장간막 동맥에서 일시적 수용체 전위 채널 아형 3에 의한 칼슘 유입 억제를 통해 

황화수소 합성 효소의 발현을 증가시키고, 

작용제에 의한 혈관 반응성을 감소시키는 것으로 나타났습니다.

 결론적으로, 

만성 타우린 보충제의 항고혈압 효과는 

혈관 기능 개선을 통해 고혈압 전단계의 치료에 유망한 것으로 나타났습니다.

Introduction

Prehypertension is highly preval‎ent worldwide.1 It is estimated that ≈30% to 50% of the population have this condition. It frequently complicates other cardiometabolic risk factors and is closely associated with coronary heart disease, stroke, and renal dysfunction.2 Early intervention in prehypertension substantially prevents the incidence of hypertension and related damage to target organs. Currently, several strategies are used to treat prehypertension, including the incorporation of therapeutic lifestyle changes, such as healthy dietary intake and regular physical activity, as well as the use of antihypertensive drugs, such as an angiotensin II receptor blocker. Although these treatments improve prehypertension, poor compliance and limitations associated with antihypertensive medications prevent their application in the general population. Thus, there is an urgent need to identify reliable and accurate measures to prevent the development of prehypertension.

Taurine (2-aminoethanesulfonic acid) is the most abundant, semiessential, sulfur-containing amino acid. It can be synthesized in vivo by cysteine in the presence of cysteine dioxygenase,3 but taurine is mainly acquired from dietary sources, such as eggs, meat, and seafood. Hydrogen sulfide (H2S) is synthesized from 2 sulfur-containing amino acids, l-cysteine and l-methionine, by the 3 enzymes, cystathionine-γ-lyase (CSE), cystathionine-β-synthetase (CBS), and 3-mercaptopyruvate sulfurtransferase.4

Taurine has several potentially beneficial cardiovascular effects that involve regulation of the nitric oxide system and endothelial function,5,6 the renin–angiotensin–aldosterone system,7,8 the oxidative stress system and sympathoadrenal activity,9 and the endoplasmic reticulum stress system.10,11 Epidemiological studies have demonstrated a reduction in plasma sulfur amino acids in hypertensive patients.12 Several clinical studies have reported that diets rich in taurine can reduce cardiovascular risks regardless of ethnicity and genetic background.13,14 In addition, animal experiments have shown that taurine depletion accelerates the development of high salt–induced hypertension.15 Although taurine has been shown to lower blood pressure (BP) in several hypertensive animal models, few rigorous and long-term clinical trials have confirmed this beneficial effect in human hypertension.9

Another key question is what is the mechanism of the antihypertensive effects of taurine supplementation?16 Recent animal and human studies have shown that taurine supplementation lowers BP and improves vascular function, possibly through suppression of renin–angiotensin–aldosterone system activity,17,18 augmentation of kallikrein activity in the blood and peripheral tissues,19 suppression of the renal sympathetic nervous system,9,20 diuretic and natriuretic activities, and vasorelaxant activity.21 H2S can regulate vascular tone through several mechanisms, such as acting on ATP-sensitive potassium channels.22–24 A recent study has found that H2S also affects transient receptor potential channels (TRPCs) in mesenchymal stem cells and regulates calcium homeostasis.4 Our previous studies have demonstrated that TRPC3-mediated calcium signaling contributes to the development of hypertension,25,26 but it is unclear whether the hypotensive effects of taurine and H2S are associated with modulation of TRPC3 channels in the vasculature. In this study, we investigated the effects of chronic taurine supplementation on BP and vascular function in prehypertension by performing a randomized, double-blind, placebo-controlled clinical trial.

소개

전고혈압은 전 세계적으로 매우 흔하게 발생합니다.1 인구의 약 30%에서 50%가 이 질환을 앓고 있는 것으로 추정됩니다. 전고혈압은 다른 심혈관 대사성 위험 요인을 복잡하게 만들고, 관상동맥 심장 질환, 뇌졸중, 신장 기능 장애와 밀접한 관련이 있습니다.2 전고혈압에 대한 조기 개입은 고혈압의 발생과 관련된 장기 손상을 크게 예방할 수 있습니다. 현재, 고혈압 전단계의 치료를 위해 여러 가지 전략이 사용되고 있습니다. 여기에는 건강한 식습관과 규칙적인 신체 활동과 같은 치료적 생활 습관 변화의 도입과 안지오텐신 II 수용체 차단제와 같은 항고혈압제의 사용이 포함됩니다. 이러한 치료가 고혈압 전단계를 개선하는 데는 도움이 되지만, 항고혈압제의 낮은 순응도와 제한적인 사용으로 인해 일반 대중에게 적용하기 어렵습니다. 따라서, 고혈압 전단계의 진행을 방지하기 위한 신뢰할 수 있고 정확한 측정 방법을 찾아야 할 긴급한 필요성이 있습니다.

타우린(2-aminoethanesulfonic acid)은

가장 풍부하고 반필수적인

황 함유 아미노산입니다.

타우린은

시스테인 디옥시게나제3의 존재 하에서

시스테인에 의해 생체 내에서 합성될 수 있지만,

주로 계란, 육류, 해산물과 같은 식이 공급원에서 얻어집니다.

황화수소(H2S)는

2개의 황 함유 아미노산인 l-시스테인과 l-메티오닌으로부터

3개의 효소인 시스타티오닌-γ-리아제(CSE), 시스타티오닌-β-신테타제(CBS), 3-머캅토피루브산 황화효소에 의해

합성됩니다.4

타우린은

산화질소 시스템과 내피 기능,5,6

레닌-안지오텐신-알도스테론 시스템,7,8

산화 스트레스 시스템과 교감신경-부신 활동,9

소포체 스트레스 시스템의 조절과 관련된

잠재적으로 유익한 심혈관 효과가 있습니다.10,11

역학 연구에 따르면

고혈압 환자의 혈장 황 아미노산이 감소하는 것으로 나타났습니다. 12

여러 임상 연구에 따르면 타우린이 풍부한 식단은

인종과 유전적 배경에 관계없이 심혈관 질환의 위험을 줄일 수 있다고 합니다.13,14

또한, 동물 실험에 따르면

타우린 결핍은 고염분으로 인한 고혈압의 발병을 촉진한다고 합니다.15

타우린이 여러 고혈압 동물 모델에서 혈압(BP)을 낮추는 것으로 나타났지만,

인간 고혈압에 대한 이 유익한 효과를 확인한 엄격하고

장기적인 임상 시험은 거의 없습니다.9

또 다른 핵심 질문은

타우린 보충제의 항고혈압 효과의 메커니즘이

무엇인지를 알아보는 것입니다. 16

최근의 동물과 인간을 대상으로 한 연구에 따르면

타우린 보충제는 레닌-안지오텐신-알도스테론 시스템의 활동을 억제하고,1718

혈액과 말초 조직에서 칼리크레인의 활동을 증가시키며,19

신장 교감 신경계를 억제하고,920

이뇨 및 나트륨 배설 작용을 촉진하고,

혈관 이완 작용을 통해 혈압을 낮추고 혈관 기능을 개선하는 것으로 나타났습니다. 21

H2S는

ATP-민감성 칼륨 채널에 작용하는 것과 같은

여러 가지 메커니즘을 통해 혈관 긴장을 조절할 수 있습니다.22-24

최근 연구에 따르면

H2S는 중간엽 줄기세포의 TRPC(transient receptor potential channels)에도 영향을 미치고

칼슘 항상성을 조절합니다. 4

이전 연구에 따르면,

TRPC3 매개 칼슘 신호가 고혈압 발생에 기여한다는 사실이 밝혀졌습니다25,26.

그러나

타우린과 H2S의 저혈압 효과가 혈관 내 TRPC3 채널의 조절과 관련이 있는지는 확실하지 않습니다.

이 연구에서는 무작위, 이중맹검, 위약 대조 임상 시험을 실시하여 고혈압 전단계의 혈압과 혈관 기능에 대한 만성 타우린 보충제의 효과를 조사했습니다.

Methods

Detailed Methods are provided in the online-only Data Supplement.

Study Design and Procedures

This study was a prospective single-center, double-blind, randomized, placebo-controlled trial that was conducted in accordance with the CONSORT (Consolidated Standards of Reporting Trials) guidelines for the presentation of clinical trials (CONSORT 2010 Explanation and Elaboration) and the principles of the Declaration of Helsinki. The protocol was approved by the ethics committee of the Daping Hospital, Third Military Medical University. The protocol is registered in the US National Library of Medicine (http://www.ClinicalTrials.gov, identifier: NCT01816698).

Participants were recruited at the Center for Hypertension and Metabolic Diseases of Chongqing from December 2012 to December 2014. They were screened for eligibility after written informed consent was obtained. The prehypertension inclusion criteria for the first visit included the following: an age of between 18 and 75 years and an systolic BP (SBP) of 120 to 139 mm Hg or a diastolic BP (DBP) of 80 to 89 mm Hg, as determined by performing repeated measurements with a mercury sphygmomanometer. The main exclusion criteria included the following: clinical evidence of recent infection, pregnancy, coronary artery disease, peripheral vascular disease, cerebrovascular disease, renal dysfunction, diabetes mellitus, hypertension, tumor, mental disease, the use of other medications, or being enrolled in another trial within the last 3 months.

In total, 120 untreated participants (51 men and 69 women; age, 56.75±8.26 years) and 58 age-matched normotensive control subjects without taurine supplementation were enrolled only as baseline comparison in the study. These untreated participants were randomly assigned to either a placebo group or a taurine group (Figure S1 in the online-only Data Supplement). All subjects completed a standardized questionnaire administered by trained personnel on their history of cardiovascular diseases and other illnesses. All subjects were asked not to alter their usual diet over the course of the 12-week study. They all underwent standardized clinical and laboratory examinations. BP was measured by a physician using a mercury sphygmomanometer after each subject had rested for at least 5 minutes in the seated position. Three measurements were obtained at 1-minute intervals, and the average was used to define the SBP and DBP. Laboratory tests were performed after an overnight fast, including measurements of fasting plasma glucose, triglyceride, cholesterol, hepatic enzyme, uric acid, blood urea nitrogen, and serum creatine levels.

Statistical Analysis

For all participants, we analyzed the changes from baseline (randomization) to 12 weeks in BP, vascular functions, biochemical and renal parameters, and other parameters. The sample size was chosen to ensure for 90% power to detect a 3-mm Hg difference in our primary outcome, a change in SBP, with a 2-sided significance level of 0.05 and assuming a dropout rate of 20%, according to previous published data and a preliminary trial of prehypertensive participants. All analyses were based on intention-to-treat populations (defined as all patients who took at least 1 dose and had at least 1 efficacy measurement available after randomization), with the last value carried forward for missing values. Comparisons of continuous variables between the placebo and taurine groups were analyzed using the Mann–Whitney test (GraphPad Prism; La Jolla, CA). Comparisons of variables before and after treatments were analyzed using the Wilcoxon signed-rank matched pair test. The χ2 test was used for categorical variables. Spearman nonparametric correlation analysis was performed to determine the relationships between BP changes and other factors. The immunoblotting results, wire myograph results, and PTI (Photon Technology International) results were compared using the Mann–Whitney test. A 2-tailed P<0.05 was considered statistically significant. The data were expressed as mean±SEM or SD for normally distributed variables and median (25th and 75th percentiles) for non-normally distributed variables, and all the results were analyzed using SPSS 18.0.

ResultsBaseline Characteristics of Participants

Compared with the normal controls, the enrolled prehypertensive participants had higher clinic and ambulatory BPs (ABPs) and increased pulse wave velocity and postprandial blood glucose values. In addition, there were no significant differences in the baseline characteristics between the placebo and taurine groups (Table S1). Of 793 participants screened in the study, 120 untreated participants were randomized; of whom, 97 completed the entire study protocol and had complete data, with a loss rate of 19.2% (Figure S1). Both the taurine and placebo interventions were well tolerated, and no serious adverse events were reported by any of the participants.

Chronic Taurine Supplementation Reduces BP in Prehypertensive Individuals

Administration of taurine for 12 weeks significantly reduced BP. The clinic SBP and DBP decreased in the taurine group by 7.2 mm Hg (95% confidence interval [CI], 3.75–10.55; P<0.001) and 4.7 mm Hg (95% CI, 2.16–7.14; P<0.001), respectively, compared with the baseline values; however, these changes were not evident in the placebo group (Figure 1A and 1B; Figure S2A and S2B; Table S2). Similarly, the 24-hour ABP in the taurine group exhibited a similar pattern, with mean decreases in the SBP and DBP of 3.8 mm Hg (95% CI, 1.97–5.56; P<0.05) and 3.5 mm Hg (95% CI, 2.14–4.81; P<0.05), respectively, compared with the baseline values; however, no changes were observed in the placebo-treated group (Figure 1C and 1D; Figure S3A and S3B; Table S2; n=44 in the placebo group and n=42 in the taurine group, respectively). Further analysis revealed that taurine treatment reduced the daytime ambulatory SBP and DBP compared with the baseline values, thereby decreasing the ambulatory SBP by 4.5 mm Hg (95% CI, 2.21–6.79 mm Hg; P<0.05) and the ambulatory DBP by 4.3 mm Hg (95% CI, 2.82–5.80 mm Hg; P<0.01; Figure S3C and S3D); however, no significant changes were observed in the placebo group. Meanwhile, the taurine treatment did not influence the nighttime ABP (Figure S3E and S3F).

Figure 1. Effect of taurine supplementation on blood pressure (BP). A and B, Clinic systolic BPs (SBPs; A) and diastolic BPs (DBPs; B) of participants treated with placebo or taurine at baseline (0 weeks, Pre) and after treatment (12 weeks, Post). The data are presented as the mean±SD; ***P<0.001, compared with baseline values. C and D, Twenty-four–hour average ambulatory BPs of the participants at 0 week and 12 weeks compared with the corresponding baseline values. n=44 in the placebo group and n=42 in the taurine group, respectively; *P<0.05. E and F, Clinic SBPs and DBPs at 0, 4, 8, and 12 weeks in the 2 groups. *P<0.05 and **P<0.01 compared with the placebo group. G and H, Comparisons of BP changes between the prehypertensive participants with high- and low-normal BPs in the taurine group. *P<0.05. ns indicates not significant.Open in viewer

Chronic taurine supplementation time dependently decreased clinic BP. Compared with the placebo group, both the clinic SBP and DBP were significantly reduced at 8 and 12 weeks after taurine administration (Figure 1E and 1F; Figure S2C and S2D). Importantly, taurine supplementation for 12 weeks greatly reduced the BPs of the prehypertensive participants with high-normal BPs (SBP, 130–139/DBP, 85–89 mmHg) compared with the prehypertensive participants with low-normal BPs (SBP, 120–129 mm Hg; DBP, 80–84 mm Hg). Changes in the SBP of 10.1 mm Hg were observed in the high-normal BP group compared with changes of 3.0 mm Hg in the low-normal BP group (P<0.05; Figure 1G). However, the changes in the DBP were similar between these 2 subgroups (Figure 1H).

Taurine Supplementation Improves Vasodilation in Prehypertensive Individuals

Chronic taurine supplementation significantly improved both endothelium-dependent vasodilation (flow-mediated dilation) and endothelium-independent vasodilation (nitroglycerin-mediated dilation) by 3.2% and 4.4%, respectively, as measured via flow-mediated vasodilation using a sonographer in the prehypertensive individuals. However, the beneficial effect of taurine supplementation on vasodilation was absent in the prehypertensive individuals treated with placebo (Figure 2A–2D).

Figure 2. Effect of taurine supplementation on vasodilation. A and B, Flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD). The data are presented as the mean±SD. **P<0.01 and ***P<0.001, compared with pretreatment with taurine (Pre). C and D, Changes in FMD and NMD in the 2 groups. *P<0.05 and **P<0.01, compared with the placebo group. ns indicates not significant.Open in viewer

Taurine Supplementation Elevates Plasma Levels of Taurine and H2S in Association With BP Changes in Prehypertensive Individuals

After treatment for 12 weeks, the plasma taurine and H2S levels were significantly higher in the prehypertensive individuals treated with taurine (plasma H2S level: 43.8±20.82 µmol/L at baseline to 87.0±24.51 µmol/L after treatment; P<0.001 and plasma taurine level: 108.3±55.27 µmol/L at baseline to 142.3±62.14 µmol/L after treatment; P<0.05); however, these changes were not observed in the participants treated with placebo (Figure 3A and 3B). Furthermore, the changes in BP were negatively correlated with both the plasma H2S and taurine levels in the taurine-treated prehypertensive individuals (Figure 3C–3F), especially in the prehypertensive participants with a high-normal BP level (Figure S4A–S4C). In contrast, these associations between BP and the plasma levels of H2S and taurine were not observed in the participants treated with the placebo (Figure S5A–S5D).

Figure 3. Effects of taurine supplementation on plasma taurine and hydrogen sulfide (H2S) levels and their associations with blood pressure (BP) changes. A and B, Changes in the plasma H2S and taurine levels. The data are presented as the mean±SEM. *P<0.05 and ***P<0.001, compared with pretreatment with taurine (Pre). C–F, Correlations between BP changes and plasma H2S and taurine levels, respectively. DBP indicates diastolic BP; ns, not significant; and SBP, systolic BP.Open in viewer

Effects of Taurine on H2S-Synthesizing Enzymes, TRPC3, and Vascular Relaxation

To elucidate the mechanisms underlying the effects of taurine on BP and vascular functions, we further examined 2 key H2S-synthesizing enzymes, CBS and CSE. We showed that CBS and CSE were expressed in the endothelia and adventitia of mesenteric arteries (MAs) from human and aortas from mice. However, TRPC3 was mainly expressed in the media of arteries (Figure 4A and 4B). Western blotting also indicated that CBS, CSE, and TRPC3 were coexpressed in MAs from humans and aortas from Trpc3+/+ wild-type (WT) mice (Figure 4C and 4G). In addition, vascular CBS/CSE expression‎ was upregulated in Trpc3−/− mice compared with WT mice (Figure 4C and 4D). Administration of taurine significantly upregulated CBS/CSE expression‎ but inhibited TRPC3 expression‎ in both aortas from spontaneously hypertensive rats treated with taurine and cultured human vascular tissues (Figure 4E–4J). After depletion of intracellular calcium storage using thapsigargin, a sarcoplasmic reticulum Ca2+-ATPase inhibitor, KCl-induced vasoconstriction was dose dependently relaxed by NaHS, a H2S donor; however, this effect was enhanced by a TRPC3 inhibitor, Pyr3, or by Trpc3 gene knockout (Figure 4K and 4L). These findings indicate that TRPC3 might be involved in H2S-mediated vascular relaxation.

Figure 4. Effects of taurine on cystathionine-β-synthetase (CBS)/cystathionine-γ-lyase (CSE), transient receptor potential channel 3 (TRPC3), and vascular relaxation. A and B, The immunofluorescence staining results showing that CBS/CSE (red) and TRPC3 (green) were coexpressed in mesenteric arteries (MAs) from humans and in aortas from wild-type mice. 4′,6-Diamidino-2-phenylindole (DAPI) was also stained to show the existence of nuclei (blue). C and D, The expression‎ levels of CBS, CSE, and TRPC3 in aortas from Trpc3+/+ and Trpc3−/− mice were detected by Western blotting. The bands from 3 independent immunoblots were quantified using Image J, and the relative expression‎ levels are shown in (D). The data are presented as the mean±SEM; *P<0.05 and ***P<0.001, compared with that of Trpc3+/+ mice. E and F, Effects of in vivo taurine supplementation on the expression‎ levels of CBS, CSE, and TRPC3. Spontaneously hypertensive rats (SHRs) were fed 2% taurine for 12 weeks from 4-week old, and then aortas were obtained for Western blotting analysis. *P<0.05, compared with that of the normal diet (ND). G–J, Effect of in vitro taurine supplementation on the expression‎ levels of CBS, CSE, and TRPC3. Human MAs were treated with taurine (at doses of 0, 20, and 40 mmol/L) for 24 hours. *P<0.05 and **P<0.01, compared with the vehicles. K and L, Reactivities of human and mice MAs. After contraction induced using 60 mmol/L KCl, NaHS (10–5 to 10–3 mol/L) was added to promote vasodilation, and then the percentage of vasodilation was plotted. n=4; *P<0.05. TG indicates thapsigargin.Open in viewer

H2S Exerts Vascular Relaxation by Targeting TRPC3-Mediated Calcium Influx

We further examined H2S-induced vascular relaxation, which occurs through the targeting of TRPC3. Intact MAs were isolated from WT and Trpc3−/− mice. Calcium influx of intact blood vessels was measured using fluorescence techniques after depletion of intracellular calcium storage in the absence of external calcium. The phenylephrine-induced increase in calcium influx in the artery was completely abolished by the TRPC3 inhibitor Pyr3 after thapsigargin treatment (Figure S6A and S6B). Administration of NaHS significantly diminished the thapsigargin- and phenylephrine-induced increase in calcium influx in human MAs (Figure S6C–S6F). Furthermore, NaHS partially inhibited the thapsigargin-induced calcium influx in the Trpc3+/+ mice, but this effect was absent in intact arteries isolated from the Trpc3−/− mice (Figure S6G–S6N).

Discussion

To the best of our knowledge, this is the first randomized, double-blind, placebo-controlled clinical trial to investigate the effects of taurine supplementation in prehypertensive individuals. Furthermore, we have provided experimental evidence to facilitate elucidation of its mechanism of action. This study has revealed that oral taurine supplementation for 12 weeks significantly reduces the clinic and 24-hour ABPs in prehypertensive individuals, especially in those with high-normal BP. In addition, taurine treatment substantially promotes vasodilation and elevates the plasma taurine and H2S levels in these individuals. Furthermore, changes in BP were negatively correlated with the plasma taurine and H2S levels. However, these beneficial effects were absent in the prehypertensive individuals treated with placebo. In experimental studies, administration of taurine has been shown to enhance the expression‎ of H2S-synthesizing enzymes (CBS/CSE) and to reduce vascular TRPC3 expression‎ in spontaneously hypertensive rats. Furthermore, the vascular relaxation induced by the H2S donor NaHS is enhanced by TRPC3 antagonist treatment. These findings indicate that taurine intervention improves vascular tone by targeting the H2S-mediated inhibition of TRPC3-induced calcium influx.

Taurine is a sulfur-containing amino acid that is both cheap and nontoxic, and it is widely used as a functional dietary factor. Seafood containing an abundance of taurine improves cardiovascular and metabolic diseases, such as obesity, diabetes mellitus, and hyperlipidemia. In addition, taurine has multiple biological effects, such as protection against liver cirrhosis and antioxidative,27 anti-inflammatory, antiatherosclerotic,28,29 and antiobesity effects.30 Unfortunately, evidence that taurine supplementation reduces BP in human hypertension is inconclusive despite the fact that multiple experimental studies have demonstrated the hypotensive effect of taurine in different hypertensive animal models.

The antihypertensive effect of taurine in humans has only been confirmed in a few clinical studies with small sample sizes (n=10–12) that were short term (7 days to 6 weeks).31 One nonrandomized placebo-controlled trial showed that oral taurine supplementation (6 g per day) for 1 week decreased the SBP by 9.0 mm Hg and the DBP by 4.1 mm Hg in borderline hypertensive patients.9 In addition, taurine supplementation has been shown to lower BP by ≈22 to 49 mm Hg in different experimental hypertensive rats.31 Therefore, it remains unknown whether oral taurine supplementation is beneficial for prehypertensive individuals. In this randomized, double-blind, placebo-controlled study, we showed that administration of low-dose taurine (1.6 g per day) for 12 weeks can time dependently lower both clinic and ABPs and improve vascular relaxation. In particular, prehypertensive individuals with high-normal BP exhibited a better response to taurine than those with low-normal BP. Our study has provided the first solid evidence of the hypotensive effect of taurine in prehypertensive individuals.

Epidemiological studies have shown that the plasma taurine level is lower in patients with essential hypertension.12 Nara et al32 have reported that this level is decreased in spontaneously hypertensive rats in relation to the severity of hypertension. The plasma taurine level is negatively correlated with BP in hypertensive patients.14 Taurine deficiency in rats accelerates high salt intake–induced hypertension through renal dysfunction.15 Galloway et al33 reported that acute taurine treatment resulted in a 13-fold increase in the plasma taurine concentration, whereas no significant change in the muscle taurine concentration was observed. In this study, we found that chronic taurine treatment for 12 weeks resulted in an almost 1.5-fold increase of plasma taurine concentration in the prehypertensive individuals and that this increase was correlated with a reduction in BP. In addition, the prehypertensive individuals with a high end point plasma taurine level exhibited a greater hypotensive response to the taurine treatment.

The manner by which taurine exerts its hypotensive effect has been studied for a long time.16 Previous studies have shown that taurine supplementation improves endothelium-dependent vasodilation through restoration of vascular redox homeostasis and improvement of nitric oxide bioavailability.34 In addition, in human studies, improvement of flow-mediated dilation has been observed in response to dietary taurine supplementation in young smokers.35 The improved vascular function may facilitate the hypotensive effect and provide extra cardiovascular benefits. Available data suggest that the hypotensive effect of taurine does not occur through 1 specific mechanism but rather through multiple mechanisms.

In addition to nitric oxide and carbon monoxide, H2S, which is another important gas transmitter, has been widely studied in the cardiovascular system in recent years,36 and its vasodilatory effects have also been reported. H2S is endogenously produced from 2 sulfur-containing amino acids, l-cysteine and l-methionine, by the 2 H2S-synthesizing enzymes, CBS and CSE.24 Mutant mice lacking CSE display pronounced hypertension and reduced endothelium-dependent vasorelaxation, but this result was not confirmed by other studies.24 However, H2S replacement has been shown to reduce the SBP in both Cse−/− and Cse+/− mice,24 suggesting that the H2S synthases/H2S pathway confer protection against hypertension. Taurine, as a sulfur-containing amino acid, functions in the methionine cycle and can be converted by cysteine in the presence of cysteine dioxygenase,3 whereas H2S is synthesized from the 2 sulfur-containing amino acids, l-cysteine and l-methionine. This study has shown that taurine is probably a substrate for the synthesis of H2S to increase CBS and CSE expression‎. Therefore, we assumed that a correlation may exist between taurine and H2S. Taurine supplementation resulted in a significant elevation in the plasma H2S level in the prehypertensive individuals, and this elevation was correlated with a decrease in BP in the taurine group. Using MAs from healthy human volunteers and aortas from spontaneously hypertensive rats that were fed taurine for 3 months, we further demonstrated that taurine administration upregulated the expression‎ of vascular CBS/CSE, which caused the increased production of H2S in blood vessels in vitro and in vivo. Thus, other mechanisms of the vasorelaxant effect of H2S have also been identified involving opening of the ATP-sensitive potassium channels,23 interaction with nitric oxide pathways, functioning as an endothelium-derived hyperpolarizing factor, and direct activation of protein kinase G.37 Recently, Cheang et al38 and Tian et al39 have reported that H2S dilates blood vessels by opening voltage-gated potassium channels in rat coronary arteries and inhibits calcium channels in rat cerebral arteries, respectively. H2S has been demonstrated to regulate the activities of TRP channels in bone marrow mesenchymal stem cells through sulfhydration.4 Our previous work has demonstrated that TRPC3 upregulation and dysfunction in monocytes and in the vasculature from both genetically hypertensive rats and essential hypertensive patients play important roles in the pathogenesis of hypertension.25,26,40,41 In this study, we further verified that the H2S donor NaHS inhibited phenylephrine- and thapsigargin-induced Ca2+ influx and relaxation in MAs from human and Trpc3+/+ WT mice; however, this effect was absent in intact arteries from Trpc3−/− mice. Our work has revealed a novel unrecognized mechanism of taurine- and H2S-induced vasorelaxation that functions by enhancing the metabolism of sulfur-containing amino acids.

토론

저희가 아는 한,

이것은 고혈압 전단계에 있는 사람들의 타우린 보충제의 효과를 조사한

최초의 무작위, 이중맹검, 위약 대조 임상 시험입니다.

또한, 저희는 그 작용 메커니즘의 해명을 촉진하기 위한 실험적 증거를 제공했습니다.

이 연구는 12주 동안 경구 타우린 보충제를 투여했을 때,

특히 고혈압 전단계에 있는 사람들과 정상 혈압에 가까운 사람들의 경우,

병원과 24시간 혈압이 현저하게 감소한다는 사실을 밝혀냈습니다.

또한,

타우린 치료는 혈관 확장을 촉진하고,

이들 개인의 혈장 타우린과 H2S 수치를 높입니다.

게다가,

혈압의 변화는

혈장 타우린과 H2S 수치와 음의 상관관계가 있었습니다.

그러나, 이러한 유익한 효과는 위약으로 치료받은 고혈압 전단계 환자들에게는 나타나지 않았습니다. 실험 연구에서 타우린 투여는 자발성 고혈압 쥐에서 H2S 합성 효소(CBS/CSE)의 발현을 강화하고 혈관 TRPC3의 발현을 감소시키는 것으로 나타났습니다. 또한, H2S 기증자 NaHS에 의해 유발된 혈관 이완은 TRPC3 길항제 치료에 의해 강화됩니다.

이 연구 결과는

타우린이 H2S 매개 TRPC3에 의한 칼슘 유입 억제를 목표로 하여

혈관 긴장도를 개선한다는 것을 보여줍니다.

타우린은 황을 함유한 아미노산으로 저렴하고 독성이 없으며,

기능성 식이 요소로 널리 사용됩니다.

타우린이 풍부한 해산물은

비만, 당뇨병, 고지혈증과 같은 심혈관 및 대사성 질환을 개선합니다.

또한,

타우린은

간경변 예방, 항산화,27 항염증, 항동맥경화,28,29 항비만 등

다양한 생물학적 효과를 가지고 있습니다.30

안타깝게도,

여러 실험 연구에서 타우린이 다양한 고혈압 동물 모델에서 저혈압 효과를 나타냈음에도 불구하고,

타우린 보충제가 인간의 고혈압에서 혈압을 감소시킨다는 증거는 결정적이지 않습니다.

타우린의 항고혈압 효과는 표본 수가 적은(n=10-12) 단기(7일에서 6주) 임상 연구에서 확인된 바 있습니다. 31 비무작위 위약 대조 시험에서 경구 타우린 보충제(하루 6g)를 1주 동안 투여한 결과, 경계성 고혈압 환자의 수축기 혈압이 9.0mmHg, 이완기 혈압이 4.1mmHg 감소한 것으로 나타났습니다.9 또한, 타우린 보충제는 다양한 실험에서 고혈압 쥐의 혈압을 22~49mmHg 정도 낮추는 것으로 나타났습니다. 31 따라서 경구 타우린 보충제가 고혈압 전단계 환자에게 유익한지는 아직 밝혀지지 않았습니다. 이 무작위, 이중맹검, 위약 대조 연구에서 저용량 타우린(하루 1.6g)을 12주 동안 투여하면 시간의 경과에 따라 임상 및 ABP를 낮추고 혈관 이완을 개선할 수 있다는 사실이 밝혀졌습니다. 특히, 고혈압 전단계에 있는 정상 혈압의 사람들은 저혈압 단계에 있는 사람들보다 타우린에 대한 반응이 더 좋았습니다. 우리의 연구는 타우린이 고혈압 전단계에 있는 사람들에게서 저혈압 효과를 발휘한다는 것을 처음으로 확실하게 입증했습니다.

역학 연구에 따르면, 고혈압 환자의 혈장 타우린 수치가 낮다고 합니다.12 나라 외32 들은 자발성 고혈압 쥐의 경우, 고혈압의 정도에 따라 이 수치가 감소한다고 보고했습니다. 고혈압 환자의 혈장 타우린 수치는 혈압과 음의 상관관계가 있습니다.14 쥐의 타우린 결핍은 신장 기능 장애를 통해 고염분 섭취로 인한 고혈압을 가속화합니다.15 Galloway et al33은 급성 타우린 치료가 혈장 타우린 농도를 13배 증가시키는 반면, 근육 타우린 농도에는 유의미한 변화가 없다고 보고했습니다. 이 연구에서 우리는 12주 동안 만성 타우린 치료를 한 결과, 고혈압 전단계 환자의 혈장 타우린 농도가 거의 1.5배 증가했으며, 이 증가가 혈압 감소와 상관관계가 있다는 것을 발견했습니다. 또한, 혈장 타우린 농도 끝점이 높은 고혈압 전단계 환자는 타우린 치료에 대한 저혈압 반응이 더 큰 것으로 나타났습니다.

타우린이 저혈압 효과를 발휘하는 방식은 오랫동안 연구되어 왔습니다.16

이전 연구에 따르면,

타우린 보충제는

혈관 산화 환원 항상성의 회복과 산화질소 생체 이용률의 개선을 통해

내피 의존성 혈관 확장을 개선하는 것으로 나타났습니다. 34

또한, 인간 연구에서 젊은 흡연자의 식이요법 타우린 보충에 대한 반응으로 흐름 매개 팽창의 개선이 관찰되었습니다.35

개선된 혈관 기능은 저혈압 효과를 촉진하고 추가적인 심혈관 건강상의 이점을 제공할 수 있습니다.

이용 가능한 데이터에 따르면 타우린의 저혈압 효과는

하나의 특정 메커니즘을 통해 발생하는 것이 아니라

여러 메커니즘을 통해 발생하는 것으로 보입니다.

산화질소와 일산화탄소 외에도,

최근 몇 년 동안 또 다른 중요한 가스 전달 물질인 H2S가

심혈관계에서 광범위하게 연구되어 왔으며,36

그 혈관 확장 효과도 보고되었습니다.

H2S는

2개의 황 함유 아미노산인 l-시스테인과 l-메티오닌으로부터

2개의 H2S 합성 효소인 CBS와 CSE에 의해 내생적으로 생성됩니다. 24

CSE가 결핍된 돌연변이 마우스는

고혈압이 뚜렷하게 나타나고 내피 의존성 혈관 이완이 감소하지만,

이 결과는 다른 연구에서 확인되지 않았습니다.24

그러나

H2S 대체는 Cse−/− 및 Cse+/− 마우스 모두에서 SBP를 감소시키는 것으로 나타났으며,24

이는 H2S 합성효소/H2S 경로가 고혈압에 대한 보호 작용을 한다는 것을 시사합니다.

황을 함유한 아미노산인 타우린은

메티오닌 순환계에서 작용하며,
시스테인 디옥시게나제(cysteine dioxygenase)가 존재하는 상태에서

시스테인에 의해 전환될 수 있습니다.3

반면,

황을 함유한 아미노산인 l-시스테인과 l-메티오닌은

황화수소(H2S)를 합성합니다.

이 연구는

타우린이 아마도 CBS와 CSE 발현을 증가시키기 위해

황화수소(H2S) 합성을 위한 기질일 수 있음을 보여줍니다.

따라서

우리는 타우린과 H2S 사이에 상관관계가 있을 수 있다고 가정했습니다.

타우린 보충은

고혈압 전단계 환자의 혈장 H2S 수치를 크게 상승시켰고,

이 상승은 타우린 그룹의 혈압 감소와 상관관계가 있었습니다.

건강한 인간 자원 봉사자의 MA와 3개월 동안 타우린을 먹인 자발성 고혈압 쥐의 대동맥을 사용하여, 타우린 투여가 혈관 CBS/CSE의 발현을 증가시켜 시험관 내 및 생체 내에서 혈관 내 H2S의 생성을 증가시킨다는 것을 추가로 입증했습니다. 따라서, H2S의 혈관 이완 효과의 다른 메커니즘도 확인되었습니다. 여기에는 ATP-민감성 칼륨 채널의 개방, 산화질소 경로와의23 상호작용, 내피 유래 과분극 인자로서의 기능, 단백질 키나아제 G의 직접 활성화 등이 포함됩니다. 37 최근에 Cheang 외38 와 Tian 외39 는 H2S가 쥐의 관상동맥에서 전압-게이트 칼륨 채널을 열어 혈관을 확장시키고, 쥐의 대뇌동맥에서 칼슘 채널을 억제한다는 사실을 보고했습니다. H2S는 황화 반응을 통해 골수 중간엽 줄기세포의 TRP 채널 활동을 조절하는 것으로 밝혀졌습니다.4 우리의 이전 연구에 따르면, 유전성 고혈압 쥐와 본태성 고혈압 환자의 단핵구와 혈관계에서 TRPC3의 상향 조절과 기능 장애가 고혈압의 발병 기전에서 중요한 역할을 한다는 사실이 밝혀졌습니다.

25,26,40,41 이 연구에서 우리는 H2S 기증자인 NaHS가 인간과 Trpc3+/+ WT 마우스의 MAs에서 페닐에프린과 타프시가르긴에 의해 유발된 Ca2+ 유입과 이완을 억제한다는 것을 추가로 확인했습니다. 그러나, Trpc3−/− 마우스의 온전한 동맥에서는 이러한 효과가 나타나지 않았습니다. 우리의 연구는 타우린과 H2S에 의한 혈관 이완의 새로운 메커니즘을 밝혀냈습니다. 이 메커니즘은 황 함유 아미노산의 대사를 촉진하는 작용을 합니다.

Study Limitations

The limitation of this study is that it was not performed across multiple centers. Further studies should validate whether this beneficial effect is present in other ethnicities and populations. In addition, the hypotensive effects of taurine have been reported to occur via the central nervous system,42,43 attenuation of the overactivity of the sympathetic system and increased urinary norepinephrine, and epinephrine excretion.31 An effect of taurine on BP occurring via the central nervous system cannot be excluded.31

Perspectives

Prehypertension plays an important role in the development of hypertension. Furthermore, prehypertension is closely associated with the morbidities of stroke, ischemic heart disease, and renal dysfunction. Although lifestyle modifications and an angiotensin II receptor blocker have been used to treat prehypertension, poor compliance and limitations of antihypertensive agents are the main obstacles of treatment. This randomized, double-blind, placebo-controlled clinical trial is the first to demonstrate that taurine supplementation significantly reduces BP and improves vascular function in prehypertensive individuals, especially in those with high-normal BP. Furthermore, changes in BP are correlated with both the plasma H2S and taurine levels in the taurine-treated prehypertensive individuals. We further demonstrate that the hypotensive effect of taurine involved the H2S-mediated inhibition of TRPC3-induced calcium influx. Taurine, as the most abundant, semiessential, sulfur-containing amino acid, is rich in seafood and easily consumed daily. Considering the elevated cardiometabolic risks of large populations of prehypertensive individuals, consumption of taurine-rich food may be a promising and cost-effective approach to prehypertension treatment.

Acknowledgments

We gratefully acknowledge the participation of all study subjects and the technical assistance of Tingbing Cao and Lijuan Wang (Chongqing Institute of Hypertension, Chongqing, China) with our experiments.

Novelty and Significance

What Is New?

•

This randomized, double-blind, placebo-controlled clinical trial is the first to demonstrate the hypotensive effect of taurine supplementation in prehypertensive individuals.

•

Taurine treatment remarkably improves blood pressure and vascular function, especially in prehypertensive individuals with high-normal blood pressure.

•

The hypotensive mechanism of taurine partially involves the hydrogen sulfide–mediated inhibition of transient receptor potential channel 3–induced calcium influx in the vasculature.

What Is Relevant?

•

Taurine supplementation results in a substantial, time-dependent reduction in blood pressure in prehypertensive individuals. Daily taurine supplementation promotes an additional decrease in blood pressure beyond that achieved with conventional lifestyle changes and pharmacotherapy.

Summary

Daily taurine supplementation is a novel strategy for lowering blood pressure in prehypertension, either as a dietary factor or in conjunction with conventional lifestyle changes.

Supplemental Material

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References

1.

Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903–1913.

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Arima H, Murakami Y, Lam TH, Kim HC, Ueshima H, Woo J, Suh I, Fang X, Woodward M; Asia Pacific Cohort Studies Collaboration. Effects of prehypertension and hypertension subtype on cardiovascular disease in the Asia-Pacific Region. Hypertension. 2012;59:1118–1123. doi: 10.1161/HYPERTENSIONAHA.111.187252.

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Ueki I, Roman HB, Valli A, Fieselmann K, Lam J, Peters R, Hirschberger LL, Stipanuk MH. Knockout of the murine cysteine dioxygenase gene results in severe impairment in ability to synthesize taurine and an increased catabolism of cysteine to hydrogen sulfide. Am J Physiol Endocrinol Metab. 2011;301:E668–E684. doi: 10.1152/ajpendo.00151.2011.

Taurine Supplementation Lowers Blood Pressure and Improves Vascular Function in Prehypertension: Randomized, Double-Blind, Placebo-Controlled Study

Qianqian Sun, Bin Wang, Yingsha Li, Fang Sun, Peng Li, Weijie Xia, Xunmei Zhou, … Show All … , and Zhiming ZhuAuthor Info & Affiliations

Hypertension

Volume 67, Number 3

https://doi.org/10.1161/HYPERTENSIONAHA.115.06624

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Abstract

Taurine, the most abundant, semiessential, sulfur-containing amino acid, is well known to lower blood pressure (BP) in hypertensive animal models. However, no rigorous clinical trial has validated whether this beneficial effect of taurine occurs in human hypertension or prehypertension, a key stage in the development of hypertension. In this randomized, double-blind, placebo-controlled study, we assessed the effects of taurine intervention on BP and vascular function in prehypertension. We randomly assigned 120 eligible prehypertensive individuals to receive either taurine supplementation (1.6 g per day) or a placebo for 12 weeks. Taurine supplementation significantly decreased the clinic and 24-hour ambulatory BPs, especially in those with high-normal BP. Mean clinic systolic BP reduction for taurine/placebo was 7.2/2.6 mm Hg, and diastolic BP was 4.7/1.3 mm Hg. Mean ambulatory systolic BP reduction for taurine/placebo was 3.8/0.3 mm Hg, and diastolic BP was 3.5/0.6 mm Hg. In addition, taurine supplementation significantly improved endothelium-dependent and endothelium-independent vasodilation and increased plasma H2S and taurine concentrations. Furthermore, changes in BP were negatively correlated with both the plasma H2S and taurine levels in taurine-treated prehypertensive individuals. To further elucidate the hypotensive mechanism, experimental studies were performed both in vivo and in vitro. The results showed that taurine treatment upregulated the expression‎ of hydrogen sulfide–synthesizing enzymes and reduced agonist-induced vascular reactivity through the inhibition of transient receptor potential channel subtype 3–mediated calcium influx in human and mouse mesenteric arteries. In conclusion, the antihypertensive effect of chronic taurine supplementation shows promise in the treatment of prehypertension through improvement of vascular function.

Introduction

Prehypertension is highly preval‎ent worldwide.1 It is estimated that ≈30% to 50% of the population have this condition. It frequently complicates other cardiometabolic risk factors and is closely associated with coronary heart disease, stroke, and renal dysfunction.2 Early intervention in prehypertension substantially prevents the incidence of hypertension and related damage to target organs. Currently, several strategies are used to treat prehypertension, including the incorporation of therapeutic lifestyle changes, such as healthy dietary intake and regular physical activity, as well as the use of antihypertensive drugs, such as an angiotensin II receptor blocker. Although these treatments improve prehypertension, poor compliance and limitations associated with antihypertensive medications prevent their application in the general population. Thus, there is an urgent need to identify reliable and accurate measures to prevent the development of prehypertension.

Taurine (2-aminoethanesulfonic acid) is the most abundant, semiessential, sulfur-containing amino acid. It can be synthesized in vivo by cysteine in the presence of cysteine dioxygenase,3 but taurine is mainly acquired from dietary sources, such as eggs, meat, and seafood. Hydrogen sulfide (H2S) is synthesized from 2 sulfur-containing amino acids, l-cysteine and l-methionine, by the 3 enzymes, cystathionine-γ-lyase (CSE), cystathionine-β-synthetase (CBS), and 3-mercaptopyruvate sulfurtransferase.4

Taurine has several potentially beneficial cardiovascular effects that involve regulation of the nitric oxide system and endothelial function,5,6 the renin–angiotensin–aldosterone system,7,8 the oxidative stress system and sympathoadrenal activity,9 and the endoplasmic reticulum stress system.10,11 Epidemiological studies have demonstrated a reduction in plasma sulfur amino acids in hypertensive patients.12 Several clinical studies have reported that diets rich in taurine can reduce cardiovascular risks regardless of ethnicity and genetic background.13,14 In addition, animal experiments have shown that taurine depletion accelerates the development of high salt–induced hypertension.15 Although taurine has been shown to lower blood pressure (BP) in several hypertensive animal models, few rigorous and long-term clinical trials have confirmed this beneficial effect in human hypertension.9

Another key question is what is the mechanism of the antihypertensive effects of taurine supplementation?16 Recent animal and human studies have shown that taurine supplementation lowers BP and improves vascular function, possibly through suppression of renin–angiotensin–aldosterone system activity,17,18 augmentation of kallikrein activity in the blood and peripheral tissues,19 suppression of the renal sympathetic nervous system,9,20 diuretic and natriuretic activities, and vasorelaxant activity.21 H2S can regulate vascular tone through several mechanisms, such as acting on ATP-sensitive potassium channels.22–24 A recent study has found that H2S also affects transient receptor potential channels (TRPCs) in mesenchymal stem cells and regulates calcium homeostasis.4 Our previous studies have demonstrated that TRPC3-mediated calcium signaling contributes to the development of hypertension,25,26 but it is unclear whether the hypotensive effects of taurine and H2S are associated with modulation of TRPC3 channels in the vasculature. In this study, we investigated the effects of chronic taurine supplementation on BP and vascular function in prehypertension by performing a randomized, double-blind, placebo-controlled clinical trial.

Methods

Detailed Methods are provided in the online-only Data Supplement.

Study Design and Procedures

This study was a prospective single-center, double-blind, randomized, placebo-controlled trial that was conducted in accordance with the CONSORT (Consolidated Standards of Reporting Trials) guidelines for the presentation of clinical trials (CONSORT 2010 Explanation and Elaboration) and the principles of the Declaration of Helsinki. The protocol was approved by the ethics committee of the Daping Hospital, Third Military Medical University. The protocol is registered in the US National Library of Medicine (http://www.ClinicalTrials.gov, identifier: NCT01816698).

Participants were recruited at the Center for Hypertension and Metabolic Diseases of Chongqing from December 2012 to December 2014. They were screened for eligibility after written informed consent was obtained. The prehypertension inclusion criteria for the first visit included the following: an age of between 18 and 75 years and an systolic BP (SBP) of 120 to 139 mm Hg or a diastolic BP (DBP) of 80 to 89 mm Hg, as determined by performing repeated measurements with a mercury sphygmomanometer. The main exclusion criteria included the following: clinical evidence of recent infection, pregnancy, coronary artery disease, peripheral vascular disease, cerebrovascular disease, renal dysfunction, diabetes mellitus, hypertension, tumor, mental disease, the use of other medications, or being enrolled in another trial within the last 3 months.

In total, 120 untreated participants (51 men and 69 women; age, 56.75±8.26 years) and 58 age-matched normotensive control subjects without taurine supplementation were enrolled only as baseline comparison in the study. These untreated participants were randomly assigned to either a placebo group or a taurine group (Figure S1 in the online-only Data Supplement). All subjects completed a standardized questionnaire administered by trained personnel on their history of cardiovascular diseases and other illnesses. All subjects were asked not to alter their usual diet over the course of the 12-week study. They all underwent standardized clinical and laboratory examinations. BP was measured by a physician using a mercury sphygmomanometer after each subject had rested for at least 5 minutes in the seated position. Three measurements were obtained at 1-minute intervals, and the average was used to define the SBP and DBP. Laboratory tests were performed after an overnight fast, including measurements of fasting plasma glucose, triglyceride, cholesterol, hepatic enzyme, uric acid, blood urea nitrogen, and serum creatine levels.

Statistical Analysis

For all participants, we analyzed the changes from baseline (randomization) to 12 weeks in BP, vascular functions, biochemical and renal parameters, and other parameters. The sample size was chosen to ensure for 90% power to detect a 3-mm Hg difference in our primary outcome, a change in SBP, with a 2-sided significance level of 0.05 and assuming a dropout rate of 20%, according to previous published data and a preliminary trial of prehypertensive participants. All analyses were based on intention-to-treat populations (defined as all patients who took at least 1 dose and had at least 1 efficacy measurement available after randomization), with the last value carried forward for missing values. Comparisons of continuous variables between the placebo and taurine groups were analyzed using the Mann–Whitney test (GraphPad Prism; La Jolla, CA). Comparisons of variables before and after treatments were analyzed using the Wilcoxon signed-rank matched pair test. The χ2 test was used for categorical variables. Spearman nonparametric correlation analysis was performed to determine the relationships between BP changes and other factors. The immunoblotting results, wire myograph results, and PTI (Photon Technology International) results were compared using the Mann–Whitney test. A 2-tailed P<0.05 was considered statistically significant. The data were expressed as mean±SEM or SD for normally distributed variables and median (25th and 75th percentiles) for non-normally distributed variables, and all the results were analyzed using SPSS 18.0.

ResultsBaseline Characteristics of Participants

Compared with the normal controls, the enrolled prehypertensive participants had higher clinic and ambulatory BPs (ABPs) and increased pulse wave velocity and postprandial blood glucose values. In addition, there were no significant differences in the baseline characteristics between the placebo and taurine groups (Table S1). Of 793 participants screened in the study, 120 untreated participants were randomized; of whom, 97 completed the entire study protocol and had complete data, with a loss rate of 19.2% (Figure S1). Both the taurine and placebo interventions were well tolerated, and no serious adverse events were reported by any of the participants.

Chronic Taurine Supplementation Reduces BP in Prehypertensive Individuals

Administration of taurine for 12 weeks significantly reduced BP. The clinic SBP and DBP decreased in the taurine group by 7.2 mm Hg (95% confidence interval [CI], 3.75–10.55; P<0.001) and 4.7 mm Hg (95% CI, 2.16–7.14; P<0.001), respectively, compared with the baseline values; however, these changes were not evident in the placebo group (Figure 1A and 1B; Figure S2A and S2B; Table S2). Similarly, the 24-hour ABP in the taurine group exhibited a similar pattern, with mean decreases in the SBP and DBP of 3.8 mm Hg (95% CI, 1.97–5.56; P<0.05) and 3.5 mm Hg (95% CI, 2.14–4.81; P<0.05), respectively, compared with the baseline values; however, no changes were observed in the placebo-treated group (Figure 1C and 1D; Figure S3A and S3B; Table S2; n=44 in the placebo group and n=42 in the taurine group, respectively). Further analysis revealed that taurine treatment reduced the daytime ambulatory SBP and DBP compared with the baseline values, thereby decreasing the ambulatory SBP by 4.5 mm Hg (95% CI, 2.21–6.79 mm Hg; P<0.05) and the ambulatory DBP by 4.3 mm Hg (95% CI, 2.82–5.80 mm Hg; P<0.01; Figure S3C and S3D); however, no significant changes were observed in the placebo group. Meanwhile, the taurine treatment did not influence the nighttime ABP (Figure S3E and S3F).

Figure 1. Effect of taurine supplementation on blood pressure (BP). A and B, Clinic systolic BPs (SBPs; A) and diastolic BPs (DBPs; B) of participants treated with placebo or taurine at baseline (0 weeks, Pre) and after treatment (12 weeks, Post). The data are presented as the mean±SD; ***P<0.001, compared with baseline values. C and D, Twenty-four–hour average ambulatory BPs of the participants at 0 week and 12 weeks compared with the corresponding baseline values. n=44 in the placebo group and n=42 in the taurine group, respectively; *P<0.05. E and F, Clinic SBPs and DBPs at 0, 4, 8, and 12 weeks in the 2 groups. *P<0.05 and **P<0.01 compared with the placebo group. G and H, Comparisons of BP changes between the prehypertensive participants with high- and low-normal BPs in the taurine group. *P<0.05. ns indicates not significant.Open in viewer

Chronic taurine supplementation time dependently decreased clinic BP. Compared with the placebo group, both the clinic SBP and DBP were significantly reduced at 8 and 12 weeks after taurine administration (Figure 1E and 1F; Figure S2C and S2D). Importantly, taurine supplementation for 12 weeks greatly reduced the BPs of the prehypertensive participants with high-normal BPs (SBP, 130–139/DBP, 85–89 mmHg) compared with the prehypertensive participants with low-normal BPs (SBP, 120–129 mm Hg; DBP, 80–84 mm Hg). Changes in the SBP of 10.1 mm Hg were observed in the high-normal BP group compared with changes of 3.0 mm Hg in the low-normal BP group (P<0.05; Figure 1G). However, the changes in the DBP were similar between these 2 subgroups (Figure 1H).

Taurine Supplementation Improves Vasodilation in Prehypertensive Individuals

Chronic taurine supplementation significantly improved both endothelium-dependent vasodilation (flow-mediated dilation) and endothelium-independent vasodilation (nitroglycerin-mediated dilation) by 3.2% and 4.4%, respectively, as measured via flow-mediated vasodilation using a sonographer in the prehypertensive individuals. However, the beneficial effect of taurine supplementation on vasodilation was absent in the prehypertensive individuals treated with placebo (Figure 2A–2D).

Figure 2. Effect of taurine supplementation on vasodilation. A and B, Flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD). The data are presented as the mean±SD. **P<0.01 and ***P<0.001, compared with pretreatment with taurine (Pre). C and D, Changes in FMD and NMD in the 2 groups. *P<0.05 and **P<0.01, compared with the placebo group. ns indicates not significant.Open in viewer

Taurine Supplementation Elevates Plasma Levels of Taurine and H2S in Association With BP Changes in Prehypertensive Individuals

After treatment for 12 weeks, the plasma taurine and H2S levels were significantly higher in the prehypertensive individuals treated with taurine (plasma H2S level: 43.8±20.82 µmol/L at baseline to 87.0±24.51 µmol/L after treatment; P<0.001 and plasma taurine level: 108.3±55.27 µmol/L at baseline to 142.3±62.14 µmol/L after treatment; P<0.05); however, these changes were not observed in the participants treated with placebo (Figure 3A and 3B). Furthermore, the changes in BP were negatively correlated with both the plasma H2S and taurine levels in the taurine-treated prehypertensive individuals (Figure 3C–3F), especially in the prehypertensive participants with a high-normal BP level (Figure S4A–S4C). In contrast, these associations between BP and the plasma levels of H2S and taurine were not observed in the participants treated with the placebo (Figure S5A–S5D).

Figure 3. Effects of taurine supplementation on plasma taurine and hydrogen sulfide (H2S) levels and their associations with blood pressure (BP) changes. A and B, Changes in the plasma H2S and taurine levels. The data are presented as the mean±SEM. *P<0.05 and ***P<0.001, compared with pretreatment with taurine (Pre). C–F, Correlations between BP changes and plasma H2S and taurine levels, respectively. DBP indicates diastolic BP; ns, not significant; and SBP, systolic BP.Open in viewer

Effects of Taurine on H2S-Synthesizing Enzymes, TRPC3, and Vascular Relaxation

To elucidate the mechanisms underlying the effects of taurine on BP and vascular functions, we further examined 2 key H2S-synthesizing enzymes, CBS and CSE. We showed that CBS and CSE were expressed in the endothelia and adventitia of mesenteric arteries (MAs) from human and aortas from mice. However, TRPC3 was mainly expressed in the media of arteries (Figure 4A and 4B). Western blotting also indicated that CBS, CSE, and TRPC3 were coexpressed in MAs from humans and aortas from Trpc3+/+ wild-type (WT) mice (Figure 4C and 4G). In addition, vascular CBS/CSE expression‎ was upregulated in Trpc3−/− mice compared with WT mice (Figure 4C and 4D). Administration of taurine significantly upregulated CBS/CSE expression‎ but inhibited TRPC3 expression‎ in both aortas from spontaneously hypertensive rats treated with taurine and cultured human vascular tissues (Figure 4E–4J). After depletion of intracellular calcium storage using thapsigargin, a sarcoplasmic reticulum Ca2+-ATPase inhibitor, KCl-induced vasoconstriction was dose dependently relaxed by NaHS, a H2S donor; however, this effect was enhanced by a TRPC3 inhibitor, Pyr3, or by Trpc3 gene knockout (Figure 4K and 4L). These findings indicate that TRPC3 might be involved in H2S-mediated vascular relaxation.

Figure 4. Effects of taurine on cystathionine-β-synthetase (CBS)/cystathionine-γ-lyase (CSE), transient receptor potential channel 3 (TRPC3), and vascular relaxation. A and B, The immunofluorescence staining results showing that CBS/CSE (red) and TRPC3 (green) were coexpressed in mesenteric arteries (MAs) from humans and in aortas from wild-type mice. 4′,6-Diamidino-2-phenylindole (DAPI) was also stained to show the existence of nuclei (blue). C and D, The expression‎ levels of CBS, CSE, and TRPC3 in aortas from Trpc3+/+ and Trpc3−/− mice were detected by Western blotting. The bands from 3 independent immunoblots were quantified using Image J, and the relative expression‎ levels are shown in (D). The data are presented as the mean±SEM; *P<0.05 and ***P<0.001, compared with that of Trpc3+/+ mice. E and F, Effects of in vivo taurine supplementation on the expression‎ levels of CBS, CSE, and TRPC3. Spontaneously hypertensive rats (SHRs) were fed 2% taurine for 12 weeks from 4-week old, and then aortas were obtained for Western blotting analysis. *P<0.05, compared with that of the normal diet (ND). G–J, Effect of in vitro taurine supplementation on the expression‎ levels of CBS, CSE, and TRPC3. Human MAs were treated with taurine (at doses of 0, 20, and 40 mmol/L) for 24 hours. *P<0.05 and **P<0.01, compared with the vehicles. K and L, Reactivities of human and mice MAs. After contraction induced using 60 mmol/L KCl, NaHS (10–5 to 10–3 mol/L) was added to promote vasodilation, and then the percentage of vasodilation was plotted. n=4; *P<0.05. TG indicates thapsigargin.Open in viewer

H2S Exerts Vascular Relaxation by Targeting TRPC3-Mediated Calcium Influx

We further examined H2S-induced vascular relaxation, which occurs through the targeting of TRPC3. Intact MAs were isolated from WT and Trpc3−/− mice. Calcium influx of intact blood vessels was measured using fluorescence techniques after depletion of intracellular calcium storage in the absence of external calcium. The phenylephrine-induced increase in calcium influx in the artery was completely abolished by the TRPC3 inhibitor Pyr3 after thapsigargin treatment (Figure S6A and S6B). Administration of NaHS significantly diminished the thapsigargin- and phenylephrine-induced increase in calcium influx in human MAs (Figure S6C–S6F). Furthermore, NaHS partially inhibited the thapsigargin-induced calcium influx in the Trpc3+/+ mice, but this effect was absent in intact arteries isolated from the Trpc3−/− mice (Figure S6G–S6N).

Discussion

To the best of our knowledge, this is the first randomized, double-blind, placebo-controlled clinical trial to investigate the effects of taurine supplementation in prehypertensive individuals. Furthermore, we have provided experimental evidence to facilitate elucidation of its mechanism of action. This study has revealed that oral taurine supplementation for 12 weeks significantly reduces the clinic and 24-hour ABPs in prehypertensive individuals, especially in those with high-normal BP. In addition, taurine treatment substantially promotes vasodilation and elevates the plasma taurine and H2S levels in these individuals. Furthermore, changes in BP were negatively correlated with the plasma taurine and H2S levels. However, these beneficial effects were absent in the prehypertensive individuals treated with placebo. In experimental studies, administration of taurine has been shown to enhance the expression‎ of H2S-synthesizing enzymes (CBS/CSE) and to reduce vascular TRPC3 expression‎ in spontaneously hypertensive rats. Furthermore, the vascular relaxation induced by the H2S donor NaHS is enhanced by TRPC3 antagonist treatment. These findings indicate that taurine intervention improves vascular tone by targeting the H2S-mediated inhibition of TRPC3-induced calcium influx.

Taurine is a sulfur-containing amino acid that is both cheap and nontoxic, and it is widely used as a functional dietary factor. Seafood containing an abundance of taurine improves cardiovascular and metabolic diseases, such as obesity, diabetes mellitus, and hyperlipidemia. In addition, taurine has multiple biological effects, such as protection against liver cirrhosis and antioxidative,27 anti-inflammatory, antiatherosclerotic,28,29 and antiobesity effects.30 Unfortunately, evidence that taurine supplementation reduces BP in human hypertension is inconclusive despite the fact that multiple experimental studies have demonstrated the hypotensive effect of taurine in different hypertensive animal models.

The antihypertensive effect of taurine in humans has only been confirmed in a few clinical studies with small sample sizes (n=10–12) that were short term (7 days to 6 weeks).31 One nonrandomized placebo-controlled trial showed that oral taurine supplementation (6 g per day) for 1 week decreased the SBP by 9.0 mm Hg and the DBP by 4.1 mm Hg in borderline hypertensive patients.9 In addition, taurine supplementation has been shown to lower BP by ≈22 to 49 mm Hg in different experimental hypertensive rats.31 Therefore, it remains unknown whether oral taurine supplementation is beneficial for prehypertensive individuals. In this randomized, double-blind, placebo-controlled study, we showed that administration of low-dose taurine (1.6 g per day) for 12 weeks can time dependently lower both clinic and ABPs and improve vascular relaxation. In particular, prehypertensive individuals with high-normal BP exhibited a better response to taurine than those with low-normal BP. Our study has provided the first solid evidence of the hypotensive effect of taurine in prehypertensive individuals.

Epidemiological studies have shown that the plasma taurine level is lower in patients with essential hypertension.12 Nara et al32 have reported that this level is decreased in spontaneously hypertensive rats in relation to the severity of hypertension. The plasma taurine level is negatively correlated with BP in hypertensive patients.14 Taurine deficiency in rats accelerates high salt intake–induced hypertension through renal dysfunction.15 Galloway et al33 reported that acute taurine treatment resulted in a 13-fold increase in the plasma taurine concentration, whereas no significant change in the muscle taurine concentration was observed. In this study, we found that chronic taurine treatment for 12 weeks resulted in an almost 1.5-fold increase of plasma taurine concentration in the prehypertensive individuals and that this increase was correlated with a reduction in BP. In addition, the prehypertensive individuals with a high end point plasma taurine level exhibited a greater hypotensive response to the taurine treatment.

The manner by which taurine exerts its hypotensive effect has been studied for a long time.16 Previous studies have shown that taurine supplementation improves endothelium-dependent vasodilation through restoration of vascular redox homeostasis and improvement of nitric oxide bioavailability.34 In addition, in human studies, improvement of flow-mediated dilation has been observed in response to dietary taurine supplementation in young smokers.35 The improved vascular function may facilitate the hypotensive effect and provide extra cardiovascular benefits. Available data suggest that the hypotensive effect of taurine does not occur through 1 specific mechanism but rather through multiple mechanisms.

In addition to nitric oxide and carbon monoxide, H2S, which is another important gas transmitter, has been widely studied in the cardiovascular system in recent years,36 and its vasodilatory effects have also been reported. H2S is endogenously produced from 2 sulfur-containing amino acids, l-cysteine and l-methionine, by the 2 H2S-synthesizing enzymes, CBS and CSE.24 Mutant mice lacking CSE display pronounced hypertension and reduced endothelium-dependent vasorelaxation, but this result was not confirmed by other studies.24 However, H2S replacement has been shown to reduce the SBP in both Cse−/− and Cse+/− mice,24 suggesting that the H2S synthases/H2S pathway confer protection against hypertension. Taurine, as a sulfur-containing amino acid, functions in the methionine cycle and can be converted by cysteine in the presence of cysteine dioxygenase,3 whereas H2S is synthesized from the 2 sulfur-containing amino acids, l-cysteine and l-methionine. This study has shown that taurine is probably a substrate for the synthesis of H2S to increase CBS and CSE expression‎. Therefore, we assumed that a correlation may exist between taurine and H2S. Taurine supplementation resulted in a significant elevation in the plasma H2S level in the prehypertensive individuals, and this elevation was correlated with a decrease in BP in the taurine group. Using MAs from healthy human volunteers and aortas from spontaneously hypertensive rats that were fed taurine for 3 months, we further demonstrated that taurine administration upregulated the expression‎ of vascular CBS/CSE, which caused the increased production of H2S in blood vessels in vitro and in vivo. Thus, other mechanisms of the vasorelaxant effect of H2S have also been identified involving opening of the ATP-sensitive potassium channels,23 interaction with nitric oxide pathways, functioning as an endothelium-derived hyperpolarizing factor, and direct activation of protein kinase G.37 Recently, Cheang et al38 and Tian et al39 have reported that H2S dilates blood vessels by opening voltage-gated potassium channels in rat coronary arteries and inhibits calcium channels in rat cerebral arteries, respectively. H2S has been demonstrated to regulate the activities of TRP channels in bone marrow mesenchymal stem cells through sulfhydration.4 Our previous work has demonstrated that TRPC3 upregulation and dysfunction in monocytes and in the vasculature from both genetically hypertensive rats and essential hypertensive patients play important roles in the pathogenesis of hypertension.25,26,40,41 In this study, we further verified that the H2S donor NaHS inhibited phenylephrine- and thapsigargin-induced Ca2+ influx and relaxation in MAs from human and Trpc3+/+ WT mice; however, this effect was absent in intact arteries from Trpc3−/− mice. Our work has revealed a novel unrecognized mechanism of taurine- and H2S-induced vasorelaxation that functions by enhancing the metabolism of sulfur-containing amino acids.

Study Limitations

The limitation of this study is that it was not performed across multiple centers. Further studies should validate whether this beneficial effect is present in other ethnicities and populations. In addition, the hypotensive effects of taurine have been reported to occur via the central nervous system,42,43 attenuation of the overactivity of the sympathetic system and increased urinary norepinephrine, and epinephrine excretion.31 An effect of taurine on BP occurring via the central nervous system cannot be excluded.31

Perspectives

Prehypertension plays an important role in the development of hypertension. Furthermore, prehypertension is closely associated with the morbidities of stroke, ischemic heart disease, and renal dysfunction. Although lifestyle modifications and an angiotensin II receptor blocker have been used to treat prehypertension, poor compliance and limitations of antihypertensive agents are the main obstacles of treatment. This randomized, double-blind, placebo-controlled clinical trial is the first to demonstrate that taurine supplementation significantly reduces BP and improves vascular function in prehypertensive individuals, especially in those with high-normal BP. Furthermore, changes in BP are correlated with both the plasma H2S and taurine levels in the taurine-treated prehypertensive individuals. We further demonstrate that the hypotensive effect of taurine involved the H2S-mediated inhibition of TRPC3-induced calcium influx. Taurine, as the most abundant, semiessential, sulfur-containing amino acid, is rich in seafood and easily consumed daily. Considering the elevated cardiometabolic risks of large populations of prehypertensive individuals, consumption of taurine-rich food may be a promising and cost-effective approach to prehypertension treatment.

Acknowledgments

We gratefully acknowledge the participation of all study subjects and the technical assistance of Tingbing Cao and Lijuan Wang (Chongqing Institute of Hypertension, Chongqing, China) with our experiments.

Novelty and Significance

What Is New?

•

This randomized, double-blind, placebo-controlled clinical trial is the first to demonstrate the hypotensive effect of taurine supplementation in prehypertensive individuals.

•

Taurine treatment remarkably improves blood pressure and vascular function, especially in prehypertensive individuals with high-normal blood pressure.

•

The hypotensive mechanism of taurine partially involves the hydrogen sulfide–mediated inhibition of transient receptor potential channel 3–induced calcium influx in the vasculature.

What Is Relevant?

•

Taurine supplementation results in a substantial, time-dependent reduction in blood pressure in prehypertensive individuals. Daily taurine supplementation promotes an additional decrease in blood pressure beyond that achieved with conventional lifestyle changes and pharmacotherapy.

Summary

Daily taurine supplementation is a novel strategy for lowering blood pressure in prehypertension, either as a dietary factor or in conjunction with conventional lifestyle changes.

Supplemental Material

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References

1.

Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903–1913.

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Arima H, Murakami Y, Lam TH, Kim HC, Ueshima H, Woo J, Suh I, Fang X, Woodward M; Asia Pacific Cohort Studies Collaboration. Effects of prehypertension and hypertension subtype on cardiovascular disease in the Asia-Pacific Region. Hypertension. 2012;59:1118–1123. doi: 10.1161/HYPERTENSIONAHA.111.187252.

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Ueki I, Roman HB, Valli A, Fieselmann K, Lam J, Peters R, Hirschberger LL, Stipanuk MH. Knockout of the murine cysteine dioxygenase gene results in severe impairment in ability to synthesize taurine and an increased catabolism of cysteine to hydrogen sulfide. Am J Physiol Endocrinol Metab. 2011;301:E668–E684. doi: 10.1152/ajpendo.00151.2011.

Taurine Supplementation Lowers Blood Pressure and Improves Vascular Function in Prehypertension: Randomized, Double-Blind, Placebo-Controlled Study

Qianqian Sun, Bin Wang, Yingsha Li, Fang Sun, Peng Li, Weijie Xia, Xunmei Zhou, … Show All … , and Zhiming ZhuAuthor Info & Affiliations

Hypertension

Volume 67, Number 3

https://doi.org/10.1161/HYPERTENSIONAHA.115.06624

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Abstract

Taurine, the most abundant, semiessential, sulfur-containing amino acid, is well known to lower blood pressure (BP) in hypertensive animal models. However, no rigorous clinical trial has validated whether this beneficial effect of taurine occurs in human hypertension or prehypertension, a key stage in the development of hypertension. In this randomized, double-blind, placebo-controlled study, we assessed the effects of taurine intervention on BP and vascular function in prehypertension. We randomly assigned 120 eligible prehypertensive individuals to receive either taurine supplementation (1.6 g per day) or a placebo for 12 weeks. Taurine supplementation significantly decreased the clinic and 24-hour ambulatory BPs, especially in those with high-normal BP. Mean clinic systolic BP reduction for taurine/placebo was 7.2/2.6 mm Hg, and diastolic BP was 4.7/1.3 mm Hg. Mean ambulatory systolic BP reduction for taurine/placebo was 3.8/0.3 mm Hg, and diastolic BP was 3.5/0.6 mm Hg. In addition, taurine supplementation significantly improved endothelium-dependent and endothelium-independent vasodilation and increased plasma H2S and taurine concentrations. Furthermore, changes in BP were negatively correlated with both the plasma H2S and taurine levels in taurine-treated prehypertensive individuals. To further elucidate the hypotensive mechanism, experimental studies were performed both in vivo and in vitro. The results showed that taurine treatment upregulated the expression‎ of hydrogen sulfide–synthesizing enzymes and reduced agonist-induced vascular reactivity through the inhibition of transient receptor potential channel subtype 3–mediated calcium influx in human and mouse mesenteric arteries. In conclusion, the antihypertensive effect of chronic taurine supplementation shows promise in the treatment of prehypertension through improvement of vascular function.

Introduction

Prehypertension is highly preval‎ent worldwide.1 It is estimated that ≈30% to 50% of the population have this condition. It frequently complicates other cardiometabolic risk factors and is closely associated with coronary heart disease, stroke, and renal dysfunction.2 Early intervention in prehypertension substantially prevents the incidence of hypertension and related damage to target organs. Currently, several strategies are used to treat prehypertension, including the incorporation of therapeutic lifestyle changes, such as healthy dietary intake and regular physical activity, as well as the use of antihypertensive drugs, such as an angiotensin II receptor blocker. Although these treatments improve prehypertension, poor compliance and limitations associated with antihypertensive medications prevent their application in the general population. Thus, there is an urgent need to identify reliable and accurate measures to prevent the development of prehypertension.

Taurine (2-aminoethanesulfonic acid) is the most abundant, semiessential, sulfur-containing amino acid. It can be synthesized in vivo by cysteine in the presence of cysteine dioxygenase,3 but taurine is mainly acquired from dietary sources, such as eggs, meat, and seafood. Hydrogen sulfide (H2S) is synthesized from 2 sulfur-containing amino acids, l-cysteine and l-methionine, by the 3 enzymes, cystathionine-γ-lyase (CSE), cystathionine-β-synthetase (CBS), and 3-mercaptopyruvate sulfurtransferase.4

Taurine has several potentially beneficial cardiovascular effects that involve regulation of the nitric oxide system and endothelial function,5,6 the renin–angiotensin–aldosterone system,7,8 the oxidative stress system and sympathoadrenal activity,9 and the endoplasmic reticulum stress system.10,11 Epidemiological studies have demonstrated a reduction in plasma sulfur amino acids in hypertensive patients.12 Several clinical studies have reported that diets rich in taurine can reduce cardiovascular risks regardless of ethnicity and genetic background.13,14 In addition, animal experiments have shown that taurine depletion accelerates the development of high salt–induced hypertension.15 Although taurine has been shown to lower blood pressure (BP) in several hypertensive animal models, few rigorous and long-term clinical trials have confirmed this beneficial effect in human hypertension.9

Another key question is what is the mechanism of the antihypertensive effects of taurine supplementation?16 Recent animal and human studies have shown that taurine supplementation lowers BP and improves vascular function, possibly through suppression of renin–angiotensin–aldosterone system activity,17,18 augmentation of kallikrein activity in the blood and peripheral tissues,19 suppression of the renal sympathetic nervous system,9,20 diuretic and natriuretic activities, and vasorelaxant activity.21 H2S can regulate vascular tone through several mechanisms, such as acting on ATP-sensitive potassium channels.22–24 A recent study has found that H2S also affects transient receptor potential channels (TRPCs) in mesenchymal stem cells and regulates calcium homeostasis.4 Our previous studies have demonstrated that TRPC3-mediated calcium signaling contributes to the development of hypertension,25,26 but it is unclear whether the hypotensive effects of taurine and H2S are associated with modulation of TRPC3 channels in the vasculature. In this study, we investigated the effects of chronic taurine supplementation on BP and vascular function in prehypertension by performing a randomized, double-blind, placebo-controlled clinical trial.

Methods

Detailed Methods are provided in the online-only Data Supplement.

Study Design and Procedures

This study was a prospective single-center, double-blind, randomized, placebo-controlled trial that was conducted in accordance with the CONSORT (Consolidated Standards of Reporting Trials) guidelines for the presentation of clinical trials (CONSORT 2010 Explanation and Elaboration) and the principles of the Declaration of Helsinki. The protocol was approved by the ethics committee of the Daping Hospital, Third Military Medical University. The protocol is registered in the US National Library of Medicine (http://www.ClinicalTrials.gov, identifier: NCT01816698).

Participants were recruited at the Center for Hypertension and Metabolic Diseases of Chongqing from December 2012 to December 2014. They were screened for eligibility after written informed consent was obtained. The prehypertension inclusion criteria for the first visit included the following: an age of between 18 and 75 years and an systolic BP (SBP) of 120 to 139 mm Hg or a diastolic BP (DBP) of 80 to 89 mm Hg, as determined by performing repeated measurements with a mercury sphygmomanometer. The main exclusion criteria included the following: clinical evidence of recent infection, pregnancy, coronary artery disease, peripheral vascular disease, cerebrovascular disease, renal dysfunction, diabetes mellitus, hypertension, tumor, mental disease, the use of other medications, or being enrolled in another trial within the last 3 months.

In total, 120 untreated participants (51 men and 69 women; age, 56.75±8.26 years) and 58 age-matched normotensive control subjects without taurine supplementation were enrolled only as baseline comparison in the study. These untreated participants were randomly assigned to either a placebo group or a taurine group (Figure S1 in the online-only Data Supplement). All subjects completed a standardized questionnaire administered by trained personnel on their history of cardiovascular diseases and other illnesses. All subjects were asked not to alter their usual diet over the course of the 12-week study. They all underwent standardized clinical and laboratory examinations. BP was measured by a physician using a mercury sphygmomanometer after each subject had rested for at least 5 minutes in the seated position. Three measurements were obtained at 1-minute intervals, and the average was used to define the SBP and DBP. Laboratory tests were performed after an overnight fast, including measurements of fasting plasma glucose, triglyceride, cholesterol, hepatic enzyme, uric acid, blood urea nitrogen, and serum creatine levels.

Statistical Analysis

For all participants, we analyzed the changes from baseline (randomization) to 12 weeks in BP, vascular functions, biochemical and renal parameters, and other parameters. The sample size was chosen to ensure for 90% power to detect a 3-mm Hg difference in our primary outcome, a change in SBP, with a 2-sided significance level of 0.05 and assuming a dropout rate of 20%, according to previous published data and a preliminary trial of prehypertensive participants. All analyses were based on intention-to-treat populations (defined as all patients who took at least 1 dose and had at least 1 efficacy measurement available after randomization), with the last value carried forward for missing values. Comparisons of continuous variables between the placebo and taurine groups were analyzed using the Mann–Whitney test (GraphPad Prism; La Jolla, CA). Comparisons of variables before and after treatments were analyzed using the Wilcoxon signed-rank matched pair test. The χ2 test was used for categorical variables. Spearman nonparametric correlation analysis was performed to determine the relationships between BP changes and other factors. The immunoblotting results, wire myograph results, and PTI (Photon Technology International) results were compared using the Mann–Whitney test. A 2-tailed P<0.05 was considered statistically significant. The data were expressed as mean±SEM or SD for normally distributed variables and median (25th and 75th percentiles) for non-normally distributed variables, and all the results were analyzed using SPSS 18.0.

ResultsBaseline Characteristics of Participants

Compared with the normal controls, the enrolled prehypertensive participants had higher clinic and ambulatory BPs (ABPs) and increased pulse wave velocity and postprandial blood glucose values. In addition, there were no significant differences in the baseline characteristics between the placebo and taurine groups (Table S1). Of 793 participants screened in the study, 120 untreated participants were randomized; of whom, 97 completed the entire study protocol and had complete data, with a loss rate of 19.2% (Figure S1). Both the taurine and placebo interventions were well tolerated, and no serious adverse events were reported by any of the participants.

Chronic Taurine Supplementation Reduces BP in Prehypertensive Individuals

Administration of taurine for 12 weeks significantly reduced BP. The clinic SBP and DBP decreased in the taurine group by 7.2 mm Hg (95% confidence interval [CI], 3.75–10.55; P<0.001) and 4.7 mm Hg (95% CI, 2.16–7.14; P<0.001), respectively, compared with the baseline values; however, these changes were not evident in the placebo group (Figure 1A and 1B; Figure S2A and S2B; Table S2). Similarly, the 24-hour ABP in the taurine group exhibited a similar pattern, with mean decreases in the SBP and DBP of 3.8 mm Hg (95% CI, 1.97–5.56; P<0.05) and 3.5 mm Hg (95% CI, 2.14–4.81; P<0.05), respectively, compared with the baseline values; however, no changes were observed in the placebo-treated group (Figure 1C and 1D; Figure S3A and S3B; Table S2; n=44 in the placebo group and n=42 in the taurine group, respectively). Further analysis revealed that taurine treatment reduced the daytime ambulatory SBP and DBP compared with the baseline values, thereby decreasing the ambulatory SBP by 4.5 mm Hg (95% CI, 2.21–6.79 mm Hg; P<0.05) and the ambulatory DBP by 4.3 mm Hg (95% CI, 2.82–5.80 mm Hg; P<0.01; Figure S3C and S3D); however, no significant changes were observed in the placebo group. Meanwhile, the taurine treatment did not influence the nighttime ABP (Figure S3E and S3F).

Figure 1. Effect of taurine supplementation on blood pressure (BP). A and B, Clinic systolic BPs (SBPs; A) and diastolic BPs (DBPs; B) of participants treated with placebo or taurine at baseline (0 weeks, Pre) and after treatment (12 weeks, Post). The data are presented as the mean±SD; ***P<0.001, compared with baseline values. C and D, Twenty-four–hour average ambulatory BPs of the participants at 0 week and 12 weeks compared with the corresponding baseline values. n=44 in the placebo group and n=42 in the taurine group, respectively; *P<0.05. E and F, Clinic SBPs and DBPs at 0, 4, 8, and 12 weeks in the 2 groups. *P<0.05 and **P<0.01 compared with the placebo group. G and H, Comparisons of BP changes between the prehypertensive participants with high- and low-normal BPs in the taurine group. *P<0.05. ns indicates not significant.Open in viewer

Chronic taurine supplementation time dependently decreased clinic BP. Compared with the placebo group, both the clinic SBP and DBP were significantly reduced at 8 and 12 weeks after taurine administration (Figure 1E and 1F; Figure S2C and S2D). Importantly, taurine supplementation for 12 weeks greatly reduced the BPs of the prehypertensive participants with high-normal BPs (SBP, 130–139/DBP, 85–89 mmHg) compared with the prehypertensive participants with low-normal BPs (SBP, 120–129 mm Hg; DBP, 80–84 mm Hg). Changes in the SBP of 10.1 mm Hg were observed in the high-normal BP group compared with changes of 3.0 mm Hg in the low-normal BP group (P<0.05; Figure 1G). However, the changes in the DBP were similar between these 2 subgroups (Figure 1H).

Taurine Supplementation Improves Vasodilation in Prehypertensive Individuals

Chronic taurine supplementation significantly improved both endothelium-dependent vasodilation (flow-mediated dilation) and endothelium-independent vasodilation (nitroglycerin-mediated dilation) by 3.2% and 4.4%, respectively, as measured via flow-mediated vasodilation using a sonographer in the prehypertensive individuals. However, the beneficial effect of taurine supplementation on vasodilation was absent in the prehypertensive individuals treated with placebo (Figure 2A–2D).

Figure 2. Effect of taurine supplementation on vasodilation. A and B, Flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD). The data are presented as the mean±SD. **P<0.01 and ***P<0.001, compared with pretreatment with taurine (Pre). C and D, Changes in FMD and NMD in the 2 groups. *P<0.05 and **P<0.01, compared with the placebo group. ns indicates not significant.Open in viewer

Taurine Supplementation Elevates Plasma Levels of Taurine and H2S in Association With BP Changes in Prehypertensive Individuals

After treatment for 12 weeks, the plasma taurine and H2S levels were significantly higher in the prehypertensive individuals treated with taurine (plasma H2S level: 43.8±20.82 µmol/L at baseline to 87.0±24.51 µmol/L after treatment; P<0.001 and plasma taurine level: 108.3±55.27 µmol/L at baseline to 142.3±62.14 µmol/L after treatment; P<0.05); however, these changes were not observed in the participants treated with placebo (Figure 3A and 3B). Furthermore, the changes in BP were negatively correlated with both the plasma H2S and taurine levels in the taurine-treated prehypertensive individuals (Figure 3C–3F), especially in the prehypertensive participants with a high-normal BP level (Figure S4A–S4C). In contrast, these associations between BP and the plasma levels of H2S and taurine were not observed in the participants treated with the placebo (Figure S5A–S5D).

Figure 3. Effects of taurine supplementation on plasma taurine and hydrogen sulfide (H2S) levels and their associations with blood pressure (BP) changes. A and B, Changes in the plasma H2S and taurine levels. The data are presented as the mean±SEM. *P<0.05 and ***P<0.001, compared with pretreatment with taurine (Pre). C–F, Correlations between BP changes and plasma H2S and taurine levels, respectively. DBP indicates diastolic BP; ns, not significant; and SBP, systolic BP.Open in viewer

Effects of Taurine on H2S-Synthesizing Enzymes, TRPC3, and Vascular Relaxation

To elucidate the mechanisms underlying the effects of taurine on BP and vascular functions, we further examined 2 key H2S-synthesizing enzymes, CBS and CSE. We showed that CBS and CSE were expressed in the endothelia and adventitia of mesenteric arteries (MAs) from human and aortas from mice. However, TRPC3 was mainly expressed in the media of arteries (Figure 4A and 4B). Western blotting also indicated that CBS, CSE, and TRPC3 were coexpressed in MAs from humans and aortas from Trpc3+/+ wild-type (WT) mice (Figure 4C and 4G). In addition, vascular CBS/CSE expression‎ was upregulated in Trpc3−/− mice compared with WT mice (Figure 4C and 4D). Administration of taurine significantly upregulated CBS/CSE expression‎ but inhibited TRPC3 expression‎ in both aortas from spontaneously hypertensive rats treated with taurine and cultured human vascular tissues (Figure 4E–4J). After depletion of intracellular calcium storage using thapsigargin, a sarcoplasmic reticulum Ca2+-ATPase inhibitor, KCl-induced vasoconstriction was dose dependently relaxed by NaHS, a H2S donor; however, this effect was enhanced by a TRPC3 inhibitor, Pyr3, or by Trpc3 gene knockout (Figure 4K and 4L). These findings indicate that TRPC3 might be involved in H2S-mediated vascular relaxation.

Figure 4. Effects of taurine on cystathionine-β-synthetase (CBS)/cystathionine-γ-lyase (CSE), transient receptor potential channel 3 (TRPC3), and vascular relaxation. A and B, The immunofluorescence staining results showing that CBS/CSE (red) and TRPC3 (green) were coexpressed in mesenteric arteries (MAs) from humans and in aortas from wild-type mice. 4′,6-Diamidino-2-phenylindole (DAPI) was also stained to show the existence of nuclei (blue). C and D, The expression‎ levels of CBS, CSE, and TRPC3 in aortas from Trpc3+/+ and Trpc3−/− mice were detected by Western blotting. The bands from 3 independent immunoblots were quantified using Image J, and the relative expression‎ levels are shown in (D). The data are presented as the mean±SEM; *P<0.05 and ***P<0.001, compared with that of Trpc3+/+ mice. E and F, Effects of in vivo taurine supplementation on the expression‎ levels of CBS, CSE, and TRPC3. Spontaneously hypertensive rats (SHRs) were fed 2% taurine for 12 weeks from 4-week old, and then aortas were obtained for Western blotting analysis. *P<0.05, compared with that of the normal diet (ND). G–J, Effect of in vitro taurine supplementation on the expression‎ levels of CBS, CSE, and TRPC3. Human MAs were treated with taurine (at doses of 0, 20, and 40 mmol/L) for 24 hours. *P<0.05 and **P<0.01, compared with the vehicles. K and L, Reactivities of human and mice MAs. After contraction induced using 60 mmol/L KCl, NaHS (10–5 to 10–3 mol/L) was added to promote vasodilation, and then the percentage of vasodilation was plotted. n=4; *P<0.05. TG indicates thapsigargin.Open in viewer

H2S Exerts Vascular Relaxation by Targeting TRPC3-Mediated Calcium Influx

We further examined H2S-induced vascular relaxation, which occurs through the targeting of TRPC3. Intact MAs were isolated from WT and Trpc3−/− mice. Calcium influx of intact blood vessels was measured using fluorescence techniques after depletion of intracellular calcium storage in the absence of external calcium. The phenylephrine-induced increase in calcium influx in the artery was completely abolished by the TRPC3 inhibitor Pyr3 after thapsigargin treatment (Figure S6A and S6B). Administration of NaHS significantly diminished the thapsigargin- and phenylephrine-induced increase in calcium influx in human MAs (Figure S6C–S6F). Furthermore, NaHS partially inhibited the thapsigargin-induced calcium influx in the Trpc3+/+ mice, but this effect was absent in intact arteries isolated from the Trpc3−/− mice (Figure S6G–S6N).

Discussion

To the best of our knowledge, this is the first randomized, double-blind, placebo-controlled clinical trial to investigate the effects of taurine supplementation in prehypertensive individuals. Furthermore, we have provided experimental evidence to facilitate elucidation of its mechanism of action. This study has revealed that oral taurine supplementation for 12 weeks significantly reduces the clinic and 24-hour ABPs in prehypertensive individuals, especially in those with high-normal BP. In addition, taurine treatment substantially promotes vasodilation and elevates the plasma taurine and H2S levels in these individuals. Furthermore, changes in BP were negatively correlated with the plasma taurine and H2S levels. However, these beneficial effects were absent in the prehypertensive individuals treated with placebo. In experimental studies, administration of taurine has been shown to enhance the expression‎ of H2S-synthesizing enzymes (CBS/CSE) and to reduce vascular TRPC3 expression‎ in spontaneously hypertensive rats. Furthermore, the vascular relaxation induced by the H2S donor NaHS is enhanced by TRPC3 antagonist treatment. These findings indicate that taurine intervention improves vascular tone by targeting the H2S-mediated inhibition of TRPC3-induced calcium influx.

Taurine is a sulfur-containing amino acid that is both cheap and nontoxic, and it is widely used as a functional dietary factor. Seafood containing an abundance of taurine improves cardiovascular and metabolic diseases, such as obesity, diabetes mellitus, and hyperlipidemia. In addition, taurine has multiple biological effects, such as protection against liver cirrhosis and antioxidative,27 anti-inflammatory, antiatherosclerotic,28,29 and antiobesity effects.30 Unfortunately, evidence that taurine supplementation reduces BP in human hypertension is inconclusive despite the fact that multiple experimental studies have demonstrated the hypotensive effect of taurine in different hypertensive animal models.

The antihypertensive effect of taurine in humans has only been confirmed in a few clinical studies with small sample sizes (n=10–12) that were short term (7 days to 6 weeks).31 One nonrandomized placebo-controlled trial showed that oral taurine supplementation (6 g per day) for 1 week decreased the SBP by 9.0 mm Hg and the DBP by 4.1 mm Hg in borderline hypertensive patients.9 In addition, taurine supplementation has been shown to lower BP by ≈22 to 49 mm Hg in different experimental hypertensive rats.31 Therefore, it remains unknown whether oral taurine supplementation is beneficial for prehypertensive individuals. In this randomized, double-blind, placebo-controlled study, we showed that administration of low-dose taurine (1.6 g per day) for 12 weeks can time dependently lower both clinic and ABPs and improve vascular relaxation. In particular, prehypertensive individuals with high-normal BP exhibited a better response to taurine than those with low-normal BP. Our study has provided the first solid evidence of the hypotensive effect of taurine in prehypertensive individuals.

Epidemiological studies have shown that the plasma taurine level is lower in patients with essential hypertension.12 Nara et al32 have reported that this level is decreased in spontaneously hypertensive rats in relation to the severity of hypertension. The plasma taurine level is negatively correlated with BP in hypertensive patients.14 Taurine deficiency in rats accelerates high salt intake–induced hypertension through renal dysfunction.15 Galloway et al33 reported that acute taurine treatment resulted in a 13-fold increase in the plasma taurine concentration, whereas no significant change in the muscle taurine concentration was observed. In this study, we found that chronic taurine treatment for 12 weeks resulted in an almost 1.5-fold increase of plasma taurine concentration in the prehypertensive individuals and that this increase was correlated with a reduction in BP. In addition, the prehypertensive individuals with a high end point plasma taurine level exhibited a greater hypotensive response to the taurine treatment.

The manner by which taurine exerts its hypotensive effect has been studied for a long time.16 Previous studies have shown that taurine supplementation improves endothelium-dependent vasodilation through restoration of vascular redox homeostasis and improvement of nitric oxide bioavailability.34 In addition, in human studies, improvement of flow-mediated dilation has been observed in response to dietary taurine supplementation in young smokers.35 The improved vascular function may facilitate the hypotensive effect and provide extra cardiovascular benefits. Available data suggest that the hypotensive effect of taurine does not occur through 1 specific mechanism but rather through multiple mechanisms.

In addition to nitric oxide and carbon monoxide, H2S, which is another important gas transmitter, has been widely studied in the cardiovascular system in recent years,36 and its vasodilatory effects have also been reported. H2S is endogenously produced from 2 sulfur-containing amino acids, l-cysteine and l-methionine, by the 2 H2S-synthesizing enzymes, CBS and CSE.24 Mutant mice lacking CSE display pronounced hypertension and reduced endothelium-dependent vasorelaxation, but this result was not confirmed by other studies.24 However, H2S replacement has been shown to reduce the SBP in both Cse−/− and Cse+/− mice,24 suggesting that the H2S synthases/H2S pathway confer protection against hypertension. Taurine, as a sulfur-containing amino acid, functions in the methionine cycle and can be converted by cysteine in the presence of cysteine dioxygenase,3 whereas H2S is synthesized from the 2 sulfur-containing amino acids, l-cysteine and l-methionine. This study has shown that taurine is probably a substrate for the synthesis of H2S to increase CBS and CSE expression‎. Therefore, we assumed that a correlation may exist between taurine and H2S. Taurine supplementation resulted in a significant elevation in the plasma H2S level in the prehypertensive individuals, and this elevation was correlated with a decrease in BP in the taurine group. Using MAs from healthy human volunteers and aortas from spontaneously hypertensive rats that were fed taurine for 3 months, we further demonstrated that taurine administration upregulated the expression‎ of vascular CBS/CSE, which caused the increased production of H2S in blood vessels in vitro and in vivo. Thus, other mechanisms of the vasorelaxant effect of H2S have also been identified involving opening of the ATP-sensitive potassium channels,23 interaction with nitric oxide pathways, functioning as an endothelium-derived hyperpolarizing factor, and direct activation of protein kinase G.37 Recently, Cheang et al38 and Tian et al39 have reported that H2S dilates blood vessels by opening voltage-gated potassium channels in rat coronary arteries and inhibits calcium channels in rat cerebral arteries, respectively. H2S has been demonstrated to regulate the activities of TRP channels in bone marrow mesenchymal stem cells through sulfhydration.4 Our previous work has demonstrated that TRPC3 upregulation and dysfunction in monocytes and in the vasculature from both genetically hypertensive rats and essential hypertensive patients play important roles in the pathogenesis of hypertension.25,26,40,41 In this study, we further verified that the H2S donor NaHS inhibited phenylephrine- and thapsigargin-induced Ca2+ influx and relaxation in MAs from human and Trpc3+/+ WT mice; however, this effect was absent in intact arteries from Trpc3−/− mice. Our work has revealed a novel unrecognized mechanism of taurine- and H2S-induced vasorelaxation that functions by enhancing the metabolism of sulfur-containing amino acids.

Study Limitations

The limitation of this study is that it was not performed across multiple centers. Further studies should validate whether this beneficial effect is present in other ethnicities and populations. In addition, the hypotensive effects of taurine have been reported to occur via the central nervous system,42,43 attenuation of the overactivity of the sympathetic system and increased urinary norepinephrine, and epinephrine excretion.31 An effect of taurine on BP occurring via the central nervous system cannot be excluded.31

Perspectives

Prehypertension plays an important role in the development of hypertension. Furthermore, prehypertension is closely associated with the morbidities of stroke, ischemic heart disease, and renal dysfunction. Although lifestyle modifications and an angiotensin II receptor blocker have been used to treat prehypertension, poor compliance and limitations of antihypertensive agents are the main obstacles of treatment. This randomized, double-blind, placebo-controlled clinical trial is the first to demonstrate that taurine supplementation significantly reduces BP and improves vascular function in prehypertensive individuals, especially in those with high-normal BP. Furthermore, changes in BP are correlated with both the plasma H2S and taurine levels in the taurine-treated prehypertensive individuals. We further demonstrate that the hypotensive effect of taurine involved the H2S-mediated inhibition of TRPC3-induced calcium influx. Taurine, as the most abundant, semiessential, sulfur-containing amino acid, is rich in seafood and easily consumed daily. Considering the elevated cardiometabolic risks of large populations of prehypertensive individuals, consumption of taurine-rich food may be a promising and cost-effective approach to prehypertension treatment.

Acknowledgments

We gratefully acknowledge the participation of all study subjects and the technical assistance of Tingbing Cao and Lijuan Wang (Chongqing Institute of Hypertension, Chongqing, China) with our experiments.

Novelty and Significance

What Is New?

•

This randomized, double-blind, placebo-controlled clinical trial is the first to demonstrate the hypotensive effect of taurine supplementation in prehypertensive individuals.

•

Taurine treatment remarkably improves blood pressure and vascular function, especially in prehypertensive individuals with high-normal blood pressure.

•

The hypotensive mechanism of taurine partially involves the hydrogen sulfide–mediated inhibition of transient receptor potential channel 3–induced calcium influx in the vasculature.

What Is Relevant?

•

Taurine supplementation results in a substantial, time-dependent reduction in blood pressure in prehypertensive individuals. Daily taurine supplementation promotes an additional decrease in blood pressure beyond that achieved with conventional lifestyle changes and pharmacotherapy.

Summary

Daily taurine supplementation is a novel strategy for lowering blood pressure in prehypertension, either as a dietary factor or in conjunction with conventional lifestyle changes.

Supplemental Material

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References

1.

Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903–1913.

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Arima H, Murakami Y, Lam TH, Kim HC, Ueshima H, Woo J, Suh I, Fang X, Woodward M; Asia Pacific Cohort Studies Collaboration. Effects of prehypertension and hypertension subtype on cardiovascular disease in the Asia-Pacific Region. Hypertension. 2012;59:1118–1123. doi: 10.1161/HYPERTENSIONAHA.111.187252.

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Ueki I, Roman HB, Valli A, Fieselmann K, Lam J, Peters R, Hirschberger LL, Stipanuk MH. Knockout of the murine cysteine dioxygenase gene results in severe impairment in ability to synthesize taurine and an increased catabolism of cysteine to hydrogen sulfide. Am J Physiol Endocrinol Metab. 2011;301:E668–E684. doi: 10.1152/ajpendo.00151.2011.

Taurine Supplementation Lowers Blood Pressure and Improves Vascular Function in Prehypertension: Randomized, Double-Blind, Placebo-Controlled Study

Qianqian Sun, Bin Wang, Yingsha Li, Fang Sun, Peng Li, Weijie Xia, Xunmei Zhou, … Show All … , and Zhiming ZhuAuthor Info & Affiliations

Hypertension

Volume 67, Number 3

https://doi.org/10.1161/HYPERTENSIONAHA.115.06624

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Abstract

Taurine, the most abundant, semiessential, sulfur-containing amino acid, is well known to lower blood pressure (BP) in hypertensive animal models. However, no rigorous clinical trial has validated whether this beneficial effect of taurine occurs in human hypertension or prehypertension, a key stage in the development of hypertension. In this randomized, double-blind, placebo-controlled study, we assessed the effects of taurine intervention on BP and vascular function in prehypertension. We randomly assigned 120 eligible prehypertensive individuals to receive either taurine supplementation (1.6 g per day) or a placebo for 12 weeks. Taurine supplementation significantly decreased the clinic and 24-hour ambulatory BPs, especially in those with high-normal BP. Mean clinic systolic BP reduction for taurine/placebo was 7.2/2.6 mm Hg, and diastolic BP was 4.7/1.3 mm Hg. Mean ambulatory systolic BP reduction for taurine/placebo was 3.8/0.3 mm Hg, and diastolic BP was 3.5/0.6 mm Hg. In addition, taurine supplementation significantly improved endothelium-dependent and endothelium-independent vasodilation and increased plasma H2S and taurine concentrations. Furthermore, changes in BP were negatively correlated with both the plasma H2S and taurine levels in taurine-treated prehypertensive individuals. To further elucidate the hypotensive mechanism, experimental studies were performed both in vivo and in vitro. The results showed that taurine treatment upregulated the expression‎ of hydrogen sulfide–synthesizing enzymes and reduced agonist-induced vascular reactivity through the inhibition of transient receptor potential channel subtype 3–mediated calcium influx in human and mouse mesenteric arteries. In conclusion, the antihypertensive effect of chronic taurine supplementation shows promise in the treatment of prehypertension through improvement of vascular function.

Introduction

Prehypertension is highly preval‎ent worldwide.1 It is estimated that ≈30% to 50% of the population have this condition. It frequently complicates other cardiometabolic risk factors and is closely associated with coronary heart disease, stroke, and renal dysfunction.2 Early intervention in prehypertension substantially prevents the incidence of hypertension and related damage to target organs. Currently, several strategies are used to treat prehypertension, including the incorporation of therapeutic lifestyle changes, such as healthy dietary intake and regular physical activity, as well as the use of antihypertensive drugs, such as an angiotensin II receptor blocker. Although these treatments improve prehypertension, poor compliance and limitations associated with antihypertensive medications prevent their application in the general population. Thus, there is an urgent need to identify reliable and accurate measures to prevent the development of prehypertension.

Taurine (2-aminoethanesulfonic acid) is the most abundant, semiessential, sulfur-containing amino acid. It can be synthesized in vivo by cysteine in the presence of cysteine dioxygenase,3 but taurine is mainly acquired from dietary sources, such as eggs, meat, and seafood. Hydrogen sulfide (H2S) is synthesized from 2 sulfur-containing amino acids, l-cysteine and l-methionine, by the 3 enzymes, cystathionine-γ-lyase (CSE), cystathionine-β-synthetase (CBS), and 3-mercaptopyruvate sulfurtransferase.4

Taurine has several potentially beneficial cardiovascular effects that involve regulation of the nitric oxide system and endothelial function,5,6 the renin–angiotensin–aldosterone system,7,8 the oxidative stress system and sympathoadrenal activity,9 and the endoplasmic reticulum stress system.10,11 Epidemiological studies have demonstrated a reduction in plasma sulfur amino acids in hypertensive patients.12 Several clinical studies have reported that diets rich in taurine can reduce cardiovascular risks regardless of ethnicity and genetic background.13,14 In addition, animal experiments have shown that taurine depletion accelerates the development of high salt–induced hypertension.15 Although taurine has been shown to lower blood pressure (BP) in several hypertensive animal models, few rigorous and long-term clinical trials have confirmed this beneficial effect in human hypertension.9

Another key question is what is the mechanism of the antihypertensive effects of taurine supplementation?16 Recent animal and human studies have shown that taurine supplementation lowers BP and improves vascular function, possibly through suppression of renin–angiotensin–aldosterone system activity,17,18 augmentation of kallikrein activity in the blood and peripheral tissues,19 suppression of the renal sympathetic nervous system,9,20 diuretic and natriuretic activities, and vasorelaxant activity.21 H2S can regulate vascular tone through several mechanisms, such as acting on ATP-sensitive potassium channels.22–24 A recent study has found that H2S also affects transient receptor potential channels (TRPCs) in mesenchymal stem cells and regulates calcium homeostasis.4 Our previous studies have demonstrated that TRPC3-mediated calcium signaling contributes to the development of hypertension,25,26 but it is unclear whether the hypotensive effects of taurine and H2S are associated with modulation of TRPC3 channels in the vasculature. In this study, we investigated the effects of chronic taurine supplementation on BP and vascular function in prehypertension by performing a randomized, double-blind, placebo-controlled clinical trial.

Methods

Detailed Methods are provided in the online-only Data Supplement.

Study Design and Procedures

This study was a prospective single-center, double-blind, randomized, placebo-controlled trial that was conducted in accordance with the CONSORT (Consolidated Standards of Reporting Trials) guidelines for the presentation of clinical trials (CONSORT 2010 Explanation and Elaboration) and the principles of the Declaration of Helsinki. The protocol was approved by the ethics committee of the Daping Hospital, Third Military Medical University. The protocol is registered in the US National Library of Medicine (http://www.ClinicalTrials.gov, identifier: NCT01816698).

Participants were recruited at the Center for Hypertension and Metabolic Diseases of Chongqing from December 2012 to December 2014. They were screened for eligibility after written informed consent was obtained. The prehypertension inclusion criteria for the first visit included the following: an age of between 18 and 75 years and an systolic BP (SBP) of 120 to 139 mm Hg or a diastolic BP (DBP) of 80 to 89 mm Hg, as determined by performing repeated measurements with a mercury sphygmomanometer. The main exclusion criteria included the following: clinical evidence of recent infection, pregnancy, coronary artery disease, peripheral vascular disease, cerebrovascular disease, renal dysfunction, diabetes mellitus, hypertension, tumor, mental disease, the use of other medications, or being enrolled in another trial within the last 3 months.

In total, 120 untreated participants (51 men and 69 women; age, 56.75±8.26 years) and 58 age-matched normotensive control subjects without taurine supplementation were enrolled only as baseline comparison in the study. These untreated participants were randomly assigned to either a placebo group or a taurine group (Figure S1 in the online-only Data Supplement). All subjects completed a standardized questionnaire administered by trained personnel on their history of cardiovascular diseases and other illnesses. All subjects were asked not to alter their usual diet over the course of the 12-week study. They all underwent standardized clinical and laboratory examinations. BP was measured by a physician using a mercury sphygmomanometer after each subject had rested for at least 5 minutes in the seated position. Three measurements were obtained at 1-minute intervals, and the average was used to define the SBP and DBP. Laboratory tests were performed after an overnight fast, including measurements of fasting plasma glucose, triglyceride, cholesterol, hepatic enzyme, uric acid, blood urea nitrogen, and serum creatine levels.

Statistical Analysis

For all participants, we analyzed the changes from baseline (randomization) to 12 weeks in BP, vascular functions, biochemical and renal parameters, and other parameters. The sample size was chosen to ensure for 90% power to detect a 3-mm Hg difference in our primary outcome, a change in SBP, with a 2-sided significance level of 0.05 and assuming a dropout rate of 20%, according to previous published data and a preliminary trial of prehypertensive participants. All analyses were based on intention-to-treat populations (defined as all patients who took at least 1 dose and had at least 1 efficacy measurement available after randomization), with the last value carried forward for missing values. Comparisons of continuous variables between the placebo and taurine groups were analyzed using the Mann–Whitney test (GraphPad Prism; La Jolla, CA). Comparisons of variables before and after treatments were analyzed using the Wilcoxon signed-rank matched pair test. The χ2 test was used for categorical variables. Spearman nonparametric correlation analysis was performed to determine the relationships between BP changes and other factors. The immunoblotting results, wire myograph results, and PTI (Photon Technology International) results were compared using the Mann–Whitney test. A 2-tailed P<0.05 was considered statistically significant. The data were expressed as mean±SEM or SD for normally distributed variables and median (25th and 75th percentiles) for non-normally distributed variables, and all the results were analyzed using SPSS 18.0.

ResultsBaseline Characteristics of Participants

Compared with the normal controls, the enrolled prehypertensive participants had higher clinic and ambulatory BPs (ABPs) and increased pulse wave velocity and postprandial blood glucose values. In addition, there were no significant differences in the baseline characteristics between the placebo and taurine groups (Table S1). Of 793 participants screened in the study, 120 untreated participants were randomized; of whom, 97 completed the entire study protocol and had complete data, with a loss rate of 19.2% (Figure S1). Both the taurine and placebo interventions were well tolerated, and no serious adverse events were reported by any of the participants.

Chronic Taurine Supplementation Reduces BP in Prehypertensive Individuals

Administration of taurine for 12 weeks significantly reduced BP. The clinic SBP and DBP decreased in the taurine group by 7.2 mm Hg (95% confidence interval [CI], 3.75–10.55; P<0.001) and 4.7 mm Hg (95% CI, 2.16–7.14; P<0.001), respectively, compared with the baseline values; however, these changes were not evident in the placebo group (Figure 1A and 1B; Figure S2A and S2B; Table S2). Similarly, the 24-hour ABP in the taurine group exhibited a similar pattern, with mean decreases in the SBP and DBP of 3.8 mm Hg (95% CI, 1.97–5.56; P<0.05) and 3.5 mm Hg (95% CI, 2.14–4.81; P<0.05), respectively, compared with the baseline values; however, no changes were observed in the placebo-treated group (Figure 1C and 1D; Figure S3A and S3B; Table S2; n=44 in the placebo group and n=42 in the taurine group, respectively). Further analysis revealed that taurine treatment reduced the daytime ambulatory SBP and DBP compared with the baseline values, thereby decreasing the ambulatory SBP by 4.5 mm Hg (95% CI, 2.21–6.79 mm Hg; P<0.05) and the ambulatory DBP by 4.3 mm Hg (95% CI, 2.82–5.80 mm Hg; P<0.01; Figure S3C and S3D); however, no significant changes were observed in the placebo group. Meanwhile, the taurine treatment did not influence the nighttime ABP (Figure S3E and S3F).

Figure 1. Effect of taurine supplementation on blood pressure (BP). A and B, Clinic systolic BPs (SBPs; A) and diastolic BPs (DBPs; B) of participants treated with placebo or taurine at baseline (0 weeks, Pre) and after treatment (12 weeks, Post). The data are presented as the mean±SD; ***P<0.001, compared with baseline values. C and D, Twenty-four–hour average ambulatory BPs of the participants at 0 week and 12 weeks compared with the corresponding baseline values. n=44 in the placebo group and n=42 in the taurine group, respectively; *P<0.05. E and F, Clinic SBPs and DBPs at 0, 4, 8, and 12 weeks in the 2 groups. *P<0.05 and **P<0.01 compared with the placebo group. G and H, Comparisons of BP changes between the prehypertensive participants with high- and low-normal BPs in the taurine group. *P<0.05. ns indicates not significant.Open in viewer

Chronic taurine supplementation time dependently decreased clinic BP. Compared with the placebo group, both the clinic SBP and DBP were significantly reduced at 8 and 12 weeks after taurine administration (Figure 1E and 1F; Figure S2C and S2D). Importantly, taurine supplementation for 12 weeks greatly reduced the BPs of the prehypertensive participants with high-normal BPs (SBP, 130–139/DBP, 85–89 mmHg) compared with the prehypertensive participants with low-normal BPs (SBP, 120–129 mm Hg; DBP, 80–84 mm Hg). Changes in the SBP of 10.1 mm Hg were observed in the high-normal BP group compared with changes of 3.0 mm Hg in the low-normal BP group (P<0.05; Figure 1G). However, the changes in the DBP were similar between these 2 subgroups (Figure 1H).

Taurine Supplementation Improves Vasodilation in Prehypertensive Individuals

Chronic taurine supplementation significantly improved both endothelium-dependent vasodilation (flow-mediated dilation) and endothelium-independent vasodilation (nitroglycerin-mediated dilation) by 3.2% and 4.4%, respectively, as measured via flow-mediated vasodilation using a sonographer in the prehypertensive individuals. However, the beneficial effect of taurine supplementation on vasodilation was absent in the prehypertensive individuals treated with placebo (Figure 2A–2D).

Figure 2. Effect of taurine supplementation on vasodilation. A and B, Flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD). The data are presented as the mean±SD. **P<0.01 and ***P<0.001, compared with pretreatment with taurine (Pre). C and D, Changes in FMD and NMD in the 2 groups. *P<0.05 and **P<0.01, compared with the placebo group. ns indicates not significant.Open in viewer

Taurine Supplementation Elevates Plasma Levels of Taurine and H2S in Association With BP Changes in Prehypertensive Individuals

After treatment for 12 weeks, the plasma taurine and H2S levels were significantly higher in the prehypertensive individuals treated with taurine (plasma H2S level: 43.8±20.82 µmol/L at baseline to 87.0±24.51 µmol/L after treatment; P<0.001 and plasma taurine level: 108.3±55.27 µmol/L at baseline to 142.3±62.14 µmol/L after treatment; P<0.05); however, these changes were not observed in the participants treated with placebo (Figure 3A and 3B). Furthermore, the changes in BP were negatively correlated with both the plasma H2S and taurine levels in the taurine-treated prehypertensive individuals (Figure 3C–3F), especially in the prehypertensive participants with a high-normal BP level (Figure S4A–S4C). In contrast, these associations between BP and the plasma levels of H2S and taurine were not observed in the participants treated with the placebo (Figure S5A–S5D).

Figure 3. Effects of taurine supplementation on plasma taurine and hydrogen sulfide (H2S) levels and their associations with blood pressure (BP) changes. A and B, Changes in the plasma H2S and taurine levels. The data are presented as the mean±SEM. *P<0.05 and ***P<0.001, compared with pretreatment with taurine (Pre). C–F, Correlations between BP changes and plasma H2S and taurine levels, respectively. DBP indicates diastolic BP; ns, not significant; and SBP, systolic BP.Open in viewer

Effects of Taurine on H2S-Synthesizing Enzymes, TRPC3, and Vascular Relaxation

To elucidate the mechanisms underlying the effects of taurine on BP and vascular functions, we further examined 2 key H2S-synthesizing enzymes, CBS and CSE. We showed that CBS and CSE were expressed in the endothelia and adventitia of mesenteric arteries (MAs) from human and aortas from mice. However, TRPC3 was mainly expressed in the media of arteries (Figure 4A and 4B). Western blotting also indicated that CBS, CSE, and TRPC3 were coexpressed in MAs from humans and aortas from Trpc3+/+ wild-type (WT) mice (Figure 4C and 4G). In addition, vascular CBS/CSE expression‎ was upregulated in Trpc3−/− mice compared with WT mice (Figure 4C and 4D). Administration of taurine significantly upregulated CBS/CSE expression‎ but inhibited TRPC3 expression‎ in both aortas from spontaneously hypertensive rats treated with taurine and cultured human vascular tissues (Figure 4E–4J). After depletion of intracellular calcium storage using thapsigargin, a sarcoplasmic reticulum Ca2+-ATPase inhibitor, KCl-induced vasoconstriction was dose dependently relaxed by NaHS, a H2S donor; however, this effect was enhanced by a TRPC3 inhibitor, Pyr3, or by Trpc3 gene knockout (Figure 4K and 4L). These findings indicate that TRPC3 might be involved in H2S-mediated vascular relaxation.

Figure 4. Effects of taurine on cystathionine-β-synthetase (CBS)/cystathionine-γ-lyase (CSE), transient receptor potential channel 3 (TRPC3), and vascular relaxation. A and B, The immunofluorescence staining results showing that CBS/CSE (red) and TRPC3 (green) were coexpressed in mesenteric arteries (MAs) from humans and in aortas from wild-type mice. 4′,6-Diamidino-2-phenylindole (DAPI) was also stained to show the existence of nuclei (blue). C and D, The expression‎ levels of CBS, CSE, and TRPC3 in aortas from Trpc3+/+ and Trpc3−/− mice were detected by Western blotting. The bands from 3 independent immunoblots were quantified using Image J, and the relative expression‎ levels are shown in (D). The data are presented as the mean±SEM; *P<0.05 and ***P<0.001, compared with that of Trpc3+/+ mice. E and F, Effects of in vivo taurine supplementation on the expression‎ levels of CBS, CSE, and TRPC3. Spontaneously hypertensive rats (SHRs) were fed 2% taurine for 12 weeks from 4-week old, and then aortas were obtained for Western blotting analysis. *P<0.05, compared with that of the normal diet (ND). G–J, Effect of in vitro taurine supplementation on the expression‎ levels of CBS, CSE, and TRPC3. Human MAs were treated with taurine (at doses of 0, 20, and 40 mmol/L) for 24 hours. *P<0.05 and **P<0.01, compared with the vehicles. K and L, Reactivities of human and mice MAs. After contraction induced using 60 mmol/L KCl, NaHS (10–5 to 10–3 mol/L) was added to promote vasodilation, and then the percentage of vasodilation was plotted. n=4; *P<0.05. TG indicates thapsigargin.Open in viewer

H2S Exerts Vascular Relaxation by Targeting TRPC3-Mediated Calcium Influx

We further examined H2S-induced vascular relaxation, which occurs through the targeting of TRPC3. Intact MAs were isolated from WT and Trpc3−/− mice. Calcium influx of intact blood vessels was measured using fluorescence techniques after depletion of intracellular calcium storage in the absence of external calcium. The phenylephrine-induced increase in calcium influx in the artery was completely abolished by the TRPC3 inhibitor Pyr3 after thapsigargin treatment (Figure S6A and S6B). Administration of NaHS significantly diminished the thapsigargin- and phenylephrine-induced increase in calcium influx in human MAs (Figure S6C–S6F). Furthermore, NaHS partially inhibited the thapsigargin-induced calcium influx in the Trpc3+/+ mice, but this effect was absent in intact arteries isolated from the Trpc3−/− mice (Figure S6G–S6N).

Discussion

To the best of our knowledge, this is the first randomized, double-blind, placebo-controlled clinical trial to investigate the effects of taurine supplementation in prehypertensive individuals. Furthermore, we have provided experimental evidence to facilitate elucidation of its mechanism of action. This study has revealed that oral taurine supplementation for 12 weeks significantly reduces the clinic and 24-hour ABPs in prehypertensive individuals, especially in those with high-normal BP. In addition, taurine treatment substantially promotes vasodilation and elevates the plasma taurine and H2S levels in these individuals. Furthermore, changes in BP were negatively correlated with the plasma taurine and H2S levels. However, these beneficial effects were absent in the prehypertensive individuals treated with placebo. In experimental studies, administration of taurine has been shown to enhance the expression‎ of H2S-synthesizing enzymes (CBS/CSE) and to reduce vascular TRPC3 expression‎ in spontaneously hypertensive rats. Furthermore, the vascular relaxation induced by the H2S donor NaHS is enhanced by TRPC3 antagonist treatment. These findings indicate that taurine intervention improves vascular tone by targeting the H2S-mediated inhibition of TRPC3-induced calcium influx.

Taurine is a sulfur-containing amino acid that is both cheap and nontoxic, and it is widely used as a functional dietary factor. Seafood containing an abundance of taurine improves cardiovascular and metabolic diseases, such as obesity, diabetes mellitus, and hyperlipidemia. In addition, taurine has multiple biological effects, such as protection against liver cirrhosis and antioxidative,27 anti-inflammatory, antiatherosclerotic,28,29 and antiobesity effects.30 Unfortunately, evidence that taurine supplementation reduces BP in human hypertension is inconclusive despite the fact that multiple experimental studies have demonstrated the hypotensive effect of taurine in different hypertensive animal models.

The antihypertensive effect of taurine in humans has only been confirmed in a few clinical studies with small sample sizes (n=10–12) that were short term (7 days to 6 weeks).31 One nonrandomized placebo-controlled trial showed that oral taurine supplementation (6 g per day) for 1 week decreased the SBP by 9.0 mm Hg and the DBP by 4.1 mm Hg in borderline hypertensive patients.9 In addition, taurine supplementation has been shown to lower BP by ≈22 to 49 mm Hg in different experimental hypertensive rats.31 Therefore, it remains unknown whether oral taurine supplementation is beneficial for prehypertensive individuals. In this randomized, double-blind, placebo-controlled study, we showed that administration of low-dose taurine (1.6 g per day) for 12 weeks can time dependently lower both clinic and ABPs and improve vascular relaxation. In particular, prehypertensive individuals with high-normal BP exhibited a better response to taurine than those with low-normal BP. Our study has provided the first solid evidence of the hypotensive effect of taurine in prehypertensive individuals.

Epidemiological studies have shown that the plasma taurine level is lower in patients with essential hypertension.12 Nara et al32 have reported that this level is decreased in spontaneously hypertensive rats in relation to the severity of hypertension. The plasma taurine level is negatively correlated with BP in hypertensive patients.14 Taurine deficiency in rats accelerates high salt intake–induced hypertension through renal dysfunction.15 Galloway et al33 reported that acute taurine treatment resulted in a 13-fold increase in the plasma taurine concentration, whereas no significant change in the muscle taurine concentration was observed. In this study, we found that chronic taurine treatment for 12 weeks resulted in an almost 1.5-fold increase of plasma taurine concentration in the prehypertensive individuals and that this increase was correlated with a reduction in BP. In addition, the prehypertensive individuals with a high end point plasma taurine level exhibited a greater hypotensive response to the taurine treatment.

The manner by which taurine exerts its hypotensive effect has been studied for a long time.16 Previous studies have shown that taurine supplementation improves endothelium-dependent vasodilation through restoration of vascular redox homeostasis and improvement of nitric oxide bioavailability.34 In addition, in human studies, improvement of flow-mediated dilation has been observed in response to dietary taurine supplementation in young smokers.35 The improved vascular function may facilitate the hypotensive effect and provide extra cardiovascular benefits. Available data suggest that the hypotensive effect of taurine does not occur through 1 specific mechanism but rather through multiple mechanisms.

In addition to nitric oxide and carbon monoxide, H2S, which is another important gas transmitter, has been widely studied in the cardiovascular system in recent years,36 and its vasodilatory effects have also been reported. H2S is endogenously produced from 2 sulfur-containing amino acids, l-cysteine and l-methionine, by the 2 H2S-synthesizing enzymes, CBS and CSE.24 Mutant mice lacking CSE display pronounced hypertension and reduced endothelium-dependent vasorelaxation, but this result was not confirmed by other studies.24 However, H2S replacement has been shown to reduce the SBP in both Cse−/− and Cse+/− mice,24 suggesting that the H2S synthases/H2S pathway confer protection against hypertension. Taurine, as a sulfur-containing amino acid, functions in the methionine cycle and can be converted by cysteine in the presence of cysteine dioxygenase,3 whereas H2S is synthesized from the 2 sulfur-containing amino acids, l-cysteine and l-methionine. This study has shown that taurine is probably a substrate for the synthesis of H2S to increase CBS and CSE expression‎. Therefore, we assumed that a correlation may exist between taurine and H2S. Taurine supplementation resulted in a significant elevation in the plasma H2S level in the prehypertensive individuals, and this elevation was correlated with a decrease in BP in the taurine group. Using MAs from healthy human volunteers and aortas from spontaneously hypertensive rats that were fed taurine for 3 months, we further demonstrated that taurine administration upregulated the expression‎ of vascular CBS/CSE, which caused the increased production of H2S in blood vessels in vitro and in vivo. Thus, other mechanisms of the vasorelaxant effect of H2S have also been identified involving opening of the ATP-sensitive potassium channels,23 interaction with nitric oxide pathways, functioning as an endothelium-derived hyperpolarizing factor, and direct activation of protein kinase G.37 Recently, Cheang et al38 and Tian et al39 have reported that H2S dilates blood vessels by opening voltage-gated potassium channels in rat coronary arteries and inhibits calcium channels in rat cerebral arteries, respectively. H2S has been demonstrated to regulate the activities of TRP channels in bone marrow mesenchymal stem cells through sulfhydration.4 Our previous work has demonstrated that TRPC3 upregulation and dysfunction in monocytes and in the vasculature from both genetically hypertensive rats and essential hypertensive patients play important roles in the pathogenesis of hypertension.25,26,40,41 In this study, we further verified that the H2S donor NaHS inhibited phenylephrine- and thapsigargin-induced Ca2+ influx and relaxation in MAs from human and Trpc3+/+ WT mice; however, this effect was absent in intact arteries from Trpc3−/− mice. Our work has revealed a novel unrecognized mechanism of taurine- and H2S-induced vasorelaxation that functions by enhancing the metabolism of sulfur-containing amino acids.

Study Limitations

The limitation of this study is that it was not performed across multiple centers. Further studies should validate whether this beneficial effect is present in other ethnicities and populations. In addition, the hypotensive effects of taurine have been reported to occur via the central nervous system,42,43 attenuation of the overactivity of the sympathetic system and increased urinary norepinephrine, and epinephrine excretion.31 An effect of taurine on BP occurring via the central nervous system cannot be excluded.31

Perspectives

Prehypertension plays an important role in the development of hypertension. Furthermore, prehypertension is closely associated with the morbidities of stroke, ischemic heart disease, and renal dysfunction. Although lifestyle modifications and an angiotensin II receptor blocker have been used to treat prehypertension, poor compliance and limitations of antihypertensive agents are the main obstacles of treatment. This randomized, double-blind, placebo-controlled clinical trial is the first to demonstrate that taurine supplementation significantly reduces BP and improves vascular function in prehypertensive individuals, especially in those with high-normal BP. Furthermore, changes in BP are correlated with both the plasma H2S and taurine levels in the taurine-treated prehypertensive individuals. We further demonstrate that the hypotensive effect of taurine involved the H2S-mediated inhibition of TRPC3-induced calcium influx. Taurine, as the most abundant, semiessential, sulfur-containing amino acid, is rich in seafood and easily consumed daily. Considering the elevated cardiometabolic risks of large populations of prehypertensive individuals, consumption of taurine-rich food may be a promising and cost-effective approach to prehypertension treatment.

Acknowledgments

We gratefully acknowledge the participation of all study subjects and the technical assistance of Tingbing Cao and Lijuan Wang (Chongqing Institute of Hypertension, Chongqing, China) with our experiments.

Novelty and Significance

What Is New?

•

This randomized, double-blind, placebo-controlled clinical trial is the first to demonstrate the hypotensive effect of taurine supplementation in prehypertensive individuals.

•

Taurine treatment remarkably improves blood pressure and vascular function, especially in prehypertensive individuals with high-normal blood pressure.

•

The hypotensive mechanism of taurine partially involves the hydrogen sulfide–mediated inhibition of transient receptor potential channel 3–induced calcium influx in the vasculature.

What Is Relevant?

•

Taurine supplementation results in a substantial, time-dependent reduction in blood pressure in prehypertensive individuals. Daily taurine supplementation promotes an additional decrease in blood pressure beyond that achieved with conventional lifestyle changes and pharmacotherapy.

Summary

Daily taurine supplementation is a novel strategy for lowering blood pressure in prehypertension, either as a dietary factor or in conjunction with conventional lifestyle changes.

Supplemental Material

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References

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Ueki I, Roman HB, Valli A, Fieselmann K, Lam J, Peters R, Hirschberger LL, Stipanuk MH. Knockout of the murine cysteine dioxygenase gene results in severe impairment in ability to synthesize taurine and an increased catabolism of cysteine to hydrogen sulfide. Am J Physiol Endocrinol Metab. 2011;301:E668–E684. doi: 10.1152/ajpendo.00151.2011.

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