Quick search in Citations
This JournalAnywhereCitation
Advanced Search
Research Article
Originally Published 11 December 2017
Free Access

Inhibition of NADPH Oxidase–Dependent Oxidative Stress in the Rostral Ventrolateral Medulla Mediates the Antihypertensive Effects of Acupuncture in Spontaneously Hypertensive Rats

Xue-Rui Wang, Jing-Wen Yang, Cai-Shuo Ji, Xiang-Hong Zeng, Guang-Xia Shi, Marc Fisher, and Cun-Zhi LiuAuthor Info & Affiliations
Hypertension
Volume 71, Number 2
https://doi.org/10.1161/HYPERTENSIONAHA.117.09759
Track CitationsAdd to favorites
PDF/EPUB

Abstract

Oxidative stress in the rostral ventrolateral medulla (RVLM), where the sympathetic nervous control center is located, contributes to neural mechanisms of hypertension. Acupuncture was previously reported to favorably affect high blood pressure. However, little is known about the effect of acupuncture on oxidative stress–modulated mechanisms in hypertension. This study was designed to evaluate the hypothesis that acupuncture exerts an antihypertensive effect via ameliorating oxidative stress and the redox-sensitive pathway in the RVLM of spontaneously hypertensive rats. Two weeks of acupuncture reduced blood pressure and sympathetic nervous system activity in spontaneously hypertensive rats. Oxidative stress in the RVLM was alleviated by acupuncture, accompanied by a decrease in nicotinamide adenine dinucleotide phosphate oxidase activity and expression of its subunits. Acupuncture significantly altered the mitogen-activated protein kinases signaling pathway as assessed by pathway enrichment analysis in a gene chip assay. The phosphorylation of p38 mitogen-activated protein kinases and extracellular signal-regulated protein kinase 1/2, but not Jun N-terminal kinase, was downregulated by acupuncture. Microinjection bilaterally of the superoxide dismutase mimetic tempol, nicotinamide adenine dinucleotide phosphate oxidase inhibitor apocynin, or diphenyleneiodonium chloride into the RVLM mimicked the antihypertensive effect of acupuncture. In contrast, the nicotinamide adenine dinucleotide phosphate oxidase agonist tetrabromocinnamic acid abolished the beneficial effects of acupuncture. Furthermore, injection of capsaicin or surgical sectioning of the sciatic nerve abolished the antihypertensive effect of acupuncture. We conclude that acupuncture decreases high blood pressure and nicotinamide adenine dinucleotide phosphate oxidase in the RVLM of spontaneously hypertensive rats. The mitogen-activated protein kinases and the sciatic nerve are involved in the mechanism of acupuncture’s amelioration of hypertension.

Introduction

See Editorial Commentary, pp 224–226
Oxidative stress caused by the imbalance between the generation and the disposal of reactive oxygen species (ROS) plays a pivotal role in hypertension. Elevated ROS cause endothelial dysfunction, change contractility, and lead to inflammation affecting vessel walls in the heart, kidney, and brain. Over production of ROS in the central nervous system, especially in the rostral ventrolateral medulla (RVLM) where the primary sympathetic projections arise, leads to increased sympathetic outflows and elevated blood pressure (BP).1–3 Centrally diminishing oxidative stress by microinjection of antioxidative agents into the RVLM reduces elevated BP in hypertension.4,5 However, in cardiovascular diseases, most available antioxidant supplements failed to demonstrate a beneficial effect in clinical trials,6 probably because of the nondiscriminant inhibition of normally functioning ROS.7 Thus, more focused antioxidative therapy may be clinically beneficial.
Among multiple enzyme sources, the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase pathway has been reported to be a major source of ROS production. NADPH oxidase consists of a membrane-bound heterodimeric subunit gp91phox and p22phox and regulatory proteins, including p47phox, p67phox, and Rac1, to transfer reducing equivalents from NADPH to oxygen and generate O2−. A growing body of evidence has implicated NADPH oxidase’s activity and the expression of its subunits as being increased with hypertension. NADPH oxidase derived O2− from neurons in the RVLM and contributes directly to neurogenic hypertension.8,9 Gene knockdown or knockout of NADPH oxidase subunits or the intracerebroventricular infusion of an NADPH oxidase inhibitor into the RVLM significantly antagonizes the pressor response and sympathetic outflows during hypertension.10,11
Recent studies have demonstrated that redox-sensitive activation of MAPKs (mitogen-activated protein kinases) contributes to the pressor responses in hypertension.12 The MAPKs typically mediate apoptosis and inflammatory responses and are markedly activated in vascular smooth muscle cells, endothelial cells, and other related cardiovascular cells during hypertension. The p38 MAPK, ERK1/2 (extracellular signal-regulated protein kinase 1/2), and JNK (c-Jun N-terminal kinase) are the most well-characterized mammalian MAPK subfamilies. Previous studies have indicated that activation of different MAPKs subfamilies in different cell types occur with hypertension. An elegant series of experiments demonstrated that the phosphorylation of p38 MAPK and ERK1/2, which requires NADPH oxidase activation and O2− generation as a crucial upstream event, plays a critical role in the development of neurogenic hypertension.11 Inhibiting NADPH homologues or MAPKs may be a potential target to limit the oxidative stress contribution to hypertension.
We and others have reported previously that acupuncture, an ancient traditional Chinese medicine treatment technique, could elicit an antioxidative effect via a redox-sensitive mechanism in various disease conditions.13–15 Previous clinical trials have also indicated that acupuncture can effectively lower the systolic blood pressure (SBP) and diastolic blood pressure (DBP) in hypertensive patients.16 However, whether the antihypertensive effect of acupuncture involves an oxidative-related mechanism is still unknown. This study was designed to evaluate the hypothesis that acupuncture lowers BP and sympathetic excitatory toxicity via central antioxidative and anti-intracellular signaling pathway mechanisms in spontaneously hypertensive rats (SHRs). Of interest, studies have also demonstrated a neural circuit modulation of acupuncture via transmission from the afferent sciatic nerve to the efferent vagus nerve to regulate the production of the neurotransmitter dopamine in systemic inflammation.17 Based on the neuroanatomy and the location of the acupoints, we also hypothesized that the sensory afferent sciatic nerve is involved in the peripheral to the central mechanism of acupuncture.

Methods

All animal care, surgical, and experimental procedures were approved by the Institutional Animal Care and Use Committee of the Capital Medical University and conformed to the US National Institutes of Health Guide for the Care and Use of Laboratory Animals. Adult (12 weeks) male SHRs or age-matched normotensive Wistar-Kyoto (WKY) rats, purchased from the Vital River Laboratory Animal Technology Co. Ltd (Beijing, China), were used. Animals received acupuncture or nonacupoint acupuncture for 2 weeks. The key experimental procedures included measurement of SBP, mean arterial pressure (MAP), and heart rate in conscious rats by radiotelemetry, microinjection into the RVLM of diphenyleneiodonium chloride (DPI), tempol, tetrabromocinnamic acid (TBCA), or apocynin, assessment of tissue ROS, detection of enzyme activity of the NADPH oxidase, superoxide dismutase (SOD), and nitric oxide synthase (NOS), determination of mRNA or protein expression by real-time polymerase chain reaction or Western blot, chemical and surgical sectioning of the sciatic nerve. A detailed Methods section is available in the online-only Data Supplement for all of these procedures.

Statistical Analysis

Data are expressed as mean±SEM. The statistical software SigmaStat (SPSS Inc) was used for data analysis. One-way or 2-way ANOVA with or without repeated measures was used, as appropriate, to assess group means, to be followed by the Scheffe multiple-range test for post hoc assessment of individual means. A P<0.05 was considered to be statistically significant.

Results

Acupuncture Attenuates Sympathetic Vasomotor Activity and BP in SHRs

We compared the effects of acupuncture at different acupoints, including LR3, ST36, and GV20 (Figure S1 in the online-only Data Supplement), in changing the SBP and DBP of SHRs to select the best treatment protocol. We found that acupuncture at LR3, ST36, or GV20 reduced the SBP and DBP (Figure S2). The LR3 group showed the best effect that reduced SBP by 35 mm Hg and DBP by 22 mm Hg. The following experiments were all performed at LR3. The SBP and MAP in WKY, SHR, SHR+acu, and SHR+non-acu groups were detected using a radiotelemetry system and analyzed at the beginning and during the acupuncture treatment. In SHRs, acupuncture significantly decreased the SBP and MAP from day 7 (Figure 1A and 1B). There was a concomitant reduction in heart rate and low-frequency (LF) components of SBP in the SHR+acu group beginning at day 5 (Figure 1C and 1D). MAP and LF were also detected at the beginning, on day 7, and day 14 in WKYs receiving acupuncture. The normal BP and the sympathetic vasomotor tone of WKYs were not changed by acupuncture (Figure S3).
Figure 1. Acupuncture attenuates sympathetic vasomotor activity and blood pressure in spontaneously hypertensive rats (SHRs). Changes in (A) mean artery pressure, (B) systolic blood pressure, (C) heart rate, and (D) power density of the low-frequency (LF) component of systolic blood pressure spectrum recorded from conscious Wistar-Kyotos (WKYs), SHRs, SHRs treated with acupuncture (SHR+acu), and SHRs treated with nonacupoint acupuncture (SHR+non-acu) from 8 am to 10 am every day for 15 d. Values are mean±SEM of 10 animals per group. *SHR vs WKY, #SHR+acu vs SHR, &SHR+non-acu vs SHR+acu, *P<0.05 of each symbol at each time point in the Scheffe multiple-range analysis, respectively.

Acupuncture Decreases ROS Production in RVLM of SHRs Without Affecting SOD or NOS Activities

We then evaluated whether acupuncture could exert a central antihypertensive effect via downregulating oxidative stress in the RVLM. The tissue level of O2− in the RVLM was increased in SHRs and significantly blunted by acupuncture treatment (Figure 2A; Figure S4). The tissue level of NOS (Figure 2B) and SOD activity (Figure 2C) in the RVLM, as well as the protein expression of their isoforms SOD1, SOD2, and SOD3 (Figure S5A through S5C), endothelial NOS, and inducible NOS (Figure S5D and S5F) showed no difference between SHRs treated with acupuncture and untreated SHRs. The protein expression of neuronal NOS was downregulated in acupuncture group compared with SHRs (Figure S5E). None of these results showed differences between SHRs treated with acupuncture and nonacupoint acupuncture.
Figure 2. Acupuncture decreases nicotinamide adenine dinucleotide phosphate (NADPH) oxidase–derived reactive oxygen species (ROS) production in rostral ventrolateral medulla (RVLM) of spontaneously hypertensive rats (SHRs). A, Tissue level of ROS, (B) nitric oxide synthase activity (NOS), (C) superoxide dismutase (SOD) activity, and (D) NADPH oxidase activity detected from RVLM of Wistar-Kyotos (WKYs), SHRs, SHR+acu, and SHR+non-acu at the end point of acupuncture treatment (day 14); (E) The mRNA levels of gp91phox, p22phox, p47phox, and p67phox were also accessed by real-time polymerase chain reaction, and values were corrected by GAPDH. F, Representative Western blots and densitometric analysis of NADPH oxidase subunits gp91phox, p22phox, p47phox, and p67phox. The same membranes were probed for NADPH oxidase subunits with β-actin. Values are mean±SEM of 10 animals in each group. *SHR vs WKY, #SHR+acu vs SHR, &SHR+non-acu vs SHR+acu, *P<0.05 of each symbol, respectively.

Acupuncture Decreases NADPH Oxidase Activity and NADPH Oxidase Subunits Expression in RVLM of SHRs

The NADPH oxidase activity in the RVLM was significantly increased in SHRs and nonacupoint SHRs compared with WKY rats. Acupuncture significantly attenuated its activity (Figure 2D). This attenuation was accompanied by decreased mRNA (Figure 2E) and protein (Figure 2F) expression of NADPH oxidase subunits gp91phox (Nox2), p22phox, and p47phox. Although the expression of p67phox showed no differences between SHRs and acupuncture group (Figure 2E and 2F), these experiments demonstrated the potential involvement of NADPH oxidase in the antihypertensive effect of acupuncture. The mRNA expression of NADPH oxidase homologues, Nox1, and Nox4 in RVLM of SHRs were also tested, and only the mRNA level of Nox2 demonstrated a difference between SHRs and SHRs treated with acupuncture (Figure S6).

Acupuncture Selectively Alleviates the Activation of MAPKs in RVLM of SHRs

To establish the effect of acupuncture in regulating the signaling pathways, mRNA microarray profiling was performed in WKYs, SHRs, and SHRs+acu rats, and ANOVA-corrected changed genes (P value and the false discovery rate <0.05) between these groups were determined. Then, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis was performed among these genes. The top 5 altered pathways that observed were the metabolic pathways, the MAPK signaling pathway, the tricarboxylic acid cycle, the insulin signaling pathway, and focal adhesion, respectively (Figure 3A). To verify the effect of acupuncture in regulating the MAPKs, Western blots were performed. Compared with WKYs, SHRs resulted in the phosphorylation of p38 MAPK, ERK1/2, and JNK (Figure 3B). The phosphorylation of p38 MAPK (Figure 3C) and ERK1/2 (Figure 3D), but not JNK, was significantly antagonized by acupuncture (Figure 3E). These changes did not elicit a discernible effect on total p38 MAPK, ERK1/2, or JNK levels in the RVLM. These results showed great consistency with the microarray pathway analysis.
Figure 3. Acupuncture selectively alleviates the activation of MAPKs (mitogen-activated protein kinases) in rostral ventrolateral medulla (RVLM) of spontaneously hypertensive rats (SHRs). A, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis. The significant pathway for differentially expressed genes compared among Wistar-Kyotos (WKYs), SHRs, and SHR+acu. -LgP is the logarithm of P value. B–E, Representative Western blots of phosphorylated or total p38 MAPK, ERK1/2 (extracellular signal-regulated protein kinase 1/2), and JNK (c-Jun N-terminal kinase) and densitometric analysis of phosphorylated protein levels detected from the RVLM of WKYs, SHRs, SHR+acu, and SHR+non-acu. *SHR vs WKY, #SHR+acu vs SHR, &SHR+non-acu vs SHR+acu, *P<0.05 of each symbol, respectively.

Acupuncture Decreases Sympathetic Vasomotor Activity and BP via Regulating the NADPH Oxidase

To further ascertain the NADPH oxidase–dependent mechanisms of acupuncture, we microinjected bilaterally into the RVLM the SOD mimetic, tempol, to abolish oxidative stress; the widely used NADPH oxidase inhibitors apocynin and DPI to antagonize NADPH oxidase; an NADPH oxidase agonist, TBCA, to activate NADPH oxidase, and to measure the changes of MAP and LF in each groups with or without acupuncture. Microinjection of tempol, apocynin, and DPI significantly reduced the MAP and LF in SHRs. The reduction of MAP was observed at day 5, day 6, and day 7 in SHRs treated with tempol (Figure 4A), DPI (Figure 4B), and apocynin (Figure 4C) respectively. The reduction of LF began at day 7 (Figure 4A through 4C). The normal BP and the sympathetic vasomotor tone of WKYs were not changed by TBCA (Figure S8). Microinjection of TBCA significantly elevated the MAP and LF in SHRs (Figure 4D). Both acupuncture and apocynin prevented the increased BP and LF caused by TBCA in SHRs (Figure 4D). Consistent with the changed hypertensive phenotype, TBCA caused elevated ROS production and NADPH oxidase activity while apocynin and acupuncture restored the deleterious effects of TBCA (Figure S9). No differences were observed in 2% dimethyl sulfoxide or artificial cerebral spinal fluid solvent controls.
Figure 4. Microinjection of tempol, diphenyleneiodonium chloride (DPI), and apocynin into rostral ventrolateral medulla (RVLM) of spontaneously hypertensive rats (SHRs) mimics the antihypertensive effect of acupuncture while tetrabromocinnamic acid (TBCA) abolishes the beneficial effect of acupuncture. Changes in mean artery pressure and the low-frequency (LF) component in SHRs that treated with acupuncture (acu) or microinjected bilaterally of the superoxide dismutase (SOD) mimetic tempol (A), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenyleneiodonium chloride (DPI; B), or apocynin (C). Changes in mean artery pressure and LF in SHRs that microinjected bilaterally of NADPH oxidase agonist tetrabromocinnamic acid with acupuncture (TBCA+acu) or without acupuncture (TBCA) or microinjected TBCA with apocynin (TBCA+apocynin; D). SHRs and SHRs microinjection bilaterally of artificial cerebral spinal fluid (aCSF) or 2% dimethyl sulfoxide (DMSO) into RVLM were served as controls. The data were continually spectrum recorded from 8 am to 10 am every day for 15 d. Values are mean±SEM of 8 animals per group. #Acu vs control (SHR), *tempol, DPI, or apocynin vs control (SHR), and &TBCA+acu vs acu at each time point in the Scheffe multiple-range analysis. *P<0.05 of each symbol, respectively.

Acupuncture Elicits NADPH Oxidase–Dependent Antihypertensive Effects via MAPK Signaling

To better correlate the activation of MAPKs and NADPH oxidase with the antihypertensive effect of acupuncture, tempol, apocynin, DPI, and TBCA were microinjected bilaterally into the RVLM of SHRs with or without acupuncture (Figure 5A). The phosphorylation of p38 MAPK, ERK1/2, and JNK was increased in SHRs compared with WKYs. Tempol, apocynin, and DPI microinjection significantly normalized the phosphorylation level of MAPKs (Figure 5B through5D). Meanwhile, TBCA significantly abolished the effect of acupuncture in decreasing the phosphorylation of p38 MAPK and ERK1/2 (Figure 5B through5D). None of those conditions elicited a discernible effect on total p38 MAPK, ERK1/2, or JNK levels in the RVLM.
Figure 5. Acupuncture elicits nicotinamide adenine dinucleotide phosphate oxidase–dependent antihypertensive effects via MAPK (mitogen-activated protein kinase) signaling. A, Representative Western blots of phosphorylated and total p38 MAPK, ERK1/2 (extracellular signal-regulated protein kinase 1/2), and JNK (c-Jun N-terminal kinase) and (B–D) the densitometric analysis of phosphorylated protein levels detected from the rostral ventrolateral medulla of Wistar-Kyotos (WKYs), spontaneously hypertensive rats (SHRs), SHR+acu, SHR+non-acu, SHRs that microinjected tempol (SHR+tempol), diphenyleneiodonium chloride (DPI; SHR+DPI), apocynin (SHR+apocynin), SHRs that microinjected tetrabromocinnamic acid (TBCA) with acupuncture (SHR+acu+TBCA) or without acupuncture (SHR+TBCA). Values are mean±SEM of 8 animals per group. #SHR+acu, SHR+tempol, SHR+DPI, or SHR+apocynin vs SHRs, *SHR+acu+TBCA or SHR+TBCA vs SHR+acu, *P<0.05 of each symbol, respectively.

Acupuncture Controls Sympathetic Vasomotor Activity and BP in SHRs via the Sciatic Nerves

To evaluate the hypothesis that acupuncture at LR3 could affect homeostasis in the brain via nerve circuit afferents from the sciatic nerve to the central nervous system, surgical sectioning of the sciatic nerve or local intramuscular injection of capsaicin, which interferes with nociceptive and voltage-dependent neuronal pathways, was performed. Surgical or chemical ablation of the sciatic nerve signals did not affect the MAP (Figure 6A and 6C), the LF (Figure 6B and 6D), the ROS production (Figure S10A), and the NADPH oxidase activity (Figure S10B) in SHRs. However, they abolished the antihypertensive effect of acupuncture. No differences were observed in PBS intramuscular injection or sham-operated controls.
Figure 6. Acupuncture controls sympathetic vasomotor activity and blood pressure in spontaneously hypertensive rats (SHRs) via the sciatic nerves. Changes in mean artery pressure and low-frequency (LF) component in SHRs that underwent surgical neurectomy of the sciatic nerve (SSX; A and B) or intramuscular injection of capsaicin (Capsaicin; C and D) with (acu) or without acupuncture. SHRs, SHRs that underwent sham surgery or intramuscular injection of PBS, were served as controls. Data were continually spectrum recorded from 8 am to 10 am every day for 15 d. Values are mean±SEM of 8 animals per group. #P<0.05 acu vs control (SHR), *P<0.05 acu+SSX or acu+Capsaicin vs acu at each time point in the Scheffe multiple-range analysis, respectively.

Discussion

It has been well documented that oxidative stress in the RVLM participates in central cardiovascular control by eliciting sympathetic excitoxicity and pressor responses. In the present study, for the first time, we identified a novel antihypertensive mechanism of acupuncture involved in regulating NADPH oxidase–derived ROS and MAPKs in the RVLM, which related to neural circuits of afferent sciatic nerve signals to the central nervous system to systemic outflows. In SHRs, acupuncture decreased LF and BP. Oxidative stress led by ROS production in the RVLM was alleviated by acupuncture, which was accompanied by decreased NADPH oxidase activity and expression of its subunits. KEGG pathway enrichment analysis demonstrated a significant alteration of the MAPK signaling pathway among WKYs, SHRs, and SHRs plus acupuncture groups. Protein expression of phosphorylated p38 MAPK and ERK1/2 in these groups showed consistency with the results of the pathway analysis. Microinjection bilaterally of tempol, apocynin, or DPI into the RVLM mimicked the antihypertensive effect of acupuncture via decreasing the sympathetic outflows and inactiving MAPKs while the NADPH oxidase agonist TBCA microinjection abolished the beneficial effects of acupuncture. Local intramuscular injection of capsaicin or surgical sectioning of the sciatic nerve abolished the antihypertensive effect of acupuncture.
Acupuncture has been reported to be a possible nonpharmacological treatment for hypertensive patients. Most of the randomized trials demonstrated that acupuncture could reduce SBP and DBP in hypertensive patients by at least 5/3 mm Hg.16,18 Decreasing BP by this level has been reported to be associated with a reduced risk of cardiovascular outcomes and mortality.19 A recent study also found a similar reduction of BP with 3 months of acupuncture treatment, together with restored levels of metabolic biomarkers in patients’ plasma.20 Perhaps, the most debatable trial for the efficacy evaluation of acupuncture was the SHARP trial (Stop Hypertension with the Acupuncture Research Program). Within 1 year, 2 studies, the SHARP21 and Flachskampf,16 were published. The Flachskampf study showed a significant difference between acupuncture and sham acupuncture but the SHARP trial did not. A few important issues were raised by the negative results of the SHARP trial.22 It is worth noting that the SHARP trial was described as a pilot trail (in the abstract). The authors enrolled 194 patients in this trail, but with a 3.5- to 4.0-mm Hg reduction in SBP, it would have required a sample size of 900 patients to demonstrate statistical significance. Another important issue is that Flachskampf study provided almost as twice as many acupuncture treatments compared with the SHARP trial over roughly the same time period. The frequency may partially be the reason why differences in outcomes were observed. In our study, we treat SHRs 14 times over 2 weeks. Our results demonstrated a significant decrease of high BP in SHRs after acupuncture, with effects on antioxidative mechanisms shown to be involved.
Acupuncture has been reported to decrease abnormal sympathetic excitation in a variety of cardiovascular diseases.23 This is probably because of the effect of acupuncture on disordered sympathetic activity. Indeed, acupuncture applied to healthy human or normal animals does not change BP or heart rate.24,25 These results are consistent with our results in WKY rats. As a crucial modulator of the sympathetic nervous system activity, RVLM has been reported to be indispensable for acupuncture-mediated antihypertensive effect. A series of experiments by Longhurst demonstrated the effect of electroacupuncture via the central mechanisms of activating gamma-aminobutyric acid receptor26 and regulating paraventricular nucleus opioid and its projection into RVLM27 to decrease the BP and sympathetic excitation during hypertension. This study, however, focused on the effect of acupuncture on regulating another direct conductor of sympathetic excitation and high BP, the oxidative stress, to further explore the underlying mechanism.
Oxidative stress caused by the overproduction of ROS plays an important role in cardiovascular pathology. With hypertension, altered ROS production directly causes endothelial dysfunction, changes contractility, and leads to vascular remodeling. Many studies have indicated that centrally diminishing oxidative stress by, for instance, overexpressing SOD, microinjection of tempol or coenzyme Q10, and gene silencing to inhibit nNOS abolish the pressor effect in hypertension.4,5 Despite the clear link between oxidative stress and the pathophysiological processes of cardiovascular diseases, most antioxidant treatments failed to demonstrate a beneficial effect on morbidity and mortality, probably because of the nondiscriminant inhibition of the normally functioning ROS.7 In recent years, more advanced antioxidant gene therapy and specific antioxidant have been studied in animals, but the effect, safety, dosage, and the pharmacokinetics in human remain untested. We and others have reported previously that acupuncture could elicit antioxidative effect during disease conditions.13–15 In this study, we found that acupuncture significantly decreased ROS production in the RVLM, and microinjection bilaterally into the RVLM of an SOD mimetic tempol imitated the effect of acupuncture. Acupuncture may be a safe nonpharmacological approach that could potentially be used to affect oxidative stress in hypertension.
Among multiple enzyme sources, NADPH oxidase has been reported to be the major source of ROS production related to the neural mechanisms of hypertension. The role of NADPH oxidase in the brain has been well characterized by centrally applied specific inhibitors or gene silencing of its subunits. We found that acupuncture downregulated NADPH oxidase activity and the expression of its subunits gp91phox (Nox2), p22phox, and p47phox in RVLM of SHRs. Previous studies have indicated that NADPH oxidase homologues, mainly Nox1, Nox2, and Nox4, are expressed in the RVLM and play a role in the pathogenesis of hypertension. In our study, we found that the mRNA expression of Nox1 and Nox4 in the RVLM showed no difference between WKYs and SHRs, and only Nox2 expression was decreased after acupuncture in SHRs. We evaluated the activity of SOD and NOS to explore how acupuncture regulates ROS production. Acupuncture did not decrease the activity of NOS and SOD or the expression of most of isoforms. nNOS expression was decreased by acupuncture, which could be a potential mechanism of the effect of acupuncture on hypertension. Mitochondria, another major source of ROS production which has been reported to play an important role in the establishment of neurogenic hypertension,1,28 were not investigated in this study. These related pathways require investigation in the future study.
Our results, for the first time, revealed the central antihypertensive effect of acupuncture and depend on reduced activation of NADPH oxidase in the RVLM. We found that apocynin and DPI mimicked the effect of acupuncture while TBCA abolished the beneficial effect of acupuncture. One limitation of this study is the unavoidable nonspecific effects of the test agents we used. Although apocynin and DPI are the most widely used NADPH oxidase inhibitors, there are studies reporting the nonspecific effect of apocynin on ROS production29 and the inhibition of distinct flavoenzymes and mitochondria by DPI.30 As a casein kinase II inhibitor, the mechanism of TBCA on selectively activating NADPH oxidase has been studied in vivo and vitro previously.31,32 However, we cannot rule out the fact that it may activate other pathways. In our study, the aggravated hypertensive phenotype and NADPH oxidase–mediated oxidative stress caused by TBCA were almost restored to normal SHR level by apocynin microinjection or acupuncture. These results were consistent with previous work by Kim et al31 which concluded that TBCA increased the neural phenotype after ischemic reperfusion resulted from NADPH oxidase–induced ROS generation.
Another intriguing finding of the present study was that the NADPH oxidase–dependent mechanism of acupuncture also mediates the activation of the MAPKs in the RVLM. The activation of MAPKs in an NADPH oxidase–dependent manner has been well characterized in vivo and in vitro during hypertension. NADPH oxidase–derived O2− selectively activate MAPKs to different cell types and tissues. For instance, it activates p38 MAPK but not ERK1/2 in fibroblasts; ERK1/2 in endothelial cells; and ERK1/2, p38 MAPK, and JNK in aorta tissue. A study by Chan et al11 raised an important issue that NADPH oxidase modulates the phosphorylation of p38 MAPK and ERK1/2 in RVLM neurons. Our KEGG pathway enrichment analysis found that the MAPK signaling pathway was the second altered pathway. The altered genes which mapped to MAPK signaling pathways in our study were FGFR, MKP, HSP 72, TAO1/2, Ras, NF1, STMN1, JNK, TGFBR, and HPK1 (data not shown). These data indicated the potential involvement of the MAPK signaling pathways at the transcription level. Because the MAPKs are known to be activated through phosphorylation by other protein kinases or by themselves, we evaluate the activation of the 3 most well-characterized mammalian MAPK subfamilies, p38, ERK, and JNK on their phosphorylation level. We found that acupuncture alleviated the preactivation of ERK1/2 and p38 MAPK in RVLM of SHRs. Microinjection of DPI and apocynin could not only mimic the antihypertensive effect of acupuncture but also decrease the activation of ERK1/2 and p38 MAPK. TBCA microinjection, however, enhanced the activation of ERK1/2, p38 MAPK, and JNK and abolished the beneficial effect of acupuncture. This coordination between NADPH oxidase and MAPKs indicated that, at least in part, the central effect of acupuncture was via this NADPH oxidase–dependent MAPKs.
While exploring the underlying mechanisms of acupuncture effects on BP, we confronted an interesting question, why acupuncture at LR3 (located in the feet) could change homeostasis in the brain and affected the sympathetic outflows? A well-know study by Torres-Rosas et al17 demonstrated that acupuncture at ST36 in the anterior tibial region could regulate systemic inflammation via a nerve circuits from the afferent sciatic nerve to the central nervous system and through efferent pathways in the vagus nerve to regulate the production neurotransmitter. This neural circuit effect of acupuncture is based on the neuroanatomy and the location of the acupoints. The sensory nerves beneath the skin of LR3 are the deep peroneal nerve and the tibial nerve, both of which are the branches of the sciatic nerve, and are supplied by similar segmental innervations (peroneal nerve, L4–S1). In human functional magnetic resonance imaging studies, it has also been shown that acupuncture at acupoints around the crus, including LR3, could affect the connection between the limbic–paralimbic–neocortical networks.33 In our study, we found that blocking the sciatic nerve signals did not affect sympathetic outflows or BP itself but could abolished the beneficial effect of acupuncture. However, the precise route by which sensory signals elicited from acupuncture transits the RVLM to activate outgoing sympathetic signals needs further investigation.

Perspectives

Our work, for the first time, revealed the central antihypertensive effect of acupuncture depends on reduced activation of NADPH oxidase. MAPKs and the sciatic nerve are also involved in mechanism of acupuncture in treating hypertension. We provide evidence that nonpharmacological approach like acupuncture could potentially be a novel therapeutic strategy against hypertension.

Novelty and Significance

What Is New?

•
Acupuncture decreases nicotinamide adenine dinucleotide phosphate oxidase–derived reactive oxygen species production and mitogen-activated protein kinases activation in the rostral ventrolateral medulla of spontaneously hypertensive rats.
•
Site-specific diminishing of oxidative stress or nicotinamide adenine dinucleotide phosphate oxidase activity in the rostral ventrolateral medulla mimics the antihypertensive effect of acupuncture, whereas nicotinamide adenine dinucleotide phosphate oxidase agonist abolishes the beneficial effect of acupuncture.
•
Chemical or surgical sectioning of the sciatic nerve abolishes the antihypertensive effect of acupuncture.

What Is Relevant?

•
Our study provided evidence that nonpharmacological approach like acupuncture could potentially be a novel therapeutic strategy against hypertension.

Summary

Acupuncture decreases high blood pressure and nicotinamide adenine dinucleotide phosphate oxidase in the rostral ventrolateral medulla of spontaneously hypertensive rats. Mitogen-activated protein kinases and the sciatic nerve are involved in mechanism of acupuncture in treating hypertension.

Supplemental Material

File (hyp_hype201709759_supp1.pdf)

References

1.
Chan SH, Wu KL, Chang AY, Tai MH, Chan JY. Oxidative impairment of mitochondrial electron transport chain complexes in rostral ventrolateral medulla contributes to neurogenic hypertension. Hypertension. 2009;53:217–227. doi: 10.1161/HYPERTENSIONAHA.108.116905.
Crossref
PubMed
Google Scholar
2.
Nagae A, Fujita M, Kawarazaki H, Matsui H, Ando K, Fujita T. Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in obesity-induced hypertension. Circulation. 2009;119:978–986. doi: 10.1161/CIRCULATIONAHA.108.824730.
Crossref
PubMed
Google Scholar
3.
Subramanian M, Hahn-Townsend C, Clark KA, MohanKumar SM, MohanKumar PS. Chronic estrogen exposure affects gene expression in the rostral ventrolateral medulla of young and aging rats: possible role in hypertension. Brain Res. 2015;1627:134–142. doi: 10.1016/j.brainres.2015.09.007.
Crossref
PubMed
Google Scholar
4.
Wu KL, Chao YM, Tsay SJ, Chen CH, Chan SH, Dovinova I, Chan JY. Role of nitric oxide synthase uncoupling at rostral ventrolateral medulla in redox-sensitive hypertension associated with metabolic syndrome. Hypertension. 2014;64:815–824. doi: 10.1161/HYPERTENSIONAHA.114.03777.
Crossref
PubMed
Google Scholar
5.
Wang YK, Yu Q, Tan X, Wu ZT, Zhang RW, Yang YH, Yuan WJ, Hu QK, Wang WZ. Centrally acting drug moxonidine decreases reactive oxygen species via inactivation of the phosphoinositide-3 kinase signaling in the rostral ventrolateral medulla in hypertensive rats. J Hypertens. 2016;34:993–1004. doi: 10.1097/HJH.0000000000000887.
Crossref
PubMed
Google Scholar
6.
Münzel T, Gori T, Bruno RM, Taddei S. Is oxidative stress a therapeutic target in cardiovascular disease? Eur Heart J. 2010;31:2741–2748. doi: 10.1093/eurheartj/ehq396.
Crossref
PubMed
Google Scholar
7.
Williams HC, Griendling KK. NADPH oxidase inhibitors: new antihypertensive agents? J Cardiovasc Pharmacol. 2007;50:9–16. doi: 10.1097/FJC.0b013e318063e820.
Crossref
PubMed
Google Scholar
8.
Zimmerman MC, Lazartigues E, Lang JA, Sinnayah P, Ahmad IM, Spitz DR, Davisson RL. Superoxide mediates the actions of angiotensin II in the central nervous system. Circ Res. 2002;91:1038–1045.
Crossref
PubMed
Google Scholar
9.
Gao L, Wang W, Li YL, Schultz HD, Liu D, Cornish KG, Zucker IH. Superoxide mediates sympathoexcitation in heart failure: roles of angiotensin II and NAD(P)H oxidase. Circ Res. 2004;95:937–944. doi: 10.1161/01.RES.0000146676.04359.64.
Crossref
PubMed
Google Scholar
10.
Zimmerman MC, Dunlay RP, Lazartigues E, Zhang Y, Sharma RV, Engelhardt JF, Davisson RL. Requirement for Rac1-dependent NADPH oxidase in the cardiovascular and dipsogenic actions of angiotensin II in the brain. Circ Res. 2004;95:532–539. doi: 10.1161/01.RES.0000139957.22530.b9.
Crossref
PubMed
Google Scholar
11.
Chan SH, Hsu KS, Huang CC, Wang LL, Ou CC, Chan JY. NADPH oxidase-derived superoxide anion mediates angiotensin II-induced pressor effect via activation of p38 mitogen-activated protein kinase in the rostral ventrolateral medulla. Circ Res. 2005;97:772–780. doi: 10.1161/01.RES.0000185804.79157.C0.
Crossref
PubMed
Google Scholar
12.
Ebrahimian T, Li MW, Lemarié CA, Simeone SM, Pagano PJ, Gaestel M, Paradis P, Wassmann S, Schiffrin EL. Mitogen-activated protein kinase-activated protein kinase 2 in angiotensin II-induced inflammation and hypertension: regulation of oxidative stress. Hypertension. 2011;57:245–254. doi: 10.1161/HYPERTENSIONAHA.110.159889.
Crossref
PubMed
Google Scholar
13.
Wang XR, Shi GX, Yang JW, Yan CQ, Lin LT, Du SQ, Zhu W, He T, Zeng XH, Xu Q, Liu CZ. Acupuncture ameliorates cognitive impairment and hippocampus neuronal loss in experimental vascular dementia through Nrf2-mediated antioxidant response. Free Radic Biol Med. 2015;89:1077–1084. doi: 10.1016/j.freeradbiomed.2015.10.426.
Crossref
PubMed
Google Scholar
14.
Shi GX, Wang XR, Yan CQ, He T, Yang JW, Zeng XH, Xu Q, Zhu W, Du SQ, Liu CZ. Acupuncture elicits neuroprotective effect by inhibiting NAPDH oxidase-mediated reactive oxygen species production in cerebral ischaemia. Sci Rep. 2015;5:17981. doi: 10.1038/srep17981.
Crossref
PubMed
Google Scholar
15.
Sun S, Chen X, Gao Y, Liu Z, Zhai Q, Xiong L, Cai M, Wang Q. Mn-SOD upregulation by electroacupuncture attenuates ischemic oxidative damage via CB1R-mediated STAT3 phosphorylation. Mol Neurobiol. 2016;53:331–343. doi: 10.1007/s12035-014-8971-7.
Crossref
PubMed
Google Scholar
16.
Flachskampf FA, Gallasch J, Gefeller O, Gan J, Mao J, Pfahlberg AB, Wortmann A, Klinghammer L, Pflederer W, Daniel WG. Randomized trial of acupuncture to lower blood pressure. Circulation. 2007;115:3121–3129. doi: 10.1161/CIRCULATIONAHA.106.661140.
Crossref
PubMed
Google Scholar
17.
Torres-Rosas R, Yehia G, Peña G, Mishra P, del Rocio Thompson-Bonilla M, Moreno-Eutimio MA, Arriaga-Pizano LA, Isibasi A, Ulloa L. Dopamine mediates vagal modulation of the immune system by electroacupuncture. Nat Med. 2014;20:291–295. doi: 10.1038/nm.3479.
Crossref
PubMed
Google Scholar
18.
Liu Y, Park JE, Shin KM, Lee M, Jung HJ, Kim AR, Jung SY, Yoo HR, Sang KO, Choi SM. Acupuncture lowers blood pressure in mild hypertension patients: a randomized, controlled, assessor-blinded pilot trial. Complement Ther Med. 2015;23:658–665. doi: 10.1016/j.ctim.2015.06.014.
Crossref
PubMed
Google Scholar
19.
Feldstein CA. Lowering blood pressure to prevent stroke recurrence: a systematic review of long-term randomized trials. J Am Soc Hypertens. 2014;8:503–513. doi: 10.1016/j.jash.2014.05.002.
Crossref
PubMed
Google Scholar
20.
Yang M, Yu Z, Deng S, Chen X, Chen L, Guo Z, Zheng H, Chen L, Cai D, Wen B, Wu Q, Liang F. A targeted metabolomics MRM-MS study on identifying potential hypertension biomarkers in human plasma and evaluating acupuncture effects. Sci Rep. 2016;6:25871. doi: 10.1038/srep25871.
Crossref
PubMed
Google Scholar
21.
Macklin EA, Wayne PM, Kalish LA, Valaskatgis P, Thompson J, Pian-Smith MC, Zhang Q, Stevens S, Goertz C, Prineas RJ, Buczynski B, Zusman RM. Stop Hypertension with the Acupuncture Research Program (SHARP): results of a randomized, controlled clinical trial. Hypertension. 2006;48:838–845. doi: 10.1161/01.HYP.0000241090.28070.4c.
Crossref
PubMed
Google Scholar
22.
Vickers A. Acupuncture for hypertension: a tale of two trials. From the perspective of the statistician–Andrew Vickers, New York, NY, USA. Forsch Komplementmed. 2007;14:371, 373–371, 374. doi: 10.1159/000110416.
Crossref
PubMed
Google Scholar
23.
Ma L, Cui B, Shao Y, Ni B, Zhang W, Luo Y, Zhang S. Electroacupuncture improves cardiac function and remodeling by inhibition of sympathoexcitation in chronic heart failure rats. Am J Physiol Heart Circ Physiol. 2014;306:H1464–H1471. doi: 10.1152/ajpheart.00889.2013.
Crossref
PubMed
Google Scholar
24.
Tjen-A-Looi SC, Li P, Longhurst JC. Prolonged inhibition of rostral ventral lateral medullary premotor sympathetic neurons by electroacupuncture in cats. Auton Neurosci. 2003;106:119–131. doi: 10.1016/S1566-0702(03)00076-6.
Crossref
PubMed
Google Scholar
25.
Li P, Ayannusi O, Reid C, Longhurst JC. Inhibitory effect of electroacupuncture (EA) on the pressor response induced by exercise stress. Clin Auton Res. 2004;14:182–188. doi: 10.1007/s10286-004-0175-1.
Crossref
PubMed
Google Scholar
26.
Tjen-A-Looi SC, Li P, Longhurst JC. Role of medullary GABA, opioids, and nociceptin in prolonged inhibition of cardiovascular sympathoexcitatory reflexes during electroacupuncture in cats. Am J Physiol Heart Circ Physiol. 2007;293:H3627–H3635. doi: 10.1152/ajpheart.00842.2007.
Crossref
PubMed
Google Scholar
27.
Tjen-A-Looi SC, Guo ZL, Fu LW, Longhurst JC. Paraventricular nucleus modulates excitatory cardiovascular reflexes during electroacupuncture. Sci Rep. 2016;6:25910. doi: 10.1038/srep25910.
Crossref
PubMed
Google Scholar
28.
Chan SH, Wu CA, Wu KL, Ho YH, Chang AY, Chan JY. Transcriptional upregulation of mitochondrial uncoupling protein 2 protects against oxidative stress-associated neurogenic hypertension. Circ Res. 2009;105:886–896. doi: 10.1161/CIRCRESAHA.109.199018.
Crossref
PubMed
Google Scholar
29.
Heumüller S, Wind S, Barbosa-Sicard E, Schmidt HH, Busse R, Schröder K, Brandes RP. Apocynin is not an inhibitor of vascular NADPH oxidases but an antioxidant. Hypertension. 2008;51:211–217. doi: 10.1161/HYPERTENSIONAHA.107.100214.
Crossref
PubMed
Google Scholar
30.
Li Y, Trush MA. Diphenyleneiodonium, an NAD(P)H oxidase inhibitor, also potently inhibits mitochondrial reactive oxygen species production. Biochem Biophys Res Commun. 1998;253:295–299. doi: 10.1006/bbrc.1998.9729.
Crossref
PubMed
Google Scholar
31.
Kim GS, Jung JE, Niizuma K, Chan PH. CK2 is a novel negative regulator of NADPH oxidase and a neuroprotectant in mice after cerebral ischemia. J Neurosci. 2009;29:14779–14789. doi: 10.1523/JNEUROSCI.4161-09.2009.
Crossref
PubMed
Google Scholar
32.
Kim GS, Jung JE, Narasimhan P, Sakata H, Yoshioka H, Song YS, Okami N, Chan PH. Release of mitochondrial apoptogenic factors and cell death are mediated by CK2 and NADPH oxidase. J Cereb Blood Flow Metab. 2012;32:720–730. doi: 10.1038/jcbfm.2011.176.
Crossref
PubMed
Google Scholar
33.
Fang J, Jin Z, Wang Y, Li K, Kong J, Nixon EE, Zeng Y, Ren Y, Tong H, Wang Y, Wang P, Hui KK. The salient characteristics of the central effects of acupuncture needling: limbic-paralimbic-neocortical network modulation. Hum Brain Mapp. 2009;30:1196–1206. doi: 10.1002/hbm.20583.
Crossref
PubMed
Google Scholar

eLetters(0)

eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.

Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.

Sign In to Submit a Response to This Article

Information & Authors

Information

Published In

Go to Hypertension
Go to Hypertension
Hypertension
Volume 71 • Number 2 • February 2018
Pages: 356 - 365
PubMed: 29229746

Copyright

© 2017 American Heart Association, Inc.

History

Received: 22 May 2017
Revision received: 1 June 2017
Accepted: 19 October 2017
Published online: 11 December 2017
Published in print: February 2018

Permissions

Request permissions for this article.

Keywords

  1. acupuncture
  2. hypertension
  3. mitogen-activated protein kinases
  4. NADPH oxidases
  5. oxidative stress

Subjects

  1. High Blood Pressure
  2. Hypertension
  3. Oxidant Stress

Authors

Affiliations

Xue-Rui Wang
From the Department of Acupuncture and Moxibustion (X.-R.W., J.-W.Y., C.-S.J., X.-H.Z., G.-X.S., C.-Z.L.) and Beijing Institute of Tradition Chinese Medicine (X.-R.W.), Beijing Hospital of Traditional Chinese Medicine affiliated to Capital Medical University; Beijing Key Laboratory of Acupuncture Neuromodulation, China (X.-R.W., J.-W.Y., C.-S.J., X.-H.Z., G.-X.S., C.-Z.L.); and the Department of Neurology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA (M.F.).
View all articles by this author
Jing-Wen Yang
From the Department of Acupuncture and Moxibustion (X.-R.W., J.-W.Y., C.-S.J., X.-H.Z., G.-X.S., C.-Z.L.) and Beijing Institute of Tradition Chinese Medicine (X.-R.W.), Beijing Hospital of Traditional Chinese Medicine affiliated to Capital Medical University; Beijing Key Laboratory of Acupuncture Neuromodulation, China (X.-R.W., J.-W.Y., C.-S.J., X.-H.Z., G.-X.S., C.-Z.L.); and the Department of Neurology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA (M.F.).
View all articles by this author
Cai-Shuo Ji
From the Department of Acupuncture and Moxibustion (X.-R.W., J.-W.Y., C.-S.J., X.-H.Z., G.-X.S., C.-Z.L.) and Beijing Institute of Tradition Chinese Medicine (X.-R.W.), Beijing Hospital of Traditional Chinese Medicine affiliated to Capital Medical University; Beijing Key Laboratory of Acupuncture Neuromodulation, China (X.-R.W., J.-W.Y., C.-S.J., X.-H.Z., G.-X.S., C.-Z.L.); and the Department of Neurology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA (M.F.).
View all articles by this author
Xiang-Hong Zeng
From the Department of Acupuncture and Moxibustion (X.-R.W., J.-W.Y., C.-S.J., X.-H.Z., G.-X.S., C.-Z.L.) and Beijing Institute of Tradition Chinese Medicine (X.-R.W.), Beijing Hospital of Traditional Chinese Medicine affiliated to Capital Medical University; Beijing Key Laboratory of Acupuncture Neuromodulation, China (X.-R.W., J.-W.Y., C.-S.J., X.-H.Z., G.-X.S., C.-Z.L.); and the Department of Neurology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA (M.F.).
View all articles by this author
Guang-Xia Shi
From the Department of Acupuncture and Moxibustion (X.-R.W., J.-W.Y., C.-S.J., X.-H.Z., G.-X.S., C.-Z.L.) and Beijing Institute of Tradition Chinese Medicine (X.-R.W.), Beijing Hospital of Traditional Chinese Medicine affiliated to Capital Medical University; Beijing Key Laboratory of Acupuncture Neuromodulation, China (X.-R.W., J.-W.Y., C.-S.J., X.-H.Z., G.-X.S., C.-Z.L.); and the Department of Neurology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA (M.F.).
View all articles by this author
Marc Fisher
From the Department of Acupuncture and Moxibustion (X.-R.W., J.-W.Y., C.-S.J., X.-H.Z., G.-X.S., C.-Z.L.) and Beijing Institute of Tradition Chinese Medicine (X.-R.W.), Beijing Hospital of Traditional Chinese Medicine affiliated to Capital Medical University; Beijing Key Laboratory of Acupuncture Neuromodulation, China (X.-R.W., J.-W.Y., C.-S.J., X.-H.Z., G.-X.S., C.-Z.L.); and the Department of Neurology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA (M.F.).
View all articles by this author
Cun-Zhi Liu
From the Department of Acupuncture and Moxibustion (X.-R.W., J.-W.Y., C.-S.J., X.-H.Z., G.-X.S., C.-Z.L.) and Beijing Institute of Tradition Chinese Medicine (X.-R.W.), Beijing Hospital of Traditional Chinese Medicine affiliated to Capital Medical University; Beijing Key Laboratory of Acupuncture Neuromodulation, China (X.-R.W., J.-W.Y., C.-S.J., X.-H.Z., G.-X.S., C.-Z.L.); and the Department of Neurology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA (M.F.).
View all articles by this author

Notes

The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.117.09759/-/DC1.
Correspondence to Cun-Zhi Liu, Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine affiliated to Capital Medical University, Meishuguan Back St, Dong Cheng District, Beijing 100010, China. E-mail [email protected]

Disclosures

None.

Sources of Funding

This study was funded by National Natural Science Foundation for Excellent Young Scholars of China (grant no. 81222050).

Metrics & Citations

Metrics

Citations

Download Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.

    • G. I. Lobov,
    Social isolation: relationship with cardiovascular diseases, Успехи физиологических наук, 55, 1, (2024).https://doi.org/10.31857/S0301179824010045
    Crossref
    • Hailun Jiang,
    • Chao Zhang,
    • Mengxuan Lin,
    • Yu Yin,
    • Shizhe Deng,
    • Wei Liu,
    • Bifang Zhuo,
    • Guang Tian,
    • Yuzheng Du,
    • Zhihong Meng,
    Deciphering the mechanistic impact of acupuncture on the neurovascular unit in acute ischemic stroke: Insights from basic research in a narrative review, Ageing Research Reviews, 101, (102536), (2024).https://doi.org/10.1016/j.arr.2024.102536
    Crossref
    • Yaxing Zhang,
    • Xian-Ming Fang,
    The Pan-liver Network Theory, Chinese Journal of Physiology, 66, 6, (401-436), (2023).https://doi.org/10.4103/cjop.CJOP-D-22-00131
    Crossref
    • Ewart Smith,
    • Ainsely Lewis,
    • Suresh S. Narine,
    • R. J. Neil Emery,
    Unlocking Potentially Therapeutic Phytochemicals in Capadulla (Doliocarpus dentatus) from Guyana Using Untargeted Mass Spectrometry-Based Metabolomics, Metabolites, 13, 10, (1050), (2023).https://doi.org/10.3390/metabo13101050
    Crossref
    • Yin-Yin Li,
    • Ji-Peng Liu,
    • Shu-Feng Shi,
    • Ke-Zhen Yang,
    • Yu Gong,
    • Jiao Sun,
    • Qi Xie,
    • Xiao-Li Wu,
    • Qing-Guo Liu,
    • Meng Xu,
    Acupuncture with twirling reinforcing and reducing manipulation shows a control of hypertension and regulation of blood pressure-related target brain regions in spontaneously hypertensive rat: a preliminary resting-state functional MRI study, Frontiers in Neuroscience, 17, (2023).https://doi.org/10.3389/fnins.2023.1161578
    Crossref
    • Zhi-Ling Guo,
    • Stephanie C. Tjen-A-Looi,
    • Anh Thingoc Nguyen,
    • Liang-Wu Fu,
    • Hou-Fen Su,
    • Yiwei D. Gong,
    • Shaista Malik,
    Adenosine A2A receptors in the rostral ventrolateral medulla participate in blood pressure decrease with electroacupuncture in hypertensive rats, Frontiers in Cardiovascular Medicine, 10, (2023).https://doi.org/10.3389/fcvm.2023.1275952
    Crossref
    • Mehmet Kanbay,
    • Cem Tanriover,
    • Sidar Copur,
    • Ibrahim B. Peltek,
    • Ali Mutlu,
    • Francesca Mallamaci,
    • Carmine Zoccali,
    Social isolation and loneliness: Undervalued risk factors for disease states and mortality, European Journal of Clinical Investigation, 53, 10, (2023).https://doi.org/10.1111/eci.14032
    Crossref
    • Zhao Li,
    • Shao Yin,
    • Jie Feng,
    • Xu Gao,
    • Qicheng Yang,
    • Fengya Zhu,
    Acupuncture combined with Chinese herbal medicine in the treatment of perimenopausal insomnia: A systematic review and meta-analysis, Medicine, 102, 45, (e35942), (2023).https://doi.org/10.1097/MD.0000000000035942
    Crossref
    • Xuqing Li,
    • Li Wang,
    • Xinwang Ying,
    • Yujun Zheng,
    • Qianqian Tan,
    • Xiaolan Yu,
    • Jiahong Gong,
    • Ming Li,
    • Xiaofeng Deng,
    • Guanhu Yang,
    • Shengcun Li,
    • Songhe Jiang,
    Electroacupuncture pre-treatment alleviates sepsis-induced cardiac inflammation and dysfunction by inhibiting the calpain-2/STAT3 pathway, Frontiers in Physiology, 13, (2022).https://doi.org/10.3389/fphys.2022.961909
    Crossref
    • Liang Chen,
    • Yang Shen,
    • Shuangmei Liu,
    • Yanyan Cao,
    Transcutaneous Electrical Acupoint Stimulation Improved Preoperative Blood Pressure in Gynecological Malignant Tumor Patients With Hypertension: A Randomized, Controlled Trial, Frontiers in Oncology, 12, (2022).https://doi.org/10.3389/fonc.2022.906528
    Crossref
  11. See more

View Options

View options

PDF and All Supplements

Download PDF and All Supplements

PDF/EPUB

View PDF/EPUB
Login options

Check if you have access through your login credentials or your institution to get full access on this article.

Personal login Institutional Login
Save for later Item saved, go to cart
Purchase Options

Purchase this article to access the full text.

Purchase access to this article for 24 hours

Inhibition of NADPH Oxidase–Dependent Oxidative Stress in the Rostral Ventrolateral Medulla Mediates the Antihypertensive Effects of Acupuncture in Spontaneously Hypertensive Rats
Hypertension
  • Vol. 71
  • No. 2

Purchase access to this journal for 24 hours

Hypertension
  • Vol. 71
  • No. 2
Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

Media

Figures

Other

Tables

Share

Share

Share article link

Share

View full text|Download PDF

Comment Response