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. 2023 Apr 5;9(4):e15291. doi: 10.1016/j.heliyon.2023.e15291

PC6 electroacupuncture reduces stress-induced autonomic and neuroendocrine responses in rats

Zhen Ye a,1, Li Zhu a,1, Xiao-jia Li a,b, He-yuan Gao f, Jie Wang a,b, Sheng-bing Wu a,b,d,e, Zi-jian Wu a,b,d,e,∗, He-ren Gao a,b,c,∗∗
PMCID: PMC10121450  PMID: 37095918

Abstract

Stress can trigger cardiovascular disease. Both imbalance of autonomic nervous activity and increase of neurohormonal output are core aspects of stress responses and can lead to cardiovascular disease. PC6 as a very important acupoint is used to prevent and treat cardiovascular disease and to improve stress-related activities. We examined the influence of electroacupuncture (EA) at PC6 on stress-induced imbalance of autonomic nervous activity and increase of neurohormonal output. EA at PC6 relieved increased cardiac sympathetic nervous activity and decreased cardiac vagal nervous activity induced by immobilization stress. Also, EA at PC6 reduced immobilization stress-induced increases of plasma norepinephrine (NE) and adrenaline (E) released from sympatho-adrenal-medullary axis. Finally, EA at PC6 reduced immobilization stress-induced increases of corticotropin-releasing hormone (CRH) in paraventricular hypothalamic nucleus and plasma cortisol (CORT) released from hypothalamic-pituitary-adrenal axis. However, EA at tail had no significant effect on the stress-induced autonomic and neuroendocrine responses. The results demonstrate the role of EA at PC6 regulating the autonomic and neuroendocrine responses induced by stress and provide insight into the prevention and treatment of EA at PC6 for stress-induced cardiovascular disease by targeting autonomic and neuroendocrine systems.

Keywords: PC6, Stress, Sympathetic nervous activity, Vagal nervous activity, Sympatho-adrenal-medullary axis, Hypothalamic-pituitary-adrenal axis

1. Introduction

Cardiovascular disease remains the major contributor to global burden of fatal illness. Stress as an emerging problem is responsible for genesis, development and maintenance of cardiovascular disease [1]. Autonomic nervous system response, sympatho-adrenal-medullary response, and hypothalamus-pituitary-adrenal response are core aspects of stress responses [2,3]. Activation of sympathetic nervous system elicits increases in norepinephrine (NE) release from sympathetic nerve terminals and adrenaline (E) secretion from the sympatho-adrenal-medullary axis; withdrawal of vagal nervous system decreases acetylcholine (ACh) release from vagal nerve terminals; activation of hypothalamus triggers corticotropin-releasing hormone (CRH) release from paraventricular hypothalamic nucleus onto pituitary receptors, ultimately stimulating cortisol (CORT) release from hypothalamic-pituitary-adrenal-cortical axis. These autonomic and neuroendocrine responses can trigger a complex chain of adverse reactions of cellular and molecular alterations in heart and vessel to lead to cardiovascular disease [2,4,5]. The autonomic and neuroendocrine responses linking stress and cardiovascular disease may be the important target for the prevention and treatment of stress-induced cardiovascular disease.

Acupuncture as a therapy of traditional Chinese medicine can modulate various aspects of body physiology, and has been increasingly used to prevent and treat human diseases. Recently, the role of acupuncture in preventing and treating various cardiovascular diseases and underlying mechanisms through which acupuncture reduces cardiovascular dysfunction have attracted interest [[6], [7], [8], [9], [10]]. Many acupoints are used to prevent and treat cardiovascular disease, but the underlying mechanisms through which acupoints acupuncture prevent and treat cardiovascular disease is still not well understood. Previous studies have found that acupuncture could reduce various stress responses [11,12]. We speculate that acupuncture might modulate stress-induced autonomic and neuroendocrine responses to prevent and treat stress-induced cardiovascular disease. The effect of acupoints acupuncture most crucially depends on the selection of acupoints. PC6 located above the wrist, between the palmaris longus tendon and the flexor carpi radialis tendon, in a region corresponding to the anatomical path of the median nerve, is a very important acupoint used to prevent and treat cardiovascular disease [8,9,13] and to improve stress-related activities [11,12]. However, it is unknown whether acupuncture at PC6 will improve stress-induced autonomic and neuroendocrine responses. Therefore, in the present study, we evaluated the contribution of electroacupuncture (EA) at PC6 on stress-induced autonomic and neuroendocrine responses which link stress and cardiovascular disease.

2. Materials and methods

2.1. Animals

We used healthy male Sprague-Dawley rats (250–280 g), housed under controlled conditions with a lighting schedule of 12 h light and 12 h dark at a temperature of 22 ± 2 °C and a relative humidity of 45 ± 5%. Standard food and water were provided ad libitum. All experiments were approved by the Experimental Animal Care and Use Committee of Anhui University of Chinese Medicine (Approval No. AHUCM-rats-2020013).

2.2. Experimental protocol

According to the random number table method, the rats were randomly assigned to four groups, inclcuding control group, stress group, stress plus PC6 EA (located at 3 mm above the wrist, between the palmaris longus tendon and the flexor carpi radialis tendon) group, and stress plus tail EA (located at half of tail length) group, 8 rats in each group. The heart rate variability test was first performed by electrocardiogram recording, and heart rate variability was blinded analyzed, and then the plasma, heart and brain tissues were collected for high-performance liquid chromatography test and analysis following a blinded procedure.

2.3. Immobilization stress

Immobilization stress is a commonly used animal model [14]. The rat was placed in a special cylinder with holes for limbs and tail. The rat was restrained in the supine position that allowed no movement for 150 min. The supine position was adopted to expose acupoints for EA.

2.4. EA stimulation

EA was conducted with pairs of unipolar stainless-steel acupuncture needles (0.2 × 13 mm). The electrical current range was set at 1.0 mA, and the stimulation lasted for 30 min from the start of immobilization stress, with a frequency of 3 Hz controlled using an electric acupuncture apparatus (SDZ-IV, Huatuo, Suzhou, China) [12]. For EA at PC6, two pairs of acupuncture needles were perpendicularly inserted into the bilateral PC6 at a depth of 3 mm. For EA at tail, two pairs of acupuncture needles were inserted into the two regions of the half of tail at a depth of 3 mm. Note that this focal electric stimulation mode, with the positive and negative electric needles separated by 1 mm.

2.5. Electrocardiogram recording

The rats were anesthetized with isoflurane (3%). Positive electrode for electrocardiogram recording was implanted subcutaneously near left hindlimb of rat. Negative electrode for electrocardiogram recording was implanted subcutaneously near right forelimb. The third electrode was placed subcutaneously near right hindlimb to serve as a ground. After recovery, the electrocardiogram signals of conscious normal rats and immobilization stress rats were recorded at the same time and in a constant environment. The wires from the electrodes were connected to an amplifier (Bio Amp, ADInstruments, Australia). The signals were recorded on a computer using a PowerLab system (ADInstruments, Australia).

2.6. Heart rate variability analysis

Heart rate variability analysis was conducted on stable segment for 5 min during conscious normal state and after 150 min immobilization stress. Heart rate variability was assessed within the frequency domains and heart rate variability parameters were quantified into low frequency band of power spectrum (LF; 0.04–1.0 Hz), high frequency band of power spectrum (HF; 1.0–3.0 Hz) and LF/HF ratio. All signals were acquired online using LabChart 7 software (ADInstruments, Australia). LF indicates cardiac sympathetic nerve activity and vagal nerve activity, HF represents cardiac vagal nerve activity, LF/HF ratio indicates balance between the sympathetic and vagal activities.

2.7. High-performance liquid chromatography

After the electrocardiogram recording, rats were deeply anesthetized with urethane (1600 mg/kg) plus α-chloralose (130 mg/kg) given intraperitoneally, blood was extracted, heart and brain were removed. The heart was dissected along atrial septum and ventricular septum, the entire left and right atrioventricular tissues were collected. Paraventricular hypothalamic nucleus tissue punches were collected according to the technique of Palkovits [15]. Frozen coronal brain slices containing the paraventricular hypothalamic nucleus were obtained by using a freezing microtome (CM 1950, Leica, Germany). Punches were collected from coronal brain slices of rats according to the rat brain atlas of Paxinos and Watson [16]. Each sample was homogenized, then centrifuged at 10,000 r/min for 10 min. The supernatant was reserved and made into standard solution. The standard solution was filtered through 0.22 μm PVDF (Millipore, MO, USA), then assessed by HPLC-MS/MS system (Aglient Technologies, Palo Alto, CA, USA). Chromatographic separation was carried out using Thermo Scientific Aquasil C18 column (2.1 × 100 mm, 1.8 μm, Thermo, US), kept at 35 °C during analysis. The mobile phase consisted of 0.05% formic acid aqueous solution (A) and acetonitrile (B). A 10 μL sample solution was injected into the Thermo Scientific Aquasil C18 column with a flow rate of 0.3 mL/min.

2.8. Statistical analysis

All statistical analyses were performed using the SPSS 23.0 software. All data were presented as the mean ± SEM. Significant differences were analyzed using one-way ANOVA followed by LSD post hoc test. P < 0.05 were considered statistically significant.

3. Results

3.1. Heart rate variability

To investigate whether EA at PC6 improves stress-induced imbalance of cardiac automatic nervous system, we examined the heart rate variability of rats in all groups. An example illustrating the power spectrum of heart rate variability in all groups was shown in Fig. 1A1. We found that the rats in stress group had higher LF (37.18 ± 2.02 nu) (P < 0.05), lower HF (39.12 ± 3.13 nu) (P < 0.01) and higher LF/HF ratio (1.00 ± 0.10) (P < 0.01) compared with the rats in control group (LF (29.55 ± 0.77 nu), HF (68.10 ± 1.62 nu) and LF/HF ratio (0.49 ± 0.02)). In addition, the rats in stress plus PC6 EA group had significantly decreased LF (25.89 ± 1.02 nu) (P < 0.01), increased HF (58.98 ± 2.87 nu) (P < 0.01) and decreased LF/HF ratio (0.45 ± 0.03) (P < 0.01) compared with the rats in stress group. However, the LF (35.02 ± 1.58 nu), HF (41.38 ± 2.99 nu) and LF/HF ratio (0.91 ± 0.07) of the rats in stress plus tail EA group had no significant change compared with heart rate variability of the rats in stress group (P > 0.05). The rats in stress plus tail EA group had higher LF, lower HF and higher LF/HF ratio compared with the rats in stress plus PC6 EA group (P < 0.01) (Fig. 1A2). These results suggest that EA at PC6 improves enhanced cardiac sympathetic nervous activity and reduced cardiac vagal nervous activity induced by stress.

Fig. 1.

Fig. 1

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The effect of EA at PC6 on stress-induced changes of LF, HF and LF/HF. (A1) The power spectrum of heart rate variability was shown in control group, stress group, stress plus PC6 EA group and stress plus tail EA group. (A2) Group data showing the average LF, HF and LF/HF in control group, stress group, stress plus PC6 EA group and stress plus tail EA group. Data are shown as mean ± SEM, n = 8. Statistical significance was determined using one-way ANOVA followed by LSD post hoc test. * indicates P < 0.05, ** indicates P < 0.01, compared with control group; ## indicates P < 0.01, compared with stress group; ^^ indicates P < 0.01, compared with stress plus PC6 EA group.

3.2. NE and ACh levels of heart tissue

Given that activation of cardiac sympathetic nervous system increases NE release from sympathetic nerve terminals and withdrawal of cardiac vagal nervous system decreases ACh release from vagal nerve terminals. We examined NE and ACh levels of heart tissue. As shown in Fig. 2, the NE levels of right heart and left heart of rats in stress group were 63.49 ± 9.10 ng/ml and 45.80 ± 10.36 ng/ml respectively, which were significantly higher compared with the NE levels of right heart (14.01 ± 3.07 ng/ml) (P < 0.01) and left heart (18.48 ± 3.54 ng/ml) (P < 0.01) of rats in control group. The NE levels of right heart and left heart of rats in stress plus PC6 EA group were 20.50 ± 2.51 ng/ml and 10.31 ± 2.71 ng/ml which were significantly decreased compared with the NE levels of heart tissue of rats in stress group (P < 0.01). However, the NE levels of right heart and left heart of rats in stress plus tail EA group were 75.22 ± 4.44 ng/ml and 30.57 ± 5.60 ng/ml which had no significant changes compared with the NE levels of heart tissue of rats in stress group (P > 0.05). And the NE levels of right heart and left heart of rats in stress plus tail EA group were significantly higher compared with the NE levels of right heart (P < 0.01) and left heart (P < 0.05) of rats in stress plus PC6 EA group. The ACh levels of right heart and left heart of rats in stress group were 9.42 ± 0.83 ng/ml and 4.69 ± 1.77 ng/ml respective, which were significantly lower compared with the ACh levels of right heart (33.30 ± 3.20 ng/ml) (P < 0.01) and left heart (33.30 ± 3.64 ng/ml) (P < 0.01) of rats in control group. The ACh levels of right heart and left heart of rats in stress plus PC6 EA group were 33.64 ± 1.11 ng/ml and 35.66 ± 2.10 ng/ml which were significantly increased compared with the ACh levels of heart tissue of rats in stress group (P < 0.01). However, the ACh levels of right heart and left heart of rats in stress plus tail EA group were 12.54 ± 0.99 ng/ml and 4.02 ± 0.77 ng/ml which had no significant changes compared with the ACh levels of heart tissue of rats in stress group (P > 0.05). And the ACh levels of right heart and left heart of rats in stress plus tail EA group were significantly lower compared with the ACh levels of heart tissue of rats in stress plus PC6 EA group (P < 0.01). The data demonstrate that EA at PC6 relieves enhanced cardiac sympathetic nervous activity and decreased cardiac vagal nervous activity induced by stress.

Fig. 2.

Fig. 2

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The effect of EA at PC6 on stress-induced changes in NE and ACh levels of heart tissue. (A) Group data showing the average NE levels in control group, stress group, stress plus PC6 EA group and stress plus tail EA group. (B) Group data showing the average ACh levels in control group, stress group, stress plus PC6 EA group and stress plus tail EA group. Data are shown as mean ± SEM, n = 6. Statistical significance was determined using one-way ANOVA followed by LSD post hoc test. ** indicates P < 0.01, compared with control group; ## indicates P < 0.01, compared with stress group; ^ indicates P < 0.05, ^^ indicates P < 0.01, compared with stress plus PC6 EA group.

3.3. Plasma NE and E levels

To investigate whether EA at PC6 improves stress-induced hyperactivation of sympatho-adrenal-medullary axis, we assessed the activity of sympatho-adrenal-medullary axis by examining the plasma NE and E levels. As shown in Fig. 3, the rats in stress group had higher plasma NE (27.44 ± 8.69 ng/ml) (P < 0.01) and E (1204.66 ± 113.00 ng/ml) (P < 0.01) levels compared with the rats in control group (plasma NE: 6.39 ± 1.08 ng/ml and E: 215.34 ± 7.65 ng/ml). In addition, the rats in stress plus PC6 EA group had significantly decreased plasma NE (8.63 ± 3.63 ng/ml) (P < 0.05) and E (516.01 ± 55.69 ng/ml) (P < 0.01) levels compared with the rats in stress group. However, the plasma NE (25.20 ± 5.30 ng/ml) and E (1149.15 ± 40.50 ng/ml) levels of rats in stress plus tail EA group had no significant changes compared with plasma NE and E levels of rats in stress group (P > 0.05). The rats in stress plus tail EA group had higher plasma NE (P < 0.05) and E (P < 0.01) levels compared with the rats in stress plus PC6 EA group. The data indicate that EA at PC6 reduces stress-induced hyperactivation of sympatho-adrenal-medullary axis.

Fig. 3.

Fig. 3

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The effect of EA at PC6 on stress-induced increases of plasma NE and E levels. (A) Group data showing the average plasma NE levels in control group, stress group, stress plus PC6 EA group and stress plus tail EA group. (B) Group data showing the average plasma E levels in control group, stress group, stress plus PC6 EA group and stress plus tail EA group. Data are shown as mean ± SEM, n = 6. Statistical significance was determined using one-way ANOVA followed by LSD post hoc test. ** indicates P < 0.01, compared with control group; # indicates P < 0.05, ## indicates P < 0.01, compared with stress group; ^ indicates P < 0.05, ^^ indicates P < 0.01, compared with stress plus PC6 EA group.

3.4. CRH level of paraventricular hypothalamic nucleus and plasma CORT level

Considering that stress triggers CRH release from paraventricular hypothalamic nucleus, ultimately stimulating CORT release, we assessed the activity of hypothalamic-pituitary-adrenal-cortical axis by examining the CRH level of paraventricular hypothalamic nucleus and plasma CORT level. An example illustrating the location of paraventricular hypothalamic nucleus in brain was shown in Fig. 4A1. We found that the rats in stress group had higher CRH level (490.76 ± 14.44 ng/ml) (P < 0.01) of paraventricular hypothalamic nucleus and plasma CORT level (1505.76 ± 59.39 ng/ml) (P < 0.01) compared with the rats in control group (CRH level (172.65 ± 22.87 ng/ml) of paraventricular hypothalamic nucleus and plasma CORT level (468.62 ± 19.93 ng/ml)). In addition, the rats in stress plus PC6 EA group had significantly decreased CRH level (231.22 ± 23.08 ng/ml) of paraventricular hypothalamic nucleus and plasma CORT level (1132.30 ± 83.51 ng/ml) compared with the rats in stress group (P < 0.01). However, the CRH level (481.31 ± 21.21 ng/ml) of paraventricular hypothalamic nucleus and plasma CORT level (1530.71 ± 34.26 ng/ml) of the rats in stress plus tail EA group had no significant changes compared with the CRH level of paraventricular hypothalamic nucleus and plasma CORT level of the rats in stress group (P > 0.05). The rats in stress plus tail EA group had higher CRH level of paraventricular hypothalamic nucleus and plasma CORT level compared with the rats in stress plus PC6 EA group (P < 0.01) (Fig. 4A2, B). The data indicate that EA at PC6 reduces stress-induced hyperactivation of hypothalamic-pituitary-adrenal-cortical axis.

Fig. 4.

Fig. 4

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The effect of EA at PC6 on stress-induced increases in CRH of paraventricular hypothalamic nucleus and plasma CORT level. (A1) Sagittal view of rat brain, localizing the paraventricular hypothalamic nucleus between − 0.96 and −2.16 mm from bregma. (A2) Group data showing the average CRH levels of paraventricular hypothalamic nucleus in control group, stress group, stress plus PC6 EA group and stress plus tail EA group. (B) Group data showing the average plasma CORT levels in control group, stress group, stress plus PC6 EA group and stress plus tail EA group. Data are shown as mean ± SEM, n = 6. Statistical significance was determined using one-way ANOVA followed by LSD post hoc test. ** indicates P < 0.01, compared with control group; ## indicates P < 0.01, compared with stress group; ^^ indicates P < 0.01, compared with stress plus PC6 EA group.

4. Discussion

We report that stress activates sympathetic nervous activity and inhibits vagal nervous activity, and increases neurohormonal output through sympatho-adrenal-medullary axis and hypothalamic-pituitary-adrenal-cortical axis. The results are consistent with previous reports [2,4,[17], [18], [19]]. Autonomic and neuroendocrine responses are the link between stress and the development of cardiovascular disease, may be useful indicators for potential cardiovascular dysfunction associated with the onset of cardiovascular disease.

Heightened cardiac sympathetic nervous activity with increased NE release results in hyper-responses of various cardiomyocytes, ultimately leads to cardiovascular dysfunction [[20], [21], [22]]. The cardiac vagal nervous system releasing ACh can inhibit sympathetic nervous system to protect heart tissue. Research have shown reduced cardiac vagal nervous activity is also associated with cardiovascular disease [23,24]. In the present study, we find that EA at PC6 relieves stress-induced increases of sympathetic nervous activity and NE release to heart, and decreases of vagal nervous activity and ACh release to heart. Sympatho-adrenal-medullary axis is also an important stress pathway [17,25]. Stress activates sympathetic nervous system to stimulate NE release from sympathetic nerve terminals, which in turn stimulate E secretion from adrenal medulla. Sustained hyperactivation of sympatho-adrenal-medullary axis with heart and vessel overexposure to E and NE is also considered to be responsible for cardiovascular disease [26,27]. In the present study, we find that EA at PC6 relieves stress-induced increases of NE and E release from sympatho-adrenal-medullary axis. Previous studies have shown that reducing sympathetic nervous activity or raising vagal nervous activity can improve cardiovascular dysfunction [[28], [29], [30], [31], [32]]. Our studies indicate that EA at PC6 relieves stress-induced activation of cardiac sympathetic nervous system and sympatho-adrenal-medullary axis and decrease of vagal nervous activity. Therefore, EA at PC6 may be an important method to prevent and treat stress-induced cardiovascular disease by regulating sympathetic nervous activity and vagal nervous activity. In addition, stress activates paraventricular hypothalamic nucleus to trigger CRH release, ultimately stimulating CORT release from adrenal cortex. Change in CORT is also associated with change of cardiovascular system which increases the risk of cardiovascular disease [25,33,34]. In the present study, we demonstrate that EA at PC6 significantly reduces stress-evoked increases in CRH of paraventricular hypothalamic nucleus and plasma CORT level, indicating that EA at PC6 may prevent and treat cardiovascular disease by inhibiting hyperactivation of hypothalamic-pituitary-adrenal-cortical axis induced by stress (Fig. 5).

Fig. 5.

Fig. 5

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Stress activates cardiac sympathetic nervous activity and inhibits cardiac vagal nervous activity, and increases neurohormonal output through sympatho-adrenal-medullary axis and hypothalamic-pituitary-adrenal-cortical axis. EA at PC6 relieves increased cardiac sympathetic nervous activity, decreased cardiac vagal nervous activity and increased neurohormonal output from sympatho-adrenal-medullary axis and hypothalamic-pituitary-adrenal axis induced by stress.

In the present study, we demonstrate a novel contribution of the PC6, a pivotal acupoint responsible for prevention and treatment of cardiovascular disease, on the effects of EA on stress-induced autonomic and neuroendocrine responses. EA at PC6 improves some markers of autonomic nervous system, sympatho-adrenal-medullary axis and hypothalamic-pituitary-adrenal-cortical axis in response to stress. Therefore, we reason that EA at PC6 has the potential to become a complementary intervention in the prevention and treatment of cardiovascular disease by permitting change in autonomic and neuroendocrine system. The study will guide the development of novel strategies for the prevention and treatment of stress-related cardiovascular disease. This study will also provide insights into the potential mechanisms of prevention and treatmeat of acupuncture in stress-induced cardiovascular disease. However, this study had some limitations. In this study, we detected the effect of EA at PC6 on autonomic and neuroendocrine responses caused by acute stress, with a small animal sample and few detection methods. Further studies are necessary to determine whether EA can prevent and treat stress-induced cardiovascular disease by regulating autonomic and neuroendocrine systems with a relatively large animal sample and multiple detection methods. In addition, we shown that EA at PC6 reduced the autonomic and neuroendocrine responses induced by stress, but the causal relationship between them remains elusive. Therefore, detailed mechanism of the interaction between them needs to be determined.

Author contribution statement

Zhen Ye; Li Zhu: Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data.

Xiaojia Li; Jie Wang: Performed the experiments.

Heyuan Gao; Shengbing Wu: Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data.

Zijian Wu; Heren Gao: Conceived and designed the experiments; Wrote the paper.

Funding statement

This work is supported by the Natural Science Foundation of Anhui Province (grant number 2208085MH274, 1908085QH341); the Natural Science Foundation of Colleges and Universities of Anhui Province (grant number KJ2020A0427); the Natural Science Foundation of Anhui University of Chinese Medicine (grant number 2021qnyc05); the Natural Science Foundation of Qinhuangdao City Science and Technology Bureau (grant number 201902A130); the National Natural Science Foundation of China (grant number 82205274, 81904095); the China Postdoctoral Science Foundation (grant number 2022M713063).

Data availability statement

Data included in article/supp. material/referenced in article.

Declaration of interest's statements

The authors declare no competing interests.

Contributor Information

Zi-jian Wu, Email: 15156096557@163.com.

He-ren Gao, Email: gaoheren19840513@126.com, hrgao@ahtcm.edu.cn.

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