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Pyridostigmine attenuates hypertension by inhibiting activation of the renin-angiotensin system in the hypothalamic paraventricular nucleus

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Abstract

Activation of the renin-angiotensin system (RAS) triggers oxidative stress and an inflammatory response in the hypothalamic paraventricular nucleus (PVN), in turn increasing the sympathetic hyperactivity that is a major cause of hypertension. Pyridostigmine has cardioprotective effects by suppressing the RAS of myocardial tissue. However, whether pyridostigmine attenuates hypertension by inhibiting the RAS of the PVN remains unclear. We thus investigated the effect and mechanism of pyridostigmine on two-kidney one-clip (2K1C)-induced hypertension. 2K1C rats received pyridostigmine, or not, for 8 weeks. Cardiovascular function, hemodynamic parameters, and autonomic activity were measured. The PVN levels of pro-/anti-inflammatory cytokines, oxidative stress, and RAS signaling molecules were evaluated. Our results showed that hypertension was accompanied by cardiovascular dysfunction and an autonomic imbalance characterized by enhanced sympathetic but diminished vagal activity. The PVN levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), reactive oxygen species (ROS), NOX-2, and malondialdehyde (MDA) increased; those of IL-10 and superoxide dismutase (SOD) decreased. Moreover, the RAS signaling pathway was activated, as evidenced by increased levels of the angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and the Ang II type 1 receptor (AT1R) and a decreased AT2R level. Pyridostigmine lowered blood pressure and improved cardiovascular function, associated with restoration of the autonomic balance. Meanwhile, pyridostigmine decreased PVN IL-6, TNF-α, ROS, NOX-2, and MDA levels and increased IL-10 and SOD levels. Additionally, pyridostigmine suppressed PVN ACE, Ang II, and AT1R levels and increased AT2R expression. Pyridostigmine attenuated hypertension by inhibiting PVN oxidative stress and inflammation induced by the RAS.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

ACE:

Angiotensin-converting enzyme

ACh:

Acetylcholine

AChE:

Acetylcholinesterase

Ang II:

Angiotensin II

AT1R:

Ang II type 1 receptor

AT2R:

Ang II type 2 receptor

BRS:

Baroreflex sensitivity

 + dp/dt and –dp/dt:

Maximum/minimum values of the first derivative of the left ventricular pressure

EF:

Left ventricular ejection fraction

FS:

Left ventricular fractional shortening

GAD-67:

67-KDa isoform of glutamate decarboxylase

HF:

High-frequency

i.g.:

Gavage

IL-6:

Interleukin-6

IL-10:

Interleukin-10

IVSd(s):

Interventricular septum thicknesses in systole and diastole

LF:

Low-frequency

LVEDP:

Left ventricular end-diastolic pressure

LVED(S)V:

End-systolic and end-diastolic left ventricular volumes

LVIDd(s):

Left ventricular internal dimensions in systole and diastole

LVPWd(s):

The thicknesses of the left ventricular posterior wall in systole and diastole

LVSP:

Left ventricular systolic pressure

NE:

Noradrenaline

PE:

Phenylephrine

ROS:

Reactive oxygen species

SDNN:

Standard deviation of normal-to-normal

SNP:

Sodium nitroprusside

TH:

Tyrosine hydroxylase

TNF-α:

Tumor necrosis factor-α

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Acknowledgements

The authors are grateful to Cun-Ye Li for her assistance with echocardiography (The Fourth Military Medical University).

Funding

This work was supported by National Natural Science Foundation of China (NO. 82071670, 82000284), Innovation project for medical Integration in XJTU, No. YXJLRH2022061. Jilin science and technology development project No. 20210502028ZP.

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Author notes

  1. Yi Lu and Yi-dong Wang these authors contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, Xi’an, China

    Yi Lu

  2. Department of Pharmacy, College of Stomatology, Xi’an Jiaotong University, Xi’an, China

    Yi Lu

  3. Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China

    Yi-dong Wang

  4. Department of Physiology and Pathophysiology, Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University School of Basic Medical Sciences, Xi’an, China

    Tian-qi Xu, Xu-he Zhao & Jin-jun Liu

  5. Department of Pharmacology, Xi’an Jiaotong University School of Basic Medical Sciences, Xi’an, China

    Jun Zhou

  6. Low Pressure and Low Oxygen Environment and Health Intervention Innovation Center, Jilin Medical University, Jilin, China

    Lian-hai Jin

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Contributions

All authors contributed to the study conception and design. Jin-jun Liu was involved in the conceptualization and design of the study; Material preparation, data collection and analysis were performed by Tian-qi Xu, Xu-he Zhao, Yi-dong Wang, Jun Zhou and Lian-hai Jin; The first draft of the manuscript was written by Yi Lu. All authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Jin-jun Liu.

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All animal protocols adhered to the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health (publication no. 85–23, revised 1996) and were approved by the Ethics Committee of Xi’an Jiao tong University.

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Lu, Y., Wang, Yd., Xu, Tq. et al. Pyridostigmine attenuates hypertension by inhibiting activation of the renin-angiotensin system in the hypothalamic paraventricular nucleus. Naunyn-Schmiedeberg's Arch Pharmacol (2024). https://doi.org/10.1007/s00210-024-03156-x

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