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Intermedin in Paraventricular Nucleus Attenuates sympathoexcitation and Decreases TLR4-Mediated Sympathetic Activation via Adrenomedullin Receptors in Rats with Obesity-Related Hypertension

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Neuroscience Bulletin 2019年第1期35卷 34-46页

作者： Jing Sun Xing-Sheng Ren Ying Kang Hang-Bing Dai Lei Ding Ning Tong Guo-Qing Zhu Ye-Bo Zhou Key Laboratory of Cardiovascular Disease and Molecular Intervention Department of PhysiologyNanjing Medical UniversityNanjing 211166China Department of Pathophysiology Xuzhou Medical CollegeXuzhou 221004China Department of Neurology Heze Municipal HospitalHeze 274000China

Intermedin/adrenomedullin-2(IMD/AM2), a member of the calcitonin gene-related peptide/AM family,plays an important role in protecting the cardiovascular system. However, its role in the enhanced sympathoexcitation in obesity-related hypertension is unknown. In this study, we investigated the effects of IMD in the paraventricular nucleus(PVN) of the hypothalamus on sympathetic nerve activity(SNA), and lipopolysaccharide(LPS)-induced sympathetic activation in obesity-related hypertensive(OH)rats induced by a high-fat diet for 12 weeks. Acute experiments were performed under anesthesia. The dynamic alterations of sympathetic outflow were evaluated as changes in renal SNA and mean arterial pressure(MAP) in response to specific drugs. Male rats were fed a control diet(12% kcal as fat) or a high-fat diet(42% kcal as fat) for 12 weeks to induce OH. The results showed that IMD protein in the PVN was downregulated, but Toll-like receptor 4(TLR4) and plasma norepinephrine(NE, indicating sympathetic hyperactivity) levels, and systolic blood pressure were increased in OH rats. LPS(0.5 lg/50 nL)-induced enhancement of renal SNA and MAP was greater in OH rats than in obese or control rats. Bilateral PVN microinjection of IMD(50 pmol)caused greater decreases in renal SNA and MAP in OH rats than in control rats, and inhibited LPS-induced sympatheticactivation, and these were effectively prevented in OH rats by pretreatment with the AM receptor antagonist AM22-52.The mitogen-activated protein kinase/extracellular signalregulated kinase(ERK) inhibitor U0126 in the PVN partially reversed the LPS-induced enhancement of SNA. However,IMD in the PVN decreased the LPS-induced ERK activation,which was also effectively prevented by AM22-52. Chronic IMD administration resulted in significant reductions in the plasma NE level and blood pressure in OH rats. Moreover,IMD lowered the TLR4 protein expression and ERK activation in the PVN, and decreased the LPS-induced sympathetic overactivity. These results indicate that IMD in the PVN attenuat

关键词： Intermedin sympathoexcitation Obesityrelated hypertension Paraventricular nucleus Toll-like receptor 4

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Chronic Intracerebroventricular Infusion of Metformin Inhibits Salt-Sensitive Hypertension via Attenuation of Oxidative Stress and Neurohormonal Excitation in Rat Paraventricular Nucleus

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Neuroscience Bulletin 2019年第1期35卷 57-66页

作者： Xiao-Jing Yu Ya-Nan Zhao Yi-Kang Hou Hong-Bao Li Wen-Jie Xia Hong-Li Gao Kai-Li Liu Qing Su Hui-Yu Yang Bin Liang Wen-Sheng Chen Wei Cui Ying Li Guo-Qing Zhu Zhi-Ming Yang Yu-Ming Kang Department of Physiology and Pathophysiology Xi’an Jiaotong University School of Basic Medical SciencesMinistry of Education Key Laboratory of Environment and Genes Related to DiseasesXi’an Jiaotong UniversityXi’an 710061China Department of Cardiology Second Affiliated Hospital of Shanxi Medical UniversityTaiyuan 030001China Department of Respiratory Medicine Affiliated Jiangyin Hospital of Southeast University Medical SchoolJiangyin 214400China Department of Cardiovascular Surgery Xijing HospitalFourth Military Medical UniversityXi’an 710032China Department of Endocrinology and Metabolism First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an Jiaotong University Health Science CenterXi’an 710061China Department of Plastic and Cosmetic Surgery Gansu Provincial HospitalLanzhou 730000China Key Laboratory of Cardiovascular Disease and Molecular Intervention Department of PhysiologyNanjing Medical UniversityNanjing 210029China

Metformin(MET), an antidiabetic agent, also has antioxidative effects in metabolic-related hypertension.This study was designed to determine whether MET has anti-hypertensive effects in salt-sensitive hypertensive rats by inhibiting oxidative stress in the hypothalamic paraventricular nucleus(PVN). Salt-sensitive rats received a highsalt(HS) diet to induce hypertension, or a normal-salt(NS)diet as control. At the same time, they received intracerebroventricular(ICV) infusion of MET or vehicle for 6 weeks. We found that HS rats had higher oxidative stress levels and mean arterial pressure(MAP) than NS rats. ICV infusion of MET attenuated MAP and reduced plasma norepinephrine levels in HS rats. It also decreased reactive oxygen species and the expression of subunits of NAD(P)H oxidase, improved the superoxide dismutase activity,reduced components of the renin-angiotensin system, and altered neurotransmitters in the PVN. Our findings suggest that central MET administration lowers MAP in saltsensitive hypertension via attenuating oxidative stress,inhibiting the renin-angiotensin system, and restoring the balance between excitatory and inhibitory neurotransmitters in the PVN.

关键词： Hypertension Paraventricular nucleus sympathoexcitation Metformin Oxidative stress

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Nitric oxide and superoxide anions in the paraventricular nucleus mediate the enhanced cardiac sympathetic afferent reflex in obese rats

Nitric oxide and superoxide anions in the paraventricular nu...

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中国生理学会第24届全国会员代表大会暨生理学学术大会

作者： Lu Qing-Bo Feng Xue-Mei Tong Ning Zhu Guo-Qing 周业波 Key Laboratory of Cardiovascular Disease and Molecular Intervention Department of PhysiologyNanjing Medical University Clinical laboratory of Luyi People's Hospital Department of Neurology Heze Municipal Hospital 南京医科大学

参加优秀poster评选Background:nucleus（PVN）is a key component of the central neurocircuitry of the cardiac sympathetic overdrive in sympathetic afferent reflex（CSAR）which involve in hypertension,chronic heart failure and diabetes.In this study,we investigated whether or not the CSAR is enhanced in obese rats and nitric oxide（NO）in the PVN participates in superoxide anions-induced CSAR enhancement and sympathoexcitation of obese rats.Methods:Rats were randomly divided into 2 groups.Control rats received ordinary diet（12%kcal as fat）and obese rats received high-fat diet（42%kcal as fat）for 12 weeks to induce obesity.CSAR was evaluated with the changes of renal sympathetic nerve activity（RSNA）and mean arterial pressure（MAP）responses to the epicardial application of capsaicin（Cap）in anaesthetized rats.Results:The CSAR,superoxide anions level and NAD（P）H oxidase activity in the PVN were significantly increased,but NO level and the n NOS protein expression were markedly decreased in the obese rats.Microinjection of tempol,a superoxide scavenger,or sodium nitroprusside（SNP）,a nitric oxide donor,into the PVN decreased CSAR and the basal sympathetic nerve activity（SNA）,whereas apocynin,NAD（P）H oxidase inhibitor,inhibitor,in synthase NO an DETC,a superoxide dismutase inhibitor,or L-NAME,the PVN enhanced the CSAR and the basal SNA in obese rats than those in normal rats.Prior microinjection of L-NAME into the PVN attenuated the tempol-induced changes,but potentiated the responses to apocynin and DETC,whereas PVN pretreatment with SNP potentiated tempol’s effects,but attenuated these The findings suggest that the responses to apocynin and DETC.Conclusions:enhanced CSAR may contribute to the sympathetic overdrive in obese rats,the increase of superoxide anions and the decrease of NO in the PVN involve in the enhanced CSAR and the reduction of NO in the PVN partly promotes superoxide anions-inducedCSAR enhancement and sympathoexcitation in obesity.

关键词： oxide superoxide anions cardiacnitric sympathetic afferent reflex paraventricular nucleus sympathoexcitation

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