Adrenomedullin in paraventricular nucleus attenuates adipose afferent reflex and sympathoexcitation via receptors mediated nitric oxide-gamma-aminobutyric acid A type receptor pathway in rats with obesity-related hypertension
Adrenomedullin in paraventricular nucleus attenuates adipose afferent reflex and sympathoexcitation via receptors mediated nitric oxide-gamma-aminobutyric acid A type receptor pathway in rats with obesity-related hypertension
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DOI：
10.1097/hjh.0000000000003301
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发表时间：
2023-02-01
影响因子：
4.9
通讯作者：
Zhou，Ye-Bo
中科院分区：
文献类型：
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作者：
Wang，Fang-Zheng;Qian，Pei;Zhou，Ye-Bo
背景：下丘脑室旁核（PVN）是肥胖相关性高血压（OH）中脂肪传入反射（AAR）增加交感神经流出和血压的重要中心部位。方法：研究PVN中一氧化氮（NO）和心血管生物活性多肽肾上腺髓质素（ADM）对高脂饮食诱导的OH大鼠AAR和交感神经活性（SNA）的影响。结果：结果显示，与对照组相比，OH大鼠PVN中ADM、总神经元NO合成酶（nNOS）及磷酸化nNOS蛋白表达水平均下调。一氧化氮供体硝普钠（SNP）在PVN急性应用后可减弱OH大鼠的增强AAR，但nNOS抑制剂nNOS- i、冠酰环化酶抑制剂（1H-[1,2,4]恶二唑[4,3 - A]喹诺沙林-1- 1，ODQ）和γ -氨基丁酸A型受体（GABA A）拮抗剂Bicuculline可增强AAR。此外，PVN ADM显微注射不仅降低了OH大鼠的基础SNA，而且减弱了ADM受体拮抗剂ADM22-52、nNOS-I、ODQ或Bicuculline预处理有效抑制的增强的AAR。双侧PVN急性显微注射ADM也引起NO和环鸟苷单磷酸（cGMP）水平和nNOS磷酸化的较大升高。腺相关病毒载体编码ADM （AAV-ADM）转染OH大鼠PVN，不仅降低了升高的AAR、基础SNA和血压，而且增加了nNOS的表达和激活。此外，AAV-ADM转染可改善OH大鼠血管重构。结论：综上所述，我们的数据突出了ADM在改善OH条件下交感神经过度激活、增强AAR和高血压中的作用，以及其与受体介导的NO-cGMP-GABA通路相关的机制。
Background:Hypothalamic paraventricular nucleus (PVN) is an important central site for the control of the adipose afferent reflex (AAR) that increases sympathetic outflow and blood pressure in obesity-related hypertension (OH).Method:In this study, we investigated the effects of nitric oxide (NO) and cardiovascular bioactive polypeptide adrenomedullin (ADM) in the PVN on AAR and sympathetic nerve activity (SNA) in OH rats induced by a high-fat diet.Results:The results showed that ADM, total neuronal NO synthase (nNOS) and phosphorylated-nNOS protein expression levels in the PVN of the OH rats were down-regulated compared to the control rats. The enhanced AAR in OH rats was attenuated by PVN acute application of NO donor sodium nitroprusside (SNP), but was strengthened by the nNOS inhibitor nNOS-I, guanylyl cyclase inhibitor (1H-[1, 2, 4] Oxadiazolo [4, 3-a] quinoxalin-1-one, ODQ) and gamma-aminobutyric acid A type receptor (GABA A) antagonist Bicuculline. Moreover, PVN ADM microinjection not only decreased basal SNA but also attenuated the enhanced AAR in OH rats, which were effectively inhibited by ADM receptor antagonist ADM22–52, nNOS-I, ODQ or Bicuculline pretreatment. Bilateral PVN acute microinjection of ADM also caused greater increases in NO and cyclic guanosine monophosphate (cGMP) levels, and nNOS phosphorylation. Adeno-associated virus vectors encoding ADM (AAV-ADM) transfection in the PVN of OH rats not only decreased the elevated AAR, basal SNA and blood pressure (BP), but also increased the expression and activation of nNOS. Furthermore, AAV-ADM transfection improved vascular remodeling in OH rats.Conclusion:Taken together, our data highlight the roles of ADM in improving sympathetic overactivation, enhanced AAR and hypertension, and its related mechanisms associated with receptors mediated NO–cGMP–GABA A pathway in OH condition.