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Exacerbated pressor and sympathoexcitatory effects of central Elabela in spontaneously hypertensive rats.

加剧自发性高血压大鼠中枢 Elabela 的升压和交感兴奋作用。

  • 影响因子:3.66
  • DOI:10.1152/ajpheart.00449.2019
  • 作者列表:"Geng Z","Ye C","Tong Y","Zhang F","Zhou YB","Xiong XQ
  • 发表时间:2020-01-01
Abstract

:Elabela (ELA) is a newly discovered peptide that acts as a novel endogenous ligand of angiotensin receptor-like 1 (APJ) receptor. This study was designed to evaluate the effects of ELA-21 in paraventricular nucleus (PVN) on blood pressure and sympathetic nerve activity in spontaneously hypertensive rats (SHR). Experiments were performed in male Wistar-Kyoto rats (WKY) and SHR. ELA expression was upregulated in PVN of SHR. PVN microinjection of ELA-21 increased renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), heart rate (HR), plasma norepinephrine, and arginine vasopressin (AVP) levels in SHR. Intravenous injection of ELA-21 significantly decreased MAP and HR in both WKY and SHR, but only induced a slight decrease in RSNA. APJ antagonist F13A in PVN abolished the effects of ELA-21 on RSNA, MAP and HR. Intravenous infusion of both ganglionic blocker hexamethonium and AVP V1a receptor antagonist SR49059 caused significant reduction in the effects of ELA-21 on RSNA, MAP and HR in SHR, while combined administration of hexamethonium and SR49059 abolished the effects of ELA-21. ELA-21 microinjection stimulated Akt and p85α subunit of phosphatidylinositol 3-kinase (PI3K) phosphorylation in PVN, whereas PI3K inhibitor LY294002 or Akt inhibitor MK-2206 almost abolished the effects of ELA-21 on RSNA, MAP, and HR. Chronic PVN infusion of ELA-21 induced sympathetic activation, hypertension, and AVP release accompanied with cardiovascular remodeling in normotensive WKY. In conclusion, ELA-21 in PVN induces exacerbated pressor and sympathoexcitatory effects in hypertensive rats via PI3K-Akt pathway.NEW & NOTEWORTHY We demonstrated that PVN microinjection of ELA-21 increases sympathetic nerve activity and blood pressure, which can be abolished by pretreatment of APJ antagonist. This is the first demonstration that central ELA can induce hypertension. The pressor effects in PVN are mediated by both sympathetic activation and vasopressin release via PI3K-Akt pathway. Our data confirm that ELA is upregulated in the PVN of SHR and so may be involved in the pressor and sympathoexcitatory effects in hypertension.

摘要

: Elabela (ELA) 是一种新发现的肽,作为血管紧张素受体样 1 (APJ) 受体的新型内源性配体。本研究旨在探讨室旁核 (PVN) ELA-21 对自发性高血压大鼠 (SHR) 血压和交感神经活动的影响。实验在雄性 Wistar-Kyoto 大鼠 (WKY) 和 SHR 中进行。在 SHR 的 PVN 中 ELA 表达上调。PVN 微量注射 ELA-21 可增加 SHR 肾交感神经活性 (RSNA) 、平均动脉压 (MAP) 、心率 (HR) 、血浆去甲肾上腺素和精氨酸加压素 (AVP) 水平。静脉注射 ELA-21 可显著降低 WKY 和 SHR 的 MAP 和 HR,但仅诱导 RSNA 轻度降低。PVN 中 APJ 拮抗剂 F13A 消除了 ELA-21 对 RSNA 、 MAP 和 HR 的影响。静脉输注神经节阻滞剂 hexamethium 和 AVP V1a 受体拮抗剂 SR49059 可显著降低 ELA-21 对 SHR RSNA 、 MAP 和 HR 的影响, 而联合应用六氨溴铵和 SR49059 消除了 ELA-21 的作用。ELA-21 显微注射刺激 PVN 中 Akt 和磷脂酰肌醇 3-激酶 (PI3K) 的 p85 α 亚基磷酸化,而 PI3K 抑制剂 LY294002 或 Akt 抑制剂几乎 MK-2206 消除 ELA-21 对 RSNA,MAP, 和 HR。慢性 PVN 输注 ELA-21 诱导交感神经激活、高血压和 AVP 释放伴随着正常血压 WKY 的心血管重塑。总之,PVN 中的 ELA-21 通过 PI3K-Akt 途径引起高血压大鼠升压和交感兴奋作用加剧。新 & 值得注意的是,我们证明 PVN 微量注射 ELA-21 可增加交感神经活性和血压,这可通过 APJ 拮抗剂预处理消除。这是首次证明中枢 ELA 可诱发高血压。PVN 中的升压效应是由交感神经激活和加压素释放通过 PI3K-Akt 途径介导的。我们的数据证实 ELA 在 SHR 的 PVN 中上调,因此可能参与高血压的升压和交感兴奋作用。

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