Central administration of TRV027 improves baroreflex sensitivity and vascular reactivity in spontaneously hypertensive rats.
Central administration of TRV027 improves baroreflex sensitivity and vascular reactivity in spontaneously hypertensive rats.
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DOI：
10.1042/cs20180222
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发表时间：
2018-07-31
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影响因子：
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通讯作者：
de França-Silva MDS
中科院分区：
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作者：
Carvalho-Galvão A;Ogunlade B;Xu J;Silva-Alves CRA;Mendes-Júnior LG;Guimarães DD;Cruz JC;Queiroz TM;Balarini CM;Braga VA;Filipeanu CM;Lazartigues E;de França-Silva MDS
TRV027 是血管紧张素 (Ang)-II 1 型受体 (AT1R) 的偏向激动剂，能够独立于 G 蛋白激活而招募 β-arrestin 2。中枢神经系统 (CNS) 中的 β-arrestin 激活被认为可以对抗 Ang-II 的作用。本研究评估中枢输注 TRV027 对动脉压 (AP)、自主神经功能、压力反射敏感性 (BRS) 和外周血管反应性的影响。自发性高血压（SH）和Wistar京都（WKY）大鼠接受TRV027治疗14天（20纳克/小时），通过渗透微型泵输送至侧脑室。在经 TRV027 (100nM) 或 Ang-II (100nM) 处理的 AT1R 和 2 型血管紧张素转化酶 (ACE2) 共转染的 HEK293T 细胞中进行了机制研究。 TRV027输注于SHrats (SHR)中可减少AP (∼20 mmHg，P<0.05)、交感血管舒缩活动(ΔMAP=-47.2 ± 2.8，与-64 ± 5.1 mmHg相比，P<0.05)和AP低频(LF)振荡(1.7 ± 0.2与5.8 ± 0.4 mmHg相比， P<0.05）与SHR对照组相比。 TRV027 还增加迷走神经张力，改善 BRS，降低肠系膜动脉对 Ang-II 的反应性，并增加血管对去氧肾上腺素 (Phe)、乙酰胆碱 (ACh) 和硝普钠 (SNP) 的敏感性。在体外，TRV027 阻止 Ang-II 诱导的 ADAM17 上调，并且与 Ang-II 相比，TRV027 对 ACE2 活性和表达水平没有影响。此外，与 Ang-II 相比，TRV027 诱导 AT1R 和 ACE2 之间的相互作用较少。总之，这些数据表明，由于 TRV027 对 β-arrestin 通路的偏向活性，TRV027 在中枢神经系统内对高血压、自主神经和血管功能具有有益影响，可能是通过保留神经元中 ACE2 代偿活性来实现的。
TRV027 is a biased agonist for the Angiotensin (Ang)-IItype 1 receptor (AT1R), able to recruit β-arrestin 2 independently of G-proteins activation. β-arrestin activation in the central nervous system (CNS) was suggested to oppose the effects of Ang-II. The present study evaluates the effect of central infusion of TRV027 on arterial pressure (AP), autonomic function, baroreflex sensitivity (BRS), and peripheral vascular reactivity. Spontaneously hypertensive (SH) and Wistar Kyoto (WKY) rats were treated with TRV027 for 14 days (20 ng/h) delivered to the lateral ventricle via osmotic minipumps. Mechanistic studies were performed in HEK293T cells co-transfected with AT1R and Ang converting enzyme type 2 (ACE2) treated with TRV027 (100nM) or Ang-II (100nM). TRV027 infusion in SHrats (SHR) reduced AP (∼20 mmHg, P<0.05),sympathetic vasomotor activity (ΔMAP=−47.2 ± 2.8 compared with −64 ± 5.1 mmHg, P<0.05) and low-frequency (LF) oscillations of AP (1.7 ± 0.2 compared with 5.8 ± 0.4 mmHg, P<0.05) compared with the SHR control group. TRV027 also increased vagal tone, improved BRS, reduced the reactivity of mesenteric arteries to Ang-II and increased vascular sensitivity to phenylephrine (Phe), acetylcholine, (ACh), and sodium nitroprusside(SNP). In vitro, TRV027 prevented theAng-II-induced up-regulation of ADAM17 and in contrast with Ang-II, had no effects on ACE2 activity and expression levels. Furthermore, TRV027 induced lesser interactions between AT1R and ACE2 compared with Ang-II. Together, these data suggest that due to its biased activity for the β-arrestin pathway, TRV027 has beneficial effects within the CNS on hypertension, autonomic and vascular function, possibly through preserving ACE2 compensatory activity in neurones