Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts.
College of Arts and Sciences, Boston University, Boston, Massachusetts.
Am J Physiol Renal Physiol. 2019 Dec 1;317(6):F1623-F1636. doi: 10.1152/ajprenal.00264.2019. Epub 2019 Oct 14.
Salt sensitivity of blood pressure is characterized by inappropriate sympathoexcitation and renal Na reabsorption during high salt intake. In salt-resistant animal models, exogenous norepinephrine (NE) infusion promotes salt-sensitive hypertension and prevents dietary Na-evoked suppression of the Na-Cl cotransporter (NCC). Studies of the adrenergic signaling pathways that modulate NCC activity during NE infusion have yielded conflicting results implicating α- and/or β-adrenoceptors and a downstream kinase network that phosphorylates and activates NCC, including with no lysine kinases (WNKs), STE20/SPS1-related proline-alanine-rich kinase (SPAK), and oxidative stress response 1 (OxSR1). In the present study, we used selective adrenoceptor antagonism in NE-infused male Sprague-Dawley rats to investigate the differential roles of α- and β-adrenoceptors in sympathetically mediated NCC regulation. NE infusion evoked salt-sensitive hypertension and prevented dietary Na-evoked suppression of NCC mRNA, protein expression, phosphorylation, and in vivo activity. Impaired NCC suppression during high salt intake in NE-infused rats was paralleled by impaired suppression of WNK1 and OxSR1 expression and SPAK/OxSR1 phosphorylation and a failure to increase WNK4 expression. Antagonism of α-adrenoceptors before high salt intake or after the establishment of salt-sensitive hypertension restored dietary Na-evoked suppression of NCC, resulted in downregulation of WNK4, SPAK, and OxSR1, and abolished the salt-sensitive component of hypertension. In contrast, β-adrenoceptor antagonism attenuated NE-evoked hypertension independently of dietary Na intake and did not restore high salt-evoked suppression of NCC. These findings suggest that a selective, reversible, α-adenoceptor-gated WNK/SPAK/OxSR1 NE-activated signaling pathway prevents dietary Na-evoked NCC suppression, promoting the development and maintenance of salt-sensitive hypertension.
血压的盐敏感性特征是在高盐摄入期间交感神经兴奋和肾钠重吸收不当。在盐抵抗动物模型中，外源性去甲肾上腺素（NE）输注可促进盐敏感性高血压，并防止饮食钠诱发的钠-氯共转运体（NCC）抑制。研究调节 NE 输注期间 NCC 活性的肾上腺素能信号通路产生了相互矛盾的结果，涉及 α-和/或β-肾上腺素受体以及磷酸化和激活 NCC 的下游激酶网络，包括无赖氨酸激酶（WNK）、STE20/SPS1 相关脯氨酸-丙氨酸丰富激酶（SPAK）和氧化应激反应 1（OxSR1）。在本研究中，我们使用选择性肾上腺素受体拮抗作用在 NE 输注的雄性 Sprague-Dawley 大鼠中研究 α-和β-肾上腺素受体在交感神经介导的 NCC 调节中的差异作用。NE 输注引起盐敏感性高血压，并防止饮食钠诱发的 NCC mRNA、蛋白表达、磷酸化和体内活性抑制。在 NE 输注大鼠高盐摄入期间 NCC 抑制受损与 WNK1 和 OxSR1 表达以及 SPAK/OxSR1 磷酸化抑制以及 WNK4 表达增加失败平行。在高盐摄入之前或盐敏感性高血压建立后拮抗 α-肾上腺素受体可恢复饮食钠诱发的 NCC 抑制，导致 WNK4、SPAK 和 OxSR1 下调，并消除高血压的盐敏感性成分。相比之下，β-肾上腺素受体拮抗作用可独立于饮食钠摄入减轻 NE 引起的高血压，但不能恢复高盐诱发的 NCC 抑制。这些发现表明，一种选择性、可逆的、α-肾上腺素能门控 WNK/SPAK/OxSR1 NE 激活信号通路可防止饮食钠诱发的 NCC 抑制，促进盐敏感性高血压的发展和维持。
