From the the Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (R.D.W., C.Y.C., J.T.K.); and Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans (R.D.W., C.L.P.).
Hypertension. 2015 Jan;65(1):178-86. doi: 10.1161/HYPERTENSIONAHA.114.04463. Epub 2014 Oct 13.
Excess dietary salt intake is an established cause of hypertension. At present, our understanding of the neuropathophysiology of salt-sensitive hypertension is limited by a lack of identification of the central nervous system mechanisms that modulate sympathetic outflow and blood pressure in response to dietary salt intake. We hypothesized that impairment of brain Gαi2-protein-gated signal transduction pathways would result in increased sympathetically mediated renal sodium retention, thus promoting the development of salt-sensitive hypertension. To test this hypothesis, naive or renal denervated Dahl salt-resistant and Dahl salt-sensitive (DSS) rats were assigned to receive a continuous intracerebroventricular control scrambled or a targeted Gαi2-oligodeoxynucleotide infusion, and naive Brown Norway and 8-congenic DSS rats were fed a 21-day normal or high-salt diet. High salt intake did not alter blood pressure, suppressed plasma norepinephrine, and evoked a site-specific increase in hypothalamic paraventricular nucleus Gαi2-protein levels in naive Brown Norway, Dahl salt-resistant, and scrambled oligodeoxynucleotide-infused Dahl salt-resistant but not DSS rats. In Dahl salt-resistant rats, Gαi2 downregulation evoked rapid renal nerve-dependent hypertension, sodium retention, and sympathoexcitation. In DSS rats, Gαi2 downregulation exacerbated salt-sensitive hypertension via a renal nerve-dependent mechanism. Congenic-8 DSS rats exhibited sodium-evoked paraventricular nucleus-specific Gαi2-protein upregulation and attenuated hypertension, sodium retention, and global sympathoexcitation compared with DSS rats. These data demonstrate that paraventricular nucleus Gαi2-protein-gated pathways represent a conserved central molecular pathway mediating sympathoinhibitory renal nerve-dependent responses evoked to maintain sodium homeostasis and a salt-resistant phenotype. Impairment of this mechanism contributes to the development of salt-sensitive hypertension.
过量的盐摄入是高血压的一个确定原因。目前，我们对盐敏感性高血压的神经病理生理学的理解受到限制，因为缺乏确定调节交感神经输出和血压以响应盐摄入的中枢神经系统机制。我们假设，脑 Gαi2-蛋白门控信号转导途径的损伤会导致交感介导的肾钠潴留增加，从而促进盐敏感性高血压的发展。为了验证这一假设，我们将未处理或去肾神经的 Dahl 盐抵抗型和 Dahl 盐敏感型（DSS）大鼠分配接受持续的侧脑室对照 scrambled 或靶向 Gαi2-寡核苷酸输注，并给予未处理的 Brown Norway 和 8 同源性 DSS 大鼠正常或高盐饮食 21 天。高盐摄入没有改变血压，抑制了血浆去甲肾上腺素，并且在未处理的 Brown Norway、Dahl 盐抵抗型和 scrambled 寡核苷酸输注的 Dahl 盐抵抗型大鼠但不是 DSS 大鼠的下丘脑室旁核中特异性地增加了 Gαi2-蛋白水平。在 Dahl 盐抵抗型大鼠中，Gαi2 的下调引起了快速的肾神经依赖性高血压、钠潴留和交感兴奋。在 DSS 大鼠中，Gαi2 的下调通过肾神经依赖性机制加重了盐敏感性高血压。同源性 8 的 DSS 大鼠表现出钠诱发的室旁核特异性 Gαi2-蛋白上调，并与 DSS 大鼠相比，减轻了高血压、钠潴留和全身交感兴奋。这些数据表明，室旁核 Gαi2-蛋白门控途径代表了一种保守的中枢分子途径，介导了维持钠平衡和盐抵抗表型的抑制性肾神经依赖性反应。该机制的损伤导致了盐敏感性高血压的发展。
