Department of Pharmacology and Experimental Therapeutics and the Whitaker Cardiovascular Institute, Boston University School of Medicine, 72 E Concord St, Boston, MA 02118, USA.
Hypertension. 2013 Feb;61(2):368-75. doi: 10.1161/HYPERTENSIONAHA.111.00014. Epub 2012 Dec 3.
In salt-resistant phenotypes, chronic elevated dietary sodium intake evokes suppression of renal sodium-retaining mechanisms to maintain sodium homeostasis and normotension. We have recently shown that brain Gαi(2) protein pathways are required to suppress renal sympathetic nerve activity and facilitate maximal sodium excretion during acute intravenous volume expansion in Sprague-Dawley rats. Here, we studied the role of brain Gαi(2) proteins in the endogenous central neural mechanisms acting to maintain fluid and electrolyte homeostasis and normotension during a chronic elevation in dietary salt intake. Naive or bilaterally renal denervated adult male Sprague-Dawley rats were randomly assigned to receive an intracerebroventricular scrambled or Gαi(2) oligodeoxynucleotide infusion and then subjected to either a normal salt (0.4%) or high-salt (8.0%) diet for 21 days. In scrambled oligodeoxynucleotide-infused rats, salt loading, which did not alter blood pressure, evoked a site-specific increase in hypothalamic paraventricular nucleus Gαi(2) protein levels and suppression of circulating norepinephrine content and plasma renin activity. In salt-loaded rats continuously infused intracerebroventricularly with a Gαi(2) oligodeoxynucleotide, animals exhibited sodium and water retention, elevated plasma norepinephrine levels, and hypertension, despite suppression of plasma renin activity. Furthermore, in salt-loaded bilaterally renal denervated rats, Gαi(2) oligodeoxynucleotide infusion failed to evoke salt-sensitive hypertension. Therefore, in salt-resistant rats subjected to a chronic high-salt diet, brain Gαi(2) proteins are required to inhibit central sympathetic outflow to the kidneys and maintain sodium balance and normotension. In conclusion, these data demonstrate a central role of endogenous brain, likely paraventricular nucleus-specific, Gαi(2)-subunit protein-gated signal transduction pathways in maintaining a salt-resistant phenotype.
在耐盐表型中，慢性高盐饮食会抑制肾脏钠潴留机制，以维持钠平衡和正常血压。我们最近表明，脑 Gαi(2)蛋白途径对于抑制急性静脉内容量扩张期间的肾交感神经活动和促进最大钠排泄是必需的。在这里，我们研究了脑 Gαi(2)蛋白在维持液体和电解质平衡以及正常血压方面的内源性中枢神经机制中的作用，这些机制在慢性高盐饮食中发挥作用。将未处理或双侧肾去神经的成年雄性 Sprague-Dawley 大鼠随机分配接受脑室内 scrambled 或 Gαi(2)寡核苷酸输注，然后接受正常盐（0.4%）或高盐（8.0%）饮食 21 天。在 scrambled 寡核苷酸输注的大鼠中，盐负荷不会改变血压，但会引起下丘脑室旁核 Gαi(2)蛋白水平的特异性增加，并抑制循环去甲肾上腺素含量和血浆肾素活性。在连续脑室内输注 Gαi(2)寡核苷酸的盐负荷大鼠中，尽管抑制了血浆肾素活性，但动物表现出钠水潴留、血浆去甲肾上腺素水平升高和高血压。此外，在盐负荷双侧肾去神经大鼠中，Gαi(2)寡核苷酸输注未能引起盐敏感型高血压。因此，在接受慢性高盐饮食的耐盐大鼠中，脑 Gαi(2)蛋白需要抑制肾脏的中枢交感传出，以维持钠平衡和正常血压。总之，这些数据表明，内源性脑，可能是室旁核特异性的，Gαi(2)-亚基蛋白门控信号转导途径在维持耐盐表型方面发挥着中枢作用。
