GABAergic Excitation of Vasopressin Neurons Possible Mechanism Underlying Sodium-Dependent Hypertension
GABAergic Excitation of Vasopressin Neurons Possible Mechanism Underlying Sodium-Dependent Hypertension
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DOI：
10.1161/circresaha.113.301814
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发表时间：
2013-12-06
影响因子：
20.1
通讯作者：
Kim, Yang In
中科院分区：
文献类型：
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作者：
Kim, Young-Beom;Kim, Yoon Sik;Kim, Yang In
理由：精氨酸加压素（AVP）分泌增加是高渗应激的一种重要生理反应，可能是高盐饮食诱发或加重高血压的部分机制。目的：采用醋酸去氧皮质酮-盐高血压模型大鼠，我们试图验证这样的假设，即在AVP分泌的大细胞神经元中GABA（A）受体介导的抑制的变化有助于Na+-Na+的产生。方法和结果：在离体室旁核和视上核的短杆菌肽穿孔记录表明，在该模型中，由于GABA平衡电位的去极化，AVP分泌神经元的GABA能抑制转化为兴奋。同时，在体视上核细胞外记录表明，大细胞神经元GABA能压力感受性抑制转变为兴奋，压力感受器激活可增加AVP的释放。去极化GABA的平衡电位转移AVP分泌神经元发生逐步超过数周的脱氧皮质酮醋酸盐治疗沿着逐渐增加血浆AVP和血压。此外，这种变化与氯转运蛋白表达的变化有关，并被布美他尼（Na+-K+-2Cl（-）协同转运蛋白抑制剂）部分逆转。在脱氧皮质酮醋酸盐治疗期间脑室内布美他尼给药阻碍了高血压的发展和血浆AVP水平的升高。视上核微量注射蝇蕈醇（GABA（A）激动剂）可使高血压大鼠血压升高，而静脉注射V1 a AVP拮抗剂则可阻止这一作用。结论：AVP神经元GABA（A）受体介导的兴奋性转换通过增加AVP释放参与了Na+依赖性高血压的形成。我们推测，正常化的GABA平衡电位可能有一定的效用，在治疗Na+依赖性高血压。
Rationale: Increased arginine-vasopressin (AVP) secretion is a key physiological response to hyperosmotic stress and may be part of the mechanism by which high-salt diets induce or exacerbate hypertension.Objective: Using deoxycorticosterone acetate-salt hypertension model rats, we sought to test the hypothesis that changes in GABA(A) receptor-mediated inhibition in AVP-secreting magnocellular neurons contribute to the generation of Na+-dependent hypertension.Methods and Results: In vitro gramicidin-perforated recordings in the paraventricular and supraoptic nuclei revealed that the GABAergic inhibition in AVP-secreting neurons was converted into excitation in this model, because of the depolarization of GABA equilibrium potential. Meanwhile, in vivo extracellular recordings in the supraoptic nuclei showed that the GABAergic baroreflexive inhibition of magnocellular neurons was transformed to excitation, so that baroreceptor activation may increase AVP release. The depolarizing GABA equilibrium potential shift in AVP-secreting neurons occurred progressively over weeks of deoxycorticosterone acetate-salt treatment along with gradual increases in plasma AVP and blood pressure. Furthermore, the shift was associated with changes in chloride transporter expression and partially reversed by bumetanide (Na+-K+-2Cl(-)cotransporter inhibitor). Intracerebroventricular bumetanide administration during deoxycorticosterone acetate-salt treatment hindered the development of hypertension and rise in plasma AVP level. Muscimol (GABA(A) agonist) microinjection into the supraoptic nuclei in hypertensive rats increased blood pressure, which was prevented by previous intravenous V1a AVP antagonist injection.Conclusions: We conclude that the inhibitory-to-excitatory switch of GABA(A) receptor-mediated transmission in AVP neurons contributes to the generation of Na+-dependent hypertension by increasing AVP release. We speculate that normalizing the GABA equilibrium potential may have some utility in treating Na+-dependent hypertension.