Hypertension in mice with transgenic activation of the brain renin-angiotensin system is vasopressin dependent
Hypertension in mice with transgenic activation of the brain renin-angiotensin system is vasopressin dependent
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DOI：
10.1152/ajpregu.00082.2013
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发表时间：
2013-05-01
影响因子：
2.8
通讯作者：
Grobe, Justin L.
中科院分区：
文献类型：
--
作者：
Littlejohn, Nicole K.;Siel, Rick B., Jr.;Grobe, Justin L.
在大多数高血压实验动物模型中，脑肾素-血管紧张素系统（RAS）发挥着不可或缺的作用。为了确定由大脑RAS激活的介导高血压的特定输出通路，我们在脑特异性RAS过度活跃的双转基因模型（“sRA”小鼠模型）中检验了精氨酸抗利尿激素（AVP）释放升高对高血压是必要的假设。由于人血管紧张素原的表达和神经元特异性人肾素的表达，sRA小鼠的脑RAS活性升高。尿中4-kDa AVP前段（copeptin）的日总损失显著升高（>= 8倍）。sRA小鼠视上核AVP免疫组化染色增加（类似2倍），但室旁核未见定量差异。慢性皮下输注非选择性AVP受体拮抗剂conivaptan （m -087, Vaprisol, 22 ng/h）或v -2选择性拮抗剂tolvaptan （OPC-41061, 22 ng/h）可使sRA小鼠的基线高血压恢复正常（类似于15 mmHg）。腹主动脉和二级肠系膜动脉显示avp特异性脱敏，对苯肾上腺素和内皮素-1的反应轻微或无变化。肠系膜动脉中V-1A受体mRNA表达明显减少，但肾脏中V-2受体表达无明显变化。慢性托伐普坦输注也使sRA小鼠（5 mmol/l）低钠血症正常化。综上所述，这些数据支持抗利尿激素在RAS脑特异性亢进小鼠高血压中的主要作用，并提示V-2受体的主要作用。
An indispensable role for the brain renin-angiotensin system (RAS) has been documented in most experimental animal models of hypertension. To identify the specific efferent pathway activated by the brain RAS that mediates hypertension, we examined the hypothesis that elevated arginine vasopressin (AVP) release is necessary for hypertension in a double-transgenic model of brain-specific RAS hyperactivity (the "sRA" mouse model). sRA mice experience elevated brain RAS activity due to human angiotensinogen expression plus neuron-specific human renin expression. Total daily loss of the 4-kDa AVP prosegment (copeptin) into urine was grossly elevated (>= 8-fold). Immunohistochemical staining for AVP was increased in the supraoptic nucleus of sRA mice (similar to 2-fold), but no quantitative difference in the paraventricular nucleus was observed. Chronic subcutaneous infusion of a nonselective AVP receptor antagonist conivaptan (YM-087, Vaprisol, 22 ng/h) or the V-2-selective antagonist tolvaptan (OPC-41061, 22 ng/h) resulted in normalization of the baseline (similar to 15 mmHg) hypertension in sRA mice. Abdominal aortas and second-order mesenteric arteries displayed AVP-specific desensitization, with minor or no changes in responses to phenylephrine and endothelin-1. Mesenteric arteries exhibited substantial reductions in V-1A receptor mRNA, but no significant changes in V-2 receptor expression in kidney were observed. Chronic tolvaptan infusion also normalized the (5 mmol/l) hyponatremia of sRA mice. Together, these data support a major role for vasopressin in the hypertension of mice with brain-specific hyperactivity of the RAS and suggest a primary role of V-2 receptors.