Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA.
Hypertension. 2013 Mar;61(3):716-22. doi: 10.1161/HYPERTENSIONAHA.111.00356. Epub 2012 Dec 24.
Although elevated renin-angiotensin system activity and angiotensinergic signaling within the brain are required for hypertension, polydipsia, and increased metabolic rate induced by deoxycorticosterone acetate (DOCA)-salt, the contribution of specific receptor subtypes and brain nuclei mediating these responses remains poorly defined. We hypothesized that angiotensin type 1a receptors (AT(1a)R) within the subfornical organ (SFO) mediate these responses. Transgenic mice carrying a conditional allele of the endogenous AT(1a)R (AT(1a)R(flox)) were administered an adenovirus encoding Cre-recombinase and enhanced green fluorescent protein (eGFP) or adenovirus encoding eGFP alone into the lateral cerebral ventricle. Adenovirus encoding Cre-recombinase reduced AT(1a)R mRNA and induced recombination in AT(1a)R(flox) genomic DNA specifically in the SFO, without significant effect in the paraventricular or arcuate nuclei, and also induced SFO-specific recombination in ROSA(TdTomato) reporter mice. The effect of SFO-targeted ablation of endogenous AT(1a)R was evaluated in AT(1a)R(flox) mice at 3 time points: (1) baseline, (2) 1 week after virus injection but before DOCA-salt, and (3) after 3 weeks of DOCA-salt. DOCA-salt-treated mice with deletion of AT(1a)R in SFO exhibited a blunted increase in arterial pressure. Increased sympathetic cardiac modulation and urine copeptin, a marker of vasopressin release, were both significantly reduced in DOCA-salt mice when AT(1a)R was deleted in the SFO. Additionally, deletion of AT(1a)R in the SFO significantly attenuated the polydipsia, polyuria, and sodium intake in response to DOCA-salt. Together, these data highlight the contribution of AT(1a)R in the SFO to arterial pressure regulation potentially through changes on sympathetic cardiac modulation, vasopressin release, and hydromineral balance in the DOCA-salt model of hypertension.
虽然脑内肾素-血管紧张素系统活性和血管紧张素能信号升高是促肾上腺皮质激素释放激素（ACTH）-盐诱导的高血压、多饮和代谢率增加所必需的，但介导这些反应的特定受体亚型和脑核的贡献仍未得到很好的定义。我们假设，脑室内的脑下器官（SFO）中的血管紧张素 1 型受体（AT（1a）R）介导这些反应。携带内源性 AT（1a）R 条件性等位基因（AT（1a）R（flox））的转基因小鼠接受编码 Cre-重组酶和增强型绿色荧光蛋白（eGFP）的腺病毒或仅编码 eGFP 的腺病毒注入侧脑室。编码 Cre-重组酶的腺病毒可降低 AT（1a）R mRNA 并在 SFO 中特异性诱导 AT（1a）R（flox）基因组 DNA 的重组，而对室旁核或弓状核无明显影响，也可诱导 ROSA（TdTomato）报告小鼠的 SFO 特异性重组。在 3 个时间点评估 SFO 靶向内源性 AT（1a）R 缺失的影响：（1）基线，（2）病毒注射后 1 周但在 DOCA-盐之前，以及（3）DOCA-盐后 3 周。SFO 中 AT（1a）R 缺失的 DOCA-盐处理小鼠的动脉压增加减弱。当 SFO 中的 AT（1a）R 缺失时，DOCA-盐小鼠的交感神经心脏调节增加和尿液 copeptin（血管加压素释放的标志物）均显著降低。此外，SFO 中 AT（1a）R 的缺失显著减弱了 DOCA-盐引起的多饮、多尿和钠摄入。总之，这些数据强调了 SFO 中 AT（1a）R 对动脉压调节的贡献，可能是通过改变交感神经心脏调节、血管加压素释放和水盐平衡在 DOCA-盐高血压模型中。
