BACKGROUND:ANG (angiotensin II) elicits dipsogenic and pressor responses via activation of the canonical Gαq (G-protein component of the AT₁R [angiotensin type 1 receptor])-mediated AT₁R in the subfornical organ. Recently, we demonstrated that ARRB2 (β-arrestin 2) global knockout mice exhibit a higher preference for salt and exacerbated pressor response to deoxycorticosterone acetate salt. However, whether ARRB2 within selective neuroanatomical nuclei alters physiological responses to ANG is unknown. Therefore, we hypothesized that ARRB2, specifically in the subfornical organ, counterbalances maladaptive dipsogenic and pressor responses to the canonical AT₁R signaling.METHODS:Male and female Arrb2^FLOX mice received intracerebroventricular injection of either adeno-associated virus (AAV)-Cre-GFP (green fluorescent protein) to induce brain-specific deletion of ARRB2 (Arrb2^ICV-Cre). Arrb2^FLOX mice receiving ICV-AAV-GFP were used as control (Arrb2^ICV-Control). Infection with ICV-AAV-Cre primarily targeted the subfornical organ with few off targets. Fluid intake was evaluated using the 2-bottle choice paradigm with 1 bottle containing water and 1 containing 0.15 mol/L NaCl.RESULTS:Arrb2^ICV-Cre mice exhibited a greater pressor response to acute ICV-ANG infusion. At baseline conditions, Arrb2^ICV-Cre mice exhibited a significant increase in saline intake compared with controls, resulting in a saline preference. Furthermore, when mice were subjected to water-deprived or sodium-depleted conditions, which would naturally increase endogenous ANG levels, Arrb2^ICV-Cre mice exhibited elevated saline intake.CONCLUSIONS:Overall, these data indicate that ARRB2 in selective cardiovascular nuclei in the brain, including the subfornical organ, counterbalances canonical AT₁R responses to both exogenous and endogenous ANG. Stimulation of the AT₁R/ARRB axis in the brain may represent a novel strategy to treat hypertension.

中文翻译：

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大脑穹窿下器官和其他室周核中 β-Arrestin 2 的基因缺失会改变体液稳态和血压

背景：ANG（血管紧张素 II）通过激活穹窿下器官中典型的 Gαq（AT ₁ R [血管紧张素 1 型受体]的 G 蛋白成分）介导的 AT ₁ R 来引发促动力和升压反应。最近，我们证明 ARRB2（β-arrestin 2）全基因敲除小鼠对盐表现出更高的偏好，并对脱氧皮质酮醋酸盐表现出加剧的升压反应。然而，选择性神经解剖核内的 ARRB2 是否会改变对 ANG 的生理反应尚不清楚。因此，我们假设 ARRB2，特别是穹窿下器官中的 ARRB2，可以平衡对典型 AT ₁ R 信号传导的适应不良的动力和升压反应。 方法：雄性和雌性Arrb2 ^FLOX小鼠接受脑室内注射腺相关病毒 (AAV)-Cre- GFP（绿色荧光蛋白）诱导大脑特异性删除 ARRB2 ( Arrb2 ^ICV-Cre )。接受 ICV-AAV-GFP 的Arrb2 ^FLOX小鼠用作对照（Arrb2 ^ICV-Control）。 ICV-AAV-Cre 的感染主要针对穹窿下器官，很少有脱靶的情况。使用 2 瓶选择范例评估液体摄入量，其中 1 瓶含有水，1 瓶含有 0.15 mol/L 氯化钠。 结果：Arrb2 ^ICV-Cre小鼠对急性 ICV-ANG 输注表现出更大的升压反应。在基线条件下，与对照组相比， Arrb2 ^ICV-Cre小鼠的盐水摄入量显着增加，导致对盐水的偏好。此外，当小鼠处于缺水或缺钠的条件下时，这会自然增加内源性 ANG 水平，Arrb2 ^ICV-Cre小鼠表现出盐水摄入量增加。结论：总的来说，这些数据表明 ARRB2 在大脑中选择性心血管核中，包括穹窿下器官，平衡对外源性和内源性 ANG 的典型 AT ₁ R 反应。刺激大脑中的AT _{1 R/ARRB 轴可能代表一种治疗高血压的新策略。}