Background:ANP (atrial natriuretic peptide), acting through NPR1 (natriuretic peptide receptor 1), provokes hypotension. Such hypotension is thought to be due to ANP inducing vasodilation via NPR1 in the vasculature; however, the underlying mechanism remains unclear. Here, we investigated the mechanisms of acute and chronic blood pressure regulation by ANP.Methods and Results:Immunohistochemical analysis of rat tissues revealed that NPR1 was abundantly expressed in endothelial cells and smooth muscle cells of small arteries and arterioles. Intravenous infusion of ANP significantly lowered systolic blood pressure in wild-type mice. ANP also significantly lowered systolic blood pressure in smooth muscle cell–specific Npr1–knockout mice but not in endothelial cell–specific Npr1–knockout mice. Moreover, ANP significantly lowered systolic blood pressure in Nos3-knockout mice. In human umbilical vein endothelial cells, treatment with ANP did not influence nitric oxide production or intracellular Ca²⁺ concentration, but it did hyperpolarize the cells. ANP-induced hyperpolarization of human umbilical vein endothelial cells was inhibited by several potassium channel blockers and was also abolished under knockdown of RGS2 (regulator of G-protein signaling 2), an GTPase activating protein in G-protein α-subunit. ANP increased Rgs2 mRNA expression in human umbilical vein endothelial cells but failed to lower systolic blood pressure in Rgs2-knockout mice. Endothelial cell–specific Npr1-overexpressing mice exhibited lower blood pressure than did wild-type mice independent of RGS2, and showed dilation of arterial vessels on synchrotron radiation microangiography.Conclusions:Together, these results indicate that vascular endothelial NPR1 plays a crucial role in ANP-mediated blood pressure regulation, presumably by a mechanism that is RGS2-dependent in the acute phase and RGS2-independent in the chronic phase.

中文翻译：

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内皮利钠肽受体 1 在心房利钠肽对急性和慢性血压的调节中起关键作用

背景：ANP（心房利钠肽）通过 NPR1（利钠肽受体 1）起作用，引起低血压。这种低血压被认为是由于 ANP 通过血管系统中的 NPR1 诱导血管舒张所致。然而，潜在的机制仍不清楚。在此，我们研究了ANP调节急性和慢性血压的机制。方法和结果：大鼠组织的免疫组织化学分析表明，NPR1在小动脉和小动脉的内皮细胞和平滑肌细胞中大量表达。静脉输注 ANP 显着降低了野生型小鼠的收缩压。ANP 还显着降低平滑肌细胞特异性Npr1敲除小鼠的收缩压，但在内皮细胞特异性Npr1中则没有——淘汰老鼠。此外，ANP 显着降低了Nos3基因敲除小鼠的收缩压。在人脐静脉内皮细胞中，用 ANP 处理不影响一氧化氮的产生或细胞内 Ca ²⁺浓度，但它确实使细胞超极化。ANP 诱导的人脐静脉内皮细胞超极化受到几种钾通道阻滞剂的抑制，并且在 RGS2（G 蛋白信号传导调节剂 2）（一种 G 蛋白 α 亚基中的 GTPase 激活蛋白）的敲低下也被消除。ANP 增加人脐静脉内皮细胞中的Rgs2 mRNA 表达，但未能降低Rgs2基因敲除小鼠的收缩压。内皮细胞特异性Npr1-过表达小鼠的血压低于不依赖RGS2的野生型小鼠，并且在同步辐射微血管造影中显示出动脉血管扩张。结论：总之，这些结果表明血管内皮NPR1在ANP介导的血压调节中起关键作用，大概是通过在急性期依赖 RGS2 而在慢性期不依赖 RGS2 的机制。