ROLE OF SENSING OF K+ INTAKE IN K+ HOMEOSTASIS

描述(由申请人提供)：细胞外(ECF)K稳态对正常的心血管和神经肌肉功能至关重要，并由肾脏和肾外机制维持。我们最近开发了一种钾钳技术，它可以在体内定量肾脏钾排泄和肾外细胞钾摄取。利用这项技术，我们证明了在缺钾过程中，肾脏的钾排泄和肾外细胞的钾摄取都受到了迅速而深刻的抑制。ECF K保守性的这些变化传统上被解释为ECF K水平下降和/或随之而来的醛固酮分泌减少。然而，我们发现，当钾摄入量减少到对照组的1/3时，在没有血浆[K]或[醛固酮]变化的情况下，这种ECF K保守的触发可以在大鼠身上发生。本项目的目的是验证一种假说，即钾摄入量是由门静脉中的钾感受器感知的，肾脏钾排泄和肾外细胞钾摄取都受这一信号的调节。为了实现这一目标，我们将与我们研究所的Casey Donovan博士合作，并采用类似于在大鼠身上演示门静脉血糖传感器存在的策略，即“局部冲洗”和门静脉去神经技术。我们的初步数据显示，仅在一个晚上(12小时)将K的摄入量减少到正常水平的1/3就足以触发显着的肾脏K保存。在拟议的研究中，我们将使用这种隔夜低钾饲养模式来解决以下具体目标。 目的1.检测门脉(或内脏)对Kv摄入量的感知及其对肾脏和肾外K的调节作用。我们将测试通过胃内或门静脉输注的并行补钾是否可以防止隔夜低饮食钾摄入量触发ECF K的保存，这将被假想的门静脉(或内脏)传感器感觉到，但不能通过全身输注的补钾来防止。 目的2.检测钾摄入量的门静脉感知在细胞外钾稳态中的作用。我们建议测试去门脉神经是否破坏门脉对Kv摄入量的感觉，如果是，是否通过延迟肾脏和肾外对改变的K摄入量的反应来损害ECF K动态平衡的急性和慢性调节。 意义：这个项目将可能确定一个重要的，以前未知的ECF K动态平衡调节因子。

DESCRIPTION (provided by applicant): Extracellular (ECF) K+ homeostasis is critical for normal cardiovascular and neuromuscular functions and is maintained by renal and extrarenal mechanisms. We recently developed the K clamp technique, which can quantify both renal K+ excretion and extrarenal cellular K+ uptake in vivo. Using this technique, we demonstrated that both renal K+ excretion and extrarenal cellular K+ uptake are rapidly and profoundly suppressed during K+ deprivation. These changes for ECF K+ conservation have been traditionally explained to arise from decreased ECF K+ levels and/or consequent decrease in aldosterone secretion. However, we found that this triggering of ECF K+ conservation can occur in rats in the absence of changes in plasma [K +] or [aldosterone] when K+ intake is reduced to 1/3 of control. The objective of this project is to test the hypothesis that K+ intake is sensed by K+ sensors in the portal vein, and both renal K+ excretion and extrarenal cellular K+ uptake are regulated by this signal. To achieve this goal, we will collaborate with Dr. Casey Donovan at our institution and employ strategies similar to those used to demonstrate the presence of portal vein glucose sensors in rats, i.e., "local irrigation" and portal denervation techniques. Our preliminary data showed that reducing K+ intake to 1/3 of normal for only one night (12 h) was sufficient to trigger marked renal K+ conservation. In the proposed studies we will use this overnight low K+ feeding model to address the following specific aims. Aim 1. Test for the existence of portal (or splanchnic) sensing of Kv intake and its regulation of renal and extrarenal K+ handling. We will test whether the triggering of ECF K+ conservation by overnight low dietary K+ intake is prevented by parallel K+ supplementation via intragastric or intraportal infusion, which would be sensed by the hypothetical portal vein (or splanchnic) sensors, but not by K+ supplementation via systemic infusion. Aim 2. Test for a role of portal sensing of K+ intake in extracellular K+ homeostasis. We propose to test whether portal denervation ablates portal sensing of Kv intake and, if so, whether it impairs the acute and chronic regulation of ECF K+ homeostasis by delaying renal and extrarenal responses to altered K+ intake. Significance: This project will potentially identify an important, previously unknown regulator of ECF K+ homeostasis.