Non-linear regulation of the renal circulation

肾循环的非线性调节

• 批准号: 7038686
• 负责人: DONALD J MARSH
• 金额: $ 24.04万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-28 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038686
• 关键词: blood pressure; computer simulation; hypertension; kidney circulation; kidney function; model design /development; renal tubule

DESCRIPTION (provided by applicant): Blood flow to single renal tubules is regulated by an ensemble of non-linear mechanisms that oscillate in normal animals. One of the mechanisms is tubuloglomerular feedback (TGF), which transmits information about tubular flow rate dependent distal tubule NaCI concentration to the renal afferent arteriole. The other is the myogenic mechanism, a pressure dependent mechanism active in the afferent arteriole that generates spontaneous vasomotion. TGF has the larger, slower oscillation, and the two interact and become phase coupled. TGF's oscillation has 3-5 times the amplitude of the myogenic mechanism's, and is 1/5 as frequent. The TGF oscillation becomes irregular in animals with chronic hypertension; the irregularity has characteristics of non-linear determinism, and the change is referred to as a bifurcation. The major goal of this project is to understand the physiological basis for the bifurcation. A computer simulation of the tubule and its blood vessels will be used to determine the cause. The model has 3 components: 1) a spatially extended model of a renal tubule, with 3 partial differential equations to express dependence of tubular flow rate, tubular pressure, and tubular NaCI concentration on tubular length and time; 2) a single non-linear ordinary differential equation to model glomerular filtration rate; and 6 non- linear ordinary differential equations to model each of two arteriolar segments. The arteriolar model expresses the interaction of K and Ca fluxes to generate action potentials and an autonomous limit cycle oscillation of intracellular Ca, and the Ca oscillation drives myosin light chain phosphorylation, which controls the contractile process and is in parallel with elastic elements. TGF input is linked to Ca entry through voltage gated Ca channels. The model provides excellent blood flow regulation, TGF and myogenic oscillations of appropriate magnitude and frequency, and quadratic phase coupling. It also predicts frequency modulation of the myogenic frequency by TGF, a prediction we have now verified in experimental records. Four hypotheses about the cause of the bifurcation will be tested: that it is caused by a 1/f process in arterial pressure that has more power in some hypertensive rats; that it is caused by increased TGF- myogenic coupling; that it is caused by increased internephron coupling in hypertension; and that it is caused by altered patterns of tubular NaCI reabsorption in hypertension. The revised proposal answers questions raised in the first review, and presents new results from simulations of coupled cortical and medullary nephrons.

描述（由申请人提供）：流向单个肾小管的血流由正常动物中振荡的非线性机制的集合调节。其中一种机制是肾小管肾小球反馈（TGF），其将关于肾小管流速依赖性远端小管NaCl浓度的信息传递到肾传入小动脉。另一种是肌源性机制，这是一种在传入小动脉中起作用的压力依赖性机制，可产生自发性血管运动。TGF具有更大、更慢的振荡，并且两者相互作用并成为相位耦合。TGF的振荡幅度是肌原性机制的3-5倍，频率是其1/5。TGF振荡在慢性高血压动物中变得不规则;不规则具有非线性决定论的特征，并且这种变化被称为分叉。这个项目的主要目标是了解分叉的生理基础。 将使用计算机模拟小管及其血管来确定原因。该模型具有3个组成部分：1）肾小管的空间扩展模型，具有3个偏微分方程以表达肾小管流速、肾小管压力和肾小管NaCl浓度对肾小管长度和时间的依赖性; 2）单个非线性常微分方程以模拟肾小球滤过率;以及6个非线性常微分方程以模拟两个小动脉段中的每一个。小动脉模型表达了K和Ca流的相互作用以产生动作电位和细胞内Ca的自主极限环振荡，并且Ca振荡驱动肌球蛋白轻链磷酸化，其控制收缩过程并且与弹性元件平行。TGF β输入通过电压门控Ca通道与Ca进入相关。该模型提供了良好的血流调节，TGF和肌源性振荡的适当幅度和频率，和二次相位耦合。它还预测了TGF对生肌频率的频率调制，我们现在已经在实验记录中验证了这一预测。 将测试关于分叉原因的四个假设：它是由动脉压中的1/f过程引起的，该过程在一些高血压大鼠中具有更大的功率;它是由TGF-肌原性偶联增加引起的;它是由高血压中肾单位间偶联增加引起的;以及它是由高血压中肾小管NaCl重吸收模式改变引起的。 修订后的建议回答了在第一次审查中提出的问题，并提出了新的结果，从耦合的皮质和髓质肾单位的模拟。