Non-linear regulation of the renal circulation

肾循环的非线性调节

• 批准号: 7128122
• 负责人: DONALD J MARSH
• 金额: $ 24.26万
• 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/7128122
• 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（申请人提供）：在正常动物中，单个肾小管的血流量是由一系列非线性振荡机制调节的。其中一个机制是小管肾小球反馈（TGF），它将小管流速依赖远端小管NaCI浓度的信息传递给肾传入小动脉。另一种是肌生成机制，这是一种在传入小动脉中活跃的压力依赖机制，可产生自发的血管舒缩。TGF振荡更大、更慢，两者相互作用，形成相耦合。TGF的振荡幅度是成肌机制的3-5倍，频率是成肌机制的1/5。慢性高血压动物TGF振荡不规则；这种不规则性具有非线性决定论的特征，这种变化被称为分岔。该项目的主要目标是了解分叉的生理基础。