A dynamic model of renal blood flow autoregulation

To test whether a mathematical model combining dynamic models of the tubuloglomerular feedback (TGF) mechanism and the myogenic mechanism was sufficient to explain dynamic autoregulation of renal blood flow, we compared model simulations with experimental data. To assess the dynamic characteristics of renal autoregulation, a broad band perturbation of the arterial pressure was employed in both the simulations and the experiments. Renal blood flow and tubular pressure were used as response variables in the comparison. To better approximate the situationin vivo where as large number of individual nephrons act in parallel, each simulation was performed with 125 parallel versions of the model. The key parameters of the 125 versions of the model were chosen randomly within the physiological range. None of the constituent models, i.e., the TGF and the myogenic, could alone reproduce the experimental observations. However, in combination they reproduced most of the features of the various transfer functions calculated from the experimental data. The major discrepancy was the presence of a bimodal distribution of the admittance phase in the simulations. This is not consistent with most of the experimental data, which shows a unimodal curve for the admittance phase. The ability of the model to reproduce the experimental data supports the hypothesis that dynamic autoregulation of renal blood flow is due to the combined action of TGF and the myogenic response.     

Role of renal NO production in the regulation of medullary blood flow

The unique role of nitric oxide (NO) in the regulation of renal medullary function is supported by the evidence summarized in this review. The impact of reduced production of NO within the renal medulla on the delivery of blood to the medulla and on the long-term regulation of sodium excretion and blood pressure is described. It is evident that medullary NO production serves as an important counterregulatory factor to buffer vasoconstrictor hormone-induced reduction of medullary blood flow and tissue oxygen levels. When NO synthase (NOS) activity is reduced within the renal medulla, either pharmacologically or genetically [Dahl salt-sensitive (S) rats], a super sensitivity to vasoconstrictors develops with ensuing hypertension. Reduced NO production may also result from reduced cellular uptake of l-arginine in the medullary tissue, resulting in hypertension. It is concluded that NO production in the renal medulla plays a very important role in sodium and water homeostasis and the long-term control of arterial pressure.     

Dynamics and contribution of mechanisms mediating renal blood flow autoregulation

We investigated dynamic characteristics of renal blood flow (RBF) autoregulation and relative contribution of underlying mechanisms within the autoregulatory pressure range in rats. Renal arterial pressure (RAP) was reduced by suprarenal aortic constriction for 60 s and then rapidly released. Changes in renal vascular resistance (RVR) were assessed following rapid step reduction and RAP rise. In response to rise, RVR initially fell 5-10% and subsequently increased approximately 20%, reflecting 93% autoregulatory efficiency (AE). Within the initial 7-9 s, RVR rose to 55% of total response providing 37% AE, reaching maximum speed at 2.2 s. A secondary RVR increase began at 7-9 s and reached maximum speed at 10-15 s. Response times suggest that the initial RVR reflects the myogenic response and the secondary tubuloglomerular feedback (TGF). During TGF inhibition by furosemide, AE was 64%. The initial RVR rise was accelerated and enhanced, providing 49% AE, but it represented only 88% of total. The remaining 12% indicates a third regulatory component. The latter contributed up to 50% when the RAP increase began below the autoregulatory range. TGF augmentation by acetazolamide affected neither AE nor relative myogenic contribution. Diltiazem infusion markedly inhibited AE and the primary and secondary RVR increases but left a slow component. In response to RAP reduction, initial vasodilation constituted 73% of total response but was not affected by furosemide. The third component's contribution was 9%. Therefore, RBF autoregulation is primarily due to myogenic response and TGF, contributing 55% and 33-45% in response to RAP rise and 73% and 18-27% to RAP reduction. The data imply interaction between TGF and myogenic response affecting strength and speed of myogenic response during RAP rises. The data suggest a third regulatory system contributing <12% normally but up to 50% at low RAP; its nature awaits further investigation.     

Mechanisms of renal blood flow autoregulation: dynamics and contributions

Autoregulation of renal blood flow (RBF) is caused by the myogenic response (MR), tubuloglomerular feedback (TGF), and a third regulatory mechanism that is independent of TGF but slower than MR. The underlying cause of the third regulatory mechanism remains unclear; possibilities include ATP, ANG II, or a slow component of MR. Other mechanisms, which, however, exert their action through modulation of MR and TGF are pressure-dependent change of proximal tubular reabsorption, resetting of RBF and TGF, as well as modulating influences of ANG II and nitric oxide (NO). MR requires < 10 s for completion in the kidney and normally follows first-order kinetics without rate-sensitive components. TGF takes 30-60 s and shows spontaneous oscillations at 0.025-0.033 Hz. The third regulatory component requires 30-60 s; changes in proximal tubular reabsorption develop over 5 min and more slowly for up to 30 min, while RBF and TGF resetting stretch out over 20-60 min. Due to these kinetic differences, the relative contribution of the autoregulatory mechanisms determines the amount and spectrum of pressure fluctuations reaching glomerular and postglomerular capillaries and thereby potentially impinge on filtration, reabsorption, medullary perfusion, and hypertensive renal damage. Under resting conditions, MR contributes approximately 50% to overall RBF autoregulation, TGF 35-50%, and the third mechanism < 15%. NO attenuates the strength, speed, and contribution of MR, whereas ANG II does not modify the balance of the autoregulatory mechanisms.     

肾素-血管紧张素系统在调节肾脏活动和慢性肾功能不全中的作用

一、肾内RAS的组成、生物学特征及肾内分布;(一)有关RAS的研究进展;(二)肾脏组织局部的RAS;(三)AngⅡ受体的亚型及其在肾内的分布;二、AngⅡ对肾脏血流动力学的影响;三、AngⅡ对肾脏的非血流动力学效应;(一)AngⅡ的促生长作用及促纤维生成效应;(二)AngⅡ作为促炎症因子的作用;四、有关RAS在肾功能不全中的临床研究     

Nonlinear interactions in renal blood flow regulation

We have developed a model of tubuloglomerular feedback (TGF) and the myogenic mechanism in afferent arterioles to understand how the two mechanisms are coupled. This paper presents the model. The tubular model predicts pressure, flow, and NaCl concentration as functions of time and tubular length in a compliant tubule that reabsorbs NaCl and water; boundary conditions are glomerular filtration rate (GFR), a nonlinear outflow resistance, and initial NaCl concentration. The glomerular model calculates GFR from a change in protein concentration using estimates of capillary hydrostatic pressure, tubular hydrostatic pressure, and plasma flow rate. The arteriolar model predicts fraction of open K channels, intracellular Ca concentration (Ca(i)), potential difference, rate of actin-myosin cross bridge formation, force of contraction, and length of elastic elements, and was solved for two arteriolar segments, identical except for the strength of TGF input, with a third, fixed resistance segment representing prearteriolar vessels. The two arteriolar segments are electrically coupled. The arteriolar, glomerular, and tubular models are linked; TGF modulates arteriolar circumference, which determines vascular resistance and glomerular capillary pressure. The model couples TGF input to voltage-gated Ca channels. It predicts autoregulation of GFR and renal blood flow, matches experimental measures of tubular pressure and macula densa NaCl concentration, and predicts TGF-induced oscillations and a faster smaller vasomotor oscillation. There are nonlinear interactions between TGF and the myogenic mechanism, which include the modulation of the frequency and amplitude of the myogenic oscillation by TGF. The prediction of modulation is confirmed in a companion study (28).     

Frequency encoding in renal blood flow regulation

With a model of renal blood flow regulation, we examined consequences of tubuloglomerular feedback (TGF) coupling to the myogenic mechanism via voltage-gated Ca channels. The model reproduces the characteristic oscillations of the two mechanisms and predicts frequency and amplitude modulation of the myogenic oscillation by TGF. Analysis by wavelet transforms of single-nephron blood flow confirms that both amplitude and frequency of the myogenic oscillation are modulated by TGF. We developed a double-wavelet transform technique to estimate modulation frequency. Median value of the ratio of modulation frequency to TGF frequency in measurements from 10 rats was 0.95 for amplitude modulation and 0.97 for frequency modulation, a result consistent with TGF as the modulating signal. The simulation predicted that the modulation was regular, while the experimental data showed much greater variability from one TGF cycle to the next. We used a blood pressure signal recorded by telemetry from a conscious rat as the input to the model. Blood pressure fluctuations induced variability in the modulation records similar to those found in the nephron blood flow results. Frequency and amplitude modulation can provide robust communication between TGF and the myogenic mechanism.     

Vitamin D regulation of the renin-angiotensin system

The renin-angiotensin system (RAS) plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis. Epidemiological and clinical studies have long suggested an association of inadequate sunlight exposure or low serum 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] levels with high blood pressure and/or high plasma renin activity, but the mechanism is not understood. Our recent discovery that 1,25(OH)(2)D(3) functions as a potent negative endocrine regulator of renin gene expression provides some insights into the mechanism. The concept of vitamin D regulation of blood pressure through the RAS opens a new avenue to our understanding of the physiological functions of the vitamin D endocrine system, and provides a basis for exploring the potential use of vitamin D analogues in prevention and treatment of hypertension.     

The contribution of prostaglandins to renal blood flow maintenance is determined by the level of activity of the renin-angiotensin system

A growing body of experimental and clinical evidence has led to the formation of the hypothesis that the contribution of intrarenal prostaglandins to the determination of renal blood flow is a function of the level of activity of renin-angiotensin system. The following is a brief review of a portion of the pertinent literature. The focus of this review is the effect of inhibition of prostaglandin synthesis on renal blood flow in diverse conditions characterized by increased activity of the renin-angiotensin system, including reduction of renal arterial pressure, ureteral obstruction, hemorrhage, the hepatorenal syndrome, and sodium depletion. Under these conditions, in contrast to the lack of effect in non-stress conditions, the renin-angiotensin system activity is high, and prostaglandin synthesis inhibition is associated with reductions in renal blood flow.     

Role of the renin-angiotensin system in tubuloglomerular feedback

The link between the renal tubule and glomerular vasculature comprised of the juxtaglomerular apparatus appears to serve two functions: the regulation of filtration rate and of renin secretion. Elevation of macula densa NaCl concentration stimulates a vasoconstrictor response, which results in a fall in filtration rate, a response that has been termed tubuloglomerular feedback (TGF). Simultaneously, renin secretion is suppressed. The two responses appear to be initiated by a furosemide-sensitive transport step probably located in the macula densa. Both show a pattern of anion specificity identical to Na/K/Cl cotransport mechanisms. An increase in intracellular calcium in the effector cells, the vascular smooth muscle, and the renin-containing granular cells is a likely effector mechanism for both reactions. Angiotensin probably does not mediate the vasoconstrictive feedback response, because changes in local (intracellular) angiotensin concentration would have to be opposite from systemic changes. However, acute changes in angiotensin levels appear to be an important modulator of the magnitude of the TGF response.