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D J Marsh

Publications and source records attributed to D J Marsh.

At least 127 records · Page 7Linked to original sources
PubMed1990

A dynamic model of the tubuloglomerular feedback mechanism.

We have reported oscillations in proximal tubular pressure and flow and in distal tubular pressure and chloride concentration in halothane-anesthetized Sprague-Dawley rats. These variables oscillated at the same frequency in each animal, approximately 35 mHz, but were out of phase with each other. We suggested that the oscillation arises within the tubuloglomerular feedback (TGF) system. As a test of this hypothesis, we have now developed a dynamic model to determine whether it can simulate the measured frequency and phase relationships with a realistic set of parameters. The model includes a detailed representation of pressure and flow in the tubules based on a reduced version of the Navier-Stokes equations. The NaCl concentration at the macula densa was used as the signal to the TGF mechanism. The tubular NaCl concentration was modeled by a partial differential equation based on conservation of mass. For a realistic set of parameter values the model accurately predicted oscillations with the same frequency and phase relationships among the oscillating variables as was found experimentally. Moreover, tubular NaCl handling significantly influenced the dynamic properties of the TGF system. Thus the model predicted a substantial phase shift of the NaCl concentration relative to the flow oscillation at the macula densa. The results are consistent with the hypothesis that the oscillations are caused by the TGF mechanism. The results further support the notion that the delays and damping caused by the tubule are responsible for the limited high-frequency response of renal autoregulation.

Animals↗
PubMed1990

TGF-initiated vascular interactions between adjacent nephrons in the rat kidney.

We sought to determine whether tubuloglomerular feedback (TGF), activated from one nephron, affects other arterioles derived from the same cortical radial artery. Surface nephrons supplied by a single cortical radial artery were identified by injecting Ringer solution containing Fast Green from a narrow-gauge polyethylene catheter inserted via a lumbar artery into a renal artery. Stop-flow pressure was measured in an identified nephron from such a grouping. In one series, increasing end-proximal flow rate from 0 to 50 nl/min of synthetic tubular fluid in one member of an identified pair of nephrons reduced stop-flow pressure by 1.3 +/- 0.2 mmHg in the other member. When the nephrons were derived from different cortical radial arteries, the stop-flow pressure changed -0.2 +/- 0.1 mmHg. In another series, increasing flow in the adjacent nephron from 0 to 50 nl/min decreased stop-flow pressure 3.9 +/- 0.9 mmHg, and increasing flow in the adjacent nephron by the same amount when flow in the first nephron was 50 nl/min decreased stop-flow pressure 3.4 +/- 0.7 mmHg. These results indicate the operation of an interaction among nephrons derived from a common cortical radial artery. Such an interaction could produce a cooperative effect larger than that predicted from measured single-nephron responses when systemic arterial pressure changes.

Animals↗
PubMed1990

Model of TGF-proximal tubule interactions in renal autoregulation.

Previous models, assuming constant reabsorption in the proximal tubule, have shown that tubuloglomerular feedback (TGF) can explain only a fraction of glomerular filtration rate (GFR) and renal blood flow autoregulation. Increased arterial pressure inhibits proximal tubule fluid reabsorption, an effect that should increase the efficacy of TGF because of the resulting increased flow rate in the loop of Henle. Models describing pressure and flow in a glomerulus and a nephron were derived to test this prediction. The models were coupled by a TGF function with tubular flow rate at the end of the proximal tubule (superficial nephron) or at the macula densa (juxtamedullary nephron) as input and with afferent arteriolar resistance as output. In agreement with others, the model predicted that TGF alone could account for about one-half of autoregulation. Pressure-dependent inhibition of proximal reabsorption increased the ability of TGF to account for autoregulation, providing compensation for increases in arterial pressure comparable to published whole kidney values. The inclusion of an approximation of an effect of arterial pressure on TGF marginally improved predicted autoregulation. Although the results suggest that the proximal tubule-TGF interaction can provide a quantitatively adequate explanation for autoregulation, they also indicate that the effect of the interaction is spent at arterial pressures greater than 130 mmHg. Additional mechanisms are required to extend this range.

Animals↗
PubMed1989

Effect of bumetanide on tubuloglomerular feedback in Necturus maculosus.

A non-invasive technique was developed to measure single-nephron glomerular blood flow (SNGBF) in Necturus maculosus. Erythrocytes labelled with rhodamine, a fluorescent dye, were injected systemically and the frequency at which labelled cells entered an arteriole was measured. Frequency was converted to flow by measuring the concentration of labelled erythrocytes in whole blood. Dependence of SNGBF on flow rate in early distal tubules was used to assess tubuloglomerular feedback (TGF). SNGBF decreased with increasing flow in the early distal tubule in a pattern typical of TGF; SNGBF decreased 25% at the highest flow rates. SNGBF increased when bumetanide was added to the perfusate, but the TGF response to flow rate persisted. IC50 (concentration that produces half-maximal inhibition) was 2.4 x 10(-10), 9.8 x 10(-10) and 1.2 x 10(-9) M bumetanide at distal perfusion rates of 5, 10 and 20 nl min-1 respectively. These results are consistent with modulation of SNGBF according to the rate of luminal entry of NaCl into early distal tubule cells. This transport rate depends on the luminal concentration of NaCl, which is tubular flow rate-dependent; NaCl and bumetanide compete.

Animals↗
PubMed1989

Oscillations of tubular pressure, flow, and distal chloride concentration in rats.

Previous experiments have shown oscillations in proximal tubular pressure in halothane-anesthetized rats. Such oscillations should be due to oscillations in flow rate and should cause periodic oscillations in both distal tubular chloride concentration and distal tubular pressure. The purpose of the study was to test these predictions. In halothane-anesthetized Sprague-Dawley rats, distal tubular chloride activity was measured with Cl- -sensitive electrodes, and late proximal flow rate was measured by pulse injection of boluses of solutions containing rhodamine dextran. Bolus velocity was detected by videomicroscopy. The time resolution was 2 s. All four variables oscillated with the same frequency, approximately 35 mHz. The amplitude of the flow and the chloride oscillations were 28 and 10%, respectively, of the mean values. Proximal fluid velocity led proximal pressure by 1.5 +/- 0.4 s, whereas distal chloride activity lagged proximal pressure by 8.9 +/- 0.8 s. The distal pressure lagged the proximal pressure by 1.05 +/- 0.38 s. It is concluded that there is a significant variation in distal chloride activity, the magnitude of which appears to be sufficient to account for the observed flow variations through the operation of the tubuloglomerular feedback mechanism.

Animals↗
PubMed1988

Autoregulation of blood flow in renal medulla of the rat: no role for angiotensin II.

Autoregulation of blood flow was assessed by a dual-slit technique in descending and ascending vasa recta of the exposed renal papillae of antidiuretic rats. There was complete autoregulation of blood flow in descending vasa recta. The lower limit of autoregulation was approximately 85 mmHg (1 mmHg = 133.3 Pa) and the upper limit was greater then 160 mmHg. Autoregulation in ascending vasa recta was also good. To test the role of angiotensin II in this autoregulation, the converting enzyme inhibitor captopril was infused. Captopril had no effect on autoregulation of blood flow in either descending or ascending vasa recta. We conclude that blood flow in vasa recta of renal medulla is efficiently autoregulated and that this autoregulation is independent of angiotensin II.

Angiotensin II↗
PubMed1988

Angiotensin II and prostaglandins in control of vasa recta blood flow.

Angiotensin II has been implicated in the regulation of medullary blood flow and is known to interact with prostaglandins at sites within the kidney. Therefore the role of angiotensin in control of vasa recta blood flow was studied in antidiuretic, Munich-Wistar rats. We also tested the hypothesis that prostaglandins act to modulate the effect of angiotensin. Total renal blood flow was measured by an electromagnetic flow probe, vasa recta blood flow by a dual-slit method. Captopril was used to confirm that angiotensin blockade increased renal blood flow (by 15 +/- 4%). Captopril and saralasin were used to show that angiotensin blockade increased vasa recta blood flow (by 23 +/- 9 and 14 +/- 7%, respectively). The results demonstrate a tonic constrictor effect of angiotensin in the renal medulla. Exogenous angiotensin II, delivered intravenously, failed to mimic the effect of endogenous angiotensin. Indomethacin did not alter blood pressure or renal blood flow but did reduce vasa recta blood flow by 20 +/- 3%, suggesting that prostaglandins act preferentially on the medullary circulation. Nor did it alter the response of blood pressure, of renal blood flow, or of vasa recta blood flow to captopril. Moreover, prior angiotensin blockade with either captopril or saralasin enhanced the medullary vasoconstrictor effect of indomethacin (P less than 0.05). These results are not consistent with the hypothesis that prostaglandins act primarily as angiotensin modulators. They suggest that the medullary interaction between angiotensin and prostaglandins differs from that in the cortex.

Angiotensin II↗
PubMed1988

Juxtaglomerular interstitial hypertonicity in Amphiuma: tubular origin-TGF signal.

One of the mechanisms mediating renal vascular autoregulation in mammals senses tubular flow rate-dependent changes in luminal NaCl concentrations and signals renal arterioles to change diameter. A similar mechanism operates in the salamander, Amphiuma means. To trace the signal, we measured chloride activity in juxtaglomerular interstitial spaces in Amphiuma during perfusion of the early distal tubule belonging to the same nephron. Interstitial Cl- activity exceeded systemic levels and increased when perfusion rate in the adjacent early distal tubule was increased, reaching values more than five times isotonic. Bumetanide, which inhibits NaCl transport by the early distal tubule, eliminated the hypertonicity. Regions of the interstitial space not a part of the juxtaglomerular apparatus (JGA) were not hypertonic. The Cl- concentration was 80% greater than isotonic in the JGA of nephrons studied under free-flow conditions. Single-nephron blood flow, measured by counting the flux of erythrocytes labeled with a fluorescent molecule, showed typical feedback inhibition with maximum sensitivity to the same rates of tubular perfusion that caused the maximum change in JGA interstitial hypertonicity. Juxtaglomerular interstitial hypertonicity could be an important part of the signal for renal autoregulation.

Animals↗
PubMed1988

Time course of proximal tubule response to acute arterial hypertension in the rat.

Acute hypertension was previously shown to cause partial inhibition of proximal tubule fluid reabsorption in perfused tubules in the rat. If the inhibition also occurs in unobstructed tubules receiving native glomerular filtrate, hypertension should increase end proximal flow rate despite autoregulation of glomerular filtration rate (GFR). We tested this prediction with a videodensitometric method recently developed for measurement of tubular flow rate that does not interrupt flow to the macula densa. Hypertension was induced by increasing total peripheral resistance in rats receiving several hormones at rates designed to maintain high levels of these agents. End proximal flow rate was increased 18% as early as 1.5-2 min following the induction of hypertension and increased over the course of the next 25-30 min to reach values 50% greater than controls as the hypertension was sustained. Whole-kidney GFR and renal blood flow were fully autoregulated. The results confirm that hypertension increases the fluid load to the loop of Henle, and are consistent with an effect on proximal tubule fluid reabsorption. This increase in fluid load could signal the macula densa and contribute to the efficacy of autoregulation; it could also provide a significant fraction of the increased fluid and salt excretion of pressure natriuresis.

Acute Disease↗
PubMed1987

GFR regulation and flow-dependent electrophysiology of early distal tubule in Amphiuma.

Tubuloglomerular feedback (TGF) in mammals and amphibians senses flow-dependent concentration changes in tubular fluid of the distal tubule and signals to arterioles to initiate changes in glomerular filtration rate. The distal tubules and afferent arterioles are situated on the surface of the kidney of Amphiuma means. Micropuncture techniques were used to measure luminal and intracellular chloride concentrations and the associated electrical potential differences, while tubular perfusion rate was varied. Transepithelial potential difference (PDte) and basolateral potential difference (PDbl) became more positive at increased tubular flow rates. Intratubular and intracellular chloride concentrations also increased significantly with perfusion rate. Single-nephron glomerular filtration rate decreased when perfusion rate was increased but this response was eliminated by the inclusion of furosemide in the perfusion solution; the drug also inhibited the flow dependence of PDte. The results suggest that local changes in PD and Cl- activity result from flow-dependent changes in the rate of hypertonic NaCl transport propagated along the length of the perfused segment; they establish a correlation between the rate of transport and the magnitude of the TGF inhibition; and, because transport and TGF can be jointly inhibited, they suggest a causal link between the two.

Animals↗
PubMed1987

Measurement of flow rate in rat proximal tubules with a nonobstructing optical method.

A method was developed for measuring volume flow rate in free-flowing proximal tubules. Multiple injections of a solution containing fluorescein isothiocyanate-dextran (mol wt 20,000) were made into the tubular fluid stream while fluorescence was detected by videomicroscopy. Progression of the dye bolus between two points along the tubule was measured to determine fluid velocity. Tubule diameter was measured by video image shearing and flow rate was calculated from the product of velocity and cross-sectional area. The technique was validated by simultaneous collections in the same tubule just downstream. There was good correlation between the results obtained with the two methods (r = 0.89). The estimated average injection volume was 0.0165 +/- 0.00016 nl. An increase in tubular volume flow caused by repetitive injections during micropuncture collections was too small to be detected. This new method should be useful in experimental situations that require uninterrupted delivery of fluid to the macula densa, or when better temporal resolution is required than can be obtained with the conventional method.

Animals↗
PubMed1987

Passive, one-dimensional countercurrent models do not simulate hypertonic urine formation.

Simulations were performed to test the ability of the countercurrent hypothesis to predict measured concentrations of NaCl and urea in the interstitium of the renal medulla. The simulations included one-dimensional representations of loops of Henle, distal tubules, collecting ducts, and vasa recta, and recent estimates of descending limb, thick ascending limb, and collecting duct transport parameters. The nonlinear two-point boundary value problem was solved numerically via quasi-linearization. The simulations failed to predict measured concentrations or concentration gradients of NaCl in the inner medulla. Including countertransport of urea and NaCl in thin ascending limbs added minimally to the performance of the system. The single most effective change in the model was the inclusion of a coefficient to permit preferential solute exchange among vasa recta. This result suggests that the three-dimensional ordering of blood vessels and tubules is an essential construct in the concentrating mechanism.

Kidney Medulla↗
PubMed1986

Fluid waves in renal tubules.

Autoregulation of renal blood flow is ineffective when arterial pressure perturbations occur at frequencies above 0.05 Hz. To determine whether wave propagation velocity to the macula densa is rate limiting, we estimated compliances of the proximal tubule and the loop of Henle, and used these values in a model of pressure and flow as functions of time and distance in the nephron. Compliances were estimated from measurements of pressures and flows in early proximal, late proximal, and early distal tubules in rats under normal and Ringer-loaded conditions. A model of steady pressure and flow in a compliant, reabsorbing tubule was fitted to these results. The transient model was a set of nonlinear, hyperbolic partial differential equations with split, nonlinear boundary conditions, and was solved with finite difference methods. The loop of Henle compliance was larger than the proximal tubule compliance, and impulses in glomerular filtration rate were attenuated in magnitude and delayed in time in the loop of Henle. Simulated step forcings revealed a similar pattern. Periodic variations of GFR were attenuated at frequencies greater than 0.05 Hz, and there was a delay of 5 s between variations in GFR and macula densa flow rate. The high compliance of the loop slows wave propagation to the macular densa and reduces the amplitude of high frequency waves originating in the glomerulus, but other parts of the signal chain also contribute to the slow response of macula densa feedback.

Animals↗
PubMed1986

Oscillations enhance the efficiency and stability of glucose disposal.

Oscillations in plasma concentrations of glucose and insulin as well as the rates of glucose disposal by liver and periphery have been observed in dogs during states of net glucose anabolism. To examine whether the existence of oscillations is important for efficient disposal of nutrients, we compared constant glucose infusion (with plasma glucose and insulin oscillations) to experiments in which glucose oscillations were suppressed using the glucose clamp. Mean glucose levels attained were the same for the two protocols (142 +/- 2 for constant glucose infusion at 10.8 +/- 0.4 mg X kg-1 X min-1, 144 +/- 1 mg/dl for clamps, P = 0.35). Despite matched mean glucose, integrated plasma insulin was 36.3 +/- 3.2 mU X ml-1 X 600 min in controls but higher in clamps (53.8 +/- 9.1 mU X ml-1 X 600 min, P = 0.017). Despite 48% higher insulin, total glucose disposed during the 10-h clamps was not greater than during constant glucose infusion (clamps, 162.1 +/- 10.7 g/600 min; infusions, 154.4 +/- 7.5 g/600 min; P = 0.19). These studies demonstrate that the presence of coordinated oscillations in glucose and insulin, during glucose infusion, are associated with more efficient disposal of glucose than when oscillations are suppressed. The results suggest that oscillations may play an important role in the efficient disposal of administered nutrient and may be an important component of normal glucose tolerance.

Animals↗
PubMed1986

Frequency domain analysis of renal autoregulation in the rat.

The frequency response of renal blood flow was estimated to test our suggestion that autoregulation had one fast and one slow component. Arterial pressure was varied periodically by a pump connected to the distal aorta or aperiodically by stimulating atrial fibrillation. There was only one regulatory mechanism, corresponding to the slow component seen earlier. Two apparent regulators were seen when pressure was measured far from the renal artery (right common carotid), rather than near (superior mesenteric). Simultaneous measurements of pressure in both arteries showed interference of the pressure wave from the heart with pressure waves from the pump in the distal aorta at frequencies near that of the heart rate. Measurements made in the superior mesenteric artery were likely to be correct. The earlier results were in error, and frequency response methods detect only one regulator. Animals made acutely hypertensive behaved similarly. The effect of the regulator appears as a phase shift at frequencies of 0.25 Hz and below and an attenuated flow magnitude at frequencies below 0.1 Hz. This frequency response is consistent with the flow propagation time to the macula densa. We conclude that macula densa feedback was the only flow-regulating mechanism detected.

Animals↗
PubMed1986

Role of proximal convoluted tubule in pressure diuresis in the rat.

The role of different nephron segments in the diuretic response to acute arterial hypertension was studied with tubular microperfusion. Early proximal convolutes were perfused with synthetic glomerular ultrafiltrate; fluid was collected from the last visible loop of the same proximal or from the first loop of the distal tubule. In late proximal collections, an increase of arterial pressure of 24 +/- 2 mmHg reduced reabsorption of tubular fluid 44 +/- 4%. Perfusate chloride concentration fell, but only 2 meq/liter, so that chloride reabsorption was inhibited in proportion to the inhibition of fluid reabsorptions, with a corresponding increase in chloride delivery to the loop of Henle. In early distal collections, there was no significant difference of the early distal flow rate with hypertension, but early distal chloride concentration increased 31 +/- 8% and chloride load increased 45 +/- 12%. Qualitatively similar increases were obtained from paired collections made from free-flowing early distal tubules. Inhibition of proximal fluid reabsorption is a primary response to acute hypertension and may contribute to pressure diuresis. In addition, this inhibition increases the strength of the luminal signal to the macula densa, enhancing the autoregulatory response to hypertension.

Absorption↗
PubMed1986

Automatic derivative evaluation in solving boundary value problems: the renal medulla.

Automatic evaluation of derivatives becomes essential when large systems of equations of many variables are to be solved. This paper presents a set of easy-to-use FORTRAN subroutines that perform automatic derivative evaluation. They were used in conjunction with the method of quasilinearization to solve a 13th-order boundary-value problem. This problem has been proposed as a test of numerical methods used to solve models of the renal concentrating mechanism. Quasilinearization gives the same result as has been reported by others with finite difference or multiple shooting methods. The approach described here offers the important potential advantage of being easier to apply to larger problems, which can be anticipated when attempts are made to simulate the three-dimensional structure of the renal medulla.

Biological Transport↗