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D J Marsh

Publications and source records attributed to D J Marsh.

At least 19 recordsLinked to original sources
PubMed1992

Dynamics of TGF-initiated nephron-nephron interactions in normotensive rats and SHR.

Proximal tubular pressure, glomerular filtration rate, and early distal tubule Cl- oscillate at 35 mHz in normotensive rats because of tubuloglomerular feedback (TGF); the oscillation bifurcates to chaos in spontaneously hypertensive rats (SHR). To examine the importance of TGF-initiated vascular interactions between nephrons in these dynamics, we measured tubular pressure simultaneously in two or more nephrons. The oscillations were synchronized in nephrons supplied by a common cortical radial artery. The correlation coefficient of pressure records from coupled nephrons was 0.86 +/- 0.02. Intratubular furosemide perfusion diminished the oscillation in both the perfused and the coupled nephron; total autospectral power in each of the nephrons and cross-spectral power were reduced to 45% of control. The correlation between noncoupled nephrons was not significant, and intratubular furosemide perfused in one nephron had no effect on adjacent but noncoupled nephrons. In SHR, the correlation coefficient of tubular pressure records was high from coupled nephrons only; furosemide diminished the autospectral power of pressure fluctuations to approximately 60-75% of control in both perfused and coupled nephrons, and cross-spectral power was affected by a similar amount. Nephron-nephron interactions, specific to vascular connectivity, persist in SHR and appear to be stronger than in normotensive rats.

Animals↗
PubMed1992

Medullary thyroid carcinoma: Australian experience with genetic testing.

Linkage analysis has been performed in four pedigrees with multiple endocrine neoplasia type 2A (MEN 2A) or familial medullary thyroid carcinoma (MTC) using pericentromeric chromosome 10 probes. Important information regarding carrier status has been provided in 10 individuals, many of whom would not have been identified by pentagastrin stimulation testing. We have also used pulsed field gel electrophoresis (PFGE) to link the probes H4.IRBP and pMCK2 to a 150 kb fragment. Using PFGE, no evidence was found in DNA from lymphocytes of a major DNA rearrangement in two individuals affected with MEN 2A and an individual with MEN 2B compared with normals. Metastatic MTC from one patient has been used to generate a cDNA library which will be used to screen for candidate MEN 2A and MEN 2B gene(s).

Carcinoma↗
PubMed1991

Tubuloglomerular feedback dynamics and renal blood flow autoregulation in rats.

To decide whether tubuloglomerular feedback (TGF) can account for renal autoregulation, we tested predictions of a TGF simulation. Broad-band and single-frequency perturbations were applied to arterial pressure; arterial blood pressure, renal blood flow and proximal tubule pressure were measured. Data were analyzed by linear systems analysis. Broad-band forcings of arterial pressure were also applied to the model to compare experimental results with simulations. With arterial pressure as the input and tubular pressure, renal blood flow, or renal vascular resistance as outputs, the model correctly predicted gain and phase only in the low-frequency range. Experimental results revealed a second component of vascular control active at 100-150 mHz that was not predicted by the simulation. Forcings at single frequencies showed that the system behaves linearly except in the band of 33-50 mHz in which, in addition, there are autonomous oscillations in TGF. Higher amplitude forcings in this band were attenuated by autoregulatory mechanisms, but low-amplitude forcings entrained the autonomous oscillations and provoked amplified oscillations in blood flow, showing an effect of TGF on whole kidney blood flow. We conclude that two components can be detected in the dynamic regulation of renal blood flow, i.e., a slow component that represents TGF and a faster component that most likely represents an intrinsic vascular myogenic mechanism.

Animals↗
PubMed1991

Three-dimensional anatomy and renal concentrating mechanism. I. Modeling results.

Simulations were performed to test the hypothesis that the three-dimensional organization of the renal medulla is essential for formation of hypertonic urine. As in previous models, representations of loops of Henle, distal tubules, collecting ducts, and vasa recta and recent estimates of tubule characteristics were included in a simulation of NaCl, urea, and fluid transport. In addition, this model specifies the relative positions of the medullary structures. By assuming that the structure of the minimum functional unit is a vascular bundle surrounded by tubules and ascending vessels, we have represented the three-dimensional organization of the medulla by a cylindrically symmetric two-dimensional model. The resulting set of equations gives rise to a nonlinear boundary value problem with linear boundary conditions, which was solved numerically via quasi linearization. Compared with previous simulations, the concentrations predicted by this model more accurately match measured quantities in two regards. First, papillary tip concentrations of NaCl and urea are significantly higher, and, second, a monotonic increase in osmolarity is observed in the inner medulla. The three-dimensional organization permitted development of local concentration gradients, which are essential to the final result.

Absorption↗
PubMed1991

Three-dimensional anatomy and renal concentrating mechanism. II. Sensitivity results.

A mathematical model has been developed to simulate hypertonic urine formation in the renal medulla. The model uses published values of membrane transport parameters, as have other models, but is unique in its representation of the three-dimensional anatomy of the medulla. The model successfully predicts measured fluid flows, osmolarities, and NaCl and urea concentrations. The model results are presented in the companion to this paper [A. S. Wexler, R. E. Kalaba, D. J. Marsh. Am. J. Physiol. 260 (Renal Fluid Electrolyte Physiol. 29): F368-F383, 1991.]. In this paper we provide tests of the sensitivity of model performance to variations in the description of the anatomy and in membrane transport parameters. From these studies we conclude that 1) strict counterflow arrangements are required in the outer stripe to prevent loss of NaCl to the systemic circulation, 2) the radial organization in the inner stripe materially improves performance of the inner medulla, 3) radial organization of the inner medulla is essential to hypertonic urine formation there, 4) the model is most sensitive to variation in collecting duct parameters, and 5) reabsorption of urea in the distal tubule improves system performance. The results support the claim that the three-dimensional structure, as captured in the model, provides a crucial framework for the production of hypertonic urine.

Absorption↗
PubMed1991

Chaos in blood flow control in genetic and renovascular hypertensive rats.

Hydrostatic pressure and flow in renal proximal tubules oscillate at 30-40 mHz in normotensive rats anesthetized with halothane. The oscillations originate in tubuloglomerular feedback, a mechanism that provides local blood flow regulation. Instead of oscillations, spontaneously hypertensive rats (SHR) have aperiodic tubular pressure fluctuations; the pattern is suggestive of deterministic chaos. Normal rats made hypertensive by clipping one renal artery had similar aperiodic tubular pressure fluctuations in the unclipped kidney, and the fraction of rats with irregular fluctuations increased with time after the application of the renal artery clip. Statistical measures of deterministic chaos were applied to tubular pressure data. The correlation dimension, a measure of the dimension of the phase space attractor generating the time series, indicated the presence of a low-dimension strange attractor, and the largest Lyapunov exponent, a measure of the rate of divergence in phase space, was positive, indicating sensitivity to initial conditions. These time series therefore satisfy two criteria of deterministic chaos. The measures were the same in SHR as in rats with renovascular hypertension. Since two different models of hypertension displayed similar dynamics, we suggest that chaotic behavior is a common feature of renal vascular control in the natural history of the disease.

Animals↗
PubMed1991

Glucose tolerance and insulin action in rats with renovascular hypertension.

To test whether hypertension can cause hyperinsulinemia or insulin resistance, we performed intravenous glucose tolerance tests at 1 month and euglycemic clamps at 3 months after induction of two-kidney, one clip renovascular hypertension in rats. At 1 month, systolic pressure was higher in 21 clipped than in 12 control animals (161 +/- 5 mm Hg, range 134-187 mm Hg versus 119 +/- 3 mm Hg, range 108-146 mm Hg; p less than 0.001). Glucose tolerance, assessed as the glucose fractional disappearance rate between 3 and 11 minutes after the glucose injection, was similar in the clipped and sham groups (0.059 +/- 0.002 versus 0.056 +/- 0.002 min-1, respectively; p greater than 0.4). The total area under the insulin curve during glucose tolerance tests was also similar in the clipped and sham groups (926 +/- 95 versus 869 +/- 126 microunits/ml x min; p greater than 0.4). There was no significant relation between systolic blood pressure and insulin area during glucose tolerance tests in the clipped group, but there was a positive rectilinear relation in the control group (r = 0.66; p = 0.01). Fourteen animals had euglycemic clamps 2 months after glucose tolerance tests. At that time, systolic pressure (direct femoral measurement) was higher in the seven clipped animals (189 +/- 13 mm Hg versus 122 +/- 5 mm Hg in controls; p less than 0.001). Insulin infusions of 1 and 4 milliunits/min/kg body wt effected similar plasma insulin levels in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Dynamics of renal blood flow autoregulation in rats.

Two separate components could be resolved in tests of the dynamic autoregulation of renal blood flow. The slow component corresponds to the frequency at which spontaneous proximal tubular pressure oscillations are found, and are most likely due to the operation of the TGF. The high frequency component most likely represents an intrinsic vascular, myogenic, mechanism. The gain maximum of the admittance in the frequency range corresponding to the autonomous tubular oscillations indicates that the dynamic characteristics responsible for the occurrence of the spontaneous tubular oscillations must be common to a significant fraction of the total nephron population.

Animals↗
PubMed1990

1/f fluctuations in arterial pressure and regulation of renal blood flow in dogs.

To determine whether renal blood flow is regulated against spontaneous fluctuations in arterial pressure and to estimate the frequency band of the regulation, we measured arterial pressure and renal blood flow continuously over several days in conscious dogs. Mean arterial blood pressure showed broad band fluctuations and behaved as a 1/f process, indicating that the blood pressure record is a fractal curve and therefore scale invariant. The fluctuations in arterial pressure caused attenuated fluctuations in renal blood flow; the gain was about -6.5 +/- 0.5 dB through all sampled frequencies greater than or equal to 4 cycle/day. The kidney did not attenuate the blood pressure signal at the lowest frequencies. The results show that renal blood flow is better regulated against fluctuations in pressure at frequencies greater than or equal to 4 cycle/day than it is at lower frequencies. Although there are no direct tests of the underlying regulatory mechanisms, we argue that the responses are generated locally and can be identified with renal autoregulation.

Activity Cycles↗
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↗