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Biomedical subjects

W M Deen

Publications and source records attributed to W M Deen.

At least 91 records · Page 5Linked to original sources
PubMed1979

Macromolecule transport across glomerular capillaries: application of pore theory.

Developments in the hydrodynamic theory of solute transport through porous membranes are reviewed, with emphasis on their application to macromolecule movement across capillary walls. A model that treats the capillary wall as a barrier containing uniform cylindrical pores, and permeating solutes as hard spheres, is shown to be successful in describing the size-selectivity of the glomerulus. Influences of various hemodynamic perturbations on solute transport are also accounted for by this approach. Possible extensions and modification of the theory, to account for the influence of molecular charge and other factors on glomerular permeability properties, are discussed.

Biological Transport↗
PubMed1979

Influence of molecular configuration on the passage of macromolecules across the glomerular capillary wall.

The influence of molecular configuration on the filtration of macromolecules across glomerular capillary walls was examined by comparing fractional clearances of two uncharged polysaccharides of distinctly different molecular configuration in the Munich-Wistar rat. The macromolecules employed were dextran, a slightly branched polymer of glucopyranose, and ficoll, a highly cross-linked copolymer of sucrose and epichlorohydrin. Differences in effective shape between these two polymers were determined from measurements of several physical properties of aqueous solutions containing either dextran or ficoll. It was found that dextran is best represented as a prolate ellipsoid with axial ratios of 4, 9, and 16 for molecules with Stokes-Einstein radii of 22, 32, and 40 A, respectively. On the other hand, ficoll is more closely approximated as spherical since the axial ratio was found to be between 1 and 2 for all molecular sizes. Fractional clearances of dextran and ficoll ranging in effective radius from 18 to 44 A were determined in each of seven Munich-Wistar rats. Fractional clearances of dextran were found to be greater than those of ficoll, the difference being significant for molecular radii ranging from 24 to 44 A. In addition, as shown previously for dextran, ficoll was found to be neither secreted nor reabsorbed by the renal tubules. These results, therefore, suggest that in addition to molecular size and charge, molecular configuration is also a determinant of the filtration of macromolecules across the glomerular capillary wall.

Animals↗
PubMed1977

Mechanism of angiotensin II-induced proteinuria in the rat.

To investigate the mechanism(s) of angiotensin II-induced proteinuria, polydisperse [3H]dextran (D) (radius = 18-42 A) was infused into seven Munich-Wistar rats before and during intravenous infusion of angiotensin II (AII), 0.35 microgram/kg per min. During AII infusion, UprotV rose approximately twofold, and the fractional clearances of D [(U/P)D/(U/P)In] increased significantly for dextrans with radii greater than 22 A. Single nephron filtration fraction increased, due to a measured rise in the glomerular transcapillary hydraulic pressure difference from 34 to 43 mmHg. Near constancy of single nephron glomerular filtration rate resulted, however, from the offsetting effect of a decrease in glomerular plasma flow rate from 83 to 60 nl/min. These measured hemodynamic changes were found, by the use of pore theory, to account to a large extent for the measured increases in (U/P)D/(U/P)In. In seven other rats, fractional clearances of polyanionic dex-ran sulfate (a more reliable marker of albumin filtration than D) were also found to increase significantly with AII, suggesting that the proteinuria induced by AII can be explained, in large part, by hemodynamic factors.

Angiotensin II↗
PubMed1977

Determinants of the transglomerular passage of macromolecules.

In addition to molecular size, at least two other factors influence the transglomerular passage of macromolecules. The hemodynamic determinants of glomerular filtration rate affect macromolecule transport by altering the volume flux through the glomerular capillary wall and the profile of macromolecule concentrations along a glomerular capillary. The electrostatic properties of the glomerular capillary wall markedly restrict the passage of circulating polyanions, relative to neutral macromolecules of similar size. In the normal animal, the combined effects of these various mechanisms ensure that only very small quantities of plasma proteins are filtered. In experimental proteinuric conditions such as nephrotoxic serum nephritis and puromycin-induced nephrosis, reduction in the fixed negative charges on the glomerular capillary wall appears to be largely responsible for the increased transglomerular passage of anionic macromolecules such as albumin. Other evidence suggests that hemodynamic factors may contribute to proteinuria under certain circumstance. The possibility of an increase in number and/or radius of glomerular "pores" being responsible for proteinuria, perhaps the most intuitively obvious and widely held view, has yet to receive direct experimental support.

Animals↗
PubMed1976

Effects of some vasodilator drugs on transcapillary fluid exchange in renal cortex.

In 23 Munich-Wistar rats with surface glomeruli, the determinants of glomerular ultrafiltration and peritubular capillary uptake of proximal reabsorbate were studied before and during intra-arterial infusions of mildly vasodepressor doses of prostaglandin E1,acetylcholine, and bradykinin. For each drug single-nephron glomerular filtration rate remained unchanged from normal hydropenic values while glomerular plasma flow rate increased, resulting in declines in single-nephron filtration fraction (SNFF). Mean glomerular transcapillary hydraulic pressure difference (delta P) increased or remained unchanged on average. Declines in SNFF were accompanied by reductions in efferent arteriolar oncotic pressure (piE). Filtration pressure equilibrium, equality between pi E and delta P, obtained before but not during drug infusions. In the latter situation values for the glomerular capillary ultrafiltration coefficient were calculated and found to be significantly reduced from published control values. Despite marked falls in pi E during drug infusion, absolute proximal reabsorption was not reduced significantly, due, it is suggested, to the opposing effects of increases in efferent arteriolar plasma flow and interstitial hydraulic pressure.

Acetylcholine↗
PubMed1976

Permeability of renal peritubular capillaries to neutral dextrans dextrans and endogenous albumin.

Renal lymph-to-renal vein concentration ratios (CL/CV) for neutral dextrans (18-42 A effective radii) and endogenous serum albumin were measured in rats before and during acute colume expansion with isoncotic plasma or Ringer solution. Under all conditions studied, CL/CV decreased with increasing dextran size, in normal hydropenia falling from 0.93 +/- 0.03 SE at 18 A to 0.24 +/- 0.02 a 42 A (n = 12). Albumin (36 A pradius) behaved in a manner similar to a 40 A dextran, CL/CV averaging 0.33 +/- 0.03 (n = 12) in hydropenia. For all dextran sizes studied and for albumin, CL/CV decreased markedly during either form of volume expansion. Ringer loading produced significantly greater decreases in CL/CV for the larger dextrans and albumin than did plasma loading, and also resulted in much greater increases in renal lymph flow, while causing increases in whole kidney fluid reabsorption similar to those with plasma loading. With a compartmental model in which diffusion of dextrans and albumin from capillary lumen to interstitium is opposed by capillary uptake of tubule reabsorbate, these results are interpreted to indicate that connective reflection coefficients for dextrans with radii great than or equal to 36 A and albumin are essentially equal to 1. Indirect evidence is therefore provided that albumin and the larger globulins exert their full osmotic pressures across the walls of peritubular capillaries.

Animals↗
PubMed1976

Transport of molecules across renal glomerular capillaries.

Direct measurements of the pressures and flows governing the formation of glomerular ultrafiltrate have been made possible in recent years by virtue of 1) the discovery of rats and monkeys possessing glomerular capillaries on the renal cortical surface, accessible to micropuncture, and 2) technological advances that permit measurement of intracapillary hydraulic pressure and assessment of the change in colloid osmotic pressure along the glomerular capillary network. Based on these direct measurements, evidence has been obtained to indicate that glomerular capillary hydraulic pressure and hence the net driving force for ultrafiltration are lower than previously believed. By the efferent end of the glomerular capillary network, net filtration of fluid ceases, owing to a reduction in the net driving force to zero. Evidence in the rat indicates that the process of ultrafiltration is highly dependent on glomerular plasma flow rate. Studies in rats with surface glomeruli have also made possible an assessment of the factors that govern the transport of macromolecules across the highly specialized capillary network. In addition to molecular size, transcapillary movement of macromolecules is influenced by the glomerular filtration rate, since total transport reflects the combined contributions of convection as well as diffusion. Molecular charge has also been found to be an important determinant of the transport of macromolecules, very likely contributing to the marked restriction to the transcapillary movement of albumin. This electrostatic restriction to the transport of polyanions such as albumin, by some fixed, negatively charged component(s) of the glomerular capillary wall, is markedly reduced in primary glomerular injury. Evidence indicates that glomerular injury results in loss of these fixed negative charges from the capillary walls, providing an attractive explanation for the enhanced filtration of albumin, and hence the proteinuria, observed in a variety of glomerulopathic states.

Albumins↗
PubMed1976

Permselectivity of of the glomerular capillary wall. Studies of experimental glomerulonephritis in the rat using neutral dextran.

Polydisperse [3h] dextran was infused into eight Munich-Wistar rats in the early autologous phase of nephrotoxic serum nephritis (NSN), thereby permitting direct measurements of pressures and flows in surface glomeruli and fractional clearances for dextrans [(U/P) dextran/(U/P) inulin] ranging in radius from 18 to 42 A. Despite glomerular injury, evidenced morphologically and by a marked reduction in the glomerular capillary ultrafiltration coefficient, the glomerular filtration rate remained normal because of a compensating increase in the mean net ultrafiltration pressure. In NSN rats, as in normal controls, inulin was found to permeate the glomerular capillary wall without measurable restriction, and dextrans were shown to be neither secreted nor reabsorbed. For dextran radii of 18, 22, 26, 30, 34, 38, and 42 A, (U/P) dextran/(U/P) inulin in NSN and control rats, respectively, averaged 0.90 vs. 0.99, 0.81 vs. 0.97, 0.63 vs. 0.83, 0.38 vs 0.55, 0.20 vs. 0.30, 0.08 vs. 0.11, and 0.02 vs. 0.03. Using a theory based on macromolecular transport through pores, the results indicate that in NSN rats, effective pore radius is the same as in controls, approximately 50 A. In NSN, however, the ratio of total pore surface area to pore length, a measure of the number of pores, is reduced to approximately 1/3 that of control, probably due to a reduction in capillary surface area. These results suggest that proteinuria in glomerular disease is not due simply to increases in effective pore radius or number of pores, as previously believed. Using a second theoretical approach, based on the Kedem-Katchalsky flux equations, dextran permeability across glomerular capillaries was found to be slightly lower, and reflection coefficient slightly higher in NSN than in control rats.

Animals↗
PubMed1976

Permselectivity of the glomerular capillary wall. Studies of experimental glomerulonephritis in the rat using dextran sulfate.

To determine whether the increased filtration of serum proteins after glomerular injury is the consequence of altered electrostatic properties of the glomerular capillary wall, we measured fractional clearances of the anionic polymer, dextran sulfate, in nine Munich-Wistar rats in the early autologous phase of nephrotoxic serum nephritis (NSN). In agreement with previous studied from this laboratory, whole kidney and single nephron glomerular filtration rates were normal in NSN rats despite histological evidence of glomerular injury, and despite a marked reduction in the glomerular capillary ultrafiltration coefficient to approximately one-third of normal. In the companion study (9), it was shown that in NSN rats the mean fractional clearances of neutral dextrans over the range of effective molecular radii from 18 to 42 A were reduced, compared to normla. In contrast, in the present study the mean fractional clearances for dextran sulfate over the same range of molecular radii were significantly greater than those found previously for normal Munich-Wistar rats. The fractional clearance of dextran sulfate molecules of the same molecular radius as serum albumin (approximately 36 A) was increased markedly, from 0.015 +/- 0.005 (SEM) in nonnephritic controls to 0.24 +/- 0.03 in NSN (P less than 0.001). The sialoprotein content of glomeruli, estimated by the colloidal iron reaction, was reduced in NSN rats as compared to normal controls. It is concluded that the abnormal filtration of anionic serum proteins, such as albumin, seen in glomerulopathies is, at least in part, the consequence of loss of fixed negative charges from the glomerular capillary wall.

Animals↗
PubMed1975

Permselectivity of the glomerular capillary wall to macromolecules. I. Theoretical considerations.

The transport of macromolecules across the renal glomerular capillary wall has been described theoretically using flux equations based on (a) restricted transport through small pores, and (b) the Kedem-Katchalsky formulation. The various assumptions and limitations inherent in these two approaches are discussed. To examine the coupling between macromolecular solute transport and the determinants of glomerular filtration rate, these flux equations were combined with mass balance relations which allow for variations in the transmembrane driving forces along a glomerular capillary. It was predicted, using both pore theory and the Kedem-Katchalsky equations, that fractional solute clearance should be strongly dependent on the determinants of glomerular filtration rate when convection and diffusion both contribute to solute transport. When convection becomes the sole mechanism for transcapillary solute transport, however, fractional solute clearance is essentially independent of changes in the determinants of glomerular filtration rate. Consequently, unless diffusion is absent, fractional solute clearances alone are insufficient to characterize the permselective properties of the glomerular capillary wall, since these values may be altered by changes in glomerular pressures and flows as well as changes in the properties of the capillary wall per se.

Animals↗
PubMed1975

Permselectivity of the glomerular capillary wall to macromolecules. II. Experimental studies in rats using neutral dextran.

To determine the permselectivity characteristics of the glomerular capillary wall, known molecular size fractions of [3H]dextran, prepared by gel chromatography, were infused into normally hydrated Wistar rats, thus permitting simultaneous measurement of Bowman's space/plasma water (BS/P) and urine/plasma water (U/P) concentration ratios, along with glomerular pressures and flows. Since (BS/P)inulin = 1.01 +/- 0.01 SE(n = 34, radius = approximately 14 A) and since (BS/P)dextran/(BS/P)inulin equaled (U/P)dextran/(U/P)inulin for dextrans ranging in molecular radius from 21 to 35 A, these findings validate that dextrans are neither secreted nor reabsorbed. For dextran radii of 20, 24, 28, 32, 36, 40, and 44 A, (U/P)dextran/(U/P)inulin averaged 0.99, 0.92, 0.69, 0.42, 0.19, 0.06, and 0.01, respectively. In accord with theoretical predictions that these fractional dextran clearances should vary appreciably with changes in glomerular transcapillary pressures and flows, an increase in glomerular plasma flow rate, induced in these same rats by plasma volume expansion, resulted in a highly significant lowering of fractional clearance of all but the smallest and largest dextrans studied. These findings emphasize that fractional solute clearances alone are inadequate to describe the permselective properties of the glomerular capillary wall unless glomerular pressures and flows are also known. This sensitivity of fractional dextran clearance to changes in plasma flow indicates that dextrans are transported across the capillary not only by bulk flow but also to an important extent by diffusion.

Animals↗
PubMed1975

Permselectivity of the glomerular capillary wall: III. Restricted transport of polyanions.

The clearance of albumin relative to that of inulin is greatly exceeded by that of uncharged dextrans of the same effective molecular radius (approximately 36A), less than 0.01 vs. 0.20 in normal hydropenic rats. This marked difference in fractional clearances of albumin and neutral dextran suggests that some factor in addition to molecular size retards the transglomerular passage of albumin. Since albumin is a polyanion in physiological solution, we tested the effect of charge on macromolecular permeability by infusing the anionic polymer, dextran sulfate (approximately 2.3 sulfate groups per glycosyl residue), into seven normal hypropenic Munich-Wistar rats. For dextran sulfate with an effective radius of approximately 36A, the fractional clearance was reduced essentially to that found for albumin (approximately 0.01). This enhanced restriction of dextran sulfate, relative to neutral dextran, was also noted for smaller and larger dextran sulfate molecules. These differences in the transport of dextran sulfate vs. dextran suggest electrostatic repulsion of charged macromolecules by some component of the glomerular capillary wall, perhaps the negatively charged sialoprotein which coats glomerular epithelial cells. Loss of this polyanionic coat, as has been reported to occur in proteinuric disorders, might thereby account for the enhanced transmural passage of albumin.

Animals↗
PubMed1975

Hydraulic and oncotic pressure measurements in inner medulla of mammalian kidney.

The vasa recta are thought to play an important role in the transfer of water andsolutes within the renal medulla. Hydraulic pressures were measured in vasa recta onthe surface of the exposed papilla in young Munich Wistar rats, and blood was collected from these microvessels for determination of total protein concentration and calculation of colloid oncotic pressure. In descending vasa recta at the base of the exposed papilla, mean hydraulic pressure was 9.2 plus or minus 0.4 (SE) mmHg and plasma protein concentration averaged 7.1 plus or minus 0.4 g/100 ml. Corresponding valuesin ascending vasa recta at the same level were 7.8 plus or minus 0.4 mmHg and 5.6 plusor minus 0.3 g/100 ml. respectively. The protein concentrations correspond to calculated oncotic pressures of 26 and 18 mmHg in descending and ascending vasa recta, respectively. We interpret these findings as evidence for net water uptake by the vasa recta in the renal inner medulla for which the driving forces are the transcapillary hydraulic and oncotic pressure differences.

Animals↗
PubMed1975

Dynamics of glomerular ultrafiltration in the rat. VIII. Effects of hematocrit.

This study was undertaken in an effort to examine the effects of selective variations in systemic hematocrit on the preglomerular, glomerular, and postglomerular micocirculation in the rat. By isovolemic exchange transfusions, systemic hematocrit (control 51 ml/100 ml) was either reduced (21 ml/100 ml, N equal 7 rats) or elevated (62 ml/100 ml, N equal 7). Single nephron glomerular filtration rate varied inversely and filtration fraction varied directly with the changes in hematocrit. The fall in filtration fraction with decreased hematocrit was due to a decline in the measured glomerular transcapillary hydraulic pressure difference and to a marked increased in the initial glomerular plasma flow rate. Afferent (RA)and efferent (RE) arteriolar resistance declined with the fall in hematocrit; RA fell proportionately more than did RE. The rise in filtration fraction with the elevation in hematocrit was due to a marked increase in in part due to a relatively greater rise in RE than in RA. These findings provide an attractive explanation for the general tendency for filtration fraction to vary directly with hematocrit in anemic and polycythemic states in man.

Animals↗