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Biomedical subjects

M F Flessner

Publications and source records attributed to M F Flessner.

At least 37 records · Page 2Linked to original sources
PubMed1996

Pressure threshold for fluid loss from the peritoneal cavity.

Ascites or dialysis fluid in the peritoneal cavity causes fluid loss from the cavity to the body. Experiments in animals and in humans have shown that the fluid loss rate increases with large increments in the intraperitoneal hydrostatic pressure (Pip). We hypothesized that there is a low-threshold Pip above which this fluid loss occurs. Because the full Pip force is exerted across the abdominal wall (AW), we further hypothesized that fluid movement into the abdominal wall would vary directly with the Pip. To address these questions, we dialyzed rats for 3 h in the supine position at constant levels of Pip with isotonic and hypertonic dialysis solutions containing a protein marker of fluid movement. We measured total fluid loss, AW fluid-marker concentration, and lymph flow. With variation of Pip from 0 to 8 cmH2O, we found that 1) lymph flows (0.61 +/- 0.03 ml/h) were not dependent on Pip, 2) measured isotonic fluid loss rate varied from 0.29 +/- 0.06 ml/h at 0 cmH2O to 0.62 +/- 0.02 at 2 cmH2O and then rose in a linear fashion to 5.06 +/- 0.10 ml/h at 8 cmH2O, 3) fluid movement into the AW paralleled the measured fluid loss rate, and 4) protein clearance from the cavity overestimated the true fluid loss because of adsorption of the marker to the peritoneal surface. We conclude that, although peritoneal lymph flow is not dependent on intraperitoneal hydrostatic or osmotic pressure, fluid loss from the cavity and fluid loss to the abdominal wall are directly proportional to Pip > 2 cmH2O. We also note that protein markers of fluid movement require correction for tissue surface adsorption for accurate results.

Adsorption↗
PubMed1996

Small-solute transport across specific peritoneal tissue surfaces in the rat.

On the basis of a theoretical analysis of peritoneal transport, the tissue-specific mass transfer coefficients (MTC) for sucrose were calculated, and the MTCliver was found to be five times the magnitude of other tissue MTC. It was hypothesized that the liver was potentially the most significant single transport organ for small solutes during peritoneal dialysis. To test this hypothesis, diffusion chambers were affixed to the peritoneal surface of the rat cecum, liver, stomach, or abdominal wall to measure the in vivo bidirectional mass transfer rates of 14C-mannitol between the plasma and the fluid contained in the diffusion chambers. It was determined that the rate of mannitol transport in either direction of transport was similar for all four tissues. The MTC for plasma-to-chamber transport varied between 1.59 x 10(-3) and 2.36 x 10(-3) cm/min with MTCliver = 1.87 +/- 0.24 x 10(-3) cm/min. MTC in the opposite direction ranged between 1.73 x 10(-3) and 2.68 x 10(-3) cm/min with the MTCliver = 2.34 +/- 0.06 x 10(-3) cm/min. The authors' hypothesis concerning the MTCliver was therefore disproved. Peritoneal dialysis was also carried out in a separate series of rats, in which the area of the dissected peritoneal tissues was measured and the mass transfer-area coefficient (MTAC) for 14C-mannitol was determined to be 0.364 +/- 0.068 cm3/min (cavity to plasma) and 0.240 +/- 0.039 cm3/min (plasma to cavity). The tissue-specific MTC were then multiplied by the corresponding tissue areas and summed to estimate an MTAC of 1.0 cm3/min, which is 3 to 4 times the measured MTAC. It was concluded that the importance of a particular tissue to plasma-peritoneal transport is primarily dependent on the surface area exposed to the dialysis solution. However, only 25 to 30% of the dissected-organ tissue area may be in contact with the dialysate fluid.

Animals↗
PubMed1996

The importance of the interstitium in peritoneal transport.

The peritoneal capillary exchange vessels are located within all the tissues which surround the peritoneal cavity and are separated from the peritoneal dialysis fluid by the tissue interstitium. The interstitium adds an additional barrier to transcapillary transport resistance and slows the diffusion of solutes from the blood to the dialysis fluid. The interstitium also alters the pressure environment of the blood capillary and has profound effects on water transport, causing fluid loss from the cavity to the body during dialysis.

Animals↗
PubMed1996

Impact of the liver on peritoneal transport.

Previously, we developed a distributed model of plasma-peritoneal small solute diffusion for specific tissues surrounding the peritoneal cavity and related the transport coefficients to the mass transport coefficient (MTC) of the "peritoneal membrane" model. Based on this theoretical analysis, we calculated tissue-specific MTCs for sucrose from microvascular data in the literature and found that the MTC for the liver was five times the magnitude of other tissues. We hypothesized that the liver was potentially the most significant single transport organ during peritoneal dialysis. To test this hypothesis, we measured the mass transfer from the plasma to fluid contained in diffusion chambers, which were glued to one of four tissues surrounding the peritoneal cavity. We determined that the rate of small solute transport from the plasma to each diffusion chamber was similar for all four tissues. We calculated the MTC of the liver to be no greater than other visceral or parietal surfaces. We therefore disproved our hypothesis concerning the liver. We conclude that the importance of a particular tissue to plasma-peritoneal transport is primarily dependent on the surface are exposed to the dialysis solution.

Animals↗
PubMed1994

Monoclonal antibody delivery to intraperitoneal tumors in rats: effects of route of administration and intraperitoneal solution osmolality.

Monoclonal antibody (MAb) transport in peritoneal tissue is dominated by convection, which is dependent on the net driving force of i.p. hydrostatic and osmotic pressure. To test the hypothesis that the i.p. osmolality has significant effects on IgG delivery to the tumor during the acute period after injection, solid tumors (FEMX-II) were transplanted into the anterior abdominal wall of nude rats. The wall is subject to well-defined pressure forces from the solution in the cavity. MAb 96.5, which specifically binds to FEMX-II cells, was simultaneously injected i.v. (111In-MAb 96.5 in Krebs Ringer solution) and i.p. (125I-MAb 96.5 in dialysis solution). Intraperitoneal hydrostatic pressure was held constant, and the osmolality of the i.p. solution was varied between isotonic and hypertonic (with the addition of 4% mannitol to an isotonic salt solution) in order to vary the direction of net convection. Plasma and peritoneal concentrations of both isotopes were measured at intervals over 200 min, and tissue concentration profiles in tumor and adjacent normal tissue were determined by dual-label quantitative autoradiography at 200 min. After i.v. administration, profiles were relatively flat and little affected by i.p. osmolality. After i.p. injection, profiles demonstrated steep concentration decreases from the peritoneal surface into the tissue for several hundred microns. Despite the change from the condition of water absorption from the cavity into the body (isotonic solution) to one of net volume gain by the cavity (hypertonic solution), tumor profiles were affected by i.p. osmolality only near the surface. Specific binding properties of the tumor were determined for the tumors studied and were consistent with high surface concentrations relative to normal tissue. Variation of the i.p. solution osmolality by changes in concentration of small molecules exerts only minor effects on the short-term MAb delivery from either systemic or regional administration to a target tumor in the anterior abdominal wall in the rat.

Abdominal Muscles↗
PubMed1994

Osmotic barrier of the parietal peritoneum.

Fluid movement into the peritoneal cavity results after instillation of a hypertonic solution. Some investigators have assumed that the peritoneum is a significant barrier to small solutes and have predicted that fluid would be drawn by an osmotic gradient into the cavity from the tissue surrounding the peritoneal cavity, resulting in tissue hydrostatic pressures well below atmospheric pressure. Contrary to this, we have previously shown that protein and fluid cross the peritoneum and enter the tissue at the same rate during either isotonic or hypertonic dialysis. To investigate the nature of the osmotic barrier of the peritoneum, the hydrostatic pressure profiles were measured in the abdominal wall of the rat during conditions of either isotonicity or hypertonicity in the peritoneal cavity and constant intraperitoneal hydrostatic pressure (Pip). Measurements were made with a micropipette mounted on a micromanipulator and connected to a servo-null pressure measurement system. No interstitial pressures below atmospheric pressure were observed with either type of solution in the peritoneal cavity. For the three Pip values tested, there were few significant differences between the corresponding pressure profiles of isotonic or hypertonic solutions. It is concluded that the parietal peritoneum is not a functional barrier to small solutes, which are often used to raise the osmolality of intraperitoneal solutions. This finding also implies that the tissue interstitium underlying the parietal peritoneum is not the source of water flow into the cavity, which is observed during hypertonic dialysis.

Abdominal Muscles↗
PubMed1994

Role of the liver in small-solute transport during peritoneal dialysis.

Peritoneal dialysis (PD) is dependent on the transport of water and solutes from the blood capillaries within the tissues that surround the peritoneal cavity. Because of their large blood supply and surface area, the viscera have been considered the most important tissues for PD transport. In animals, however, removal of the gastrointestinal tract decreases PD small-solute mass transfer by only 10 to 27%. To investigate the theoretical basis for these observations, a distributed model of peritoneal transport was extended to take into account the transport characteristics of four tissue groups that surround the cavity: the liver, the hollow viscera, the abdominal wall, and the diaphragm. The mass transfer-area coefficient (MTAC) of sucrose for each tissue was calculated from the following: MTAC = ([D(pa)]0.5)A, where D is the effective solute interstitial diffusivity, pa is the solute transcapillary permeability-area per unit tissue volume, and A is the apparent peritoneal surface area of the tissue. Our results for the adult human predict that the MTAC for the liver is comparable to that of all of the other viscera and makes up 43% of the total MTAC for the peritoneal cavity. The predicted MTAC is 4 cm3/min (plasma) or 6 cm3/min (blood), in good agreement with published values. It is concluded that the liver is responsible for a major portion of the small-solute MTAC. This also explains the earlier observations in eviscerated animals whose PD transport was likely preserved by intact livers.

Abdominal Muscles↗
PubMed1993

Ammonium and bicarbonate transport in isolated perfused rodent long-loop thin descending limbs.

Ammonium accumulates in the renal medullas of antidiuretic mammals. The accumulation process is thought to involve countercurrent multiplication, energy-dependent recycling between the ascending and descending limbs of Henle's loop. To investigate the role of the long-loop thin descending limb (LDL) in countercurrent multiplication of ammonium, we have perfused outer medullary and inner medullary subsegments of the chinchilla LDL (and inner medullary subsegments of rat LDL) in vitro and measured the fluxes of total ammonia and total CO2. No spontaneous fluxes of total ammonia or total CO2 occurred in the absence of imposed concentration gradients. When transepithelial concentration gradients were imposed, passive total ammonia and total CO2 transport were observed in all subsegments, although the permeabilities varied with distance along the descending limb. Passive total ammonia transport occurred through a combination of NH3 and direct NH4+ permeation. The outer medullary segment was the most permeable to NH4+. The deep inner medullary segment was the most permeable to bicarbonate. Addition of carbonic anhydrase to the lumen accelerated passive NH3 entry in the outer medullary LDL, indicating that little or no luminal carbonic anhydrase is endogenously present. The passive secretion of NH4+ and NH3 into the LDL may contribute to the countercurrent multiplication of ammonium in the rodent renal medulla.

Ammonia↗
PubMed1993

Model of ammonium and bicarbonate transport along LDL: implications for alkalinization of luminal fluid.

Luminal fluid exiting the proximal convoluted tubule of a juxtamedullary nephron is alkalinized as it passes through the long-loop thin descending limb of Henle (LDL). Three potential mechanisms of alkalinization are: 1) concentration of bicarbonate by water abstraction, 2) direct bicarbonate entry, and 3) NH3 entry. We have used a mathematical model of the LDL to investigate these mechanisms. With permeabilities of HCO3-, NH3, and NH4+ measured for subsegments of the chinchilla LDL [M. F. Flessner, R. Mejia, and M. A. Knepper. Am. J. Physiol. 264 (Renal Fluid Electrolyte Physiol. 33):F388-F396, 1993], the osmotic water permeability of each segment [C.-L. Chou and M. A. Knepper. Am. J. Physiol. 263 (Renal Fluid Electrolyte Physiol. 32):F417-F426, 1992], and appropriate parameters from the literature, we have used the model to calculate hypothetical pH, HCO3- concentration, and NH3 concentration of the luminal fluid as it descends the LDL within an assumed interstitium. After eliminating each mechanism in turn by setting the appropriate permeability to zero, we recalculated the axial profiles. Our results suggest that, although all three mechanisms individually contribute to LDL alkalinization, NH3 entry likely plays the dominant role.

Ammonia↗
PubMed1993

Ammonium and bicarbonate transport in isolated perfused rodent ascending limbs of the loop of Henle.

Ammonium accumulates in the renal medullas of antidiuretic animals, presumably due to countercurrent multiplication, driven by NH4+ absorption from ascending loops of Henle in the outer and inner medulla. Active absorption of NH4+ occurs in the thick ascending limb (TAL). But the passive transport properties of NH3 in the TAL and the transport of ammonium or HCO3- in the ascending thin limb (ATL) have not been studied in rodents. To investigate the potential role of the ascending limb segments in medullary accumulation of ammonium, we perfused isolated subsegments of the chinchilla ATL and of the rat ATL and TAL. After imposing concentration gradients of total ammonia or total CO2 across ATL subsegments, we found very high rates of transfer of both substances, implying that at physiological flow rates the tubule luminal fluid quickly equilibrates with the interstitium. In the medullary TAL, we found a passive NH4+ permeability of 17 x 10(-5) cm/s but a relatively low NH3 permeability of < 0.003 cm/s. The low NH3 permeability prevents backleak of NH3 when NH4+ is actively transported from the lumen. We conclude that the ATL acts as an equilibrating segment and the TAL has special permeability properties that enhance net ammonium absorption and therefore enhance medullary ammonium accumulation.

Ammonia↗
PubMed1992

Ammonium and bicarbonate transport in rat outer medullary collecting ducts.

Previous in vitro studies have demonstrated spontaneous bicarbonate absorption in the outer stripe portion of the rat outer medullary collecting duct (OMCD) and inner medullary collecting duct, but net acid transport has not been studied in the inner stripe of the rat OMCD (OMCDIS). When we perfused isolated OMCDIS segments with identical bath and perfusate solutions containing HCO-3 and NH4Cl, HCO-3 was spontaneously absorbed, and total ammonia was spontaneously secreted at rapid rates in tubules from both deoxycorticosterone (DOC)-treated and untreated rats. We next measured the NH3 flux due to imposed NH3 concentration gradients. Carbonic anhydrase (CA), when added to the lumen, enhanced the NH3 flux, implying an absence of endogenous CA. The NH3 permeability was 0.0042 +/- 0.0007 cm/s. By measuring the luminal pH in perfused OMCDIS segments with an imposed lumen-to-bath NH3 gradient, we determined the pH at the end of the lumen to be 0.23 units below the equilibrium pH calculated from the simultaneously measured total CO2 concentration in collected fluid, confirming the lack of luminal CA. These results are consistent with the view that ammonium secretion in the OMCDIS occurs predominantly by H+ secretion and parallel NH3 diffusion. A luminal disequilibrium pH due to H+ secretion in the absence of endogenous luminal CA enhances the NH3 entry rate. Spontaneous net acid secretion appears to occur more rapidly in the OMCD than in other parts of the rat collecting duct system.

Ammonia↗
PubMed1992

Bidirectional peritoneal transport of immunoglobulin in rats: compartmental kinetics.

Protein transport to and from fluid in the peritoneal cavity is observed during clinical procedures. Dialysate osmolality is a major determinant of net fluid flux into the cavity. We carried out experiments in rats to determine the plasma, peritoneal, and tissue concentrations of immunoglobulin (Ig) G resulting from either intravenous (iv) or intraperitoneal (ip) administration during hypertonic or isotonic dialyses. After iv injection of IgG, overall mass transfer into the cavity was not affected by the osmolality. After ip injection, tissue concentrations were dependent on the dialysis duration. Protein absorption from the hypertonic dialysate into the surrounding tissue was quantitatively less than the absorption from an isotonic dialysis solution at 20 min. By 200 min, total protein transport was not affected by dialysate osmolality. Lymphatic transport to the plasma amounted to 20-25% of the total protein loss from the peritoneal cavity; approximately 60% of the absorbed dose was found in tissues surrounding the cavity at both 20 and 200 min, with particularly high concentrations in parietal areas. We conclude that immunoglobulin transport in the peritoneal tissue, resulting from either iv or ip injection, is influenced by route of administration but is little affected by dialysate osmolality. Peritoneal absorption of proteins occurs directly into the surrounding tissue interstitial space as a result of hydrostatic pressure-driven convection and diffusion.

Absorption↗
PubMed1992

Bidirectional peritoneal transport of immunoglobulin in rats: tissue concentration profiles.

Protein transport occurs between the blood and the peritoneal cavity during clinical procedures, but events within the surrounding tissue space are poorly understood. We used quantitative autoradiography to examine the tissue concentration profiles of immunoglobulin G (IgG) in regions surrounding the peritoneal cavity. We have varied the route of administration (intravenous or intraperitoneal), the osmolality of the dialysis solution (isotonic or hypertonic), and the time of analysis (20 or 200 min). After intravenous injection, IgG profiles were relatively flat in most tissues and were not affected by time or osmolality. Concentrations corresponded to the capillary density in specific tissues. After intraperitoneal administration, the IgG tissue profiles were significantly steeper than after intravenous administration. The tissue concentrations increased with time but decreased when a hypertonic solution was substituted for an isotonic solution. Hypertonic dialysis causes a water flux into the cavity, which dilutes the contents but does not prevent penetration of protein into the surrounding tissue. Based on IgG movement in tissue during hypertonic dialysis, the peritoneum appears to function as a heterogeneous structure, which allows osmotically induced water transport into the cavity in some regions with simultaneous transport of hydrostatic pressure-driven water and solute flow from the cavity into the tissue in other regions.

Animals↗
PubMed1992

Net ultrafiltration in peritoneal dialysis: role of direct fluid absorption into peritoneal tissue.

'Net ultrafiltration' in peritoneal dialysis refers to the difference between the osmotically induced ultrafiltration into the peritoneal cavity and the fluid loss from the cavity during dialysis. Recent research has demonstrated that, during a 3- to 4-hour experimental dialysis, 5-25% of the total fluid loss is via lymphatics and the remaining fluid is absorbed directly into the tissue surrounding the peritoneal cavity. The driving force for this convection into tissue is the hydrostatic pressure gradient between the peritoneal cavity and the tissue, which ranges from 2 to 8 mm Hg during the typical 2-liter dialysis in humans. Because the convection from the cavity occurs during periods of a positive net ultrafiltration, the peritoneum and its underlying tissue cannot be represented as a single membrane but function as a composite of 'tight' and 'loose' membranes. More data on the mechanical properties of the peritoneal tissue space and its response to hydrostatic pressure in the cavity are required before we fully understand fluid transport at the tissue level.

Absorption↗
PubMed1991

Permeabilities of rat collecting duct segments to NH3 and NH4+.

We have measured NH3 and NH4+ permeability coefficients in collecting ducts from the cortex, outer medulla, and inner medulla of the rat kidney. Isolated collecting duct segments of the rat were perfused with bicarbonate-buffered solutions containing carbonic anhydrase to eliminate any pH disequilibrium in the tubule lumen. NH3 or NH4+ concentration gradients were set up between the bath and the lumen. By measuring the total CO2 and total ammonia concentrations in the bath, the perfusate, and collected fluid, the NH3 and NH4+ concentrations were determined. Then, using the flow rate in the tubule and the tubule dimensions, we calculated the apparent permeability in each collecting duct segment for NH3 and NH4+. The NH3 permeabilities were as follows: 0.002 cm/s in the inner medullary collecting duct, 0.012 cm/s in the outer medullary collecting duct, and 0.024 cm/s in the cortical collecting duct. The NH4+ permeabilities for all segments were on the order of 10(-5) cm/s or less. The relative permeability values for the two ammonium species are consistent with the view that the secretion observed in vivo in collecting ducts is due to passive diffusion of NH3 from the interstitium to the lumen of the duct, parallel with H+ secretion.

Ammonia↗
PubMed1991

Distribution of luminal carbonic anhydrase activity along rat inner medullary collecting duct.

The isolated perfused tubule technique was utilized to determine whether endogenous luminal carbonic anhydrase is present in the initial or terminal parts of the inner medullary collecting duct (IMCD) of the rat. This was accomplished by measuring the luminal disequilibrium pH in the presence of a large luminal proton source created by perfusing the lumen with a solution containing 10 mM NH4Cl. (NH3 efflux causes H+ to be released from NH+4 in the lumen). The disequilibrium pH was calculated by subtracting the equilibrium pH from the measured pH at the end of the tubule lumen. The end-luminal equilibrium pH was calculated from the total CO2 concentration in the collected fluid, as measured by microcalorimetry. The end-luminal pH was determined by measuring the fluorescent signal from the the pH-sensitive dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF), which was added to the luminal perfusate in its nonesterified form. In the initial IMCD, there was no measurable disequilibrium pH. With the addition of the carbonic anhydrase inhibitor acetazolamide to the luminal fluid, a significant acidic pH disequilibrium was elicited. In the terminal IMCD under control conditions a statistically significant acidic disequilibrium pH was measured. The disequilibrium was obliterated when exogenous carbonic anhydrase was added to the luminal perfusate. These findings were verified by measuring total ammonia flux by ultramicrofluorometry. The results demonstrate endogenous luminal carbonic anhydrase activity in the initial IMCD but a lack of enzyme activity in the terminal IMCD.

Ammonia↗
PubMed1991

Peritoneal transport physiology: insights from basic research.

Clinical uses of the peritoneal cavity, such as i.p. chemotherapy or peritoneal dialysis, depend on underlying physiological mechanisms of transport between the blood and the peritoneal cavity. Clinical models of peritoneal transport have focused on an idealized "peritoneal membrane." However, such a membrane does not physically exist. Transport actually occurs between the peritoneal cavity and blood which is contained in discrete capillaries distributed in the tissue interstitium surrounding the cavity. To integrate the properties of the capillaries and the interstitium, the "distributed model" approach couples pore theory, which simulates transendothelial transport, with diffusion and convection within the tissue space. The distributed theory can explain why the peritoneal membrane, when compared with the artificial kidney, appears tight to urea but leaky to protein. The additional resistance to urea transport has been attributed to "unstirred layers" adjacent to the peritoneal membrane. These can now be defined physiologically by examining diffusion in the tissue space. Absolute rates of convection into and out of the cavity cannot yet be accurately predicted, but the physiological forces can be specified. Net "ultrafiltration" during dialysis results from not only high osmotic pressure in the peritoneal dialysate but also from a small but significant hydrostatic pressure which drives convection in the opposite direction. Recent implications from protein absorption studies that lymphatics are the cause of the decrease in net ultrafiltration are only partly true. Analysis of data from the tissue space has shown that the deposition of protein occurs from the cavity into the tissue interstitium with a slow uptake into lymphatics.

Animals↗