Transmural Transport Research Articles

Images in cardiovascular medicine. Avoiding papillary muscle infarction with myocardial contrast echocardiographic guidance of nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy.

Intracoronary myocardial contrast echocardiography (MCE) can be used to guide the delivery of ethanol during nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy. The echocardiographic contrast agent is injected immediately before the injection of ethanol, down the lumen of the inflated balloon that resides in the target septal coronary artery. This is the artery that supplies the area of the septum involved with the mitral leaflet(s) in causing dynamic outflow tract obstruction. MCE provides a direct visualization of the myocardial territory that should receive ethanol and consequently undergo infarction. In rare instances, the cannulated vessel does not supply the culprit septal segment(s) but supplies instead …

A region-based model framework for the rat urine concentrating mechanism

The highly structured organization of tubules and blood vessels in the outer medulla of the mammalian kidney is believed to result in preferential interactions among tubules and vessels; such interactions may promote solute cycling and enhance urine concentrating capability. In this study, we formulate a new model framework for the urine concentrating mechanism in the outer medulla of the rat kidney. The model simulates preferential interactions among tubules and vessels by representing two concentric regions and by specifying the fractions of tubules and vessels assigned to each of the regions. The model equations are based on standard expressions for transmural transport and on solute and water conservation. Model equations, which are derived in dynamic form, are solved to obtain steady-state solutions by means of a stable and efficient numerical method, based on the semi-Lagrangian semi-implicit method and on Newton’s method. In this application, the computational cost scales as O(N 2) , where N is the number of spatial subintervals along the medulla. We present representative solutions and show that the method generates approximations that are second-order accurate in space and that exhibit mass conservation.

A numerical method for renal models that represent tubules with abrupt changes in membrane properties

The urine concentrating mechanism of mammals and birds depends on a counterflow configuration of thousands of nearly parallel tubules in the medulla of the kidney. Along the course of a renal tubule, cell type may change abruptly, resulting in abrupt changes in the physical characteristics and transmural transport properties of the tubule. A mathematical model that faithfully represents these abrupt changes will have jump discontinuities in model parameters. Without proper treatment, such discontinuities may cause unrealistic transmural fluxes and introduce suboptimal spatial convergence in the numerical solution to the model equations. In this study, we show how to treat discontinuous parameters in the context of a previously developed numerical method that is based on the semi-Lagrangian semi-implicit method and Newton's method. The numerical solutions have physically plausible fluxes at the discontinuities and the solutions converge at second order, as is appropriate for the method.

Preferential interaction and inverse problem algorithms in models of renal concentrating mechanism

Formulas for transmural transport parameters between two adjacent interacting tubes are derived. Results of computational experiments with a mathematical model of the kidney are given. These results show that only four of optimal parameters, obtained by an inverse algorithm, need to be different from experimental values, to get fairly good concentration profiles. Preferential interaction is shown to result in further improvement to these profiles.

Numerical modelling of shear-dependent mass transfer in large arteries

SUMMARY A numerical scheme for the simulation of blood flow and transport processes in large arteries is presented. Blood flow is described by the unsteady 3D incompressible Navier‐Stokes equations for Newtonian fluids; solute transport is modelled by the advection‐diffusion equation. The resistance of the arterial wall to transmural transport is described by a shear-dependent wall permeability model. The finite element formulation of the Navier‐Stokes equations is based on an operator-splitting method and implicit time discretization. The streamline upwind=Petrov‐Galerkin (SUPG) method is applied for stabilization of the advective terms in the transport equation and in the flow equations. A numerical simulation is carried out for pulsatile mass transport in a 3D arterial bend to demonstrate the influence of arterial flow patterns on wall permeability characteristics and transmural mass transfer. The main result is a substantial wall flux reduction at the inner side of the curved region. # 1997 John Wiley & Sons, Ltd.

Numerical modelling of shear‐dependent mass transfer in large arteries

A numerical scheme for the simulation of blood flow and transport processes in large arteries is presented. Blood flow is described by the unsteady 3D incompressible Navier–Stokes equations for Newtonian fluids; solute transport is modelled by the advection–diffusion equation. The resistance of the arterial wall to transmural transport is described by a shear-dependent wall permeability model. The finite element formulation of the Navier–Stokes equations is based on an operator-splitting method and implicit time discretization. The streamline upwind/Petrov–Galerkin (SUPG) method is applied for stabilization of the advective terms in the transport equation and in the flow equations. A numerical simulation is carried out for pulsatile mass transport in a 3D arterial bend to demonstrate the influence of arterial flow patterns on wall permeability characteristics and transmural mass transfer. The main result is a substantial wall flux reduction at the inner side of the curved region. © 1997 John Wiley & Sons, Ltd.

Local Synthesis of Natriuretic Peptides in the Eel Intestine

The intestine is a major osmoregulatory organ in euryhaline fishes which allows them to survive in the sea, and natriuretic peptides have been implicated in regulation of transmural transport. Atrial (ANP) and ventricular natriuretic peptide (VNP) were identified in eel intestine. Elution profiles of ANP and VNP from high-performance liquid chromatography (HPLC) were determined by radioimmunoassay using highly specific antisera. Elution times of immunoreactive ANP and VNP in HPLC were identical to those of authentic peptide standards and were consistent with the relative molecular masses of these peptides. Tissue localization of ANP and VNP was accomplished by fluorescence immunohistochemistry. Immunoreactive cells were observed in the epithelium of anterior, middle, and posterior regions of intestine. Reverse transcription of mRNA isolated from intestine and subsequent polymerase chain reaction amplification yielded appropriate-size products consistent with ANP and VNP expression. Together, these data show that natriuretic peptides are synthesized locally in eel intestine, rather than trapped from the circulation.

Intestinal excretion of unconjugated bilirubin in man and rats with inherited unconjugated hyperbilirubinemia.

Patients with Crigler-Najjar syndrome and Gunn rats cannot form bilirubin glucuronides owing to a lack of bilirubin UDP-glucuronosyltransferase activity. Because increased serum and tissue bilirubin levels remain constant, an alternative excretory route has to substitute for this deficiency. Gunn rats excrete in bile only 2-13% of the bilirubins eliminated in Wistar rats. In contrast, the biliary excretion rate of urobilinogen in Gunn and Wistar rats is comparable. The sum of bilirubins and urobilinogen excreted in the bile of Gunn rats amounts to 10-30% of pigments excreted in Wistar rats. Despite this low biliary excretion, the intestinal content and fecal excretion of bile pigments in Gunn and Wistar rats were similar. These data support an extrabiliary entrance of unconjugated bilirubin into the intestine. Additional proof for this was found in that the intestinal lumen of Gunn rats still contains a high amount of bilirubins and urobilinogen after 3 d of external biliary drainage. A similar procedure in Wistar rats resulted in the complete disappearance of bile pigments from the intestine. The direct transmural transport of bilirubin from blood to all parts of the intestinal lumen was demonstrated by injecting 14C-bilirubin i.v. into Gunn rats with isolated parts of small and large intestine. In Crigler-Najjar and Gilbert's syndrome patients, the biliary excretion of bile pigments has previously been shown to be strongly reduced. Their stools, however, contained approximately the same amount of bile pigments as in normal subjects. Although only traces of unconjugated bilirubin were detected in the stool of normal persons (4 +/- 3% of total bile pigments), higher amounts were found in patients with Crigler-Najjar disease (20 +/- 12&). These results suggest a direct intestinal permeation of unconjugated bilirubin in severe unconjugated hyperbilirubinemia both in man and rats.

Mechanism of β-adrenergic agonist-induced transmural transport of glucose in rat small intestine : Regulation of phosphorylation of SGLT1 controls the function

The perfusion of rat small intestine with 10 μM epinephrine (Epi) or 10 μM norepinephrine resulted in significant increases in the amount of 3- O-[methyl- 3H]- d-glucose transported from the mucosal to serosal side. The Epi-induced increases in glucose transport were coupled with selective increases in β-adrenoceptor density in the mucosal membranes. Treatment with 0.1 μM okadaic acid increased glucose transport even in the absence of Epi, but that with 1 μM staurosporine or 60 μM N-[2-(methylamino)ethyl]-5-isoquinoline-sulfonamide dihydrochloride completely inhibited the increases in glucose transport induced by 10 μM Epi or 10 μM dibutyryl cAMP. The maximal binding sites ( B max) of [ 3H]phlorizin in brush border membrane (BBM) from tissues perfused with Epi was increased, showing increases in the binding ability of the Na +/glucose cotransporter (SGLT1) to glucose. Phosphorylation and dephosphorylation of BBM with protein kinase A (PKA) and alkaline phosphatase resulted in increases and decreases in B max of [ 3H]phlorizin, respectively. The phosphorylation state of SGLT1 immunoprecipitated from BBM incubated with [ γ- 32P]ATP-Mg 2+ and PKA, and the analysis of phosphoamino acids composed of SGLT1 in rats given [ 32P]orthophosphate indicate the presence of potential sites for PKA-mediated phosphorylation of SGLT1 at serine. These findings indicate that the regulation of phosphorylation of SGLT1 leads to an alteration of its function and results in the control of glucose transport in the rat small intestine.

The influence of luminal pH on transport of neutral and charged dipeptides by rat small intestine, in vitro

Four hydrolysis-resistant dipeptides ( d-phenylalanyl- l-alanine, d-phenylalanyl- l-glutamine, d-phenylalanyl- l-glutamate and d-phenylalanyl- l-lysine) were synthesized to investigate the effects of net charge on transmural dipeptide transport by isolated jejunal loops of rat small intestine. At a luminal pH of 7.4 and a concentration of 1 mM the two dipeptides with a net charge of −1 and +1 were transported at substantially slower rates (18±1.3 and 8.4±1.3 nmol min −1 (g dry wt.) −1, respectively) than neutral d-phenylalanyl- l-alanine and d-phenylalanyl- l-glutamine (87±0.2 and 197±14 nmol min −1 (g dry wt.) −1, respectively). We investigated the effects of luminal pH on dipeptide transport by varying the NaHCO 3 content of Krebs Ringer perfusate equilibrated with 95%O 2/5% CO 2. The pH changes did not affect water transport, but serosal glucose appearance increased significantly at pH 6.8. Transmural transport of d-phenylalanyl- l-alanine and d-phenylalanyl- l-glutamine at pH 6.8 was stimulated ( P<0.01) by 61% and 49%, respectively, whereas the lower pH increased the rate for negatively charged d-phenylalanyl- l-glutamate by 306% ( P<0.01) and decreased that for positively charged d-phenylalanyl- l-lysine by 46% ( P<0.05). Increasing luminal pH to 8.0 inhibited d-phenylalanyl- l-alanine transport by 60%, whereas d-phenylalanyl- l-lysine transport was 60% faster.

O-63 - The mechanisms of transmural transport of glucose and tetracycline stimulated by epinephrine

O-63 - The mechanisms of transmural transport of glucose and tetracycline stimulated by epinephrine

P-385 - The effect of catecholamine on transmural transport of glucose in rat intestine

P-385 - The effect of catecholamine on transmural transport of glucose in rat intestine

Mechanical basis of ANP secretion in beating atria: atrial stroke volume and ECF translocation.

To investigate the mechanism by which an increase in pacing frequency or distension increases the secretion of atrial natriuretic peptide (ANP), the changes in atrial volume during contraction (atrial stroke volume), transmural transport of the extracellular fluid (ECF), and ANP secretion were quantified in the beating perfused rabbit atria. The atrium was stimulated by transmural field stimulation or by atrial distension induced by an increase in intraatrial pressure. Atrial stretch and incremental increases in pacing frequency up to 2 Hz activated the secretion of ANP coincident with an increase in atrial stroke volume and the transendocardial translocation of the ECF. These results showed positive relationships between changes in the secretion of ANP and the atrial stroke volume or the translocation of the ECF. The translocation of the ECF was also positively correlated with the change in atrial stroke volume. The accentuated secretion of ANP and translocation of the ECF waned at higher stimulating rates to show a peak value. Even under this condition, the secretion of ANP was a function of the translocation of the ECF. These data suggest that the increases in atrial stroke volume and translocation of ECF are fundamental factors in the ANP stimulation in response to atrial stretch and increases in atrial rate.

Effect of hypothyroidism on glucose transport and metabolism in rat small intestine

The effect of experimental hypothyroidism on the absorption, transmural transport and metabolism of glucose was studied by perfusion of isolated loops of rat jejunum in vitro. When expressed on a dry weight basis, the rate of absorption was enhanced by 32% ( P < 0.01); when expressed on a length basis there was no significant change, since the enhancement per unit weight was almost exactly compensated by a diminution in mass per unit length in the hypothyroid state. When expressed in either units, there was a significant enhancement in transmural transport (+123% and +77%, respectively, both P < 0.001), which reflected in part a diminution in the rate of glucose utilization (−29%, P < 0.01 and −43%, P < 0.001, respectively). The changes in glucose utilization were matched by changes in lactate production. Three factors contributed to the diminution in glucose utilization in the hypothyroid state: a diminution in the concentration of 6-phosphofructo-1-kinase (−35%, P < 0.05), and increase in the S 0.5 of 6-phosphofructo-1-kinase for fructose 6-phosphate from 0.4 to 0.6 mM and a fall in the mucosal concentration of fructose 2,6-bisphosphate (−56%, P < 0.05). From the point of view of the whole animal, there is little if any change in the capacity of the intestine to absorb glucose from the lumen, but there is a large enhancement of transmural transport that is metabolically driven.

Extracellular fluid translocation in perfused rabbit atria: implication in control of atrial natriuretic peptide secretion.

1. Transmural transport of 22Na+, 51Cr-EDTA, [3H]inulin and [14C]Dextran (57 kDa) was measured in perfused rabbit atria. The radiolabelled extracellular space (ECS) markers and [14C]Dextran were introduced into the pericardial space or atrial lumen. Atrial volume changes were induced by steps up and down in atrial pressure. 2. Basal rates of transmural transport of radiolabelled ECS markers across the atrial wall were relatively stable up to 70 min. Atrial stretch and release resulted in a rapid but transient, and reversible increase in the ECS fluid (ECF) translocation. The increased translocation of the ECF into the atrial lumen occurred within 15 s of the reduction of atrial distension and returned to the baseline level within 60 s. 3. Transmural transport of [3H]inulin across the atrial wall was bidirectional. 4. The clearance of radiolabelled ECS markers was molecular-size dependent. The transmural clearance of [3H]inulin was dependent on the distension-reduction volume changes induced by atrial stretch and release. Little transport of [14C]Dextran across the atrial wall was observed. 5. The ECF translocation across the atrial wall was not influenced by changes in external Ca2+ but was suppressed by low temperature. 6. Dynamic changes in the ECS of the atrium were observed in response to atrial distension and reduction. The ECS of the atrium increased on distension and decreased on reduction of atrial distension. 7. Reduction in atrial distension resulted in an increase in the secretion of immunoreactive atrial natriuretic peptide (ANP) which coincided with an increase in the translocation of the ECF. The secretion of immunoreactive ANP was a function of the translocation of the ECF. 8. It is suggested that atrial stretch and release may play a role in driving fluid flow within the interstitium and fluid translocation out of the interstitium. This fluid movement presumably leads to convective transport of released ANP into the atrial lumen.

Effect of nordihydroguaiaretic acid on glucose absorption, metabolism and (Na + + K +)-ATPase activity in rat jejunum

A regulatory role of endogenously synthesized eicosanoids on the absorption, transmural transport and metabolism of glucose in perfused, isolated loops of jejunum in vitro was investigated using the lipoxygenase/cyclooxygenase inhibitor, nordihydroguaiaretic acid (NDGA). NDGA diminished glucose absorption over the range 100–500 μM: maximal inhibition at 500 μM NDGA was 52 ± 9 and 64 ± 9% (mean ± SE, P < 0.001) for jejuna from fed rats and rats maintained on glucose water for 48 hr, respectively. In each instance, transmural transport was effectively abolished. The vectorial disposition of lactate release was also changed such that the ratio of luminal to serosal production was increased from 0.19 ± 0.02 to 1.72 ± 0.12 (P < 0.001) in fed rats, indicating inhibition of the Na + pump. NDGA inhibited (Na + + K +)-ATPase activity in whole mucosal homogenates with a concentration dependence similar to that observed for glucose absorption. However, NDGA also inhibited Mg 2+-ATPase activity in whole homogenates and purified rabbit skeletal muscle phosphofructokinase under the same conditions. The results are discussed in terms of the dissipation of the transmembrane Na + gradient via direct inhibition of the (Na + + K +)-ATPase by NDGA. Inhibition of the ATPase precludes the use of NDGA as a suitable drug with which to investigate the role of endogenously synthesized eicosanoids in the regulation of intestinal function.

Rapid stimulation of intestinal D-glucose transport in teleosts by 17 alpha-methyltestosterone.

Effects of 17 alpha-methyltestosterone (MT) on transmural transport of 0.5 mM D-[3H]-glucose across upper intestine of the herbivorous teleost, Oreochromis mossambicus, were examined using modified Ussing chambers containing a physiological saline. Treatment tissues were preincubated with MT on the serosal surface for 30 min, while control tissues were incubated with an equivalent volume of 70% ethanol. Stimulation of mucosal-to-serosal D-glucose flux (Jm----s) by MT was dose dependent with maximal transport enhancement at 15 ng MT/ml saline (215% of control) and inhibition of sugar transfer occurring at 50 ng MT/ml (60% of control). Hormone treatment (15 ng MT/ml) significantly (P less than 0.05) increased net transmural D-glucose flux (Jnet; control = 0.36 +/- 0.084, MT = 0.75 +/- 0.130 nmol.cm-2.min-1) as a result of enhancing Jm----s (control = 0.52 +/- 0.048; MT = 0.91 +/- 0.078 nmol.cm-2.-1) without having a significant effect on the serosal-to-mucosal flux (Js----m). Mucosal addition of 1 mM phloridzin significantly (P less than 0.05) reduced glucose transport Jm----s in the presence and absence of MT, without altering the respective Js----m fluxes. Serosal addition of the hormone led to significant increases in Jm----s and Jnet in less than 20 min. This rapid intestinal response to MT was abolished by serosal addition of 1 mM colchicine, and therefore an increased insertion rate of performed glucose carriers is a suggested mechanism of hormone action.

Gestational changes in electrolyte transport, electrical activity, and permeability of the porcine placenta

1. The electrolyte transport capacities of the porcine placenta and fetal membranes (amnion, chorion, and allantois) during gestation (47-112 days) were assessed in vitro and in the absence of electrochemical, osmotic, or hydrostatic driving forces. Net transmural transport of 22Na and 36Cl across sections of porcine allantochorion-endometrium (ALCE), amniochorion-endometrium (AMCE), and allantoamnion (AA) mounted in Ussing chambers could not be detected at any stage of gestation. 2. These tissues were characterised throughout gestation by low electrical potential difference (PD; less than 5 mV, fetal side positive with respect to maternal side) and short circuit current (SCC; less than 16 microA.cm-2) which were amiloride and iodoacetate sensitive. 3. A periparturitent reversal in the polarity of PD to fetal side negative and a change in the direction of the SCC was observed in tissues obtained from sows (n = 3) at 111-112 day gestation. These changes were accompanied by a 73% increase in electrical resistance (R) and a 2-10-fold decrease in the permeability of tissues to Na and Cl. 4. Morphological studies revealed a decrease in the thickness of allantoamnion and a decrease in the height of epithelia from ALCE, AMCE, and AA during gestation, indicating a decrease in activity. These morphological changes only partly explained the pre-term electrophysiological changes in these tissues.

Macromolecular transport across arterial and venous endothelium in rats. Studies with Evans blue-albumin and horseradish peroxidase.

Atherosclerotic lesions are characterized by lipid infiltration in regions with high rates of endothelial cell turnover. The present investigation was designed to elucidate the route of macromolecular transport across vascular endothelium. The aorta and vena cava of male Sprague-Dawley rats were perfusion-fixed after the intravenous injection of Evans-blue albumin (EBA) or horseradish peroxidase (HRP). Fluorescence microscopic examination of en face preparation of the aorta stained with hematoxylin allowed the identification of endothelial cells that underwent mitosis, together with the localization and quantification of fluorescent spots for EBA leakage. The HRP specimens were subjected to histochemical treatment, and HRP leakage was seen as brown spots under the light microscope. Silver nitrate stain was added in both EBA and HRP studies to outline cell boundaries and to visualize stigmata, stomata, and dead cells. In the aorta, almost every dividing cell showed junctional leakage to albumin and HRP, with clustering of leaky spots around the branch orifices. Time-dependent studies showed gradual increases in the diameter and number of these heterogeneously sized leaky spots, which finally fused to sizes corresponding to the "blue areas" for EBA or "brown areas" for HRP. Compared with arteries, veins had fewer mitotic cells, but more dead cells and diffuse dye-staining areas, indicating a more rapid transport of macromolecules. The leaky spots in the artery were associated mainly with mitotic cells, dead cells, and stigmata, whereas those in the vein occurred primarily at regions with dead cells. These results suggest that the preferential association of the enhanced transport of macromolecules with mitosis in the arterial as compared to venous endothelium and the differential behavior in transmural transport between arteries and veins may form the basis for the predilection of atherosclerosis in arteries.

Site and mechanism of enhanced gastrointestinal absorption of aluminum by citrate

Clinical and experimental studies have shown that citrate markedly enhances the intestinal absorption of aluminum (Al), but the site and mechanism of enhanced absorption are unknown. To determine where in the gastrointestinal tract aluminum citrate (Alcitr) was absorbed. Alcitr was gavaged with D-[1-3H] glucose in male Sprague-Dawley rats. Plasma Al levels increased rapidly and simultaneously peaked with D-[1-3G] glucose, suggesting early proximal bowel absorption. In in vitro duodenal and jejunal everted gut preparations, Alcitr incubation resulted in increased tissue Al levels and markedly enhanced transmural transport of Al and citr. Unlike citr, the transmural movement of Al was independent of temperature (37 degrees C vs. 4 degrees C). On the other hand, Al lactate (al Lac) increased tissue associated Al levels but had no effect on transmural Al movement. To determine if this large flux of Al following Alcitr administration was due to paracellular movement, ruthenium red and Ussing chamber studies were used to evaluate the morphologic and functional integrity of cellular tight junctions. Alcitr, as opposed to AlCl3, markedly increased ruthenium red deposits in intercellular spaces, especially around goblet cells, and induced a prolonged significant reduction in transmural resistance. Alcitr also resulted in rapid and nearly complete (99.7%) chelation of free calcium, an event known to disrupt cellular tight junction integrity. Taken together, these data suggest that enhanced Al absorption following administration of Alcitr occurs in the proximal bowel via the paracellular pathway due to the opening of cellular tight junctions.