Histamine is known to cause a substantial increase in the permeability of venules to both water and proteins. However, this increase is transient, i.e. the initially elevated permeability escapes even during continuous histamine stimulation. This project was designed to identify the mechanisms underlying this permeability-escape phenomenon. The project was conducted in two stages. In the first stage, three series of experiments were performed to test the hypothesis that the permeability-escape phenomenon is due to the reclosure of endothelial gaps. Firstly, the time course of permeability changes to a-lactalbumin during continuous histamine stimulation was obtained from single venules of rat mesentery. It was found that, after the start of histamine treatment, permeability initially increased, peaked around the third minute and then declined towards its control level. Secondly, the temporal development of endothelial gaps during histamine treatment was studied with electron microscopy. The number of gaps underwent a similar development, i.e. an initial increase, peaking at 3 minutes, and a subsequent decrease toward control. Lastly, both permeability and gap morphology were obtained from the same individual venules subjected to different periods of histamine treatment. It was found that the temporal development of the gaps was mirrored by that of permeability. Since both permeability and endothelial gaps followed similar developmental patterns during histamine treatment, the result supports the hypothesis that the permeability-escape phenomenon is due to the reclosure of endothelial gaps. In the second stage, the chemical signal initiating the permeability escape was identified. Specifically, we tested whether histamine's binding to H2 receptors and/or the production of prostacyclin by endothelial cells were involved. The time course of venular permeability changes during histamine stimulation was measured in the presence of H2 receptor antagonist and of prostacyclin synthetase inhibitor, respectively. It was found that, while blocking H2 receptors did not have any effect on the escape of permeability, inhibiting prostacyclin synthesis suppressed or even abolished the permeability-escape phenomenon. Therefore, we concluded that the production of prostacyclin by endothelial cells may serve as one chemical signal to initiate the escape of permeability.

Call number: LD2668 .T4 1950 P46 / Master of Science

Thesis--Catholic University of America. / Bibliography: p. 23-26.

Not available / text

Thesis. 1978. Ph.D.--Massachusetts Institute of Technology. Dept. of Mechanical Engineering. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND ENGINEERING. / Vita. / Includes bibliographical references. / by Thomas H. Papanek. / Ph.D.

A system was developed to study membrane transport in isolated human fibroblast plasma membrane vesicles, avoiding potential complications of intracellular binding and metabolism in the intact cell. Ten-fold enrichment of plasma membranes after subcellular fractionation was confirmed with appropriate markers. Transport competence was established by the following criteria: osmotic sensitivity, stereospecificity, temperature dependence, sodium gradient stimulation, response to ions and ionophores, saturability, and exchange properties. Methotrexate uptake was osmotically sensitive, temperature sensitive, saturable, and inhibited by folinic acid and phosphate. Measurement of lysine uptake was complicated by binding and lack of sodium dependence, but was stimulated by an interior-negative membrane potential, and intravesicular lysine or arginine. Exchange properties of the lysine carrier were exploited to assess its function in fibroblasts from patients with the Mendelian phenotype, lysinuric protein intolerance (LPI). LPI vesicles were not different from controls in their lysine transport phenotype.

No description available.

vi, 208 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Botany, 1976

Femetinide is a synthetic retinoid with chemotherapeutic activity against various malignancies. After oral administration to animals, femetinide was found to be incompletely absorbed and excreted primarily in feces. The purpose of this study was to investigate the mechanism(s) responsible for the transport of femetinide across Caco-2 cell monolayers with an aim to determine the possible reasons for poor oral absorption of fenretinide. Fenretinide was found to be highly lipophilic (log P = 7.4) and practically insoluble in water. The water solubility of fenretinide was enhanced by formulating it as a Povidone K 25 solid dispersion. The Transepithelial Electrical Resistance (TEER) and antipyrine permeability (transcellular marker) were not affected after treatment with 0.5% PVP K 25 on the apical side. The apparent permeability coefficient (Papp) of fenreti nide was extremely low [(8.8 ± 0.5) x 10-8 cm/sec] even in the presence of 4% bovine serum albumin (BSA) in the receiver. The apical to basolateral (AP-BL) transport appeared linearly related to the fenretinide concentration ( 125-640 μM), thereby indicating that femetinide penneates the Caco-2 monolayer by passive diffusion within the concentration range. Transport studies at different donor (apical) pH conditions (6.0 or 7.4) revealed that no pH-dependent transporters were involved in the apical to basolateral transport of fenretinide across the Caco-2 monolayer. Efflux transporters like P-glycoprotein (P-gp) and the paracellular pathway did not play a significant role on the permeability of fenretinide. The partitioning of highly lipophilic molecules like fenretinicle from the cell membrane into the receiver depends on the composition of the receiving medium. The permeability of fenretinide increased with an increase in the bovine serum albumin (BSA) concentration (0 to 4 %) in the receiver. The addition of RBP to the receiving medium containing 4 % BSA increased the permeability of femetinicle clue to a greater binding affinity of fenretinicle for RBP. Significant amount (13-15% of the initial amount) of drug was found to accumulate in the cell membrane. The permeation of femetinide in Caco-2 monolayers is limited due to extensive accumulation in the cell membrane and poor partitioning from the cell membrane into the receiver medium.

No description available.