The transendothelial passage of horseradish peroxidase, injected intravenously into mice, was studied at the ultrastructural level in capillaries of cardiac and skeletal muscle. Peroxidase appeared to permeate endothelial intercellular clefts and cell junctions. Abnormal peroxidase-induced vascular leakage was excluded. Neutral lanthanum tracer gave similar results. The endothelial cell junctions were considered to be maculae occludentes, with gaps of about 40 A in width between the maculae, rather than zonulae occludentes. Some observations in favor of concurrent vesicular transport of peroxidase were also made. It is concluded that the endothelial cell junctions are most likely to be the morphological equivalent of the small pore system proposed by physiologists for the passage of small, lipid-insoluble molecules across the endothelium.

/pdf/the-ultrastructural-basis-of-capillary-permeability-studied-5dsina2wex.pdf

The ultrastructural basis of capillary permeability studied with peroxidase as a tracer

The blood–brain barrier (BBB) prevents the brain uptake of most pharmaceuticals. This property arises from the epithelial-like tight junctions within the brain capillary endothelium. The BBB is anatomically and functionally distinct from the blood–cerebrospinal fluid barrier at the choroid plexus. Certain small molecule drugs may cross the BBB via lipid-mediated free diffusion, providing the drug has a molecular weight <400 Da and forms <8 hydrogen bonds. These chemical properties are lacking in the majority of small molecule drugs, and all large molecule drugs. Nevertheless, drugs can be reengineered for BBB transport, based on the knowledge of the endogenous transport systems within the BBB. Small molecule drugs can be synthesized that access carrier-mediated transport (CMT) systems within the BBB. Large molecule drugs can be reengineered with molecular Trojan horse delivery systems to access receptor-mediated transport (RMT) systems within the BBB. Peptide and antisense radiopharmaceuticals are made brain-penetrating with the combined use of RMT-based delivery systems and avidin–biotin technology. Knowledge on the endogenous CMT and RMT systems expressed at the BBB enable new solutions to the problem of BBB drug transport.

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.2012.126

Drug transport across the blood-brain barrier.

Why do girls tend to earn better grades in school than boys? Why are men still far more likely than women to earn degrees in the fields of science, technology, engineering, and mathematics? And why are men on average more likely to be injured in accidents and fights than women? These and many other questions are the subject of both informal investigation in the media and formal investigation in academic and scientific circles. In his landmark book "Male, Female: The Evolution of Human Sex Differences", author David Geary provided the first comprehensive evolutionary model to explain human sex differences. Using the principles of sexual selection such as female choice and male-male competition, the author systematically reviewed and discussed the evolution of sex differences and their expression throughout the animal kingdom, as a means of not just describing but explaining the same process in Homo sapiens. Now, over ten years since the first edition, Geary has completed a massive update, expansion and theoretical revision of his classic text. New findings in brain and genetic research inform a wealth of new material, including a new chapter on sex differences in patterns of life history development; expanded coverage of genetic research (e.g. DNA finger printing to determine paternity as related to male-male competition in primates); fatherhood in humans; cross-cultural patterns of sex differences in choosing and competing for mates; and, genetic, hormonal, and socio-cultural influences on the expression of sex differences. Finally, through his motivation to control framework (introduction in the first edition and expanded in "The Origin of Mind", 2005), Geary presents a theoretical bridge linking parenting, mate choices, and competition, with children's development and sex differences in brain and cognition. The result is an even better book than the original - a lively and nuanced application of Darwin's insight to help explain our heritage and our place in the natural world.

Male, Female: The Evolution of Human Sex Differences

Literature data on compounds both well- and poorly-absorbed in humans were used to build a statistical pattern recognition model of passive intestinal absorption. Robust outlier detection was utilized to analyze the well-absorbed compounds, some of which were intermingled with the poorly-absorbed compounds in the model space. Outliers were identified as being actively transported. The descriptors chosen for inclusion in the model were PSA and AlogP98, based on consideration of the physical processes involved in membrane permeability and the interrelationships and redundancies between available descriptors. These descriptors are quite straightforward for a medicinal chemist to interpret, enhancing the utility of the model. Molecular weight, while often used in passive absorption models, was shown to be superfluous, as it is already a component of both PSA and AlogP98. Extensive validation of the model on hundreds of known orally delivered drugs, “drug-like” molecules, and Pharmacopeia, Inc. compounds, whic...

Prediction of drug absorption using multivariate statistics.

Blood-brain barrier delivery.

The mechanism by which active solute transport causes water transport in isotonic proportions across epithelial membranes has been investigated. The principle of the experiments was to measure the osmolarity of the transported fluid when the osmolarity of the bathing solution was varied over an eightfold range by varying the NaCl concentration or by adding impermeant non-electrolytes. An in vitro preparation of rabbit gall bladder was suspended in moist oxygen without an outer bathing solution, and the pure transported fluid was collected as it dripped off the serosal surface. Under all conditions the transported fluid was found to approximate an NaCl solution isotonic to whatever bathing solution used. This finding means that the mechanism of isotonic water transport in the gall bladder is neither the double membrane effect nor co-diffusion but rather local osmosis. In other words, active NaCl transport maintains a locally high concentration of solute in some restricted space in the vicinity of the cell membrane, and water follows NaCl in response to this local osmotic gradient. An equation has been derived enabling one to calculate whether the passive water permeability of an organ is high enough to account for complete osmotic equilibration of actively transported solute. By application of this equation, water transport associated with active NaCl transport in the gall bladder cannot go through the channels for water flow under passive conditions, since these channels are grossly too impermeable. Furthermore, solute-linked water transport fails to produce the streaming potentials expected for water flow through these passive channels. Hence solute-linked water transport does not occur in the passive channels but instead involves special structures in the cell membrane, which remain to be identified.

http://jareddiamond.org/Jared_Diamond/Further_Reading_files/Diamond%201964.pdf

The mechanism of isotonic water transport.

A simple and reproducible method has been developed for following fluid transport by an in vitro preparation of mammalian gall bladder, based upon weighing the organ at 5 minute intervals. Both guinea pig and rabbit gall bladders transport NaCl and water in isotonic proportions from lumen to serosa. In the rabbit bicarbonate stimulates transport, but there is no need for exogenous glucose. The transport rate is not affected by removal of potassium from the bathing solutions. Albumin causes a transient weight loss from the gall bladder wall, apparently by making the serosal smooth muscle fibers contract. Active NaCl transport can carry water against osmotic gradients of up to two atmospheres. Under passive conditions water may also move against its activity gradient in the presence of a permeating solute. The significance of water movement against osmotic gradients during active solute transport is discussed.

/pdf/transport-of-salt-and-water-in-rabbit-and-guinea-pig-gall-3s5epmod00.pdf

Transport of salt and water in rabbit and guinea pig gall bladder.

Role of long extracellular channels in fluid transport across epithelia.

The relations between the chemical structure of non-electrolytes and their ability to permeate cell membranes are analysed at the level of molecular forces, using the measurements of reflexion coefficients in gall-bladder epithelial cells tabulated in the preceding paper. Stronger solute: water forces and weaker solute: membrane forces are associated with lower permeating power. The portions of the membrane controlling non-electrolyte permeation behave as nearly pure hydrocarbons with very few hydrogen-bonding sites. Most substituents (hydroxyl, ether, carbonyl, ester, amino, amide, urea, nitrile) are shown to decrease permeation in proportion to the number and strength of intermolecular hydrogen bonds which they form with water, while intramolecular hydrogen bonding accelerates permeation. Carbon-carbon double bonds and triple bonds and aromatic residues decrease permeability due to hydrogen bonds involving $\pi $ electrons. Inductive effects, in which a substituent indirectly modifies permeability by withdrawing or releasing electrons at an adjacent hydrogen bonding site, are most noticeable for halogens, the nitro group, double and triple bonds, and branched alkyl groups. Altered forces between membrane hydrocarbons and the solute retard the permeation (weaker forces) of fluorine compounds and branched compounds, and slightly accelerate the permeation (stronger forces) of other halogen derivatives and compounds with long carbon chains. The main factor in the increase of permeability with increasing hydrocarbon chain length is an entropy effect associated with a change in local water structure; and this effect is partly responsible for the decrease in permeability with chain branching, whose origin is particularly complex.

Molecular forces governing non-electrolyte permeation through cell membranes.

Reflexion coefficients (σ’s) for epithelial cells of rabbit gall-bladder for 206 non-electrolytes have been measured and analysed. In general, σ’s decrease from 1.0 to 0 with increasing lipid :water partition coefficients, so that the intermolecular forces governing permeation of most non-electrolytes are the same as those governing partition between a bulk lipid phase and water. The two classes of deviations to this pattern are related to the specific structure of cell membranes. First, highly branched molecules have higher σ’s (permeate more slowly) than expected from partition coefficients, an effect attributed to an isotropy of membrane lipids. Secondly, the smallest, most lipid-insoluble molecules have lower σ’s (permeate more readily) than expected, and are also anomalous in that: effects of changes in their structure on or disobey Overton’s rules; the inverse relation between or and temperature is less steep for them than for other so lutes; and their σ’s are little affected by decreases in pH which increase σ’s of other solutes. These anomalies are interpreted to mean that small polar solutes in transit through the membrane interact minimally or not at all with hydrocarbon tails of membrane lipids, but in stead follow a route formed by localized concentrations of membrane polar groups associated with ‘frozen’ water molecules, where the coupling phenomena between permeating water, ions, and small polar-electrolytes observed in cell membranes may also occur.

Jared M. Diamond

Papers

The mechanism of isotonic water transport.

Transport of salt and water in rabbit and guinea pig gall bladder.

Role of long extracellular channels in fluid transport across epithelia.

Molecular forces governing non-electrolyte permeation through cell membranes.

Patterns of non-electrolyte permeability.