Pharmacology and Therapeutics - Research Publications
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ItemThe absence of autonomic perivascular nerves in human colorectal liver metastases(NATURE PUBLISHING GROUP, 1996-02-01)The peptidergic/aminergic innervation of normal liver and tumour blood vessels was investigated in order to determine vascular control with a view to improving the efficacy of hepatic arterial cytotoxic infusion in the treatment of colorectal liver metastases. Selected areas of liver metastases and macroscopically normal liver from resection specimens (n = 13) were studied using light microscope immunohistochemistry for the presence of protein gene product 9.5 (PGP), vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP), substance P (SP) and tyrosine hydroxylase (TH). The ultrastructure of blood vessels supplying liver metastases and their perivascular innervation were also examined by transmission electron microscopy. In the normal liver, perivascular immunoreactive nerve fibres containing PGP, NPY and TH were observed around the interlobular blood vessels and along the sinusoids and the central vein of the hepatic lobule. The greatest density of immunoreactive nerve fibres was seen for PGP, followed (in decreasing order) by NPY and TH. VIP, SP and CGRP immunoreactivity was observed only in nerve bundles associated with the large interlobular blood vessels. In contrast, no perivascular immunoreactive nerves were observed in colorectal liver metastases. Electron microscopy confirmed the absence of perivascular nerves in liver metastases. In addition, it showed that the walls of these blood vessels were composed of a layer of endothelial cells surrounded by an incomplete or, very rarely in the periphery of the tumour, a complete, layer of synthetic phenotype of smooth muscle-like cells. These results imply that the blood vessels supplying liver metastases are bereft of normal neuronal regulation; whether there is a role for endothelial cell control of blood flow in these vessels is not yet known.
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ItemFine structure of smooth muscle cells grown in tissue culture.(Rockefeller University Press, 1971-04)The fine structure of smooth muscle cells of the embryo chicken gizzard cultured in monolayer was studied by phase-contrast optics and electron microscopy. The smooth muscle cells were irregular in shape, but tended to be elongate. The nucleus usually contained prominent nucleoli and was large in relation to the cell body. When fixed with glutaraldehyde, three different types of filaments were noted in the cytoplasm: thick (150-250 A in diameter) and thin (30-80 A in diameter) myofilaments, many of which were arranged in small bundles throughout the cytoplasm and which were usually associated with dark bodies; and filaments with a diameter of 80-110 A which were randomly orientated and are not regarded as myofilaments. Some of the aggregated ribosomes were helically arranged. Mitochondria, Golgi apparatus, and dilated rough endoplasmic reticulum were prominent. In contrast to in vivo muscle cells, micropinocytotic vesicles along the cell membrane were rare and dense areas were usually confined to cell membrane infoldings. These cells are compared to in vivo embryonic smooth muscle and adult muscle after treatment with estrogen. Monolayers of cultured smooth muscle will be of particular value in relating ultrastructural features to functional observations on the same cells.
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ItemPostsynaptic specialization of smooth muscle at close neuromuscular junctions in the guinea pig sphincter pupillae.(Rockefeller University Press, 1972-06)
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ItemCORRELATION OF FINE STRUCTURE AND PHYSIOLOGY OF THE INNERVATION OF SMOOTH MUSCLE IN THE GUINEA PIG VAS DEFERENS.(Rockefeller University Press, 1963-12)An electron microscope study of the innervation of smooth muscle of the guinea pig vas deferens was undertaken in order to find a structural basis for recent electrophysiological observations. The external longitudinal muscle coat was examined in transverse section. Large areas of the surfaces of adjacent muscle cells were 500 to 800 A apart. Closer contacts were rare. A special type of close contact suggested cytoplasmic transfer between neighbouring cells. Groups of non-myelinated axons from ganglia at the distal end of the hypogastric nerve ramified throughout the muscle. Some small axon bundles and single axons lay in narrow fissures within closely packed muscle masses. Many axons contained "synaptic vesicles." About 25 per cent of the muscle fibres in the plane of section were within 0.25 micro of a partly naked axon; of these 15 per cent were within 500 A of the axon, and about 1 per cent made close contact (200 A) with a naked axon. It is unlikely that every muscle fibre is in close contact with an axon, and it is not possible for every fibre to have many such contacts. Muscle fibres are probably activated by both diffusion of transmitter from naked portions of axons a fraction of a micron distant, and electrotonic spread of activity from neighbouring cells.
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ItemNerve-myoepithelium and nerve-glandular epithelium contacts in the lacrimal gland of the sheep.(Rockefeller University Press, 1967-09)
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ItemDemonstration of "gap junctions" between smooth muscle cells.(Rockefeller University Press, 1970-01)
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ItemFREEZE-FRACTURE STUDIES OF NEXUSES BETWEEN SMOOTH-MUSCLE CELLS - CLOSE RELATIONSHIP TO SARCOPLASMIC-RETICULUM(ROCKEFELLER UNIV PRESS, 1977-01-01)The freeze-fracture appearance of the nexus was compared in the smooth muscle of guinea pig sphincter pupillac, portal vein, pulmonary artery, taenia coli, uretzr, and vas diferens, mouse vas deferens, chicken gizzard and anterior mesenteric artery, and toad stomach. Nexuses are particularly numerous in the guinea pig sphincter pupillae; they are usually oval and their average area is 0.15 mum2, although some as large as 0.6 mum2 were seen. Small aggregations of particles were observed which would not be recognizable as nexuses in thin section. What constitutes the minimum size of a nexus is discussed. It is estimated that the number of nexuses per cell in this preparation is of the order of tens rather than hundreds. All nexuses examined had 6-9-nm particles in the PF face, with corresponding 3-4-nm pits on the EF face forming a polygonal tending towards a hexagonal lattice. The nexuses are arranged in rows parallel to the main axis of the cell, usually alternating with longitudinal rows of plasmalemmal vesicles. Many nexuses in the guinea pig sphincter pupillae, chicken gizzard, and toad stomach show a close relationship with sarcoplasmic reticulum. The possibility that this may have some role in current flow across this specialized junction is discussed.
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ItemNITRITE IS PRODUCED BY ELICITED BUT NOT BY CIRCULATING NEUTROPHILS(RAPID SCIENCE PUBLISHERS, 1993-10-01)The generation of nitrite (NO(2) (-)) was used as an index of the production of nitric oxide by human and rat polymorphonuclear leukocytes (PMN) and rat peritoneal macrophages. Human peripheral blood PMN did not produce significant levels of NO(2) (-). Attempts to induce NO(2) (-) generation in human PMN by incubation with GM-CSF (1 nM), TNFalpha (0.3 nM), endotoxin (1 mug/ml) or formyl-Met-Leu-Phe (100 nM) for up to 16 h were not successful. Addition of human PMN primed by GM-CSF (1 nM) to rabbit aortic ring preparations precontracted with phenylephrine had no effect on tone. In contrast to these observations, PMN, isolated from the peritoneum of oyster glycogen treated rats, generated NO(2) (-) via a pathway sensitive to inhibition by the nitric oxide synthase inhibitor, N(G)-monomethyl L-arginine. However, peripheral blood rat PMN obtained from the same animals did not produce NO(2) (-), even during prolonged incubation for periods of up to 16 h. It is suggested that detectable NO production by PMN requires NO synthase activity to be induced either by the process of PMN migration or by exposure to certain cytokines produced locally at the site of inflammation.
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ItemCytoplasmic filaments in developing and adult vertebrate smooth muscle.(Rockefeller University Press, 1971-08)An extensive study of adult and developing smooth muscle has revealed the widespread occurrence of a distinct filament with an average diameter of about 100 A (termed the 100 A filament). Unlike that of myofilaments, their appearance in longitudinal section is uniform, but in transverse section they have a round profile, occasionally exhibiting a less electron-opaque core. The 100 A filaments are almost invariably preserved under a variety of fixation procedures, whereas myofilaments, particularly the thicker filaments, are preserved inconsistently. The 100 A filaments appear to be randomly oriented throughout the cytoplasm, either singly or in small groups, although they are sometimes concentrated in the juxtanuclear region of the smooth muscle cells. The intimate association of 100 A filaments with dark bodies, in both developing and adult smooth muscle cells, may indicate that these filaments either play a role in dark body formation or, at least, constitute a part of the dark body. The 100 A filaments are conspicuous in developing smooth muscle cells and occasionally form networks or clusters; they appear to decrease in relative number as maturation proceeds, but considerable numbers are still present in adult tissue.
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ItemInduction of integral membrane PAM expression in AtT-20 cells alters the storage and trafficking of POMC and PC1.(Rockefeller University Press, 1999-02-08)Peptidylglycine alpha-amidating monooxygenase (PAM) is an essential enzyme that catalyzes the COOH-terminal amidation of many neuroendocrine peptides. The bifunctional PAM protein contains an NH2-terminal monooxygenase (PHM) domain followed by a lyase (PAL) domain and a transmembrane domain. The cytosolic tail of PAM interacts with proteins that can affect cytoskeletal organization. A reverse tetracycline-regulated inducible expression system was used to construct an AtT-20 corticotrope cell line capable of inducible PAM-1 expression. Upon induction, cells displayed a time- and dose-dependent increase in enzyme activity, PAM mRNA, and protein. Induction of increased PAM-1 expression produced graded changes in PAM-1 metabolism. Increased expression of PAM-1 also caused decreased immunofluorescent staining for ACTH, a product of proopiomelanocortin (POMC), and prohormone convertase 1 (PC1) in granules at the tips of processes. Expression of PAM-1 resulted in decreased ACTH and PHM secretion in response to secretagogue stimulation, and decreased cleavage of PC1, POMC, and PAM. Increased expression of a soluble form of PAM did not alter POMC and PC1 localization and metabolism. Using the inducible cell line model, we show that expression of integral membrane PAM alters the organization of the actin cytoskeleton. Altered cytoskeletal organization may then influence the trafficking and cleavage of lumenal proteins and eliminate the ability of AtT-20 cells to secrete ACTH in response to a secretagogue.