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PubMed1960

Electron microscope study of the lathyritic rat aorta.

Six weanling rats were fed a diet containing 0.4 per cent BAPN fumarate and sacrificed after 5 to 33 days on the diet. The ascending aortae were fixed with OsO(4), embedded in methacrylate and araldite, sectioned, stained with lead hydroxide, and examined with the electron microscope. The descending thoracic aortae were examined by light microscopy. Compared with pair-fed controls, the experimentals showed definite changes which became more marked as the disease progressed. The wall became thicker with wider interlaminar spaces, radial orientation of the smooth muscle cells, progressive loss of desmosomes, and progressive increase in a dense, finely stippled material that coated the edges of the elastic laminae and extended outwards between the muscle cells and separated the ends of these cells from the laminae. This stippled material occurred at the same sites as the increase in PAS-positive and azan-positive material seen with the light microscope. There was an increase in subendothelial and interlaminar collagen, and electron microscopy clearly showed that the cells were smooth muscle and not fibroblasts. The possible bearing of the morphological changes on the formation of aortic aneurysms is discussed.

Aminopropionitrile↗
PubMed1959

Morphologic evidence for collagen changes in chick embryos treated with beta-aminopropionitrile.

Electron microscope analysis of thin sections of intact skin from 17 day chick embryos injected with beta-aminopropionitrile 3 days earlier, revealed markedly increased dispersion in fibril diameter both above and below the narrow distribution of normal fibril size. Extraction with cold 1 M neutral saline caused a dissolution of the fibrils to fine filaments of varying diameters. Histologic examination of the connective tissue of lathyritic skin prior to extraction revealed little difference from the normal. After extraction the collagen either disappeared almost entirely or was observed as a homogeneous smear. These results of morphologic analysis are consistent with previous chemical studies, supporting the thesis that lathyrogenic agents induce disruption of intermolecular cross-linking within normally insoluble collagen fibrils, allowing them to dissolve in cold neutral salt solutions.

Aminopropionitrile↗
PubMed1961

The lathyrogenic effect of isonicotinic acid hydrazide (INAH) on the chick embryo and its reversal by pyridoxal.

When applied to the chorio-allantoic membrane of the chick embryo, isoniazid was shown to produce an increase in the fragility of the embryo and in the amount of collagen which was extractable from the bones with cold 1 M sodium chloride. The administration of pyridoxal reversed these phenomena almost completely. The effect of isoniazid differed from that of beta-aminopropionitrile in that the latter was of greater magnitude, and was not affected by pyridoxal; whereas beta-aminopropionitrile caused skeletal deformities, isoniazid even at 12 times the concentration produced no deformities. The aldehyde group of pyridoxal was shown to be necessary for its interaction with isoniazid.

Aminopropionitrile↗
PubMed1961

Structural requirements for lathyrogenic agents.

Using the chick embryo assay system, a series of organic compounds was tested for lathyrogenic activity; lathyrogenic compounds were shown to fall into 4 groups-nitriles, ureides, and 2 new groups-hydrazides and hydrazines, forming a spectrum of diminishing potency in their ability to produce solubility of collagen and skeletal deformities. Pyridoxal was seen to reverse to a great degree the effects on collagen solubility and skeletal deformity produced by the ureides and hydrazides, though not by the nitriles; its effect was considered to be due to the formation of a Schiff's complex between the aldehyde and the terminal amine of the lathyrogen. Evidence is presented to show that lathyrogens do not act as inhibitors of monoamine oxidases or as chelate-forming agents, nor, in the case of isoniazid, as an anti-nicotinamide agent.

Animals↗
PubMed1962

Studies on the mode of action of lathyrogenic compounds.

The lathyrogenic effect of INAH in the chick embryo may be measured by the increase in the extractibility of collagen from the bones with 1 M NaCl. Incubation of these bones in vitro with carbonyl compounds diminishes the amount of extractible collagen; with D-L-glyceraldehyde the reversal of the INAH effect is complete. This reversal effect is dependent on the time and temperature of incubation and on the quantity of D-L-glyceraldehyde, but is independent of the pH of the incubating medium, the optical form of the glyceraldehyde, or the metabolism of the cells; this suggests that it depends on a simple chemical combination. D-L-glyceraldehyde also reverses completely the extractibility of collagen from the bones of embryos rendered lathyrogenic with BAPN, semicarbazide, and hydrazine hydrate. The hypothesis has been advanced "that lathyrogenic agents act by blocking carbonyl groups on the collagen molecule, thus preventing cross-linking essential to normal maturation; normal maturation may be restored by the addition of carbonyl groups which act by competing either for the lathyrogen or for functional sites on the collagen molecule." In support of this hypothesis, it has been shown that purified lathyritic guinea pig collagen takes up lesser amounts of 2,4-dinitrophenylhydrazine-a compound which combines with carbonyl groups-than does normal collagen; it has been shown that lathyritic collagen still possesses the ability to form segment-long-spacing (SLS) collagen, but that these fibres are much thinner than normal; this is due perhaps to blockade of groups essential for lateral cross-linking of the tropocollagen unit. It has also been shown that normal, purified guinea pig collagen which has been pretreated with INAH, takes up lesser amounts of 2,4-dinitrophenylhydrazine and forms much thinner SLS fibres than the untreated controls.

Animals↗