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At least 343 records · Page 19Linked to original sources
PubMed1980

Chronic lathyrism and atheromatosis in the rat. Protective effect of metformin.

Chronic administration of beta-aminopropionitrile fumarate (BAPN) (1 g/kg/day for 9 weeks) produced morphological changes of the aorta wall and in dermis, and biochemical changes of the aortic wall in the rat. Chronic administration of BAPN did not produce plasma lipid abnormalities such as those due to hyperlipidic diet. 9 weeks of BAPN followed by 10 months of a hyperlipidic diet increased the aortic cholesterol level and induced atheroma. The diet alone only produced an endothelial lipid overload and increased the aortic cholesterol level but less than BAPN and hyperlipidic diet together. Addition of metformin to BAPN prevented the formation of atheromatous lesions in the aorta and minimized the level of lipids in the aortic wall and of the dermis.

Aminopropionitrile↗
PubMed1984

Increased solubility of newly synthesized collagen in retinal capillary pericyte cultures by nonenzymatic glycosylation.

The effect of increasing glucose concentration on the solubility of newly synthesized collagen was studied in bovine retinal capillary pericyte (BRCP) cultures. Synchronized pericytes were labeled with [3H]-proline in media containing either 5, 10, 20 or 40 mM glucose, or 5 mM glucose and 100 micrograms/ml beta-aminopropionitrile fumarate (BAPN). The relative rate of collagen synthesis in the medium (soluble collagen) was significantly increased, and the rate in the cell layer (insoluble collagen) was decreased, by an elevated glucose concentration. The increase in collagen solubility with 20 and 40 mM glucose (over normal, 5 mM glucose) was 14 and 42%, respectively, of that obtained with BAPN. BAPN and 4-deoxypyridoxine inhibited BRCP lysyl oxidase activity, but elevated glucose concentrations did not. Increased nonenzymatic glycosylation of newly synthesized collagen was demonstrated in BRCP cultures co-labeled with L-[14C]-glucose and L-[3H]-proline. The increase in collagen solubility with elevated glucose concentrations therefore appears to be the result of the inhibition of lysyl-derived cross-link formation because of an increased nonenzymatic glycosylation of the epsilon-amino groups of lysyl residues of newly synthesized collagen in culture.

Aminopropionitrile↗
PubMed1997

Genetic susceptibility to experimental cerebral aneurysm formation in the rat.

BACKGROUND AND PURPOSE: The susceptibility to experimental cerebral aneurysm formation in arteries of the circle of Willis was studied in four strains of rats presenting different susceptibilities to the spontaneous rupture of the internal elastic lamina in extracerebral arteries: Brown-Norway (BN) > Wistar > Long-Evans (LE) > LOU. METHODS: Rats (150 g body weight) of the four strains were subjected to hypertension and a change in local cerebral blood flow by ligation of one common carotid artery for about 7 months. Six-month-old BN and LE rats were subjected to carotid ligation only for 11 to 13.5 months and treated or not (from 3 to 7 months of age) with an inhibitor of connective tissue fiber maturation, beta-aminopropionitrile (BAPN). RESULTS: Aneurysmal structures (AS) occurred mainly in the anterior cerebral/anterior communicating arterial complex and proximal part of the posterior artery. In hypertensive rats, the AS incidence was LE, 56%; Wistar, 33%; BN, 17%; and LOU, 11%. When normotensive and subjected to carotid ligation only, LE rats showed an even greater susceptibility to AS formation (86%) than BN (7%). BAPN treatment did not influence AS formation: LE (60%) versus BN (8%). CONCLUSIONS: These results suggest that genetic factors are involved in cerebral aneurysm formation in the rat. The susceptibility of the internal elastic lamina of extracerebral arteries to spontaneous rupture does not appear to be a determinant genetic trait in the propensity to develop aneurysms in arteries of the circle of Willis. The comparison of these different rat strains may be very useful for studying factors contributing to cerebral aneurysm pathogenesis.

Aminopropionitrile↗
PubMed1998

Intrapulmonary gas mixing in panacinar- and centriacinar-induced emphysema in rats.

We studied ventilation distribution using the single-breath washout technique in rats with two types of induced emphysema: panacinar-like (by instilled elastase) and centriacinar-like (by inhaled CdCl2 combined with oral intake of beta-aminopropionitrile). Morphologically, panacinar and centriacinar groups presented a similar degree of airspace enlargement, which was irregularly distributed and also accompanied by fibrosis only in the centriacinar group. In terms of mechanical properties, the centriacinar group presented lower end-expiratory flows and lower compliance than the panacinar group. The ventilation distribution patterns were also different between both groups. Single-breath washout phase III slopes, reflecting mainly diffusion-convection-dependent inhomogeneities in rat lungs, were largest in the centriacinar group. The SF6-He slope difference, which was reversed in both emphysema groups with respect to the control group, could be attributed mainly to He slope changes in the panacinar group and to SF6 slope changes in the centriacinar group. In addition, the respective He and SF6 slope decrease as a function of end-inspiratory breath-hold time, was only different from the control group in the centriacinar group. The observed ventilation distribution patterns can be explained by interacinar elastic changes in the panacinar group and severe interacinar structural alterations in the centriacinar group.

Administration, Inhalation↗
PubMed1987

Damage and repair of lung connective tissue in rats exposed to toxic levels of oxygen.

We studied damage and repair of lung connective tissue in rats exposed to toxic amounts of oxygen by measuring lung content of collagen and elastin and the number of collagen fragments in lung lavage fluid after exposure to 98% O2 for 60 h. Lung collagen was decreased 17%, and collagen fragments in lavage fluid were increased 4- to 5-fold in O2-exposed rats compared with those in control rats. No biochemical evidence of elastin degradation was found. Mild emphysematous changes and a leftward shift of fluid-filled, pressure-volume curves were induced within 2 wk after recovery from exposure to O2. Administration of the lathyrogen beta-aminopropionitrile worsened the emphysematous lesion produced by hyperoxia, suggesting that replacement of connective tissue during repair limits the extent of emphysema. We conclude that lung collagen is degraded and an emphysematous lesion is produced by relatively short exposure to toxic amounts of oxygen.

Aging↗
PubMed1998

Pharmacologic inhibition of collagen in an experimental model of subglottic stenosis.

Subglottic stenosis occurs as a complication of prolonged endotracheal intubation secondary to inflammation with development of scar tissue and subsequent fibrosis. Collagen I and III levels increase during the healing process. Steroids alter the inflammatory response, decreasing recruitment of macrophages and fibroblasts. Beta-aminopropionitrile (betaAPN) inhibits the development of collagen cross-linking. A mechanism that would minimize hypertrophic scarring was sought. Eighteen dogs were anesthetized, had tracheostomies performed, and later had cautery of the mucosa and inner layer of the cricoid cartilage. Of 18 survivors, 6 animals were used as controls, 6 animals received oral Decadron, 2 mg/d, and 6 animals received oral betaAPN, 40 mg/d. There were 9 early deaths--5 in the steroid group. Animals were painlessly sacrificed, and the specimens were sectioned at the cricoid cartilage level and were stained immunohistochemically for antibodies to collagen types I to VI. Analysis of the area of scar and the intensity of stain was performed with Mocha image analysis software. Collagen III increased in control animals to 14.38 +/- 1.85 (intensity stain index), but this reaction was reduced by betaAPN (5.77 +/- 1.78, p < .01). Steroids had no significant effect on formation of any type of collagen. Lathyrogens (betaAPN) may offer a pharmacologic tool to reduce scar tissue.

Aminopropionitrile↗
PubMed1989

Transcription of the Spec 1-like gene of Lytechinus is selectively inhibited in response to disruption of the extracellular matrix.

The influence of the extracellular matrix (ECM) on differential gene expression during sea urchin development was explored using cell-type-specific cDNA probes. The ECM of three species of sea urchin, Strongylocentrotus purpuratus, Lytechinus variegatus and Lytechinus pictus, was disrupted with the lathrytic agent beta-aminopropionitrile (BAPN), which inhibits collagen deposition in the ECM and arrests gastrulation (Wessel & McClay, Devl Biol. 121: 149, 1987). The levels of several mRNAs (Spec 1, Spec 2, CyIIa actin, CyIIIa actin and collagen in S. purpuratus, and metallothionine, ubiquitin and LpS3 in L. pictus and L. variegatus) were compared in BAPN-treated and control embryos. These mRNAs accumulated normally during BAPN treatment, even though the embryos did not gastrulate. To determine if the expression of any gene product is sensitive to ECM disruption, a differential cDNA screen compared poly (A+) RNA from BAPN-arrested and control embryos in Lytechinus. A cDNA clone was isolated from this screen that represented a 2.1 kb mRNA that did not accumulate during BAPN treatment. Removal of BAPN resulted in the accumulation of this transcript coincident with the onset of gastrulation. This cDNA clone encodes a L. variegatus homologue of LpS1, recently demonstrated to be an ancestral homologue of the aboral ectoderm-specific Spec 1-Spec 2 gene family in S. purpuratus. Nuclear run-on assays in L. pictus suggested that transcriptional activity of LpS1 was selectively inhibited by BAPN treatment. Thus, although the accumulation of many gene products occurred independently of the embryonic collagenous matrix, the accumulation of LpS1 and LvS1 appeared to be mediated by the ECM.

Actins↗
PubMed1974

Pharmacology of fibrosis and tissue injury.

Methods controlling tissue fibrosis are classified into those specifically inhibiting various metabolic aspects of collagen selectively in the injured tissue (ascorbic acid deficiency, effect of agent chelating Fe(2+), proline analogs, lathyrogens). The most promising method seems to be the blocking of crosslinks formation among collagen molecules by beta-aminopropionitrile, a competitive inhibitor of a crosslinking enzyme, lysyl oxidase. The second group of methods is called nonspecific, as they affect any stage of inflammatory process preceding the activation of fibroblasts. The importance of activated macrophages in the stimulation of fibroblast is discussed. Finally, a new concept is proposed, indicating the function of zinc ions in the control of the integrity of biomembrances, tissue reactivity to noxious agents. It is suggested that zinc may control NADPH dependent lipid peroxidation at the membrane level by inhibiting NADPH oxidase activity. The implication of these ideas to lung fibrosis induced by silica or asbestos is discussed.

Aminopropionitrile↗
PubMed1980

Improvement of gliding function of flexor tendons by topically applied enriched collagen solution.

The long flexor tendons of the second, third and fourth toes of 94 chickens were cut and sutured. After operation the birds were divided into three groups. To reduce peritendinous adhesions, an aqueous solution of beta-aminopropionitrile (BAPN) was added to a solution of enriched native collagen (ECS) and applied to the cut tendons of one group; untreated controls and controls treated with collagen solution alone comprised the other groups. Chickens from each group were killed one, two, three, four and five weeks after operation. The results were evaluated both biomechanically and biochemically. It was found that the collagen solution alone had the same effect as the treatment with BAPN. It is suggested that the exogenous collagen present at the site of injury binds the collagenase inhibitor released by tendon cells, thus providing enough active collagenase to control the formation of fibrous adhesions. The inefficiency of BAPN in these experiments might have been due to either inadequate dosage or wrong timing, or both.

Aminopropionitrile↗
PubMed1980

Evaluation of the assay for serum monoamine oxidase -- an index of hepatic fibrosis.

At present, neither the diagnostic efficiency, the analytic reliability nor the practicability of clinical chemical tests for estimation of the degree and/or activity of the fibrotic transformation of the chronically injured liver are satisfactory. Among the various parameters proposed, the determination of the activity of monoamine oxidase (monoamine: O2 oxidoreductase, EC 1.4.3.4) in serum seems to be advantageous. To facilitate its routine use we studied some important practical aspects of the new colorimetric assay for the activity of monoamine oxidase in serum. The reaction proceeds linearly with time for at least two hours and with enzyme concentrations up to kU/l. The buffer composition influences markedly the function of the enzyme; in Tris-HCl buffer (pH 7.2) at 37 degree C the activity is 1.35 time higher than in phosphate buffer (pH 7.3) and the temperature correlation factors are also different for both buffer systems. 0.003 mol/l of the lathyrogenic compound beta-aminopropionitrile inhibits the activity by about 50% whereas Cu2+ up to 130 mu mol/l does not affect enzyme function. Intra- and interassay precision and characterized by a CV of 3.6 and 12%, respectively. Hemolysis and hyperbilirubinemia do not interfere significantly with the determination but in hyperlipemic sera elevated enzyme activities were noticed. During storage of serum at room temperature the catalytic function decrease by about 30%/day. Of the 26 quality control sera tested, only a few contained monoamine oxidase activity that was quantitatively (i.e. similar catalytic activity in tris phosphate buffer) similar to that in human serum, and were therefore suitable for routine precision control analysis.

Aminopropionitrile↗
PubMedDate not supplied

Impact of antifibrotic treatment of the course of Schistosoma mansoni infection in murine model.

Administration of an antifibrotic agent as an adjunct to antihelmintic treatment with the objective of morbidity reduction was investigated in the murine schistosomiasis mansoni model. Antifibrotic, beta-aminopropionitrile treatment has a profound effect on the cellular matrix composition of the liver granuloma of Schistosoma mansoni infected mice when given alone, resulting in increase macrophage infiltration. These macrophages, in response to stimulation with soluble egg antigen or lipopolysaccharide produced elevated levels of nitric oxide but low levels of tumor necrosis factor alpha compared to untreated infected mice. This also correlated with reduced liver granuloma size. In spite of low numbers of eggs in the liver, mice receiving a combine treatment had a high level of resistance to a challenge infection compared with mice receiving only praziquantel. Those mice also exhibited a reduced lymphocyte proliferative response, similar to that of infected untreated mice. Antifibrotic treatment has an impact on the dynamic of the cellular nature of granulomas and impacts on the host immunity of infection.

Aminopropionitrile↗
PubMed1981

Inhibition of collagen cross-linking: a new approach to ocular scarring.

A method for the production of alkali-induced conjunctival scarring in rabbits with minimal corneal involvement is presented. The lathyritic agent Beta-aminopropionitrile (BAPN), an inhibitor of collagen cross-linking, was applied topically for a period of 21 days after induction of injury. There was a statistically significant (p less than .025) increase in both the interpalpebral fissure length and width of scarred treated animals compared with the scarred control group. BAPN did not affect the interpalpebral fissure measurements of unscarred rabbit eyes. No clinical adverse effects were observed after the treatment period. Histological evaluation of the treated scar tissue was consistent with lathyrism.

Aminopropionitrile↗
PubMed1985

Elastin-proteoglycans association revealed by cytochemical methods.

By using various cytochemical stains, proteoglycans are shown to be present inside elastic fibers in aortas of beta-aminopropionitrile-induced lathyritic chicks. Depending on the characteristics of the dyes, the shape, size and distribution of the proteoglycan-revealing precipitates are described. The monocationic dye toluidine blue O and the tetracationic dye Alcian blue in the presence of 0.3 M MgCl2 give the most detailed results. With these stains the proteoglycans inside lathyritic elastin appear to be lateral branches of matrix proteoglycans, lying on the external surface of the elastic fibers. A possible general biological significance of elastin-proteoglycan association is briefly discussed.

Aminopropionitrile↗
PubMed1989

Comparative sensitivities of purified preparations of lysyl oxidase and other amine oxidases to active site-directed enzyme inhibitors.

Recent evidence has revealed that lysyl oxidase, plasma amine oxidase and diamine oxidase each contain copper and pyrroloquinoline quinone at their active sites as cofactors essential to their catalytic functions. It thus seems likely that these enzymes will share similar mechanisms of action. Since mechanism-based inhibitors of lysyl oxidase have important chemotherapeutic potential for the control of fibrotic disease, the relative inhibitory potential of such agents toward catalytically similar amine oxidases was assessed in the present study using purified preparations of lysyl oxidase, diamine oxidase, plasma amine oxidase and the flavin-dependent mitochondrial monoamine oxidase A and B. The results indicate that there is sufficient difference between the sensitivities of lysyl oxidase and the other amine oxidases to beta-aminopropionitrile to warrant its consideration as an antifibrotic agent in vivo, while also revealing that aminoguanidine, clorgyline and deprenyl are sufficiently selective for diamine oxidase, monoamine oxidase A and monoamide oxidase B, respectively, to differentiate between lysyl oxidase and these enzymes at appropriate concentrations.

Amine Oxidase (Copper-Containing)↗
PubMed1990

BAPN dose dependence of mature crosslinking in bone matrix collagen of rabbit compact bone: corresponding variation of sonic velocity and equatorial diffraction spacing.

Crosslinking density in demineralized bone matrix collagen was found to depend on the beta-aminopropionitrile (BAPN) dose level for compact bone from rabbit femurs. The dependence was demonstrated for the hydroxypyridinium (HP) concentration, a mature crosslink. A more consistent dependence on BAPN dosage was observed for the fraction of the demineralized bone matrix insoluble in 0.5 M acetic acid (AIF) corresponding to the remaining crosslinked collagen. The average HP concentration in 21 week old controls was 0.24 moles HP/mole collagen which decreased to 0.13 +/- 0.04 for the same age rabbits dosed with 1 gm BAPN/kg/day for 13 wks. The comparable mean AIF values were 0.91 for controls and 0.75 for maximum dose level. Most of the effect of BAPN on crosslinking was observed at the lower dosages below 0.2 g/kg/day. On the other hand, overt osteolathyritic symptoms are seen only for BAPN dosages greater than 0.2 g/kg/day. The mean sonic plesio-velocity was previously found to decrease from 3.4 to 3.03 km/sec as the BAPN dosage was increased. A similar close relationship was discovered for the equatorial diffraction spacing in fully mineralized bone which increased from 1.235 for normal rabbit bone to 1.28 nm for maximum dose. Most of the effect on these physical properties is exhibited at the highest BAPN dosage after much of the decrease in mature crosslinking density has been observed and when the further decrease in mature crosslinking density proceeds very slowly with increased drug dosage. These observations suggest that osteolathyrism does not become manifest until practically all mature crosslinking that can be affected has been inhibited. The mineralization process apparently can be maintained in the newly laid collagen even in the presence of severe osteolathyritic conditions. Intermolecular crosslinking in bone collagen appears to play an important role in the development of bone properties whether by direct or indirect processes. Much of the effects on bone properties occur at the higher BAPN dosages where overt osteolathyrism is observed and where there seem to be only small changes in crosslinking density.

Acetates↗
PubMed1991

The influence of aminoguanidine on borohydride reducible collagen cross-links and wound strength.

The mechanical strength of skin wounds as well as the deposition of hydroxyproline and KB3H4 reducible hydroxylysinonorleucine (HLNL) and dihydroxylysinonorleucine (DHLNL) cross-links in subcutaneously implanted cellulose sponges have been investigated in rats treated with aminoguanidine (AG) or beta-aminopropionitrile (BAPN). Treatment with AG (25 mg/kg BW/day) did not influence the mechanical strength of the wounds, the deposition of hydroxyproline or the pattern of reducible collagen cross-links, whereas AG (125 mg/kg BW/day) reduced the maximum load by 17%, but did not influence the deposition of hydroxyproline or reducible cross-linking pattern. Treatment with BAPN (333 mg/kg BW/day) reduced the strength of the wounds by 59%, the HLNL by 50% and the DHLNL 57%, whereas the deposition of hydroxyproline did not seem to be influenced by BAPN treatment. In conclusion, AG at moderate dosage does not seem to influence the formation of lysyl oxidase dependent reducible cross-links of collagen.

Aminopropionitrile↗
PubMed1993

Interactions of elastin and microfibrils in elastogenesis of human pulmonary fibroblasts in culture.

The interaction of elastin and microfibrils in elastogenesis in vitro was investigated with electron microscopy and immunohistochemistry. Fetal human pulmonary fibroblasts were cultured with or without beta-aminopropionitrile (BAPN). One week after seeding, the extracellular microfibrils were loosely arranged without elastin deposition. Two and six week culture in controls, mature elastic fibers and microfibril bundles were formed. In cultures with BAPN, the microfibrils were loosely arranged, and a few microfibril bundles and no amorphous components were formed. Immunoelectron microscopy for elastin showed the reaction at the outer zones of amorphous components in controls, though the loosely-arranged microfibrils reacted diffusely in cultures with BAPN. Six week culture with BAPN, aggregated masses of elastin, which were dissociated from microfibrils, were found. In conclusion, deposition and maturation of elastin on microfibrils are necessary to form the microfibril bundles in normal elastogenesis, and vaguely outlined aggregated masses of elastin are formed under the inhibition of lysyl oxidase.

Aminopropionitrile↗
PubMed1980

Experimental intracranial aneurysms in rats. A gross and microscopic study.

Experimental cerebral aneurysms were induced in rats in which the left carotid artery was ligated. The rats were rendered hypertensive by the Goldblatt procedure, and fed a diet containing beta-aminopropionitrile. These intracranial aneurysms have significant gross and microscopic similarities to human berry aneurysms. The procedures and microscopic observations indicate that this experimental model could be useful for studying the development, pathophysiology, and therapy of saccular aneurysms.

Aminopropionitrile↗