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PubMed1987

Experimental induction of cerebral aneurysms in monkeys.

Saccular cerebral aneurysms were successfully induced in two monkeys treated with ligation of the common carotid artery, experimental hypertension, and beta-aminopropionitrile feeding. The cerebral aneurysms developed on the large arteries at the base of the brain, such as the anterior communicating artery and the internal carotid artery at the origin of the posterior communicating artery. Because of the similarity of the monkey to man as a species, the present results strongly suggest the significance of postnatal aggravating factors in the development of cerebral aneurysms in man.

Aminopropionitrile↗

PubMed2000

Hydrogen peroxide-mediated, lysyl oxidase-dependent chemotaxis of vascular smooth muscle cells.

Lysyl oxidase (LO), an enzyme secreted by vascular smooth muscle cells (VSMC), initiates the covalent crosslinking of polypeptide chains within collagen and elastin. The present study reveals that purified LO strongly induces directional migration of VSMC in an in vitro assay system. LO-dependent chemotaxis, but not chemokinesis, was abolished by beta-aminopropionitrile, an active site inhibitor of LO, or by catalase, as well as by prior heat denaturation. This indicates that the H(2)O(2) product of amine oxidation by LO is critical to the expression of its chemotactic activity. The results indicate that the chemotactic response requires direct access between LO and a substrate molecule (or molecules) tightly associated with the VSMC. The addition of LO to VSMC elevated the levels of intracellular H(2)O(2), enhanced stress fiber formation, and focal adhesion assembly, is consistent with the induction of the chemotactic response.

Actin Cytoskeleton↗

PubMed1998

[Effects of 764-3 on collagen deposition in hypertensive pulmonary arteries in hypoxic rats].

OBJECTIVE: To investigate the changes of collagen deposition in pulmonary arteries in chronic hypobaric hypoxic rats and the roles of 764-3. METHODS: Wistar rats were divided into 10 groups. The hypoxic (50.7 kPa) rats were treated with 764-3 (20 mg/kg, once daily) and beta-aminopropionitrile (BAPN, 150 mg/kg, twice daily), respectively. At the end of treatment, the hemodynamic morphological and chemical parameters were measured. RESULTS: Comparing with the normals, hydroxyproline (HYP) content of extrapulmonary artery (EPA) increased obviously in hypoxic rats, the smooth muscle cells (SMC) in the media of muscular intra-acinar pulmonary artery showed hypertrophy with change in phenotype, and a striking increment of collagen accumulation (P < 0.001); 764-3 could reduce HYP content of EPA (P < 0.05-0.001), and most of SMC in the media became thin and elongated with reversion of change of SMC phenotype, and collagen accumulation was reduced (P < 0.001). In addition, BAPN was more effective than 764-3 (P < 0.05). CONCLUSIONS: Excessive collagen accumulation in pulmonary arteries plays an important role in the maintenance of hypoxic pulmonary hypertension. 764-3 can partially inhibit collagen deposition in pulmonary arteries, attenuate hypoxic pulmonary hypertension, and has a moderate influence on collagen deposition in compared with BAPN.

Aminopropionitrile↗

PubMed1992

Alteration of elastic architecture in the lathyritic rat aorta implies the pathogenesis of aortic dissecting aneurysm.

Weanling Sprague-Dawley rats received beta-aminopropionitrile (BAPN) and/or hypertensive treatment, namely, heminephrectomy and administration of deoxycorticosterone acetate-NaCl. The BAPN-treated rats (lathyritic rats) died of dissecting aneurysm, and the victims with hypertensive treatment was greater in number and died earlier than those without the treatment, indicating that the rise of blood pressure promoted the onset of dissecting aneurysm. The elastic architecture of the ascending aortic media was examined not only by transmission electron microscopy with tannic acid stain and/or toluidine blue O stain, but also by scanning electron microscopy after hot formic acid treatment, and the area of interlaminar elastic fibers were morphometrically analyzed by a point counting method using transmission electron microscopic photographs. In the lathyritic rats, interlaminar elastic fibers showed a significant reduction compared with the control rats, and elastic fibers tended to become round-shaped and were frequently spotted with glycosaminoglycan, which suggest a disturbance of elastogenesis. On the other hand, elastic laminae were not disrupted and smooth muscle cells were well preserved. These results suggest that the alteration of the elastic architecture causes an unstable connection between each elastic lamina, and is related to the initiation and the progression of dissecting aneurysm.

Aminopropionitrile↗

PubMed2006

Periodontal & systemic bone changes in rats with experimental lathyrism.

BACKGROUND & OBJECTIVE: It is not clear how lathyrism affects the systemic bone metabolism. We therefore undertook a study to observe periodontal and systemic bone changes by performing radiological, metabolic, and bone densitometric evaluations in rats with experimental lathyrism. METHODS: A total of 30 rats were used. Experimental lathyrism was induced by once daily subcutaneous administration of beta-aminopropionitrile (beta-APN), at a dose of 5 mg beta-APN/0.4 ml per 100 g of body weight for 40 days. After 40 days, vertebral bone mineral density was analyzed by means of dual energy X-ray absorbtiometry in both groups. Blood was drawn by cardiac puncture and the animals were decapitated. Serum calcium levels were measured. Right mandibles were removed and radiographs were obtained. Alveolar bone level was determined in the radiographs. RESULTS: In all lathyritic rats, alveolar bone level was pathologically decreased with visible resorption. Vertebral bone mineral density values of lathyritic rats did not differ significantly from those of the control group. Compared to controls, there was a statistically significant decrease in serum calcium levels in the lathyritic group (P<0.001). INTERPRETATION & CONCLUSION: Significant alveolar bone resorption without alterations in vertebral bone mineral density indicated that lathyrogen administration for 40 days presumably has not caused systemic demineralization. This model could be used for studying the role of local and systemic agents on periodontal alveolar bone resorption.

Alveolar Process↗

PubMed1991

[Histochemical model investigations of the action mechanisms of lathyrogenic substances].

In histochemical model studies, aminoacetonitrile and 3-aminopropionitrile can form hydrolysis-stable azomethines (Schiff bases) with periodate-induced aldehyde groups of tissue slices. Both substances and triethylentetramine do not inhibit the histochemical monoaminoxidase activity, they even can act as substrates of this enzyme. These substances cause an inhibition of the histochemical aminopeptidase M activity, but this inhibition was recognized as a methodological error due to the formation of complexes between diazonium salts and aliphatic amines. The results indicate that the inhibition of the lysyl oxidase will not be the only mechanism of action of lathyrogenic substances.

Aminoacetonitrile↗

PubMed1991

Evaluation of drug treatments for proliferative vitreoretinopathy using vitreous microtensiometry.

The effectiveness of antimetabolic and anticollagen agents against proliferative vitreoretinopathy (PVR) was assessed by vitreous microtensiometry, a new technique that measures in situ the tensile strength of vitreous membranes. Two PVR models were produced in rabbits by intravitreal injection of bovine retinal pigment epithelial (RPE) or fibroblast cells, and the animals subsequently were treated with 5-fluorouracil (5-FU) and beta-aminopropionitrile (BAPN), administered alone or in combination. The fibroblast PVR model produced high-strength membranes that did not respond significantly to these therapies. The RPE model gave lower-strength membranes that showed marginally significant decreases in strength with intravitreal 5-FU and systemic BAPN treatments. However, combination therapy showed a highly significant decrease in membrane strength and a clinically encouraging reduction in retinal detachment.

Aminopropionitrile↗

PubMed1990

Effect of lathyrogen on collagen of methylcholanthrene-induced sarcoma of rat.

Since the lathyrogen beta-aminopropionitrile is known to affect the fibrogenic and physical properties of collagen polymers, we have examined its effects on collagenous components of methylcholanthrene-induced fibrosarcoma in rat. Lathyrogen treatment reduced total collagen content of tumours from approximately 17 to 12 mg collagen/g tissue. It also proportionately increased the solubility of specific collagen fractions, the summation of all extractable solubilized collagens reflecting 37 and 67% of total collagen content for control and lathyric tumours, respectively. Although lathyrogen had no significant effect on the growth and overall size of fibrosarcoma, histological studies confirmed that changes had occurred to appearance and distribution of collagenous components of extracellular matrix.

Aminopropionitrile↗

PubMed1985

Lathyrism: mini-review and a comment on the lack of effect of protease inhibitors on osteolathyrism.

Lathyrism has been reviewed in respect to four overlapping phases: finding an animal model for neurolathyrism, characterizing osteolathyrism in respect to its possible use as an animal model for human diseases, such as Marfan's syndrome, idiopathic juvenile scoliosis, etc., use of beta-aminopropionitrile (BAPN) as a tool to study collagen, and use of BAPN as a therapeutic agent in man. Because it has been suggested that the lathyrogen, BAPN, may stimulate the release of proteases, the protease inhibitors Trasylol and epsilon-aminocaproic acid (EACA) were given alone or in combination to BAPN-treated rats. The protease inhibitors did not reduce the effects of BAPN as measured by exostosis formation or collagen extractability.

Aminocaproates↗

PubMed1988

Inhibition of angiogenesis through modulation of collagen metabolism.

Combinations of angiostatic steroids and heparin induce basement membrane breakdown, capillary retraction, and endothelial cell rounding as part of their antiangiogenic action (Ingber DE, Madri JA, Folkman J: Endocrinology 119:1768, 1986). Specific modulators of matrix metabolism were examined for their effects and on capillary development in the growing chick chorioallantoic membrane to explore the possibility that structural alterations of extracellular matrix (ECM) could be causally involved in the antiangiogenic mechanism. Regression of growing capillaries was induced by proline analogs (1-azetidine-2-carboxylic acid, cis-hydroxyproline,d,L-3,4-dehydroproline, thioproline) and an inhibitor of prolyl hydroxylase (alpha,alpha-dipyridyl) which interfere with triple helix formation and prevent collagen deposition. Beta-aminopropionitrile, an inhibitor of collagen cross-linking, was also antiangiogenic although an inhibitor of glycosaminoglycan deposition (beta-methyl d-xyloside) was not. Combination of suboptimal doses of active collagen modulators with either angiostatic steroids or heparin resulted in great potentiation of their antiangiogenic effects. Coadministration of proline analogs, angiostatic steroids, and heparin resulted in complete inhibition of angiogenesis (avascular zones in 100% of chorioallantoic membranes) and larger and more extensive avascular zones than previously observed with steroid-heparin combinations. The antiangiogenic effects of these compounds (alone and in combination) were found to be directly related to their ability to inhibit collagen accumulation. Screening of additional compounds that are known to alter ECM turnover resulted in identification of a new angiogenesis inhibitor, all trans-retinoic acid. These findings suggest that growing capillaries may be "switched" into a regressive mode through alterations of collagen metabolism that result in loss of ECM structural integrity. Identification of ECM turnover as a major control point in angiogenesis may also provide a more rational approach for development of new antiangiogenic regimens.

Allantois↗

PubMed1989

Collagen cross-link synthesis in cultured vascular endothelium.

Cultured vascular endothelium secretes the enzyme lysyl oxidase which cross-links both collagen and elastin. The major reducible cross-link synthesized by cultured human umbilical arterial and venous endothelium is dihydroxylysinonorleucine (di-OH-LNL). Treatment of the cultures with the lathyrogen beta-aminopropionitrile (BAPN), which inhibits lysyl oxidase, inhibited synthesis of this cross-link. Cultured porcine aortic endothelium synthesized three major reducible lysine-derived cross-links: dihydroxylysinonorleucine (di-OH-LNL), hydroxylysinonorleucine (OH-LNL) and lysinonorleucine (LNL); BAPN also inhibited synthesis of these three cross-links. Earlier in-vivo observations on BAPN-treated chick embryos had shown a 20% increase in the hydration of cartilage and other tissues; the likeliest explanation was that cross-link disruption permitted the proteoglycans in cartilage to express their hydrophilic nature when freed of their collagenous network. Capillary basement membrane contains laminin, proteoglycan and type IV collagen. Following the finding of oedema in lathyritic cartilage, we would propose that agents which disrupt collagen cross-links in cultured vascular endothelium, damaging capillary basement membrane, be considered as one possible mechanism in the pathogenesis of oedema.

Aminopropionitrile↗

PubMed1987

Type XI collagen is a heterotrimer with the composition (1 alpha, 2 alpha, 3 alpha) retaining non-triple-helical domains.

Three collagen chains, 1 alpha, 2 alpha, and 3 alpha, have previously been identified in the cartilaginous extracellular matrix and have been referred to collectively as type XI collagen. The structure of type XI is poorly defined. Neither the organization of these collagen chains into trimeric molecules nor the extent of proteolytic processing has been adequately determined. Formaldehyde-derived covalent cross-links were introduced into the native molecules. As judged by velocity sedimentation, the cross-links formed were predominantly intramolecular and led to the formation of covalent trimeric molecules. Chromatographic analysis of trimers is most consistent with a heterotrimer (1 alpha, 2 alpha, 3 alpha) being the predominant form. To investigate the structure of type XI as it occurs in the matrix, sterna from chick embryos treated with beta-aminopropionitrile were solubilized without proteolysis with pepsin. Electrophoretic analysis revealed that all three chains of type XI retain non-triple-helical domains. Some heterogeneity was observed in the size of the 1 alpha chain. Metabolic labeling and long term chase experiments suggested that this heterogeneity in the size of 1 alpha may be due to slow or incomplete posttranslational proteolytic processing.

Aminopropionitrile↗

PubMed1987

[Formation of disruptions of the internal elastica lamina, spontaneous and BAPN induced, in arteries of stroke-prone spontaneously hypertensive rats].

In the caudal and renal arteries of the male Wistar rat, interruptions in the internal elastic lamina (IEL) form spontaneously with age. beta-aminopropionitrile (BAPN), which is an inhibitor of the enzyme lysyl oxidase implicated in the synthesis of elastin, is able to induce in the young Wistar rat interruptions in the IEL which are morphologically very similar to those which form spontaneously. The spontaneously hypertensive strain (SHR), together with the Stroke-Prone spontaneously hypertensive substrain (SHR-SP) which is susceptible to cerebrovascular accidents early in life, have been selected from the Wistar strain. We have compared the incidence of IEL interruptions in caudal and renal arteries from SHR-SP aged 12 and 23 weeks with that observed in age-matched SHR. In addition, we have studied the effect of BAPN, administered from weaning during two weeks, on the formation of interruptions in the IEL in the caudal artery of SHR-SP, SHR and normotensive Wistar and WKY rats. Interruptions in the IEL were quantified by light microscopy on longitudinal semi-thin sections. Results showed that, in the caudal and renal arteries of SHR-SP, the number of interruptions in the IEL which form spontaneously was greater than in SHR. Moreover, BAPN administered between the age of 3 and 5 weeks led to the premature formation of a higher level of interruptions in the IEL in SHR-SP than in the 3 other strains of rat. The SHR was the strain which developed the least.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed1978

Pharmacological control of surgical scar tissue.

Pharmacological control of unwanted scar tissue theoretically is possible in human beings and has been proven to be practical and effective treatment in laboratory animals. The most advanced research involves prevention of the development of helical structure and transport of collagen by administration of proline analogues and controlled induction of lathyrism by administration of Beta-aminopropionitrile. The toxicity of proline analogues has prevented human testing; BAPN presently is being tested or has been tested in patients with scleroderma, flexor tendon adhesions, posterior urethral strictures, and surface keloids. At this time, highly purified BAPN appears generally non-toxic and is capable of exerting a higly selective and significant lathyrogenic effect on the healing wound. The combination of BAPN and other drugs, such as Colchicine, which increases collagenolytic activity, probably will make safe control of clinical properties of scar tissue possible within the next 24 months.

Aminopropionitrile↗

PubMed1986

The effect of collagen cross-linkage inhibitors on rabbit corneas after radial keratotomy.

The inhibition of collagen cross-linkage by beta-aminopropionitrile (BAPN) and D-penicillamine was tested in an attempt to enhance the myopic correction achieved by radial keratotomy. Two groups of six rabbits each underwent radial keratotomy in both eyes; one eye of each rabbit was treated with BAPN (33% in white petrolatum) or D-penicillamine (1.5 M in sterile water) three times a day for 6 weeks, while the other eye received only vehicle. In spite of previous reports of positive results with BAPN, neither BAPN nor penicillamine was found to affect keratometry readings or corneal topography after radial keratotomy. Our results suggest that factors other than collagen cross-linkage exert major influences in determining the outcome of this refractive procedure.

Aminopropionitrile↗

PubMed1985

Effect of phenytoin and/or beta-aminoproprionitrile on a surgically induced periosteal wound.

Phenytoin has a beneficial effect on wound healing and on the healing of bone fractures, while beta-aminopropionitrile (BAPN) has an adverse effect on both. BAPN causes what appears to be a repair response in the periosteum at sites of muscle attachment, but phenytoin does not alter that response. The effect of phenytoin and/or BAPN on the repair of a surgically induced periosteal wound at the insertion of the adductor longus and pectineus muscles was studied in rats at 7 days post-wounding. Phenytoin facilitated and BAPN exacerbated the repair process, as indicated by the size of the periosteal response. Phenytoin increased the percentage of bone present in the responses, and both phenytoin and BAPN reduced the amount of cartilage present. The possible role of inflammation in obtaining the beneficial effects of phenytoin in wound healing is discussed.

Administration, Oral↗

PubMed1985

Processing of soluble elastin in cultured neonatal rat smooth muscle cells.

The synthesis and extracellular deposition of elastin by cultured neonatal rat aorta smooth muscle cells has been followed. The addition of beta-aminopropionitrile to the culture medium promotes accumulation of soluble precursors of elastin. Under such conditions, a protein possessing characteristics of a soluble elastin precursor with an apparent molecular weight of 77,000 was detected and partially purified. Pulse-chase studies suggested that this 77-kDa protein undergoes an extracellular, enzymatically catalyzed process to a 71-kDa protein. This 71-kDa protein is strikingly similar to tropoelastins isolated from other tissue systems, in which no evidence for higher molecular weight soluble precursors is at present available. Data presented in this communication suggest that the 77-kDa protein, which we have designated protropoelastin, represents a precursor to the tropoelastin moiety produced in the neonatal rat smooth muscle cell culture.

Aminopropionitrile↗

PubMed1979

Experimentally induced cerebral aneurysms in rats: Part III. Pathology.

Experimentally induced cerebral aneurysms in rats treated with unilateral ligation of the common carotid artery, deoxycorticosterone and salt hypertension, and beta-aminopropionitrile, were studied macroscopically and with light-microscopy. The material consisted of 13 aneurysms located on the anterior cerebral-anterior communicating arterial complex and one on the posterior cerebral artery. The findings were generally in accordance with that of spontaneous lesions in man. The results show the validity of these experimental aneurysms as a model for saccular cerebral aneurysms in man.

Aminopropionitrile↗