SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Beta-aminopropionitrile (BAPN) is an inhibitor of pig plasma benzylamine oxidase. BAPN is oxidized by benzylamine oxidase. Inhibition develops in a time-dependent fashion upon incubation of BAPN with the enzyme in the absence of substrate. The product of oxidation of BAPN by benzylamine oxidase, cyanacetaldehyde, was identified and prepared by synthesis. It is an irreversible inhibitor of the enzyme.
Beta-aminopropionitrile, an inhibitor of collagen cross-linking, effectively limited the degree of posttraumatic vitreous proliferation in rabbits three weeks after double perforating injury. Light microscopic examination of the sites of perforating injury after five weeks showed minimal intravitreal fibrous proliferation in treated animals. Electron micrographs of the cicatricial vitreous collagen showed fragmentation of collagen into smaller fibrils and disintegration into amorphous areas. Inhibition of collagen cross-linking may undermine the strength of the vitreous scaffold by making vitreous and cicatricial collagen more sensitive to tissue collagenases produced during inflammation. The failure of fibrovascular membranes to grow into the vitreous may be a secondary effect of weakened vitreous support.
(1) No toxic signs or symptoms and no unusual laboratory determinations were observed in five patients with posterior urethral strictures treated by dilatation of the urethra and administration of 1 gm per day of beta-aminopropionitrile (BAPN) for twenty-one days. (2) Patients treated with 1 gm daily of BAPN for twenty-one days showed an increase in cold saline-extractable and acid-extractable collagen in proplast sponge-collected and dermal scar tissue comparable with that reported previously after doses of 3 to 5 gm of BAPN daily. (3) Significant reduction in the breaking strength of newly synthesized connective tissue was observed in patients treated with BAPN. (4) None of the patients in this study showed abnormalities in net collagen synthesis or in synthesis of noncollagenous protein. (5) The difference in the results of this study and two previous trials of BAPN in human beings which were discontinued because of toxic and or hypersensitivity signs and symptoms is hypothesized to be the result of development of highly purified BAPN fumarate.
The in vitro mechanical properties of this ligament were examined by analysing the stress-strain curve obtained from a transverse section of the mandible. Mechanical measures were compared between normal rats and lathyritic rats given drinking water containing 0.2% of beta-aminopropionitrile (BAPN) for 20 days, and between the velocity of loading at 10(4) and 1 mm/24 h. The daily dose of BAPN decreased gradually because the body weight increased gradually. At the velocity of 10(4) mm/24 h, the maximum shear stress, elastic stiffness and failure strain energy density in the experimental subgroup fell to 43-50% of the control values, and at 1 mm/24 h to 71-80%. The maximum strains were not significantly different between the control and experimental subgroups either at 10(4) or at 1 mm/24 h. In the control subgroups, the maximum shear stress, elastic stiffness and failure strain energy density at 1 mm/24 h fell to 0.04-0.30% of those at 10(4) mm/24 h, and in the experimental subgroups to 0.08-0.43%. The maximum strains at 1 mm/24 h were 1.7-1.8 times greater than those at 10(4) mm/24 h in both the control and experimental subgroups. It is assumed that changes in the mechanical properties of the periodontal ligament were caused by inhibition of maturation of the periodontal collagen fibres. Assuming that the periodontal ligament is viscoelastic in nature, it is suggested that the main component reacting at 10(4) mm/24 h was an elastic one and that both components, with emphasis on the viscous one, interact at 1 mm/24 h.(ABSTRACT TRUNCATED AT 250 WORDS)
When beta-aminopropionitrile (BAPN) is added to neonatal rat aortic smooth muscle cell cultures there is a decrease in insoluble elastin accumulation with a concomitant increase in tropoelastin and tropoelastin fragments in the culture medium. The experiments described here examine the biological significance of this fragmentation. BAPN, as well as purified tropoelastin fragments isolated from spent medium of cells grown in the presence of BAPN, were added to cultures. A decrease in elastin mRNA was observed in cultures grown in the presence of BAPN and also in those cultures to which the purified tropoelastin moieties were added. These studies indicate that the inhibition of lysyl oxidase by BAPN prevents elastin crosslinking which results in an increase in tropoelastin moieties, thus leading to a down regulation of the steady state levels of elastin mRNA.
In cultures of rat dorsal root ganglion (DRG) treated with beta-aminopropionitrile (BAPN), the following abnormalities were observed. Abnormalities in the size and the shape of collagen fibers; longer periodicity of collagen fibers in BAPN (70 +/- 5 nm) than in control (66 +/- 6 nm) (P less than 0.025); lack of basal lamina of both unmyelinated and myelinated Schwann cells; and abundant amorphous materials in the interstitial area between fibroblasts or peripheral cells and Schwann cells associated with neurites. Detachment of the explant from the collagen substratum also occurred and showed dose dependency. In contrast to the alterations of connective tissue, the neurites were well preserved in this experimental regimen.
We have studied the effects of beta-aminopropionitrile (BAPN) administration on the formation of spontaneous arterial lesions, characterized principally by a rupture in the internal elastic lamina (IEL) in the caudal and renal arteries of the Wistar rat. Treatment with BAPN (an inhibitor of lysyl oxidase) increased the formation of these lesions in rats up to 12 weeks of age but had differential effects on the caudal and renal artery in older rats. Administration of the nitrile to weanling rats led to the premature formation of lesions in caudal arteries of both male and female rats which morphologically resemble lesions which form spontaneously later in life. Dietary supplements of copper or pyridoxine were without effect on the formation of spontaneous caudal artery lesions when given from 5 wks of age but a copper supplement from midgestation slightly inhibited lesion formation only in male rats. This suggests that if copper deficiency is involved in spontaneous lesion formation, it is only a contributory factor. Quantification of either caudal or renal artery lesions within different litters of Wistar rats showed that there exists a familial aggregation in the frequency of spontaneous lesion formation, certain litters showing significantly higher levels of lesions than others. Adult Sprague-Dawley rats also appear to be more susceptible to the development of renal artery IEL defects than Wistar rats. The possibility of a hereditary disorder leading to a minor defect in elastic fibre structure which could be responsible for the spontaneous lesions is discussed.
beta-Aminopropionitrile (beta-APN), a lathyrogen, alters the physical characteristics of fibrous scar tissue and as such may have potential clinical use in treatment of injured spinal cord and peripheral nerve by reducing the physical barrier to axon regeneration. For beta-APN to exert its lathyrogenic effect, it must permeate the injury site and gain access to the developing collagenous scar. To investigate the diffusion characteristics, beta-[14C]APN solution was applied as an immersion bath to rat sciatic nerve using both in vivo and in vitro preparations for intervals of 15 to 90 min. The four experimental groups studied were (a) intact nerve, (b) hemisected nerve, (c) nerve with epineurium removed, and (d) nerve with both epineurium and perineurium removed. The isotope labeling index determined by autoradiography and scintillation counting indicated the perineurium as the primary barrier to significant diffusion of beta-APN in normal nerve. When perineurium was incised or removed, beta-APN entered the endoneurial matrix. beta-APN concentration in the epineurium and perineurium increased with increasing bathing time in vitro; but it decreased markedly after 15 min of in vivo bathing. These findings indicate that topical application of beta-APN to injured peripheral nerve would be a successful method of exposing fibrogenic intraneural tissue to the inhibitory effect on lysyl oxidase enzymes. Continuous application, however, will be necessary because of the rapid beta-APN removal documented in the vivo preparation.
The changes of connective tissue in granuloma development were studied up to 20 days following subcutaneous implantation of polyvinyl alcohol (PVA) sponges in rats. The total protein and collagen content were found to increase from the 4th to 12th days of implantation while the content of DNA continuously decreased with the age of the granuloma. Administration of beta-aminopropionitrile (beta APN) fumarate on the intact skin overlying the implanted PVA sponge in the presence and absence of dimethyl sulfoxide (DMSO) during the growth phase of granuloma development (4th through 12th days after implantation) was accompanied by significant inhibition of collagen polymerization. This was documented by a significant increase of collagen extractable into 1 N NaCl, by a significantly reduced content of aldehydes in collagens extractable into neutral salt solution, and by a significant increase of alpha subunits and alpha/beta ratio. Topical beta APN administration had no effect on the content of DNA, noncollagenous proteins, or total hydroxyproline. We conclude that topically administered beta APN fumarate onto the intact skin penetrates the stratum corneum and effectively inhibits collagen crosslinking in the underlying granuloma tissue. The extent of the effectiveness was found to be significantly greater in the presence of DMSO.
A lathyrogen, [C14]aminopropionitrile (beta APN), was administered to 34 rats either in K-Y jelly or saline vehicles onto intact shaven skin or onto a healed splinted deep excision wound. The dynamics of beta APN transport and content in the skin or repair tissue was observed after 2, 5, 8, and 24 hr of topical administration. The repair tissue quickly absorbed the lathyrogen and reached maximum at the 2-hr sampling. The content of beta APN in the repair tissue was twice as high as that in K-Y jelly vehicle and remained high and stable for at least 24 hr only when beta APN was administered through a saline vehicle. The transport of beta APN through intact skin, irrespective of the vehicle tested, was slow and continuously increased. The study showed that almost 20% of the beta APN administered onto the wounded skin area was transported into the repair tissue within 2 hr. We suggest that, due to the absence of epidermal stratum corneum from the repair tissue, drugs, such as beta APN, penetrate quickly into the wound.
Integrative repair of cartilage was previously found to depend on collagen synthesis and maturation. beta-aminopropionitrile (BAPN) treatment, which irreversibly blocks lysyl oxidase, inhibited the formation of collagen crosslinks, prevented development of adhesive strength, and caused a buildup of GuHCl-extractable collagen crosslink precursors. This buildup of crosslink precursor in the tissue may be useful for enhancing integrative repair. We tested in vitro the hypothesis that pre-treatment of cartilage with BAPN, followed by washout before implantation, could be a useful therapeutic strategy to accelerate subsequent collagen maturation. In individual cartilage disks, collagen processing was reversibly blocked by BAPN treatment (0.1 mM) as indicated by a BAPN-induced increase in the total and proportion of incorporated radiolabel that was extractable by 4M guanidine-HCl, followed by a decrease, within 3-4 days of BAPN washout, in the proportion of extractable radiolabel to control levels. With a similar pattern, integration between pairs of apposed cartilage blocks was reversibly blocked by BAPN treatment, and followed by an enhancement of integration after BAPN washout. The low and high levels of integration were associated with enrichment in [(3)H]proline in a form that was susceptible and resistant, respectively, to extraction. With increasing duration up to 7 days after BAPN pre-treatment, the levels of [(3)H]proline extraction decreased, and the development of adhesive strength increased. Thus, BAPN can be used to modulate integrative cartilage repair.
Modulations of the extracellular matrix and scar formation following central nervous system (CNS) injuries are considered prohibitive for axon regeneration, thus restricting functional recovery. Recent findings indicating that lysyl oxidase, an extracellular matrix-forming enzyme, appears in a time-dependent manner at brain injury sites have suggested that inhibition of this enzyme may be conducive for regeneration and functional recovery. Here, we report that after unilateral spinal cord transection in adult mice, daily treatment (for 20 days) with the lysyl oxidase inhibitor beta-aminopropionitrile (100 mg/kg intraperitoneal) resulted in accelerated and more complete functional recovery. The mode of functional recovery, however, indicates that axonal regeneration of long descending tracts did not occur.
We have developed a model of aortic smooth muscle necrosis in adult Sprague Dawley rats by feeding them two vascular toxins (allylamine HCl, or AA, and beta-aminopropionitrile, or betaAPN) in concert for 10 days. Either toxin given alone does not cause aortic lesions. In order to shed light on the mechanism of the synergistic action of these two toxins we fed known modulators of AA or betaAPN toxicity to rats concurrently with the two toxins. As modulators we used (a) semicarbazide (98 mg/kg/day, given 4 h prior to toxins), a known inhibitor of the vascular enzyme SSAO which metabolizes AA; (b) L-cysteine (1.5% in rat chow, beginning 3 days prior to toxins), which has been shown to reduce the toxic effects of betaAPN; and (c) phenelzine sulphate (3 mg/kg/day, given 4 h prior to toxins), an inhibitor of SSAO and potentiator of betaAPN toxicity. Rats were fed various combinations of the toxins and modulators by gavage: water (n = 8); (AA, 100 mg/kg/day) AA + phenelzine (n = 8); AA + semicarbazide (n = 8); AA + L-cysteine (n = 11); (betaAPN, 1 g/kg/day) betaAPN + phenelzine (n = 8); betaAPN + semicarbazide (n = 8); betaAPN + L-cysteine (n = 8); (AA, 100 mg + betaAPN, 1 g/kg/day) AA + betaAPN + phenelzine (n = 9), AA + betaAPN + semicarbazide (n = 8); AA + betaAPN + L-cysteine (n = 12); phenelzine (3 mg/kg/day) (n = 4); semicarbazide (98 mg/kg/day) (n = 4) and L-cysteine (1.5% in rat chow) (n = 4). We found that phenelzine sulphate (a drug previously used in the treatment of hypertension) when given with AA reproduced the AA + betaAPN induced aortic lesions. Phenelzine + betaAPN caused no lesions, but when combined with AA + betaAPN, aortic lesions were intensified and included marked secondary degeneration of the vascular wall. Semicarbazide was found to completely obviate the vascular toxicity of AA + betaAPN. L-Cysteine feeding markedly decreased the incidence and severity of vascular lesions in AA + betaAPN treated rats, but did not change the incidence or severity of heart lesions caused by AA alone. These data indicate that the synergistic necrotizing toxicity of AA + betaAPN is primarily an AA effect. We postulate that some modulating influence of betaAPN (or phenelzine) on tissue distribution, metabolism, or detoxification pathways of AA increases AA's acute vascular toxicity, whereas semicarbazide offers protection by inhibiting the initial deamination of AA to a highly reactive aldehyde.
Allylamine (AA; 3-aminopropene) and beta-aminopropionitrile (betaAPN) combined treatment (AA + betaAPN) results in myocardial protection from AA-induced subendocardial necrosis and a rapid and extensive aortic medial smooth muscle injury in rats. To determine the mechanisms of AA + betaAPN-induced vascular toxicity, cardiovascular parameters were monitored during a 10-day exposure by gavage in male Sprague-Dawley rats (180-200 g). Water intake and urine output were measured in rats treated with water, AA (100 mg kg(-1) body weight), betaAPN (1 g kg(-1) body weight), and AA + betaAPN for 10 days in metabolic cages. Plasma and urine samples were analyzed for blood urea nitrogen, CO2, creatinine, hematocrit, electrolytes (Na+, K+, Cl-), and osmolality. Heart and plasma semicarbazide-sensitive amine oxidase metabolic capacity (SSAO)was also measured following 1, 3 and 10 days of treatment. Following 10 day exposure to control or AA + betaAPN treatment, thoracic aortic rings (approximately 3 mm) were removed, and aortic reactivity to contractile and relaxant agonists was tested in vitro. In addition, cultured rat aorta vascular smooth muscle cells or rat heart beating myocytes were exposed to various concentrations of AA and betaAPN or AA metabolites and betaAPN to test for synergism in vitro. Several of the changes in in vivo cardiovascular parameters were shared, both in direction and magnitude, between the AA + betaAPN and the AA alone or the betaAPN alone treatments. This suggests that these effects (e.g. increased water intake and urine flow, decreased hematocrit, decreased heart and plasma SSAO metabolic capacity) were dependent on an AA alone or a betaAPN alone effect and were not AA + betaAPN specific effects. Significant inhibition of plasma and heart SSAO metabolic capacity occurred in the betaAPN alone and the AA + betaAPN treatments, but not in the AA alone treatment. Aortic rings from AA + betaAPN treated rats were contracted significantly less than anatomically-matched control rat aortic rings by 100 mM potassium chloride or by 10 microM norepinephrine. BetaAPN offered substantial protection against AA cytotoxicity in cultured vascular smooth muscle cells and beating myocytes, but did not alter the cytotoxicity of AA metabolites (i.e. acrolein, H2O2, or ammonia) in vascular smooth muscle cells as determined by the MTT viability assay. Overall, these data suggest that myocardial protection from AA injury that occurs in the combined AA + betaAPN treatment is likely due to inhibition of plasma SSAO. This may result in an increase in the AA dose accumulation and metabolism in the aorta leading to the severe aortic medial injury.
In the present study we describe changes in aorta at the protein level associated with allylamine (AA) and beta-aminopropionitrile (beta APN) induced vascular toxicity in a rat model. This model represents a remarkable synergistic, necrotizing toxic effect of these combined toxins, and our rationale was to examine protein expression in order to shed light on the mechanisms underlying this synergism. Rats were given AA (100 mg/kg body weight/day) and beta APN (1 g/kg body weight/day) by gavage for 10 d; this protocol has been shown to result in smooth-muscle necrosis, but no visible connective tissue changes. Soluble and insoluble fractions from AA + beta APN- or from beta APN-treated aorta showed enhanced expression of three high-molecular-weight protein bands (ranges between approximately 120 and 95 kD). The time course of induction of proteins showed the appearance of AA + beta APN-induced specific proteins at d 3 of AA + beta APN treatment. Partial purification and characterization suggested that AA + beta APN specific proteins are likely to be collagen proteins (type I). Thus, the data presented in this article help in understanding the vascular toxicity induced by AA + beta APN or by beta APN, in that we have described an altered phenotypic expression of collagenous proteins indicative of selective medial vascular toxicity.
Wound contraction is a clinically important biological process because it frequently results in contractures, strictures, and stenosis. If collagen synthesis could be altered to minimize the contracture, then the outcome could be improved. Lathyrism produces poorly cross-linked collagen in healing anastomosis, keeping a larger portion of the synthesized collagen soluble. Ultimately, the amount of contracting collagen is reduced, lowering the bulk and lessening the contracture. The aim of this study was to observe the effects of a lathyrogen, beta-aminopropionitrile (BAPN), on the healing of colonic anastomosis. Thirty rats were divided into three groups. Colostomy and anastomosis were performed on all rats. Intraperitoneal saline solution (control) and either intraperitoneal (ip) or oral (po) BAPN were administered. The rats were killed 1 week later. Anastomotic healing was assessed by bursting pressure and the hydroxyproline content of the anastomotic tissues. Granulation tissue thickness, number of fibroblasts, inflammatory cells, and growing capillaries in granulation tissue per unit area were determined. Collagen fibril diameters were estimated, and spatial arrangements of fibrils were examined by an electron microscope. All results were evaluated by Mann-Whitney U-test. The analyses of anastomotic tissues from BAPN-treated rats showed a significantly reduced mean bursting pressure (158.9 +/- 12.3, 171.3 +/- 13.9, ip and po, respectively), hydroxyproline content (8.9 +/- 2.6, 10.1 +/- 2.7), granulation tissue thickness (24.3 +/- 2.6, 16.1 +/- 5.2), number of inflammatory cells (37.8 +/- 4.3, 25 +/- 4.3), fibroblasts (3.2 +/- 1.1, 2.8 +/- 0.7), and a significantly reduced collagen fiber diameter (15 +/- 2, 20 +/- 3) compared with those of control group (236.9 +/- 9, 14 +/- 4.4, 26.8 +/- 4.8, 39 +/- 2.6, 6.9 +/- 1.1, and 35 +/- 5, respectively). As a result, collagen fibers were flimsy, and lost their regular parallel alignment in the BAPN groups. On the other hand, a number of growing capillaries were found to be significantly increased in these groups (16.5 +/- 1.1, 18.2 +/- 0.7) compared to the control (6.7 +/- 1.3). Thus, it is suggested that BAPN may be useful in the prevention of gastrointestinal stricture formation.
The lathyrogenic agents, beta-aminopropionitrile and semicarbizide, when applied to the chorio-allantoic membrane of the chick embryo produced a dramatic increase in fragility of the embryo. This alteration was not associated with a change in the concentration of collagen, except in aorta, but was accompanied by a sharp increase in the amount of collagen extractible in cold 1 M NaCl from skin, bone, and aorta. Increase in fragility and extractible collagen began within 3 hours after introduction of the agent and rose steadily for at least 72 hours. Essentially no collagen could be extracted from tissues of normal chick embryos. Both fragility and amount of extractible collagen were dosage- and time-dependent. It is concluded that the extractible collagen in lathyrism consists of a large proportion of dissolved fibers previously insoluble and formed prior to administration of the agent. The data also suggest that the "lathyritic" collagen in vivo is not in molecular dispersion but in an aggregate or fibrillar form. It is dispersed by cooling. The extracted collagen could be reconstituted to typical striated fibrils in vitro and the molecule appeared to be normal in the gross, with regard to asymmetry ratio and intramolecular helical structure. The evidence at hand suggests that at least one of the defects induced by lathyrogenic agents is an interference with the normal intermolecular cross-linking within the collagen fibril.
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.