Pharmacological profile of AA-861, A 5-lipoxygenase inhibitor

Ashida, Yuzuru; Saijo, Taketoshi; Kuriki, Hisashi; Makino, Haruhiko; Terao, Shinji; Maki, Yoshitaka

doi:10.1016/0090-6980(83)90157-0

Cited by 124 publications

(52 citation statements)

References 26 publications

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“…Our experiments with the antioxidant 5-lipoxygenase inhibitor AA-861 (Ashida et al, 1983) indicate that leukotrienes are unlikely to play a significant role in the augmentation of epithelial permeability associated with eosinophil-dependent cellular injury. However.…”

Section: Discussionmentioning

confidence: 94%

“…Furthermore, although position 2 was not tested, placement 1 was effective at inhibiting the action of stimulated neutrophils. In order to establish whether products of the 5-lipoxygenase pathway were responsible in any way for the increased bronchial epithelial flux of albumin resulting from the exposure to stimulated eosinophils, a series of experiments was performed using the 5-lipoxygenase inhibitor AA-861 (Ashida et al, 1983). After preincubation of the eosinophils with AA-861 for 5 min the cells were added to the chamber together with Net flux (fmol cm -2 min -)…”

Section: Methodsmentioning

confidence: 99%

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In vitro modulation of the eosinophil‐dependent enhancement of the permeability of the bronchial mucosa

Herbert

Edwards

Boot

et al. 1991

British J Pharmacology

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Basolateral to apical albumin flux has been measured in sheets of bovine bronchial and tracheal mucosa mounted in vitro. Addition of guinea‐pig peritoneal eosinophils or neutrophils to the basolateral side of such tissues had no significant influence on the transmucosal flux of albumin in either the bronchial or tracheal mucosa. Stimulation of eosinophils or neutrophils by the calcium ionophore A23187, or by their presentation to an opsonized airways mucosa, resulted in a significant increase in the transbronchial flux of albumin. This effect was seen after only 60 min incubation of the leucocytes with the bronchial mucosa, and was no greater when the contact time was extended to 180 min. Incubation of bronchial mucosal tissues with 1 mg ml−1polyarginine for 3 h produced a significant increase in albumin flux, but was ineffective at 0.5 mg ml−1. In contrast to the bronchial mucosa, the tracheal mucosa appeared resistant to the effects of stimulated eosinophils and neutrophils. The lipoxygenase inhibitor AA‐861 failed to influence the ability of eosinophils to augment the transmembrane flux of albumin. However, insertion of a Millipore filter mask between the eosinophils and the bronchial mucosa significantly inhibited the eosinophil‐dependent enhancement of mucosal permeability. The broad spectrum antiproteinase α2‐macroglobulin achieved almost total ablation of the action of stimulated eosinophils in the bronchial mucosa. These results suggest that proteinases may make a significant contribution to the genesis of epithelial injury, whereas leukotrienes do not.

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Section: Discussionmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

In vitro modulation of the eosinophil‐dependent enhancement of the permeability of the bronchial mucosa

Herbert

Edwards

Boot

et al. 1991

British J Pharmacology

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“…This manuscript describes the fermentation, isolation and purification, structural identification, and some biological properties of the inhibitors. [5,6,8,9,11,12,14,15-3H]5-HETE (60.0 mCi/mmol) and [5,6,8,9,11,12,14,15-3H]thromboxane B2 (150 mCi/mmol) were obtained from New England Nuclear (Boston). 12-HETE was a generous gift from Dr. D. H. NUGTEREN (Uniliver Research Laboratorum Vlaardingen).…”

mentioning

confidence: 99%

Studies on lipoxygenase inhibitors. II KF8940 (2-n-heptyl-4-hydroxyquinoline-N-oxide), a potent and selective inhibitor of 5-lipoxygenase, produced by Pseudomonas methanica.

et al. 1986

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Pseudomonas methanica KY4634 was found to produce 5-lipoxygenase inhibitor designated KF8940, MY12-62a and MY12-62c. The inhibitors were purified by solvent extraction, silica gel column chromatography, reversed-phase low pressure liquid chromatography and crystallization. The chemical structures of KF8940, MY12-62a and MY12-62c were determined to be 2-n-heptyl-4-hydroxyquinoline-N-oxide, 2-n-heptyl-4-hydroxyquinoline and 3-n-heptyl-3-hydroxy-1,2,3,4-tetrahydroquinoline-2,4-diore, respectively, on the basis of their physico-chemical properties. Among them, KF8940 was the most potent inhibitor. The compound inhibited 5-lipoxygenase of rat basophilic leukemia cells in a dose-dependent manner and the half maximal inhibitory concentration (IC,0) was 1.5 x 10 M. At this concentration, KF8940 did not inhibit bovine platelet 12-lipoxygenase and cyclooxygenase, and the IC,,0 values for these enzyme were 3.5 x 10-5 M and 1.7 x 10-4 M, respectively. The results indicated that KF8940 is a potent and selective inhibitor of 5-lipoxygenase. The IC50 value of MY12-62c for 5-lipoxygenase was 1.9 x 10 M and that of MY12-62a was 1.9 x 10-5M.Much attention has been focused on 5-lipoxygenase inhibitors as anti-asthmatic and anti-inflammatory agents since SAMUELSSON and co-workersl,2) showed that slow reacting substances of anaphylaxis (SRS-A), potent mediators generated during anaphylactic reaction, were oxidative products of arachidonate 5-lipoxygenase. The enzyme is mainly distributed in leukocytes3) and catalizes the oxygenation of arachidonic acid at C-5 position to produce 5-HPETE. The product can be either reduced enzymatically to its hydroxy derivative, 5-HETE, or transformed to the peptide LTs and LTB4. LTB4 was proposed to be implicated in inflammatory reactions because of its potent chemotactic activity4).Many compounds have recently been reported as 5-lipoxygenase inhibitors5-9) and some of them exhibited anti-asthmatic activities10,11). In the course of screening for lipoxygenase inhibitors from microbial origin, we found that Pseudomonas methanica KY4634 produced potent 5-lipoxygenase inhibitors. The compounds, designated KF8940, MY12-62a and MY12-62c, were isolated from the culture broth and their structures were determined. Among them, KF8940, 2-n-heptyl-4-hydroxyquinoline-N-oxide, was a potent and selective inhibitor of the enzyme. This manuscript describes the fermentation, isolation and purification, structural identification, and some biological properties of the inhibitors.

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“…[Melittin] (-log M) Bradykinin-relaxation in trachea 830 ± 77 mg, respectively (n = 5). AA861 (1 gsM), a 5-lipoxygenase inhibitor (Ashida et al, 1983), did not modify the responses to bradykinin in the presence or absence of indomethacin ( Figure the contractile response to histamine. In tracheal preparations without epithelium, the highest bradykinin concentration used (3 gM) led to the reversal of 42 ± 4% (n = 5) of the histamine-induced contraction.…”

Section: Methodsmentioning

confidence: 99%

Involvement of B₂ receptors in the bradykinin‐induced relaxation of guinea‐pig isolated trachea

Silva

Amrani

Landry

1995

British J Pharmacology

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1 The aim of this study was to determine the receptor type and involvement of arachidonic acid metabolites in bradykinin-induced relaxation of the guinea-pig isolated trachea. 2 In the resting tracheal preparation, bradykinin (0.1 nM-30 LM induced a concentration-related contractile response (pD2 = 8.8 ± 0.3). The maximal tension (1056 ± 321 mg) was observed at 0.3 4M bradykinin. In contrast, when tracheal preparations were pre-contracted with histamine (30 LM leading to a half-maximum response), a concentration-related relaxation was observed with bradykinin. At the highest concentration of bradykinin used (3 LM), a reversal of 63 ± 13% of the contractile response to histamine was observed. Both effects of bradykinin were inhibited by the cyclo-oxygenase inhibitor, indomethacin (1I M). In concentration-response curves, melittin (1O nM-1 jM), a direct activator of phospholipase A2, mimicked both effects of bradykinin. The highest concentration of melittin used (1 tM), induced a tension of 813 ± 120 mg and led to the reversal of 41 ± 8% of the contractile response to histamine. The contractile effect of melittin was inhibited in the presence of both indomethacin (1 jM) and AA861 (1 jM), a 5-lipoxygenase inhibitor. . 4 These data demonstrate that bradykinin-induced relaxation of guinea-pig trachea occurs via the activation of bradykinin B2-receptors. The stimulation of B2-bradykinin receptors induces the activation of the cyclo-oxygenase pathway, leading either to contraction or relaxation depending on the tone of the trachea.

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Pharmacological profile of AA-861, A 5-lipoxygenase inhibitor

Cited by 124 publications

References 26 publications

In vitro modulation of the eosinophil‐dependent enhancement of the permeability of the bronchial mucosa

In vitro modulation of the eosinophil‐dependent enhancement of the permeability of the bronchial mucosa

Studies on lipoxygenase inhibitors. II KF8940 (2-n-heptyl-4-hydroxyquinoline-N-oxide), a potent and selective inhibitor of 5-lipoxygenase, produced by Pseudomonas methanica.

Involvement of B₂ receptors in the bradykinin‐induced relaxation of guinea‐pig isolated trachea

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Pharmacological profile of AA-861, A 5-lipoxygenase inhibitor

Cited by 124 publications

References 26 publications

In vitro modulation of the eosinophil‐dependent enhancement of the permeability of the bronchial mucosa

In vitro modulation of the eosinophil‐dependent enhancement of the permeability of the bronchial mucosa

Studies on lipoxygenase inhibitors. II KF8940 (2-n-heptyl-4-hydroxyquinoline-N-oxide), a potent and selective inhibitor of 5-lipoxygenase, produced by Pseudomonas methanica.

Involvement of B2 receptors in the bradykinin‐induced relaxation of guinea‐pig isolated trachea

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Involvement of B₂ receptors in the bradykinin‐induced relaxation of guinea‐pig isolated trachea