Selective inhibition of arachidonate 5‐lipoxygenase by novel acetohydroxamic acids: effects on bronchial anaphylaxis in anaesthetized guinea‐pigs

Payne, A.N.; Garland, L.G.; Lees, Ian W.; Salmon, John A.

doi:10.1111/j.1476-5381.1988.tb11558.x

Cited by 40 publications

(16 citation statements)

References 12 publications

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“…Since it has been reported that both BW A4C, a 5-lipoxygenase inhibitor, and FPL55712 inhibited anaphylactic bronchoconstriction in guinea pigs pretreated with indomethacin and mepyr amine (27), SRS-A is one of the main mediators of anaphylactic bronchoconstriction in this widely used model of "asthma" (28)(29)(30). From the fact that ONO 1078 (3 -10 mg/kg, p.o.)…”

Section: Discussionmentioning

confidence: 99%

In Vivo Pharmacologic Profile of ONO-1078: A Potent, Selective and Orally Active Peptide Leukotriene (LT) Antagonist.

et al. 1992

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ABSTRACT-We investigated the in vivo antagonistic activity of ONO-1078 against peptide leuko trienes (LTs) in guinea pigs. ONO-1078, when administered p.o. (0.3-3 mg/kg), caused a dose-depend ent reduction of LTC4-, LTD4 and LTE4-induced bronchoconstriction, LTD4-induced airway micro vascular leakage and LTD4-induced increase in cutaneous vascular permeability. When administered in travenously, ONO-1078 (3 30 ,u g/kg) inhibited these responses approximately 200 600 fold more potently than FPL55712. When guinea pigs were treated with indomethacin to examine the antagonism of ONO-1078 on the direct action against peptide LTs, intravenous (3 30 ,u g/kg) and oral (0.3-3 mg/kg) administration of ONO-1078 also inhibited LTC4 and LTD4-induced bronchoconstriction, and its activity was approximately 300 500 fold more potent than that of FPL55712. ONO-1078 (10 mg/kg, i.v.) had no inhibitory effect on bronchoconstrictions induced by histamine, acetylcholine, serotonin, arachidonic acid, LTB4, prostaglandin (PG) F2a , PGD2, 9a ,11,Q-PGF2, a stable thromboxane A2 mi metic agent and platelet activating factor. Furthermore, oral administration of ONO-1078 (1-10 mg/kg) inhibited slow-reacting substance of anaphylaxis mediated bronchoconstriction induced by antigen in a dose-dependent manner. These results indicate that ONO-1078 is an extremely potent, selective and orally active peptide LT antagonist and that oral administration of ONO-1078 antagonizes not only ex ogenously administered peptide LTs but also endogenous peptide LTs.

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Section: Discussionmentioning

confidence: 99%

In Vivo Pharmacologic Profile of ONO-1078: A Potent, Selective and Orally Active Peptide Leukotriene (LT) Antagonist.

et al. 1992

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“…Effects of P2-adrenoceptor agonists, terbutaline, salmeterol and formoterol, alone or in combination with sotalol, a P-receptor antagonist, on the secretion of LTB4, PGE2 or IL-1p in human monocyte cultures were investigated. Moreover, the effects of V-agonists were compared with the effects of a potent corticosteroid, budesonide (Dahlberg et al, 1983) and a potent 5-lipoxygenase inhibitor, BW A4C (Payne et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

The effects of β₂‐adrenoceptor agonists and a corticosteroid, budesonide, on the secretion of inflammatory mediators from monocytes

Linden¹

1992

British J Pharmacology

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1 The in vitro effects of the P2-adrenoceptor agonists (1 x 10-9-90-1 M), terbutaline, salmeterol, and formoterol, on the release of inflammatory mediators, i.e. the eicosanoids leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) and the cytokine interleukin-lp , were assessed in cultures of human blood monocytes. For comparison, the effects of a 5-lipoxygenase inhibitor, BWA4C (1 x l0--10-5 M), and a corticosteroid, budesonide (1 x 10-II 10-5 M) were also examined. Sotalol was used to investigate whether the actions of P2-agonists were mediated through P-adrenoceptors.2 Terbutaline, like budesonide, had no significant effect on LTB4 release, whereas BW A4C (IC50 = 2 X 10-M) was a potent inhibitor. All concentrations of formoterol approximately halved the LTB4 secretion, whereas high concentrations (1 X 10--10-5 M) only, of salmeterol, inhibited release. Only salmeterol, at high concentrations (> 1 X 10-6 M), lowered the secretion of PGE2 in monocyte cultures.Formoterol and salmeterol reduced the secretion of IL-1P only at the highest dose (1 x 10-5 M). In contrast, budesonide (> 1 x 10-9 M) was a potent suppressant of this secretion. 3 Treatment of monocyte cultures with sotalol (1 x 10-5 M) did not significantly antagonize the inhibitory effects of salmeterol and formoterol. These results suggest that the inhibitory action of these P2-agonists on the release of eicosanoids or IL-1p, is not mediated via P2-adrenoceptors. 4 This study does not support a therapeutic importance of the anti-release effects of P2-agonists since high concentrations were generally required. Furthermore, the anti-secretory action of P2-agonists was distinct from that of corticosteroids.

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“…Sulphidopeptide leukotrienes are known to stimulate TXA2 synthesis in guinea-pig lung and it has recently been shown that VIP inhibits leukotriene synthesis and release from guinea-pig lung (Beaubien et al, 1984;Samhoun et al, 1987;Di Marzo et al, 1989). Therefore, we have tested the effect of VIP infusion in the presence of the lipoxygenase inhibitor BWA4c at a dose that produces a nearly maximal inhibition of this enzyme in vitro (Payne et al, 1988;Higgs et al, 1988). Lipoxygenase inhibition did not modify the bronchodilator response nor the reduction in thromboxane release induced by VIP, suggesting that VIP directly affects TXA2 synthesis in guinea-pig lung.…”

Section: Discussionmentioning

confidence: 99%

“…Exogenous VIP was given as an infusion over 1 min through the pulmonary artery in control non-sensitized lungs or after pretreatment with the lipoxygenase inhibitor BWA4c (N-(3-phenoxycinnamyl)-acetohydroxamic acid; Payne et al, 1988). The latter compound was dissolved in the perfusion medium at a concentration 3.5 x 10-5 M and the lungs were perfused with this solution throughout the experiment.…”

Section: Vip Infusionmentioning

confidence: 99%

Effects of vasoactive intestinal polypeptide on antigen‐induced bronchoconstriction and thromboxane release in guinea‐pig lung

Ciabattoni

Montuschi

Currò

et al. 1993

British J Pharmacology

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1 Exogenous vasoactive intestinal polypeptide (VIP) infused into the pulmonary artery of isolated and ventilated lungs of guinea-pigs decreased, in a dose-dependent fashion (1.0-10.0 nmol), airway resistance and thromboxane B2 (TXB2, the stable hydrolysis product of TXA2) release in the perfusion medium. Prostacyclin (PGI2) synthesis, as reflected by the release of its stable hydrolysis product 6-oxo-PGFI,,, was unaffected. Pretreatment with the 5-lipoxygenase inhibitor BWA4c (3.5 x 10-' M) did not modify the bronchodilatory effect of VIP or its inhibitory action on TXB2 release. 2 Basal release of immunoreactive VIP from perfused lungs decreased from an initial value of 0.96 ± 0.10 ng min-' (mean ± s.e.mean) in the first 2 min to an average of 0.58 ± 0.10 ng min-' in the following 15-20 min. 3 Antigen challenge with ovalbumin (0.1%) in sensitized lungs caused an anaphylactic reaction in 45% of tested lungs, concomitant with a 5 fold increase in both VIP and TXB2 release. Tetrodotoxin pretreatment (10-6 M) reduced basal VIP release by >80% and abolished the VIP increase observed during anaphylaxis, without modifying TXB2 release or the bronchoconstrictor response. 4 Indomethacin (10-6 M) inhibited TXB2 synthesis and release by > 90%, delayed the bronchoconstrictor response and blunted the increased VIP release during lung anaphylaxis, without influencing basal VIP release. 5 The 5-lipoxygenase inhibitor BWA4c (3.5 x 10-5 M) blunted the increase of TXB2 and VIP release from guinea-pig lung and attenuated the bronchoconstrictor response following ovalbumin challenge. 6 The administration of exogenous VIP as a continuous infusion (10-8 M) attenuated the bronchoconstriction and the release of cyclo-oxygenase metabolites following antigen challenge.7 Acetylcholine (10-6-Il-5 M) infused into the pulmonary artery induced a dose-dependent bronchoconstriction not associated with enhanced VIP or TXB2 release.8 The TXA2 mimetic U-46619 (0.1-1.0 nmol) caused dose-dependent increases in airway resistance, concomitant with an up to 10 fold increase in VIP release. VIP inhibited arachidonate-induced in vitro aggregation of washed rabbit platelets in a dose-dependent manner over a dose range 10-8 10-6 M. Despite the antiaggregatory effect of VIP, TXB2 and PGE2 synthesis was reduced only to a minor extent, and there was no redirection of arachidonate metabolism from TXA2 to PGE2, indicating that VIP does not act as a TX synthase inhibitor in vitro. 9 We conclude that VIP may play a role in regulating bronchial smooth muscle reactivity in lung anaphylaxis by inhibiting the synthesis and release of TXA2, a potent vasoactive and bronchoconstrictor agent. TXA2, on the other hand, strongly enhances neuronal VIP release.

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Selective inhibition of arachidonate 5‐lipoxygenase by novel acetohydroxamic acids: effects on bronchial anaphylaxis in anaesthetized guinea‐pigs

Cited by 40 publications

References 12 publications

In Vivo Pharmacologic Profile of ONO-1078: A Potent, Selective and Orally Active Peptide Leukotriene (LT) Antagonist.

In Vivo Pharmacologic Profile of ONO-1078: A Potent, Selective and Orally Active Peptide Leukotriene (LT) Antagonist.

The effects of β₂‐adrenoceptor agonists and a corticosteroid, budesonide, on the secretion of inflammatory mediators from monocytes

Effects of vasoactive intestinal polypeptide on antigen‐induced bronchoconstriction and thromboxane release in guinea‐pig lung

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Selective inhibition of arachidonate 5‐lipoxygenase by novel acetohydroxamic acids: effects on bronchial anaphylaxis in anaesthetized guinea‐pigs

Cited by 40 publications

References 12 publications

In Vivo Pharmacologic Profile of ONO-1078: A Potent, Selective and Orally Active Peptide Leukotriene (LT) Antagonist.

In Vivo Pharmacologic Profile of ONO-1078: A Potent, Selective and Orally Active Peptide Leukotriene (LT) Antagonist.

The effects of β2‐adrenoceptor agonists and a corticosteroid, budesonide, on the secretion of inflammatory mediators from monocytes

Effects of vasoactive intestinal polypeptide on antigen‐induced bronchoconstriction and thromboxane release in guinea‐pig lung

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The effects of β₂‐adrenoceptor agonists and a corticosteroid, budesonide, on the secretion of inflammatory mediators from monocytes