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Query: UMLS:C0850803 (anaphylaxis)
 8,092 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Ovalbumen (100 micrograms)-induced coronary vasoconstriction and decrease in cardiac developed tension were studied in isolated perfused hearts from sensitized guinea-pigs. Leukotriene-like material released in the cardiac effluent was assayed against synthetic leukotriene C4 (LTC4). 2. LTC4 was released in a time-dependent fashion, and release was enhanced when hearts were challenged in the presence of indomethacin (2.8 microM). The release was maximal at 2-3 min and detectable for as long as 10 min following ovalbumen challenge. Immunoreactive (ir) thromboxane-B2 (TxB2) was also detected in cardiac effluent which had been partially purified using C18 Sep-Paks. 3. CGS 8515 (0.03-1.0 microM), an inhibitor of 5-lipoxygenase, dose-dependently inhibited ovalbumen-induced coronary vasoconstriction and leukotriene-C4 release. CGS 8515 inhibited ovalbumen-induced decreases in cardiac developed tension at 0.3 and 1.0 microM, but did not antagonize coronary vasoconstriction induced by synthetic LTC4. 4. The release of cyclo-oxygenase products following ovalbumen challenge was not inhibited by CGS 8515, but was markedly inhibited by indomethacin (2.8 microM) pretreatment. 5. We conclude that leukotrienes have a major role in guinea-pig cardiac anaphylaxis, and that CGS 8515 has a cardio-protective action. The results obtained in these experiments in vitro show that CGS 8515 is a potent and selective 5-lipoxygenase inhibitor.
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PMID:Inhibition of leukotriene release in anaphylactic guinea-pig hearts by a 5-lipoxygenase inhibitor, CGS 8515. 314 1

A number of 2-benzylaminophenols, prepared from the corresponding 2-aminophenols by reductive alkylation, have been identified as highly potent inhibitors of 5-lipoxygenase with IC50 values in the nanomolar range. Most compounds were also shown to inhibit the release of the peptidoleukotrienes when administered intraperitoneally in a rat model of peritoneal anaphylaxis. Two compounds evaluated for their effects on anaphylactic contractions in isolated human lung were shown to attenuate the leukotriene-induced component of the response.
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PMID:Inhibition of mammalian 5-lipoxygenase by 2-benzylaminophenols. 318 76

Calcium (Ca) ions play an important pathophysiologic role in allergic reactions. Thus, mediator release from mast cells, synthesis of some newly formed chemical mediators, airway smooth muscle contraction, and nerve-impulse conduction are all dependent on the availability and flux of Ca ions. It is likely, therefore, that Ca antagonists would modify allergic bronchoconstriction. In vitro, Ca antagonists have been demonstrated to inhibit mediator release (histamine, slow-reacting substance of anaphylaxis, and platelet-activating factor) from mast cells, passively sensitized human lung fragments, and leukocytes. Ca antagonists have also been found to inhibit synthesis of leukotrienes in rat lungs and cyclooxygenase products in sheep, possibly by inactivating phospholipase A2 and/or 5-lipoxygenase. In addition, nifedipine, verapamil, and gallopamil have demonstrated inhibition of airway smooth muscle contractions to histamine, carbachol, and antigen in various species. In vivo effects of Ca antagonists are variable, depending on the species, experimental design, the stimulus or the agonist, and the Ca antagonist used. Animal studies have demonstrated the inhibition of histamine, methacholine, citric acid, and prostaglandin F2 alpha-induced bronchoconstriction in guinea pigs and dogs by intravenous nifedipine. In contrast, verapamil inhibited antigen-induced bronchoconstriction in allergic sheep without any effect on histamine- and carbachol-induced responses. Ca antagonists (nifedipine and verapamil) have been of limited value in human subjects and generally have no significant bronchodilating activity. Both nifedipine and verapamil prevent the exercise-induced asthma and partly attenuate the histamine and methacholine-induced bronchoconstriction. Oral nifedipine is generally more effective than oral verapamil against acute antigen-induced bronchoconstriction; however, this efficacy may be limited by systemic side effects. Inhaled Ca antagonists may be more effective and free of systemic side effects, as demonstrated by greater efficacy of inhaled verapamil. A new Ca antagonist, gallopamil (a methoxy derivative of verapamil), is being investigated as an aerosol, and preliminary studies in animals and humans have found it fourfold to seventeenfold more potent than verapamil. In sheep, gallopamil has been found to attenuate histamine, carbachol, and platelet-activating factor-induced bronchoconstriction, as well as to inhibit early and late-phase allergic airway responses. Studies in human subjects have also demonstrated the inhibition of antigen-induced bronchoconstriction by inhaled gallopamil, with efficacy comparable or better than cromolyn sodium.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The role of calcium antagonists in bronchial reactivity. 327 58

The role of leukotrienes and other mediators of vascular changes in anaphylaxis were studied in rats sensitized with monoclonal anti-DNP IgE and challenged with DNP-BSA. Microvascular changes in the mesentery were followed by intravital fluorescent microscopy and in the skin by exudation of Evans blue dye. Administration of Ag i.v. caused a marked increase in the peristaltic movement of the intestine, plasma exudation, and arteriolar constriction in the mesentery. The microvascular changes were accompanied by a profound fall in blood pressure, which was biphasic. The first phase lasted for approximately 2 min. The second phase was very prolonged and the hypotension was still maintained 40 min after Ag challenge. The changes observed were dose dependent with regard to Ag. Intradermal application of Ag resulted in dose-dependent extravasation of Evans blue dye in the skin. Plasma exudation was partially inhibited by pyrilamine and methysergide. However, their effect seemed to be more pronounced in the skin than in the mesentery. The leukotriene D4-R antagonist L-649,923 and the 5-lipoxygenase inhibitor ONO-LP-049, alone or in combination with other inhibitors, did not alter the plasma leakage in the skin. In the mesentery, the leukotriene antagonists alone had a moderate effect on vascular permeability. However, the combination of these agents with pyrilamine completely inhibited macromolecular extravasation. The hypotension was modulated by the antihistamines as well as the leukotriene and serotonin antagonists. Pyrilamine inhibited the first phase and the second phase. The major effect of methysergide was a decrease in the duration of the hypotension. This was especially evident when it was administered in combination with other inhibitors. The leukotriene antagonists when given alone had moderate effects on the blood pressure changes. However, in combination with pyrilamine, the hypotension was substantially reduced. Leukotrienes appeared to be important mediators of the vascular changes in the mesentery but not in the skin (passive cutaneous anaphylaxis). They markedly potentiated the action of histamines.
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PMID:Role of leukotrienes in vascular changes in the rat mesentery and skin in anaphylaxis. 335 3

Possible chemical mediators contributing to 48 hour passive cutaneous anaphylaxis (PCA) in rats were investigated. Forty-eight hour PCA was inhibited considerably by mepyramine and methysergide given intravenously, a finding suggestive of a major role for histamine and serotonin in the reaction. AA-861, a selective 5-lipoxygenase inhibitor did not inhibit the PCA, and leukotriene (LT)D4 or LTE4 and the combination with prostaglandin (PG)E2 had no significant skin reaction. In addition, only small amounts of slow reacting substance of anaphylaxis (SRS-A) were detected in skin fragments, in vitro. Although CV-3988, a selective platelet activating factor (PAF) antagonist, dose-dependently inhibited the PAF-induced skin reaction, the PCA was not affected by treatment with this compound. Indomethacin also had no inhibitory activity on PCA. Thus, sulfidopeptide LTs, PAF and arachidonate cyclooxygenase metabolites probably do not contribute to PCA, at least in rats.
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PMID:Lack of involvement of leukotriene and platelet activating factor in passive cutaneous anaphylaxis in rats. 340 49

The hydroxamic acid functionally can be incorporated into simple molecules to produce potent inhibitors of 5-lipoxygenase. The ability of many of these hydroxamates to inhibit leukotriene synthesis in vivo has been measured directly with a rat peritoneal anaphylaxis model. Despite their potent enzyme inhibitory activity in vitro, many orally dosed hydroxamic acids only weakly inhibited leukotriene synthesis in vivo. This discrepancy is attributable at least in part to the rapid metabolism of hydroxamates to the corresponding carboxylic acids, which are inactive against the enzyme. A study of the structural features that affect this metabolism revealed that 2-arylpropionohydroxamic acids are relatively resistant to metabolic hydrolysis. Several members of this class of hydroxamates are described that are orally active inhibitors of leukotriene synthesis.
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PMID:In vivo characterization of hydroxamic acid inhibitors of 5-lipoxygenase. 366 19

The synthesis and structure--activity profile of 2-substituted benzimidazol-4-ols as inhibitors of cell-free RBL-1 5-lipoxygenase are discussed, and their potency is compared with that of the standard inhibitors phenidone, AA 861, BW 755C, and nordihydroguaiaretic acid. In contrast to the standard compounds, most did not inhibit the release of slow-reacting substance of anaphylaxis (SRS-A) in vivo when administered at 200 microM ip to rats subjected to peritoneal anaphylaxis, although five compounds containing a methoxylated benzyl group (compounds 36, 39, 42, and 43) or hydroxylated benzyl group (41) showed similar activity to that of phenidone, nordihydroguaiaretic acid, and AA 861. Of the many compounds tested, two, 5-tert-butyl-7-methyl-2-(trifluoromethyl)-1H-benzimidazol-4-ol (57) and 2-(4-methoxybenzyl)-7-methyl-1H-benzimidazol-4-ol (36), like dexamethasone, inhibited monocyte accumulation in a pleural exudate model of inflammation. Standard lipoxygenase inhibitors such as phenidone, BW 755C, and AA 861 were inactive in this system.
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PMID:Novel 1H-benzimidazol-4-ols with potent 5-lipoxygenase inhibitory activity. 368 91

A series of new substituted arylmethyl phenyl ethers has been prepared. These compounds were tested as inhibitors of 5-lipoxygenase (5-LO) in rat neutrophils, in vitro antagonists of leukotriene-induced contraction of guinea pig (GP) lung parenchymal strips, and inhibitors of slow reacting substance of anaphylaxis (SRS-A) mediated bronchospasm in the GP in vivo. Most representatives of this new class of potential antiallergic/antiinflammatory agents showed potent inhibition of 5-LO activity in rat PMNs. The most potent compound, 2-[[3-(1-hydroxyhexyl)phenoxy]-methyl]quinoline (33), had an I50 of 0.12 microM in the rat PMN 5-LO assay and an I50 of 3.6 microM in the leukotriene-induced contraction of GP lung parenchymal strips, and it also showed 91% inhibition of SRS-A-mediated bronchospasm in the GP in vivo at 10 mg/kg, administered intraduodenally. Some of the compounds in this series were also leukotriene antagonists in vitro, and several of them showed in vivo activity against SRS-A-mediated bronchospasm in the GP.
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PMID:Substituted arylmethyl phenyl ethers. 1. A novel series of 5-lipoxygenase inhibitors and leukotriene antagonists. 380 7

AA-861, a selective 5-lipoxygenase inhibitor, suppressed A23187-induced formations of 5-HETE and LTB4 in rat peritoneal macrophages. Immunologically-stimulated generation of SRS-A was also inhibited in guinea pig lung and rat peritoneal cavity. AA-861 had no effects on histamine release from rat mast cells or passive cutaneous anaphylaxis in rats. Essentially no antagonistic activity to LTD4 or histamine was observed. This compound exerted an obvious inhibition of allergic bronchoconstriction in guinea pigs and a moderate reduction of carrageenin-induced paw edema and pleurisy in rats. These findings suggest that SRS-A plays an important role in asthmatic and inflammatory reactions.
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PMID:Pharmacological profile of AA-861, a 5-lipoxygenase inhibitor. 608 55

This paper reviews the leukotrienes, a new group of biologically active compounds in the metabolism of eicosapolyenoic acids. The leukotrienes are acyclic eicosanoids that arise through the 5-lipoxygenase pathway from eicosatrienoic, eicosatetraenoic, and eicosapentaenoic acid. Of these eicosatetraenoic acid, arachidonic acid, is the most important source of leukotrienes. Leukotriene B4 (LTB4), a dihydroxy metabolite, has been shown to exert marked chemotactic effect in many different animal species. LTB4 probably plays a role in inflammatory responses, and has been detected in several pathologic conditions. Reaction of LTA4, another lipoxygenase metabolite of arachidonic acid, with glutathione yields peptidolipid leukotrienes, LTC4, LTD4, and LTE4; these are components of slow reacting substance (SRS and SRS-A). The peptidolipid leukotrienes are potent bronchoconstrictors and enhance mucus production in the lungs. Furthermore, they constrict coronary arteries and have a negative inotropic effect. They probably play an important role in asthma and anaphylaxis. LTB4 and the peptidolipid leukotrienes may be important in several other organs, too, e.g., the skin and the eye. They may exert effects on a variety of smooth muscles and have neuronal and immunological effects.
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PMID:The leukotrienes. 609 44


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