Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.13.11.12 (lipoxygenase)
8,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study has quantitated the effects of topically-applied leukotriene C4 (LTC4) upon vessel diameters, red blood cell velocities and vascular permeability to macromolecules in an animal model, namely, the dorsal skin-fold preparation of Syrian golden hamsters. Furthermore, we studied the efficacy of the leukotriene receptor blocking agent FPL 55712 in this preparation in order to establish a model for testing antiinflammatory compounds possibly involved in the lipoxygenase cascade.
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PMID:The dorsal skin-fold preparation of awake Syrian golden hamsters for assessment of microvascular permeability and microhaemodynamics with leukotriene C4. 332 54

The effect of lipoxygenase inhibition, leukotriene agonists and antagonists, and 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) was examined in the rat pineal gland in organ culture. To study melatonin secretion pineal explants were incubated for 6 h in tissue culture medium 199 with the different drugs. Melatonin concentration in the pineal gland and the medium was measured by RIA. Exposure of explants to norepinephrine (NE) brought about a 2- to 5-fold increase in both parameters, an effect that was reduced but not abolished, by the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA; 10(-5) M). Lilly 171883 (10(-5) M) or FPL 55712 (10(-5) M; both antagonists of leukotrienes) reduced NE-induced melatonin production. Neither NDGA nor Lilly 171883 affected melatonin production in the absence of NE. Leukotrienes C4 and D4 increased melatonin release to the media at all concentrations tested (1-1,000 nM) with a maximum effect at 1 nM (leukotriene C4) and 10 nM (leukotriene D4). Significantly higher tissue melatonin concentrations as compared to controls were observed after exposure of pineal explants to 1 and 100 nM of leukotriene C4, or 100 nM of leukotriene D4. Another 5-lipoxygenase metabolite, 5-HETE, increased pineal melatonin content at concentrations of 1, 10 and 100 nM whereas only 1,000 nM stimulated melatonin release. These results suggest that the 5-lipoxygenase pathway plays a significant role in NE-stimulated melatonin production by the rat pineal gland.
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PMID:Involvement of 5-lipoxygenase pathway in norepinephrine stimulation of rat pineal melatonin synthesis. 343 57

Bradykinin (100 pM to 1 microM) contracted the rabbit urinary detrusor in vitro. The sensitivity to bradykinin was about 1000 times higher than that to acetylcholine (ACh) on a molar basis. The contractile response to bradykinin was unaffected by atropine, diphenhydramine, FPL-55712, methysergide, prazosin or tetrodotoxin, indicating that the contraction was not mediated via the release of ACh, histamine, peptide leukotrienes, serotonin or catecholamine. The bradykinin-induced contraction was, however, inhibited by indomethacin (5 microM), a cyclooxygenase inhibitor. Caffeic acid (10 microM), a lipoxygenase inhibitor, did not affect the contraction. Bradykinin (1 nM to 100 nM) stimulated the release of prostaglandin E2 from the detrusor in a concentration-dependent manner, and the release was abolished by treatment with indomethacin (5 microM). Prostaglandin (PG) E2 contracted the urinary detrusor with an EC50 of about 0.1 microM. Adenosine 5'-triphosphate (ATP), a stimulator of PG synthesis, also contracted the muscle with an EC50 of about 100 microM. [14C]Arachidonic acid was converted to PGE2 and F2 alpha when it was incubated with the 700 X g supernatant of the muscle homogenate. However, neither bradykinin nor ATP stimulated the PG synthesis in the supernatant. These results showed that bradykinin and ATP did not affect the cyclooxygenase and/or PG degradation system. On the other hand, when the intact detrusor muscle was incubated with [14C]arachidonic acid, bradykinin and ATP stimulated the PG synthesis, and the stimulated synthesis was inhibited by indomethacin. Mepacrine, a phospholipase A2 inhibitor, more potently inhibited the bradykinin- and ATP-induced contractions than the ACh-induced one.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Contribution of prostaglandin E2 to bradykinin-induced contraction in rabbit urinary detrusor. 347 93

1-0-Alkyl-2-Acetyl-sn-Glycero-3-Phosphocholine (AGEPC) produced dose-dependent (75-500 ng/site) increases in cutaneous vascular permeability (CVP) in rats as measured by extravasation of Evans blue dye. In contrast, lyso-AGEPC, at 1000 ng/site, was without effect. Pyrilamine, methysergide, and phenoxybenzamine, antagonists of mast-cell derived mediators, did not affect the AGEPC-induced increase in CVP. Likewise, agents capable of inhibiting mast cell mediator release, such as disodium cromoglycate, PRD-92-EA, theophylline, or nifedipine, had no effect. The cyclooxygenase inhibitor indomethacin produced significant inhibition of the response to AGEPC, whereas the lipoxygenase inhibitor nordihydroguiaretic acid (NDGA) and the peptide leukotriene antagonist FPL 55712 were without effect. The response to AGEPC was enhanced by the vasodilator PGE2 and inhibited by the vasoconstrictor phenylephrine. The selective AGEPC antagonist CV-3988 provided marked inhibition of the response. Unaccountably, the combination of indomethacin and CV-3988 provided no greater inhibition of the responses than either agent alone. These observations indicate that the AGEPC-induced increase in CVP in rats is mediated in part by products of the cyclooxygenase pathway and in part by activation of an AGEPC receptor.
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PMID:Pharmacologic analysis of 1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine-induced increases in cutaneous vascular permeability in the rat. 357 57

Canine and human epicardial coronary arteries were tested for their ability to metabolize exogenous arachidonic acid to lipoxygenase products. Unextracted medium from incubations of canine or human arteries with arachidonic acid and the calcium ionophore, A23187, contained a substance which exhibited a leukotriene (LT)-like smooth muscle contracting activity when tested on the superfused guinea pig lung parenchymal strip bioassay. This activity could be blocked by the LT antagonist, FPL-55712. Compounds present in these media were purified by high-performance liquid chromatography and identified as LTC4, LTD4 and LTE4 by liquid scintillation counting, bioassay and radioimmunoassay. In addition, coronary artery rings converted synthetic [3H]LTC4 to [3H]LTD4 with a half-life of 44 +/- 8 min. LTD4 metabolism to LTE4 was also demonstrated. The metabolism of [3H]LTC4 was abolished by incubation of the arterial rings with a gamma-glutamyl transpeptidase inhibitor, serineborate. Production of monohydroxyeicosatetraenoic acids (5-, 12- and 15-HETE) which have been isolated previously from vascular tissue incubations was confirmed. Production of HETE was inhibited by nordihydroguaiaretic acid and unaffected by indomethacin. These findings indicate that coronary vessels can metabolize exogenous arachidonic acid by the lipoxygenase pathway. In addition to HETE, the vessels were shown to synthesize LTC4, LTD4 and LTE4, compounds which possess potent biological actions on the coronary circulation.
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PMID:Leukotriene biosynthesis by canine and human coronary arteries. 359 1

Platelet activating factor (PAF; 1-o-alkyl-2-0-acetyl-sn-glycero-3-phosphocholine-3-phosphocholine) a potential mediator of anaphylaxis, stimulates secretion of mucin by explants of trachea from four separate rodent species (guinea pig, rat, rabbit, ferret) in organ culture. Enhanced secretion is not a result of cell damage or release of histamine by cells within the explants (e.g., platelets). It is inhibited by equimolar concentrations of the potent PAF-receptor antagonist, Ro 19-3704. PAF provokes production of immunoreactive peptidyl leukotrienes (ir-LTC4, LTD4, LTE4) within the explants. The stimulatory effect of PAF on mucin secretion is blocked by equimolar concentrations of nordihydroguiaretic acid (NDGA) a "mixed" inhibitor of both cyclo- and lipoxygenase pathways of arachidonic acid metabolism. Leukotrienes are localized within tracheobronchial epithelium by immunohistochemical staining, and physical removal of epithelium from explants inhibits production of leukotrienes in vitro under nonstimulated conditions and after exposure to PAF. In addition, the stimulatory effect of PAF on mucin secretion is not altered by FPL-55712, a receptor antagonist of LTD4. These results are consistent with the hypothesis that PAF stimulates secretion of mucin by activating biosynthesis of lipoxygenase products (e.g., peptidyl leukotrienes) within epithelial cells of the respiratory mucosa.
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PMID:Platelet activating factor stimulates secretion of mucin by explants of rodent airways in organ culture. 365 44

During exercise or dry air-induced asthma, airway walls cool. However, the role of temperature in the regulation of airway tone is not clear. Protein kinase C (PKC) is an important second messenger in the mediation of cell responses. To explore whether changes in temperature affect pathways involving PKC in airways, we examined the effects of phorbol esters, potent activators of PKC, in guinea pig tracheal rings at various temperatures. Phorbol-12,13-diacetate (PDA) caused a reduction in tracheal tone at 37 degrees C and an increase in tone when temperature was reduced to 22 degrees C. Increases in tone were also produced by PDA when cell membranes were depolarized by ouabain (10 microM) or KCl (30 mM) at 37 degrees C. Contractions produced by PDA at 22 degrees C were inhibited by lipoxygenase inhibitors [ETYA (5,8,11,14-eicosatetraynoic acid), NDGA (nordihydroguaiaretic acid) and phenidone] and a leukotriene receptor antagonist [FPL 55712 (sodium 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxyl] -4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate)]. Contractions produced by PDA at 37 degrees C or 22 degrees C in the presence of ouabain (10 mM) or KCl (30 mM) were not affected by these drugs. These results indicate that changes in temperature have profound effects on responses resulting from PKC activation. At low temperature, the lipoxygenase pathway mediates responses. Thus, cooling has the potential to modify a major intracellular pathway regulating physiological responses of the airways.
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PMID:Protein kinase C and tracheal contraction at low temperature. 366 58

The myometrial contractile responses to synthetic 1-0-octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (platelet-activating factor, PAF) and to oxytocin were evaluated in vitro on uterine (lower segment) strips obtained from pregnant women at term (39th week), undergoing elective cesarean section. Contractility was measured isometrically in an isolated organ bath using a superfusion technique. PAF in a concentration range between 5 and 100 nM as well as oxytocin (0.1-10 mU/ml) induced a dose-dependent contraction which could be categorized in two patterns, depending on whether spontaneous activity was present. In resting strips, oxytocin induced a prompt (0.5-1 min) development of active tension, followed by a prolonged (6-18 min), slow contraction and a final relaxation. However, at variance with oxytocin, PAF-induced contractions were rhythmic (3-8/hr), and characterized by a prompt (0.5-2 min) development of tension, followed by a brief (0.5-2 min) plateau, and a final, rapid relaxation. In spontaneously active strips, both stimuli induced a marked potentiation of the contractile activity. PAF response was dependent on both cyclooxygenase- and lipoxygenase-derived products as inferred from the abrogating effects of indomethacin and FPL 55712. A receptor-mediated mechanism of action was inferred from the occurrence of specific desensitization to PAF (but not to oxytocin), and from the blocking effect of CV 3988, a specific PAF receptor antagonist. The present study indicates that PAF stimulates the contraction of human myometrium in vitro and suggests that this mediator may have a role in labor.
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PMID:Platelet-activating factor contracts human myometrium in vitro. 379 21

Platelet-activating factor (PAF) evoked myometrial contractions in two different patterns, depending on whether spontaneous activity was present. In spontaneously active myometrial strips (58%), both PAF and oxytocin enhanced the amplitude of myometrial contractions. In quiescent myometrial strips, PAF induced contractions characterized by a prompt development of tension, a plateau, and a final, rapid relaxation. In 54% of these strips, PAF-induced contraction was followed by rhythmic activity. PAF contractile response was dependent upon the concentration (0.1-100 nM); the minimal effective concentration of PAF was 0.1 nM and the EC50 was 1 nM. The response to oxytocin (0.01-10 mU/ml), assumed as reference stimulus, was characterized by a prompt development of tension, which was followed by a sustained, slow contraction and relaxation. PAF response was almost completely dependent on cyclooxygenase and partially on lipoxygenase pathways, as inferred from studies with indomethacin and FPL 55712, respectively. A receptor mediated mechanism of PAF action was suggested by specific desensitization of the myometrium to a second challenge with an equimolar concentration of PAF (but not with oxytocin) and the blocking effect of CV 3988, a specific PAF receptor antagonist.
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PMID:In vitro contractile effect of platelet-activating factor on guinea-pig myometrium. 379 92

A study was made of the responses of guinea pig tracheal muscle in vitro after sensitization by either subcutaneous or intraperitoneal administration of antigens. No difference was observed in the responses of strips from either group to cumulative or single doses of antigen. The responses of the tracheal muscle to antigen were analyzed as to magnitude (relative to maximal carbachol responses), time to peak contraction, and time to half decay. Pyrilamine, an H1-receptor antagonist, slowed the onset of contraction and decay. The latter result suggested a role for histamine in controlling the release of or the response to other mediators and the former was consistent with previous evidence that histamine release augments the initial response. An inhibitor of 5'-lipoxygenase and cyclooxygenase (5,8,11,14-eicosatetraynoic acid), indomethacin, and the slow-reacting substance of anaphylaxis (SRS-A) antagonist FPL-55712 all shortened the time to half decay of the contraction, presumably by different mechanisms. The release and actions of leukotrienes may have been limited by eicosatetraynoic acid and FPL55712, respectively, but the action of indomethacin suggests a modulating role for prostanoids in leukotriene action or release. Nordihydroguaiaretic acid both reduced the maximum response and accelerated decay of this response, suggesting that the maximum response depends upon leukotriene release. Cromoglycate, methysergide, and an inhibitor of thromboxane synthetase were without effect. Both tetrodotoxin and atropine delayed the time to peak contraction and tetrodotoxin also delayed the decay of the contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of response to antigen in isolated guinea pig trachea after active sensitization. 382 3


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