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At least 811 records · Page 45Linked to original sources
PubMed1984

Release of slow reacting substance from the guinea-pig lung by phospholipases A2 of Vipera russelli snake venom.

Phospholipases A2 (PLA2) of Vipera russelli venom were isolated by column chromatography. The ability of PLA2 fractions to release slow reacting substance (SRS) was studied in the guinea-pig lung perfused with Krebs' solution. The relationship between the perfusion pressure change produced by PLA2 and SRS release was also studied. Two PLA2 fractions (II-5 and III-3; 3-100 micrograms), injected into the lung increased the perfusion pressure and released SRS. Pretreatment of the lung with indomethacin (10 micrograms) reduced the pressure response induced by the PLA2 fractions. The SRS released in the lung effluent by PLA2 was identified by bioassay as a mixture of thromboxane A2 (TXA2), prostacyclin (PGI2) and leukotrienes. TXA2 and PGI2 release was also quantitated by radioimmunoassay of the degradation products TXB2 and 6-keto-PGF1 alpha, respectively. There was a positive linear correlation between the pressure increases and the ratios of TXB2 to 6-keto-PGF1 alpha (r = 0.87). It appears that the relative amounts of TXA2 and PGI2 released determine the effects of PLA2 fractions on the guinea-pig lung. The release of arachidonic acid metabolites, prostaglandins and leukotrienes may account for part of the hypotensive action of PLA2.

6-Ketoprostaglandin F1 alpha↗
PubMed1977

On the structure of slow reacting substance of anaphylaxis: evidence of biosynthesis from arachidonic acid.

The mononuclear cells in peritoneal washings from normal rats can be induced to produce large amounts of slow reacting substance of anaphylaxis by incubation with 10 mM cysteine in the presence of the calcium ionophore A-23187. This production of slow reacting substance could be inhibited by the addition of non-steroidal anti-inflammatory drugs, e.g., indomethacin, ibuprofen and flurbiprofen, Furthermore, mediator production was inhibited by eicosatetraynoic acid, the substrate analog of arachidonic acid, and by 9,11-azoprosta-5, 13-dienoic acid (AZO analog 1), a structural analog of the prostaglandin endoperoxide, PGH2, which known to inhibit thromboxane synthesis. Relatively high concentrations of hydrocortisone acetate inhibited mediator production; this inhibition could be partly reversed by the addition of arachidonic acid or to a lesser extent by eicosatrienoic acid. Preliminary results suggest that a small fraction of the 3H-labled arachidonic acid which was taken up by these cells in vitro was associated with slow reacting substance. We postulate that slow reacting substance of anaphylaxis may be derived from a prostaglandin endoperoxide which is formed during the oxidation of arachidonic acid by the prostaglandin fatty acid cyclooxygenase.

Anaphylaxis↗
PubMed1977

Prostaglandin release by slow reacting substance from guinea pig and human lung tissue.

Slow reacting substance (SRS) injected into the pulmonary artery released prostaglandins E (PGE) and F2alpha (PGF2alpha) and the 15-keto-13, 14-dihydro PG metabolites from non-sensitized and ovalbumin sensitized, isolated, perfused guinea pig lungs. PGs were also released from lungs incubated with SRS. Sensitized lungs released more PGs in both types of preparations. Indomethacin inhibited the effect of SRS. Passively sensitized human lung fragments, in parallel to guinea pig lung, released PGE, PGF2alpha and the metabolites when incubated with SRS or antigen. In in vivo experiments, SRS and arachidonic acid given intravenously increased the airway insufflation pressure in anesthetized quinea pigs. These effects, but not the action of injected PGF2alpha and histamine, were abolished by indomethacin. The results indicate that one of the modes of SRS action is by release of PGs, and are consistent with the hypothesis that PGs are predominantly "secondary" mediators (in the temporal sense) of the antigen-antibody reaction.

Airway Resistance↗
PubMed1979

Characterization of the two major species of slow reacting substance from rat basophilic leukemia cells as glutathionyl thioethers of eicosatetraenoic acids oxygenated at the 5 position. Evidence that peroxy groups are present and important for spasmogenic activity.

The most prominent slow reacting substance from rat basophilic leukemia cells (type I) was characterized by radiochemical, chemical and physical methods and shown to contain a C20 unsaturated fatty acid oxygenated at the 5 position and a sulfur containing side chain in thioether linkage at the 6 position. Its spasmogenic action on guinea pig ileal muscle was largely inactivated under reducing conditions which suggested that a peroxy group was present and important for contractile activity. This was supported by ferrous thiocyanate analysis. The peroxy group is almost certainly at the 5 position, probably in the form of a peroxy ester or hydroperoxide. Based on amino acid hydrolysis (0.85 moles of glycine and 0.30 moles of glutamic acid per mole SRS), the sulfur containing side chain is apparently a mixture of glutathione and cysteinyl-glycine, but by chromatography the side chain is predominantly glutathione and the low yield of glutamic acid may be due to complexing of its alpha COOH group in a peroxy ester linkage. The fatty acid moiety has 3 conjugated double bonds, probably at the 7,8, 9,10 and 11,12 positions. Type II SRS, the second major species, differs in that the sulfur containing side chain is linked at the 12 or 13 position and is almost certainly glutathione and in the failure of alkaline borohydride to produce inactivation. These observations strongly implicate the lipoxygenase pathway in slow reacting substance biosynthesis.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1980

Slow reacting substances (SRSs): the structure identification of SRSs from rat basophil leukaemia (RBL-1) cells.

Slow Reacting Substances have been produced from RBL-l cells by calcium ionophore A23187 and purified to homogeneity by high pressure liquid chromatography (HPLC). The structure of the major biologically active species has been determined by mass spectrometric examination of the intact molecule as a derivative, together with amino-acid analysis and sequence determination. The characteristic triene chromophore which we originally identified in immunologically generated SRS-A is present in RBL-l SRS, and we determine the structure of this SRS as the thio-substituted dipeptide, 5-hydroxy-6-cysteinylglycinyl-7,9,11,14-eicosatetraenoic acid.

Amino Acid Sequence↗
PubMed1980

Sequential conversion of the glutathionyl side chain of slow reacting substance (SRS) to cysteinyl-glycine and cysteine in rat basophilic leukemia cells stimulated with A-23187.

In rat basophilic leukemia (RBL-1) cells stimulated with A-23187, the major slow reacting substance (SRS) species contain glutathione, cysteinyl-glycine, or cysteine in their side chains, corresponding or closely related to leukotrienes LTC4, LTD4, and LTE4, respectively. Evidence is presented that most of the SRS produced during the first few minutes of stimulation by the ionophore has a glutathionyl side chain which is sequentially converted to cysteinyl-glycine and cysteine.

Animals↗
PubMed1980

Aryl sulfatase inactivation of slow reacting substance. Evidence for proteolysis as a major mechanism when ordinary commercial preparations of the enzyme are used.

Type II B arylsulfatases are known to inactivate slow reacting substance (SRS), but the mechanism is unclear. In the present study, ordinary commercial preparations of Sigma limpet arylsulfatase largely inactivated the glutathionyl and cysteinyl-glycyl forms of SRS, but the cysteinyl form of SRS was largely resistant to the enzyme. Evidence is presented which established that a major mechanism for the inactivation of the glutathionyl and cysteinyl-glycyl SRS types, at least by the particular enzyme preparations we have studied, involves cleavage of the glycine moiety from the sulfur containing side chain. This was confirmed by digestion studies with glutathione itself. In addition, there is some evidence to indicate that the enzyme may destabilize the double bond structure of the SRS molecule, contributing to the overall inactivation.

Animals↗
PubMed1981

Tetraene and pentaene leukotrienes: selective production from murine mastocytoma cells after dietary manipulation.

A neoplastic mast cell tumor was grown in mice which had been raised since birth on a diet enriched with eicosapentaenoic acid. Intact harvested mastocytoma cells were stimulated with calcium ionophore A23187 to produce lipoxygenase products from the polyunsaturated fatty acids liberated from the cellular membranes. Leukotriene B4, B5, C4, and C5 were isolated and characterized by HPLC retention time, ultraviolet absorption spectrometry and mass spectrometry. The arachidonic acid content of the mast cell tumor lipids was altered from 9.2 to 3.9 mole % while eicosapentaenoic acid increased from 0.5 to 4.5 mole % in response to the fish oil-supplemented diet. The relative amounts of arachidonic and eicosapentaenoic acids (3.9 and 4.5 mole % respectively) were associated with similar amounts of LTB4 and LTB5 synthesized by the cells. These results suggest that the epoxide leukotriene (LIA) derivative can be made efficiently from either arachidonic or eicosapentaenoic acids when both are present in cellular lipids. In contrast, the ratio of LTC4 to LTC5 (10 to 1) indicates that the reaction of LTA with glutathione may be critically dependent upon the structure of the unsaturated fatty acid with the ratio of LTC4/LTB4 (2.0) more than 10 times greater than that (0.16) for LTC5/LTB5.

Animals↗
PubMed1981

The mechanism of action of leukotrienes C4 and D4 in guinea-pig isolated perfused lung and parenchymal strips of guinea pig, rabbit and rat.

The biological actions of pure slow-reacting substance of anaphylaxis (SRS-A) from guinea-pig lung, pure slow-reacting substance (SRS) from rat basophilic leukaemia cells (RBL-1) and synthetic leukotrienes C4 (LTC4) and D4 (LTD4) have been investigated on lung tissue from guinea pig, rabbit and rat. In the guinea pig, the leukotrienes released cyclo-oxygenase products from the perfused lung and contracted strips of parenchyma. The effects of SRS-A, SRS and LTD4 were indistinguishable. LTC4 and LTD4 had similar actions although LTD4 was more potent than LTC4. Indomethacin (1 microgram/ml) inhibited the release of cyclo-oxygenase products from perfused guinea-pig lung and caused a marked reduction in contractions of guinea-pig parenchymal strips (GPP) due to LTC4 and LTD4. The residual contraction of the GPP was abolished by FPL 55712 (0.5 - 1.0 microgram/ml). It appears, therefore, that a major part of the constrictor actions of LTC4 and LTD4 in guinea-pig lung are mediated by myotropic cyclo-oxygenase products, i.e. thromboxane A2 (TxA2) and prostaglandins (PGs). In rabbit and rat lung, however, SRS-A, SRS and the leukotrienes were much less potent in contracting parenchymal strips and there was little evidence of the release of cyclo-oxygenase products. FPL 55712 at a concentration of 1 microgram/ml failed to antagonise leukotriene-induced contractions.

Animals↗
PubMed1984

Airway smooth muscle, asthma, and calcium ions.

The intracellular concentration of free Ca2+ ions regulates many functions of cells including secretion, contraction, transport processes, and motility, among others. All of the pathogenetic processes in asthmatic airways are Ca2+-dependent phenomena: excitation-contraction coupling in smooth muscle, stimulus-secretion coupling in mast cells and mucous glands, nerve impulse initiation and conduction, and the development of inflammatory infiltration. Ca2+ entry blockers such as nifedipine and verapamil may affect exercise-induced asthma, airway tone, mast cell mediator release, and experimental anaphylaxis. Calmodulin-active drugs can inhibit smooth muscle contraction and mediator release. A new generation of Ca2+ antagonists may find a role in the management of asthma.

Asthma↗
PubMed1979

Is a slow reacting substance-like compound involved in rat platelet agglutination.

Endoperoxide analogs at doses 100-fold higher than those required to aggregate human platelet-rich plasma (PRP), were ineffective on rat PRP. Indomethacin (20 microM) and imidazole did not affect arachidonate-induced aggregation of rat PRP. On the other hand, prostaglandin (PG) E1 inhibited aggregation at doses similar to those effective on human PRP, while high doses of PGI2 failed to inhibit arachidonate aggregation in the rat. Eicosatetraynoic acid (10 microgram) blocked the second phase of aggregation; the Ca2+-ionophore A 23187 potentiated the arachidonate effect. Thus, it appears that endoperoxides or thromboxane A2 may not be involved in rat platelet aggregation and that the formation of aggregants from arachidonate shares many properties with the biosynthesis of slow reacting substance, a metabolite of arachidonic acid containing a sulphate group. To test this, rat PRP was incubated with labeled sulphate and aggregated with arachidonate. After column and thin layer chromatography a labeled lipid was identified having a mobility higher than phospholipids but lower than PGF2 alpha. Treatment with arylsulphatase decreased radioactivity by at least 70%.

Adenosine Diphosphate↗
PubMed1981

Lipoxygenase pathway and hydroperoxy acids: possible relevance to aspirin-induced asthma and hyperirritability of airways in asthmatics.

The precise mechanisms(s) responsible for airway hyperreactivity to spasmogenic agents (for example, cholinergic stimulants, alpha-adrenergic agonists, histamine, PGF2 alpha and several other nonspecific stimuli) in asthmatics is not known. Substantial evidence exists fo the mediator, as well as modulatory, roles of the products of arachidonic acid metabolism operating via the cyclo-oxygenase pathway in the pathophysiology of lung diseases. Aspirin and other inhibitors of cyclo-oxygenase induce severe bronchospasm and asthmatic attacks in a significant population of asthmatic patients. This adverse effect of aspirin is often attributed to inhibition of the synthesis and release of defensive "modulatory" endogenous prostaglandins (PGD and PGI2?) in the lungs. Thus, removal of their "negative feedback" mechanism on the allergic release of chemical mediators (e.g., histamine and SRS-A: leukotriene C and D) from lung mast cells could lead to an enhancement of the release of mediators and severity of asthmatic attacks. In addition to these mechanisms, recent work suggests the diversion of arachidonic acid (AA) metabolism via the lipoxygenase pathway (especially after cyclo-oxygenase inhibition by aspirin and indomethacin), thereby leading to the formation of a new class of biologically active lipids: hydroperoxy acids (HPETE and HETE), leukotrienes (LTA, B, C, D, E) and SRS or SRS-A (LTC, LTD). The inherent or drug (aspirin)-induced deficiency or blockade of cyclo-oxygenases(s) and/or peroxidases in the lungs (and/or other body tissues, including leukocytes) leading to diversion of AA into the formation and accumulation of SRS (leukotrienes), especially in sensitive individuals, could explain the mechanism of aspirin-induced asthma, and probably the generalized syndrome of aspirin-tolerance. Furthermore, the hydroperoxy acids, leukotrienes, (SRS) may also sensitize receptors for other mediators and common nonspecific irritants, and/or induce airway contractions directly. Collectively, these mechanisms could account for airway hyperreactivity in asthma.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1980

Two rat mononuclear cell-derived slow reacting substances: kinetic evidence that the peripheral airways-selective spasmogen is derived from a nonselectively acting precursor.

The purpose of this study was to extend our knowledge of two slow reacting substances that are formed in rat mononuclear cells upon stimulation by the ionophore A 23187. Slow reacting substance (SRS) preparations were further purified through the sequential high performance liquid chromatographic procedures starting with exudates from cells that had been prelabeled with tritiated arachidonate. Approximately 2% of the released radioactivity (0.3% of the radioactivity that was taken up by the cells) cochromatographed with biologic activity in both preparations. Kinetic studies revealed that one of the SRSs was formed more rapidly than the other and analysis by nonlinear computer modeling techniques suggests a possible product-precursor relationship between the two substances. Activity of the preparations on guinea pig lung parenchyma and trachea was compared using a histamine standard; only the more slowly formed substance had the selective activity on the parenchyma that we associate with slow reacting substance of anaphylaxis (SRS-A). Taken together, these findings suggest that a material which may be a precursor of SRS-A, if it is also formed and accumulated in vivo, may contribute to the more central airway constriction which is seen in some asthmatics.

Animals↗