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T Simmet

Publications and source records attributed to T Simmet.

At least 37 records · Page 2Linked to original sources
PubMed1988

Formation of cysteinyl-leukotrienes by human brain tissue.

Using sensitive radioimmunoassay techniques, the formation of cysteinyl-leukotrienes (LT) and prostaglandin (PG) F2 alpha was investigated in human brain tissue slices in vitro. Under basal conditions spontaneous release of considerable amounts of LTC4-like material and PGF2 alpha could be detected from slices of both human grey and white matter. Ionophore A23187 stimulated the release of large amounts of LTC4-like material while leaving unaffected the formation of the cyclo-oxygenase product PGF2 alpha. Incubation of grey or white matter in the presence of the cyclo-oxygenase inhibitor indomethacin inhibited the release of PGF2 alpha but did not affect that of LTC4-like material. Preincubation of brain tissue in the presence of the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) abolished the ionophore A23187-induced release of LTC4-like material from both grey and white matter and also significantly reduced the spontaneous release of LTC4-like material from white matter slices. Formation of PGF2 alpha was not affected by NDGA. Using the isolated guinea pig ileum the LTC4-like material was shown to possess biological activity which could be antagonized with the slow-reacting substance of anaphylaxis (SRS-A) antagonist FPL 55712. By reversed phase HPLC the immunoreactive LTC4-like material from human grey matter was shown to coelute with authentic LTC4, LTD4 and LTE4, while material from human white matter coeluted with authentic LTD4 and LTE4. The capacity of human brain tissue to synthesize cysteinyl-LT may be important for cellular functions in the central nervous system.

Brain↗
PubMed1988

[Fibrinolytic activity, thrombocyte function and pharmacokinetics during intra-arterial or intravenous prostaglandin E1 infusion in patients with chronic arterial occlusive disease].

Monitoring various parameters of fibrinolytic activity in 6 patients with arterial occlusive disease during intra-arterial (i.a.) or intravenous (i.v.) prostaglandin (PG) E1 infusions indicated activation of the endogenous fibrinolytic system. However, due to the small number of patients not all test parameters revealed significant changes. None of the PGE1 infusion regimens used (1.25 or 2.5 ng/kg/min i.a. or 5 or 10 ng/kg/min i.v. for 120 min in each case) led to any significant change in various parameters checked for ex-vivo platelet function. In agreement with these data the radioimmunological determination of PGE1 in venous plasma did not reveal any significant rise. On the other hand, the circulating metabolite of PGE1, 15-keto-13, 14-dihydro-PGE1, reached plasma levels which correlated well with expected theoretical values taking the infusion rate into consideration. A potential mechanism by which even low plasma concentrations of PGE1 might affect platelet function in vivo is discussed.

Alprostadil↗
PubMed1988

Effect of muscarinic receptor stimulation on release of cysteinyl-leukotrienes and thromboxane B2 from anaphylactic guinea-pig hearts.

The effects of muscarinic receptor stimulation by infusions of methacholine (6.25 x 10(-8) mol/min or 1.9 x 10(-7) mol/min) into isolated perfused, spontaneously beating sensitized guinea-pig hearts on the anaphylactic release of cysteinyl-leukotrienes (LT) and thromboxane (TX) B2 were investigated. Methacholine increased coronary flow and decreased heart rate under basal conditions. Furthermore, infusions of methacholine (1.9 x 10(-7) mol/min) significantly increased the anaphylactic release of TXB2 as well as of immunoreactive cysteinyl-LT, which were demonstrated by reversed phase high pressure liquid chromatography to consist of a mixture of LTC4, LTD4 and LTE4. Infusions of atropine (1.3 x 10(-7) mol/min) alone did not significantly affect coronary flow and heart rate prior to ovalbumin injection nor anaphylactic release of cysteinyl-LT. The anaphylactic release of TXB2 was, however, significantly decreased in the presence of atropine. Atropine (1.3 x 10(-7) mol/min) infused in addition to methacholine (1.9 x 10(-7) mol/min) abolished the effects of the muscarinic receptor agonist on spontaneous heart rate and significantly antagonized the increase in coronary flow prior to ovalbumin injection. Similarly, the simultaneous infusion of atropine abolished the effects of methacholine on the anaphylactic release of TXB2 and cysteinyl-LT. After antigen challenge hearts infused with methacholine, atropine or the combination of both drugs did not exhibit any differences with respect to anaphylactic changes of heart rate or the time course of anaphylactic coronary flow reduction. Thus, in the isolated perfused anaphylactic guinea-pig heart, muscarinic receptor stimulation significantly enhanced the release of the arachidonic acid-derived mediators TXB2 and cysteinyl-LT.(ABSTRACT TRUNCATED AT 250 WORDS)

Anaphylaxis↗
PubMed1988

Inhibition of cysteinyl-leukotriene production by azelastine and its biological significance.

Azelastine is a phthalazinone derivative with a wide spectrum of pharmacological activities. Actively sensitized guinea pigs were used to examine the broncholytic effect of azelastine in vivo. Furthermore, the influence of azelastine on the production of arachidonic acid (AA) metabolites was investigated in vitro and compared to the effects of nordihydroguaiaretic acid (NDGA), indomethacin and ketotifen. In vivo, azelastine protected actively sensitized guinea-pigs against ovalbumin-induced bronchospasm with an ID50 of 0.08 mg/kg orally. Ketotifen was similarly active (ID50 = 0.05 mg/kg). Antigen-induced contraction of isolated tracheal rings of sensitized guinea-pigs was concentration-dependently inhibited by azelastine and NDGA with IC50-values of 94.1 and 34.2 mumol/l, respectively. Ketotifen exerted only weak inhibitory activity (18% at 100 mumol/l). The arachidonic acid-induced contraction of isolated guinea-pig tracheal rings was also inhibited both by azelastine (IC50 = 92.6 mumol/l) and NDGA (IC50 = 20.4 mumol/l). Ketotifen was inactive on this model. Antigen challenge of chopped lung tissue from sensitized guinea-pigs resulted in the release of cysteinyl-leukotrienes (LT) which were identified by reversed phase high pressure liquid chromatography (HPLC) as LTD4 and LTE4. The release of cysteinyl-LT from sensitized guinea-pig lung tissue induced by antigen challenge was concentration-dependently inhibited by azelastine (IC50 = 35.2 mumol/l) and NDGA (IC50 = 8.4 mumol/l) but not by ketotifen and indomethacin. By contrast, indomethacin caused a pronounced augmentation of cysteinyl-LT release. The concentration of indomethacin, which augmented cysteinyl-LT release by 50% was 0.19 mumol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Characterization of seizure-induced cysteinyl-leukotriene formation in brain tissue of convulsion-prone gerbils.

Tonic-clonic seizures elicited in convulsion-prone gerbils resulted in a large increase in immunoreactive prostaglandin (PG) F2 alpha and in a smaller increase in immunoreactive leukotriene (LT) C4-like material in brain tissue. Brain tissue contents of both eicosanoids were found to reach a maximum at 6 min after the onset of seizures and were still elevated at 54 min after the beginning of convulsions. By reversed phase HPLC the immunoreactive LTC4-like material was identified as LTC4 and LTD4 at 6 min after the onset of convulsions, whereas at 54 min after the onset, transformation of LTD4 to LTE4 could be detected as well. In gerbils showing only weak seizure activity a small increase in PGF2 alpha but no increase in immunoreactive LTC4-like material could be detected at 6 min after the onset of convulsions. Pretreatment with indomethacin abolished the formation of PGF2 alpha but significantly enhanced the biosynthesis of immunoreactive LTC4-like material at 18 min after the beginning of seizures. The results demonstrate formation of cysteinyl-LT following tonic-clonic convulsions in spontaneously convulsing gerbils which could be enhanced by inhibition of the cyclooxygenase pathway of arachidonic acid metabolism. Since cysteinyl-LT have potent biological actions in various organs this finding warrants further investigations on the potential role of cysteinyl-LT in the CNS.

Animals↗
PubMed1988

Radioreceptor assay for leukotriene B4. Use for determination of leukotriene B4 formation by whole human blood.

A crude membrane fraction from guinea-pig splenic tissue containing leukotriene (LT) B4-binding sites was prepared and used in a radioreceptor assay for the quantitative determination of LTB4 in clotting whole human blood as well as in eluates from reversed-phase HPLC. Binding of [3H]LTB4 to the binding sites was inhibited by 50% with 0.31 ng LTB4. The relative cross-reaction of 20-OH-LTB4, 20-COOH-LTB4 and 12-hydroxyeicosatetraenoic acid (HETE) was 9.51%, 0.41% and 0.03%, respectively. The relative cross-reaction of various other prostanoids, cysteinyl-LT, mono-HETE's and arachidonic acid was below 0.01%. The spleen binding sites are useful for a rapid, simple and specific quantification of LTB4 in biological material.

Animals↗
PubMed1988

Quantitative determination of eicosanoids in biological material.

Radioimmunoassay is the most widely used method for determination of eicosanoids in biological material. Although this technique is, in principle, simple, radioimmunological data generally require extensive validation procedures. Here some examples for such methods are presented with special emphasis on the determination of cysteinyl-leukotrienes.

Animals↗
PubMed1987

Modulation of the contractile activity of the guinea-pig lung parenchymal strip by exogenous 5,8,11,14,17-eicosapentaenoic acid.

Exogenous eicosapentaenoic acid (EPA, 16.5 mumol/l or 33 mumol/l) inhibited dose-dependently the anaphylactic contractile response of guinea-pig lung parenchymal strips suspended in an organ bath. As determined by radioimmunoassay, EPA inhibited in a dose-dependent manner the anaphylactic release of the cyclooxygenase products thromboxane (TX) B2 and 6-keto-prostaglandin (PG) F1 alpha but simultaneously enhanced the release of sulfidopeptide (SP)-leukotrienes (LT). Indomethacin (2.8 mumol/l) abolished the release of cyclooxygenase products but potentiated the release of SP-LT. However, indomethacin treatment did not affect the inhibitory action of EPA on the contractile response of the anaphylactic lung strips. The lipoxygenase inhibitor, esculetin (50 mumol/l), inhibited the release of SP-LT and also that of cyclooxygenase products of polyunsaturated fatty acid metabolism. The combination of esculetin and EPA resulted in enhanced inhibition of the anaphylactic contractile response as compared to EPA alone. By reversed phase high pressure liquid chromatography (HPLC), SP-LT from anaphylactic lung parenchymal strips was shown to consist of LTD4 and LTE4. EPA-pretreated lung strips released upon immunologic challenge additional immunoreactivity comigrating with authentic LTC4, LTC5, LTD5 and LTE5. While anaphylactic control strips also released LTB4, in the bath fluid of EPA-treated strips, an additional immunoreactive compound migrating with the retention time of LTB5 was observed. In non-sensitized guinea-pig lung parenchymal strips EPA inhibited the myotropic activity of exogenous mediators such as histamine (9 mumol/l), LTC4 (16 nmol/l) and the TX mimetic U 46619 (28.4 nmol/l), an effect which was neither affected by indomethacin (2.8 mumol/l) nor by the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA, 10 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1987

Formation of sulphidopeptide-leukotrienes in brain tissue of spontaneously convulsing gerbils.

Five minutes after the onset of seizures high amounts of immunoreactive prostaglandin (PG) F2 alpha and smaller amounts of sulphidopeptide (SP)-leukotriene (LT)-like immunoreactivity could be detected in gerbil brain tissue. Bilateral carotid artery ligation followed by 15 min of reperfusion even more enhanced brain tissue contents of PGF2 alpha and SP-LT-like material. Analysis of the immunoreactive SP-LT-like material by reversed phase high pressure liquid chromatography (h.p.l.c.) revealed immunoreactivity co-eluting with authentic LTC4 and LTD4.

Animals↗
PubMed1987

Formation of cysteinyl-containing leukotrienes by human arterial tissues.

Human arterial rings incubated in modified Tyrode solution released small amounts of leukotriene (LT) C4-like material spontaneously and larger amounts upon stimulation with the ionophore A23187 as determined by radioimmunoassay. By reversed phase high pressure liquid chromatography (HPLC) LTC4-like material was found to comigrate with authentic LTC4, LTD4 and LTE4. Nordihydroguaiaretic acid (NDGA) significantly inhibited the ionophore A23187-induced release of LTC4-like material, while indomethacin was without effect. Simultaneously the arterial rings released much larger amounts of 6-keto-prostaglandin (PG) F1 alpha, which were significantly decreased by indomethacin. The results demonstrate that human arterial tissue has the capacity to synthesize cysteinyl-containing LT from endogenous arachidonic acid.

Adult↗
PubMed1987

Effect of exogenous 5,8,11,14,17-eicosapentaenoic acid on cardiac anaphylaxis.

The effects of infusions of eicosapentaenoic acid (EPA) (6 X 10(-8) mol min-1 and 15 X 10(-8) mol min-1) on the coronary constriction and the release of immunoreactive sulphidopeptide-leukotrienes (SP-LT), thromboxane B2(TXB2) and 6-keto-prostaglandin F1 alpha (PGF1 alpha) from perfused anaphylactic guinea-pig hearts were investigated. EPA dose-dependently inhibited the profound early coronary flow reduction after antigen injection. The less pronounced late phase of anaphylactic coronary flow reduction was, however, not significantly affected. EPA (15 X 10(-8) mol min-1) significantly shortened the average duration of antigen-induced arrhythmias. EPA dose-dependently decreased release of immunoreactive TXB2 and 6-keto-PGF1 alpha from anaphylactic guinea-pig hearts. Release of immunoreactive SP-LT was dose-dependently increased after antigen challenge in the presence of EPA. Inhibiton of the release of SP-LT by the lipoxygenase inhibitor esculetin (1 X 10(-7) mol min-1) was accompanied by a significant attenuation of flow reduction during the late phase of anaphylactic vasoconstriction. Reversed phase h.p.l.c. of perfusates from anaphylactic guinea-pig hearts revealed immunoreactivity comigrating with authentic leukotriene C4 (LTC4), LTD4, and LTE4. In perfusates from hearts treated with EPA infusions, additional immunoreactivity was detected comigrating with LTC5, LTD5 and LTE5. In addition to immunoreactivity migrating with LTB4, as observed in control heart perfusates, in perfusates from EPA-treated hearts, a second peak was observed, which coincides with the retention time described for LTB5. Exogenous LTC5 (1 X 10(-12) mol min-1 and 20 X 10(-12) mol min-1) induced dose-dependent reductions of coronary flow and was found to be a slightly weaker constrictor than LTC4, but no significant differences were observed. Coronary vasoconstriction elicited by infusion of exogenous LTC4 (20 X 10(-12) mol min-1) was dose-dependently inhibited by infusions of EPA. However, the negative inotropic effect of LTC4 remained unaffected. Thus, in the isolated anaphylactic heart of the guinea-pig exogenous EPA was effectively metabolized via the 5-lipoxygenase pathway whereas the cyclo-oxygenase pathway of polyunsaturated fatty acid metabolism was found to be inhibited. The results are in agreement with the suggestion that cyclo-oxygenase products are mediators of the early phase of the anaphylactic coronary constriction, while vasoconstrictor SP-LT are involved in the later phase. However, in spite of enhanced release of SP-LT, EPA infusion did not result in increased coronary constriction. Considering the fact that EPA antagonizes LTC4-induced coronary constriction, it seems possible, that EPA might act as a functional antagonist of vasoconstrictor eicosanoids including EPA-derived SP-LT.

6-Ketoprostaglandin F1 alpha↗