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P J Piper

Publications and source records attributed to P J Piper.

At least 73 records · Page 4Linked to original sources
PubMed1988

The metabolism "in vitro" of leukotriene B4 in blood of normal subjects and asthmatic patients.

The metabolism of exogenous leukotriene B4 (LTB4) was investigated in venous blood obtained from normal and asthmatic subjects. Using specific radioimmunoassay (RIA) and reverse-phase high performance liquid chromatography (RP-HPLC) techniques we have demonstrated that LTB4 is relatively stable during a 2 hr incubation period at 37 degrees C in our system in vitro. Nevertheless, chromatographic analysis revealed the presence of two products which had retention times identical to 20-hydroxy LTB4 (20-0H LTB4) and 20-carboxy LTB4 (20-C00H LTB4) in which the dicarboxylic derivative was the main metabolite present after 15 min incubation. The amount of LTB4 and its w-oxidation products observed after a 2 hr incubation period was 73% and 24% respectively. There was no basal release of LTB4 from blood. The appearance of these oxidative products was totally suppressed at 4 degrees C and with incubations performed with either venous plasma or Hartmann's control. No significant difference was observed in substrate metabolism between normal and asthmatic subjects. Our results demonstrate that LTB4 is slowly degraded in human whole blood through a cellular dependent process of w-oxidation which may be an important pathway for regulating the availability of this potent biologically active substance.

Asthma↗
PubMed1988

Vasodilator actions of acetylcholine, A23187 and bradykinin in the guinea-pig isolated perfused heart are independent of prostacyclin.

1. The involvement of prostacyclin (PGI2) in the vasodilator responses to acetylcholine (ACh), A23187 and bradykinin (Bk) has been investigated in guinea-pig, isolated, Krebs-perfused hearts. 2. ACh (0.01-10 nmol), A23187 (0.1-1.0 nmol) and Bk (0.3-10 pmol) each elicited dose-related and shortlasting (approximately 2 min) reductions in perfusion pressure. Larger maximal responses were obtained in preparations with coronary vascular tone elevated by platelet-activating factor (100 pmol) than in preparations at basal perfusion pressure. 3. Bk and A23187 elicited dose-related increases in the generation of PGI2 as measured by its chemically-stable breakdown product, 6-oxo-PGF1 alpha. Indomethacin (2.8 microM) prevented both basal and the stimulated generation of 6-oxo-PGF1 alpha, whereas the magnitudes of the vasodilator responses were unaffected. 4. Attempts to identify the release of vasodilator materials by on-line superfusion bioassay of cardiac effluent were unsuccessful, indicating a possible role for a labile vasodilator such as endothelium-dependent relaxing factor (EDRF). In addition, the inhibitors of EDRF action/production, mepacrine (3 microM) or diethylcarbamazine (300 microM), attenuated vasodilator responses to ACh without altering those to the endothelium-independent vasodilator, verapamil (1 nmol). 5. Haemoglobin (10 microM) reduced vasodilator responses to ACh, Bk and verapamil and abolished those induced by A23187. Inhibition of the endothelium-independent vasodilator, verapamil, was significantly less than that for the other compounds. 6. The present data indicate the existence of an indomethacin-resistant vasodilator mechanism in the coronary microcirculation in response to ACh, A23187 and Bk. EDRF is a candidate for mediating these responses; however, a direct vasodilator action of these substances cannot be excluded.

Acetylcholine↗
PubMed1988

Inhibition of leukotriene release in anaphylactic guinea-pig hearts by a 5-lipoxygenase inhibitor, CGS 8515.

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.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1987

The detection of 5-lipoxygenase and cyclo-oxygenase products in sputum of patients with chronic bronchitis and bronchiectasis.

Leukotrienes (LTs) and prostanoids (Ps) were detected in sputum of patients with chronic bronchitis and/or bronchiectasis (CB/B) using selective superfusion bioassay and radioimmunoassay (RIA) techniques. Analysis of sputum extracts showed a 4-fold increase in the level of LTB4 compared to the cysteinyl-containing LTs (LTC4/LTD4). The measurement of cyclo-oxygenase products (COPs) indicated relatively greater amounts of the vasodilator prostaglandin E2 (PGE2) and prostacyclin (PGI2) compared to the vasoconstrictor prostaglandin F2 alpha (PGF2 alpha) and thromboxane A2 (TxA2) agents (70:30% of total COPs respectively). The presence of eicosanoids (LTs and Ps) in sputum of patients with CB/B suggest that these biologically active substances may act as mediators of bronchoconstriction and inflammation in these diseases.

Adult↗
PubMed1987

The effect of an oral leukotriene antagonist L-649,923 on histamine and leukotriene D4-induced bronchoconstriction in normal man.

We have studied the effect of prior treatment with an oral leukotriene (LT) antagonist L-649,923, on histamine and LTD4-induced bronchoconstriction in 12 normal male subjects in a double-blind, placebo-controlled, randomized, crossover trial. L-649,923 had no effect on histamine-induced bronchoconstriction but antagonized LTD4-induced bronchoconstriction, causing a mean shift to the right of the dose-response curves of 3.8-fold. This study demonstrates that LT antagonism is possible and safe in man and that LTD4-inhalation challenge testing can be used to detect LT antagonism.

Adult↗
PubMed1987

Leukotrienes.

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Animals↗
PubMed1987

Detection of sputum eicosanoids in cystic fibrosis and in normal saliva by bioassay and radioimmunoassay.

We have measured arachidonic acid (AA) metabolites, leukotrienes (LTs) and prostanoids (Ps), in sputum of patients with cystic fibrosis (CF) and in normal saliva using bioassay and radioimmunoassay (RIA). Almost three times as much LTB4 is present in CF extracts compared with slow reacting substances (SRSs). Leukotrienes were not detected in normal saliva. In CF sputum there is a three-fold increase in the level of the vasodilator prostanoid prostaglandin E2 (PGE2) and the stable metabolite of prostacyclin, 6-oxo PGF1 alpha compared with the vasoconstrictor prostaglandin F2 alpha (PGF2 alpha) and thromboxane B2 (TxB2), a hydrolysis product of thromboxane A2. Experiments with BW755c (25 micrograms ml-1, n = 3) indicated that the majority of this activity was not produced during the extraction procedure. The detection of LTs and Ps in sputum of CF patients shows that these substances are present at biologically active concentrations and may contribute to the pathophysiology of this disease.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1987

The role of blood vessels in the bioconversion of leukotrienes in the pig.

Porcine pulmonary artery has the ability to convert leukotriene C4 (LTC4) to LTD4 and then to LTE4. In this vessel, there appears to be no further metabolism beyond LTE4. LTC4 (1 nM) is converted rapidly to LTD4, whereas the conversion of LTD4 to LTE4 is somewhat slower. The conversion of LTC4 to LTD4 is inhibited by the gamma-glutamyl transpeptidase inhibitor, serine-borate (45 mM). The conversion of LTD4 to LTE4 is inhibited by the aminopeptidase inhibitor, L-cysteine (10 mM). LTB4 did not appear to be metabolized by porcine pulmonary artery. These results suggest that the vessel wall may play a role in the early stages of leukotriene metabolism.

Animals↗
PubMed1987

Antagonism of vasoconstriction induced by platelet-activating factor in guinea-pig perfused hearts by selective platelet-activating factor receptor antagonists.

Platelet-activating factor (Paf) is a potent coronary vasoconstrictor in rat, guinea-pig, dog and pig. The present study investigated the mechanism and duration of Paf in guinea-pig isolated, Krebs-perfused hearts. Dose-related and sustained decreases in cardiac contractility and increases in coronary perfusion pressure were elicited by bolus doses of Paf (0.3-100 pmol). Platelet-activating factor (30 pmol) induced increases in the production of immunoreactive thromboxane B2 (TXB2), leukotriene B4 (LTB4) and LTC4, but not 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). In addition, the release of leukotriene-like material following Paf was observed using on-line superfusion bioassay. The coronary vasoconstrictor actions of Paf were partially antagonized by the leukotriene receptor antagonist, FPL 55712 (1.9 microM), or by indomethacin (2.8 microM). The combined use of these compounds did not result in further significant inhibition. The Paf receptor antagonists, BN 52021 (30 microM) and L 652, 731 (10 microM), antagonized both the increase in coronary perfusion pressure and the decrease in cardiac contractility induced by Paf (10-100 pmol) in a surmountable and relatively selective manner. The effects of a bolus dose of 100 pmol Paf were sustained in excess of 18 min. Exogenous Paf underwent little metabolism on passing through the coronary circulation with only 2% being converted to lyso-Paf and approximately 4% being retained by the heart after 18 min of perfusion. These results suggest that the coronary vasoconstrictor actions of Paf are partially dependent on the release of vasoactive arachidonic acid metabolites. The extraordinary potency and the long-lasting action of Paf indicate a potential role for this pro-inflammatory mediator in disorders of the coronary circulation.

Animals↗
PubMed1987

Human umbilical arteries and veins: generation of leukotrienes and response to exogenous leukotrienes.

When human umbilical arteries and veins were challenged with calcium ionophore A23187 they released a leukotriene (LT)-like material. On bioassay using guinea-pig ileal smooth muscle, the release was equivalent to 37.4 +/- 7.5 ng LTD4 (mean +/- SEM) per gram of arterial tissue, and 29.0 +/- 4.7 ng LTD4/g of venous tissue. The LT was further purified by high pressure liquid chromatography, and characterised as LTC4 by bioassay and radioimmunoassay of purified fractions. Longitudinal strips from human umbilical arteries in vitro did not contract to doses of synthetic LTD4 in the range 5 X 10(-11) to 10(-9) mol.

Humans↗
PubMed1987

Lipid mediators in cystic fibrosis and chronic obstructive pulmonary disease.

In order to investigate the possible role of arachidonic acid metabolites as lipid mediators in cystic fibrosis and chronic obstructive pulmonary disease (COPD), sputum from patients with cystic fibrosis, chronic bronchitis, or bronchiectasis was analyzed for various eicosanoids using a combination of radioimmunoassay and bioassay. Leukotriene (LT) B4, cysteinyl-containing LTs, and prostaglandins (PGs) E2, F2 alpha, 6-oxo-PGF1 alpha, and thromboxane B2 were found in all sputum samples. Saliva, which can contaminate sputum, contained low concentrations of prostanoids but not LTs. Inflammatory cells, including polymorphonuclear leukocytes (PMNs) are present in sputum. Because LTB4 generated by these cells is chemotactic for PMNs, it is suggested that this dihydroxy acid contributes to the inflammation of cystic fibrosis and other diseases characterized by airway obstruction. The source of the cysteinyl-containing LTs is less clear; these LTs may constrict respiratory smooth muscle and/or stimulate mucus formation.

Adult↗