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Biomedical subjects

P Borgeat

Publications and source records attributed to P Borgeat.

At least 163 records · Page 9Linked to original sources
PubMed1982

Metabolism of arachidonic acid in leukocytes: isolation of a 5,15-dihydroxy-eicosatetraenoic acid.

A novel metabolite of arachidonic acid was isolated from incubations of peripheral blood leukocytes with the fatty acid and the ionophore A23187. The compound was purified by high performance liquid chromatography and identified by ultraviolet photometry and gas chromatography-mass spectrometry as a 5,15-dihydroxy-6,8,11,13-eicosatetraenoic acid. The compound was also isolated from incubations of human leukocytes with the 15S-hydroperoxy-5,8,11,13(Z,Z,Z,E)-eicosatetraenoic acid, suggesting a double dioxygenation mechanism in the formation of this new metabolite of arachidonic acid. A 5S,15S-dihydroxy-6,8,11,13(E,Z,Z,E)-eicosatetraenoic acid was obtained from incubations of 5S-hydroxy-6,8,11,14(E,Z,Z,Z)-eicosatetraenoic acid with the soybean lipoxygenase and reduction with stannous chloride, and was used as reference compound.

Animals↗
PubMed1982

Comparative activity of natural mono-, di- and tri-hydroxy derivatives of arachidonic acid on guinea-pig lungs: myotropic effect and stimulation of cyclooxygenase activity.

The activity of natural 5,6-Dihydroxy-eicosatetraenoic acid (5,6-DiHETE; 2 isomers), 5S,15S-DiHETE, 8S,15S-DiHETE, 5S,12S-DiHETE, delta 6-trans-leukotriene B4, 12-epi-delta 6-trans-leukotriene B4, omega-hydroxy-leukotriene B4, omega-carboxy-leukotriene B4, 15S-hydroxyeicosatetraenoic acid (15S-HETE), 12S-HETE, 5S-HETE and 12S-hydroxy-heptadecatrienoic acid was compared to LTB4 on the guinea-pig lung parenchymal strip and on the release of prostaglandins and thromboxanes by the perfused guinea-pig lungs. The omega-hydroxy-LTB4 appeared more potent than LTB4 both for inducing a contraction and for releasing prostanoids whereas the omega-carboxy-LTB4 was much less active on the parenchyma and did not release prostanoids at the dose used. All other hydroxy acids tested were either very weakly active or inactive in the two systems used with the exception of the 5,6-DiHETEs which showed significant activity. These di-hydroxy acids induced contractions of the lung parenchymal strip which could be blocked by FPL-55712 but were inactive on the guinea-pig ileum. The 5S-HETE, 12S-HETE and 15S-HETE were also tested for possible myotropic activity on selected smooth muscle preparations. Our results provide further informations on the structural requirements for LTB4 (and other hydroxy acids) actions on the guinea-pig lungs.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1982

Studies on the mechanism of formation of the 5S, 12S-dihydroxy-6,8,10,14(E,Z,E,Z)-icosatetraenoic acid in leukocytes.

Incubation of peripheral blood leukocytes with arachidonic acid (and ionophore A23187) led to the formation of leukotriene B4, delta 6-trans-leukotriene B4, delta 6-trans-12-epi-leukotriene B4, 5-hydroxy-icosatetraenoic acid, 12-hydroxy-icosatetraenoic acid and of 5S,12S-dihydroxy-6,8,10,14-(E,Z,E,Z)-icosatetraenoic acid (5S,12S-DiHETE). Incubation of leukocytes with leukotriene A4 resulted in the formation of leukotriene B4 and of its two delta 6-trans-isomers but not of the 5S, 12S-DiHETE. 18O2 labeling experiments have shown that the hydroxyl groups at C5 and C12 in the 5S,12S-DiHETE are derived from molecular oxygen. The tetraacetylenic analog of arachidonic acid was found to be potent inhibitor of the formation of the 5S,12S-DiHETE whereas it potentiated the synthesis of the 5-hydroxy acid and of leukotriene B4. Addition of the 12-hydroxy-icosatetraenoic acid to leukocytes, or of the 5-hydroxy-icosatetraenoic acid to a suspension of platelets caused the formation of the 5S,12S-DiHETE. It is concluded that the 5S,12S-DiHETE is not derived from leukotriene A4 but is a product of the successive reactions of arachidonic acid with two lipoxygenases of different positional specificities.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1982

The actions of 5-, 12-, and 15-HETE on tracheobronchial smooth muscle.

In view of the likelihood that monohydroxyeicosatetraenoic acids (HETEs) are produced in asthma we investigated the actions of these lipoxygenase products on a range of tracheobronchial smooth muscle preparations. 5- and 15-HETE contracted human isolated bronchial muscle and guinea-pig lung strip but were less potent and less effective than histamine. In contrast 5-, 12- and 15-HETE were inactive on guinea-pig and cat tracheae. In addition to its direct action, subthreshold doses of 5-HETE (0.001-0.01 micrograms ml-1) potentiated histamine-induced contractions of human isolated bronchial muscle. The latter effect may suggest that 5-HETE plays a significant role in the airway hyperreactivity commonly associated with asthma.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1982

Evidence for a mediator role of thromboxane A2 in the myotropic action of leukotriene B4 (LTB4) on the guinea-pig lung.

The mechanism of action of LTB4 has been investigated on the guinea-pig lung parenchymal strip. Mepacrine (20 microgram/ml), an inhibitor of phospholipase A2, abolished the action of LTB4 on parenchymal strips. Eicosatetraynoic acid (10 microgram/ml) and BW755C (40 microgram/ml) which are inhibitors of cyclooxygenase and lipoxygenase pathways, produced a marked inhibition of the lung strip contraction to LTB4. Similarly, aspirin (30 micrograms/ml) and flufenamate (1 microgram/ml) showed a strong inhibition of the contraction of parenchymal strips to LTB4; these results suggested that cyclooxygenase products mediate the action of LTB4. The response to LTB4 was unaffected by 15-hydroperoxyeicosatatraenoic acid (15-HPETE; 1 microgram/ml) while L8027 (25 ng/ml) reduced the contraction by 50%, suggesting that thromboxane A2 rather than prostacyclin was involved. Since parenchymal strips do not appear to be very sensitive to PGF2 alpha, PGE2 and the endoperoxides, and since effluents from LTB4-treated lungs produced contractions of lung strip and rabbit aorta which were reduced after 5 min. at 25 degrees, thromboxane A2 was postulated to mediate the lung effect of LTB4. The release of thromboxane B2 (TxB2) from lungs stimulated with LTB4 was confirmed by gas-chromatography-mass spectrometric (GC-MS) analyses.

Animals↗
PubMed1982

Stimulation of leukotriene biosynthesis in human blood leukocytes by platelet-derived 12-hydroperoxy-icosatetraenoic acid.

Addition of arachidonic acid to suspensions of human blood leukocytes induces the synthesis of small amounts only of the C-5 lipoxygenase products as demonstrated by HPLC. However, the coincubation of blood platelets with the leukocytes always resulted in an activation of the C-5 lipoxygenase and formation of (5S)-5-hydroxy-6,8,11,14-icosatetraenoic acid, (5S,12S)-5,12-dihydroxy-6,8,10,14-icosatetraenoic acid, and leukotriene B4 from exogenous arachidonic acid. It was found that the activation of arachidonic acid metabolism in leukocytes was caused by a labile compound because the synthesis of the C-5 lipoxygenase products did not occur when platelets were preincubated for 1 min or more with the substrate prior to the addition of the leukocytes. The use of cyclooxygenase inhibitors did not suppress the activation of the leukocytes by the platelets. However, the addition of 5,8,11,14-icosatetraynoic acid, an inhibitor of cyclooxygenase and C-12 and C-15 lipoxygenases, completely suppressed the formation of leukotrienes, although this substance is not an inhibitor of the C-5 lipoxygenase in human leukocytes. This indicated that a product of the C-12 lipoxygenase was likely the mediator of the stimulatory effect of platelets on leukocyte arachidonic acid metabolism. The finding that the direct addition of (12S)-12-hydroperoxy-5,8,10,14-icosatetraenoic acid, but not of the corresponding hydroxy derivative, could activate the leukocyte's C-5 lipoxygenase confirmed this hypothesis. These data demonstrate that an interaction between C-12 and C-5 lipoxygenases can promote the formation of leukotrienes and support the possibility of a cooperation between platelets and leukocytes in inflammation and hypersensitivity reactions. Furthermore, the finding provides a new interest for the platelet C-12 lipoxygenase.

Arachidonic Acid↗
PubMed1982

Evidence against a role for lipoxygenase-derived products of arachidonic acid in the lamb ductus arteriosus.

The effects of leukotrienes, the leukotriene antagonist FPL55712 (sodium 7-(3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2-hydroxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate), and inhibitors of arachidonate lipoxygenase and cyclo-oxygenase (compound BW755C, 3-amino-1-(m-(trifluoromethyl)-phenyl)-2-pyrazoline; ETYA, 5,8,11,14-eicosatetraynoic acid) were studied in an isolated preparation of ductus arteriosus from mature foetal lambs. Leukotrienes (LT) C4 and D4 produced a modest relaxation of the ductus but only at the highest concentrations tested (10(-7) to 10(-6) M) and under hypoxic conditions (PO2, 6--9 Torr (1 Torr = 133.322 Pa)). LTB4 had no effect at any concentration tested. BW755C (10(-6) to 10(-5) M) and FPL55712 (10(-5) M) contracted the hypoxic ductus; however, their action was abolished by pretreatment of the tissue with the cyclooxygenase inhibitor indomethacin (2.8 x 10(-6) M). Indomethacin-treated preparations were also unresponsive to ETYA 3 x 10(-5) M. The contraction of hypoxic tissues to either BW755C or FPL55712 increased further upon raising the oxygen tension of the medium (PO2 591--691 Torr). These findings indicate that leukotrienes and allied compounds formed from lipoxygenase-catalysed reactions do not contribute to prenatal patency of the ductus and are unlikely to have a role in its closure at birth. It is also confirmed that prostaglandin E2 is essential for keeping the vessel patent in the foetus.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1982

Characterization of the secretory activity of leukotriene B4 toward rabbit neutrophils.

We have described in det ail the secretory activity of leukotriene B4 toward rabbit neutrophils. Leukotriene B4 rapidly and vigorously degranulates rabbit neutrophils. This activity is stereospecific, cytochalasin B-dependent, and is enhanced by extracellular calcium. Pretreatment with leukotriene B4 deactivates rabbit neutrophils, i.e., cells so treated do not respond to stimulation by an additional bolus of leukotriene B4. In addition, the secretory activity of leukotriene B4 is sharply dependent on the simultaneous presence of cytochalasin B. Rabbit neutrophils therefore exhibit the previously described desensitization to the effect of cytochalasin B. In these and other discussed respects the characteristics of the leukotriene B4-induced degranulation of rabbit neutrophils are strikingly similar to those of the chemotactic factors. These results support the hypothesis that leukotriene B4 mediates, at least in part, the secretory, and possibly other, activities of chemotactic factors.

Animals↗
PubMed1981

Cellular regulatory role of leukotriene B4: its effects on cation homeostasis in rabbit neutrophils.

We have found that exogenous leukotriene B4 modifies calcium homeostasis in rabbit neutrophils in a manner essentially analogous to that of the chemotactic peptide f-Met-Leu-Phe. Leukotriene B4 causes a rapid and dose-dependent increase in membrane permeability to calcium and a release of calcium from previously unexchangeable intracellular pool(s). The net result of these changes is to transiently elevate the intracellular level of exchangeable calcium. A stereoisomer of leukotriene B4 with greatly reduced secretory activity toward neutrophils (5S, 12S-di HETE) is essentially without effect on the rate of 45Ca uptake at concentrations equal to those that produce near maximal enhancement by leukotriene B4. Leukotriene B4, in addition to its effects on calcium metabolism, also increases the rate of 22Na influx into rabbit neutrophils. The relationships between the action of leukotriene B4 on calcium homeostasis and the neutrophil-directed activities of arachidonic acid and its lipoxygenase metabolites are discussed

Animals↗
PubMed1981

In vivo effects of leukotriene B4, C4 and D4. Evidence that changes in blood pressure are mediated by prostaglandins.

Intra-jugular nanomole injections of leukotrienes B4, C4 and D4 (LTB4, LTC4, LTD4) in anesthetized guinea-pigs have been shown to cause dose-dependent increases of the mean arterial blood pressure. While the responses to LTB4 were monophasic, the responses to LTC4 and LTD4 were characterized by a fast (10-50 sec), medium high, first pressor phase followed by a second, longer lasting (3-9 min), more important pressor phase. Like antigen-antibody reactions, leukotrienes induced cardiac effects such as tachycardia and rhythm disturbances as well as respiratory difficulties, convulsions and sometimes death of the animals. The prostaglandin synthesis inhibitor, indomethacin, reduced the pressor response and the tachyarrhythmic effects of LTB4, C4 and D4. These results raise the possibility that leukotrienes produce their hemodynamic effects in guinea-pigs by stimulating the synthesis and release of biologically active derivatives of arachidonic acid.

Animals↗
PubMed1981

The lung parenchymal strip as a sensitive assay for leukotriene B4.

Leukotriene B4 (LTB4) (3 X 10(-11) to 1.5 X 10(-9) mole; 10 ng to 500 ng) contracted the guinea-pig lung parenchymal strips in a dose-dependent manner. The contractile effect of LTB4 was not affected by methysergide (0.2 microgram/ml), propranolol (3.0 microgram/ml), phenoxybenzamine (0.1 microgram/ml), atropine (0.1 microgram/ml), diphenhydramine (0.1 microgram/ml) and FPL-55712 (1.0 microgram/ml), but was nearly completely abolished by indomethacin (20 microgram/ml). It is concluded that the contraction of the parenchymal strip to LTB4 may constitute a simple, sensitive and selective bioassay which could be either used for the determination of LTB4 in biological material or for studies on structure-activity relationship.

Animals↗