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Y Landry

Publications and source records attributed to Y Landry.

At least 73 records · Page 4Linked to original sources
PubMed1990

[Neuropeptides and inflammation: presumed mechanisms in neurogenic inflammation].

Neuropeptides, among which substance P, VIP (Vasoactive intestinal peptide), somatostatin, neurotensin, dynorphin and enkephalins, are able to modulate inflammatory processes. Increasing interest is now devoted to these peptides in different inflammatory diseases, concerning skin, lung and joins. The effect of substance P can be dependent on its C-terminal moiety implicating by this way an interaction with specific neurokinin receptors or can be dependent on its N-terminal moiety which does not involve a specific membrane receptor. Such diversity of the action mechanisms of peptides should influence the evolution of the anti-inflammatory therapeutic.

Arthritis↗
PubMed1990

Sialic acid residues as catalysts for M2-muscarinic agonist-receptor interactions.

The role of sialic acid residues in the interactions of muscarinic agonists with the cardiac M2 muscarinic receptor was investigated by competitive binding experiments using the lipophilic radioligand (-)-[benzilic-4,4-3H]quinuclidinyl benzilate ([3H]QNB) and the hydrophilic ligand [N-methyl-3H]scopolamine methyl chloride ([3H]NMS). Direct labeling of the agonist binding sites was performed with the radiolabeled agonist [methyl-3H]oxotremorine M acetate ([3H]oxo-M). Neuraminidase decreased the affinity of the M2-selective agonist carbamylcholine in competitive binding experiments performed with [3H]QNB and [3H]NMS. The binding of the M1-selective agonist (4hydroxy-2-butynyl)trimethylammonium chloride m-chlorocarbanilate (McN-A-343), of the M1-selective antagonist pirenzepine, and of the M2-selective antagonist 11-([2-[(diethylamino)methyl]-1 piperidinyl]acetyl)-5,11-dihydro-6H-pyrido(2,3b)(1,4)benzodiazepin -6-on (AF-DX-116) were not affected by neuraminidase. Neuraminidase did not modify the binding parameters of 3H-antagonists but reduced the number of agonist binding sites revealed by [3H]oxo-M. The removal of sialic acid decreased the half-life of the receptor-agonist complex. The present results suggest that removal of sialic acid reduces the formation of super-high affinity agonist-receptor complexes. Sialic acid may catalyze macroscopic binding by enhancing accumulation of the agonist at the membrane surface.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1990

Activation of Gi-like proteins, a receptor-independent effect of kinins in mast cells.

The peptide hormones bradykinin and kallidin (Lys-bradykinin), as well as their analogues [des-Arg9]-bradykinin, a selective B1 agonist, [des-Arg9,Leu8]-bradykinin, a selective B1 antagonist, and [Thi5,8,D-Phe7]-bradykinin and D-Arg0-[Hyp3,D-Phe7]-bradykinin, two selective B2 antagonists, induced rapid histamine release from purified rat peritoneal mast cells. In contrast, the N-terminal fragment bradykinin-(1-5) was inactive. These peptides also activate the GTPase activity of GTP-binding proteins (G proteins) (Go/Gi) purified from calf brain, with an order of potency identical to that observed on mast cells, [Thi5,8,D-Phe7]-bradykinin much greater than kallidin greater than bradykinin greater than D-Arg0-[Hyp3,D-Phe7]-bradykinin greater than [des-Arg9]-bradykinin greater than [des-Arg9,Leu8]-bradykinin greater than bradykinin-(1-5). This correlation suggested that G proteins are the targets of kinins in mast cells. Accordingly, the concomitant increase in inositol trisphosphates and release of histamine elicited by kinins were inhibited by pertussis toxin pretreatment of mast cells. The inhibitory effect of benzalkonium chloride showed that the G proteins involved belong to the Gi type. GTPase activity was measured in the supernatant of homogenized mast cells but not in the membranous fraction. This activity was stimulated by kinins and by the venom peptide mastoparan. The potency of peptides was similar to that observed with purified bovine G proteins. Sodium dodecyl sulfate-gel electrophoresis of mast cell supernatant revealed pertussis toxin-induced ADP-ribosylation of two proteins, in the Mr 41,000 and 40,000 range, i.e., similar to purified alpha-subunits of Gi1 and Gi2 or Gi3 subtypes. The data support the proposal that bradykinin and analogues act like mastoparan, substance P, and compound 48/80, interacting first with sialic acid residues of the cell surface and then with Gi-like proteins, inducing phospholipase C activation and intracellular calcium mobilization.

Adenosine Diphosphate Ribose↗
PubMed1990

[Oxatomide and calcium: mechanisms involved in the secretion of mast cell mediators].

Human cutaneous mast cells and their experimental model rat peritoneal mast cells, can be stimulated by an IgE-dependent process or by peptides through the direct activation of G proteins. Both activation pathways lead to the increase of cytosolic Ca2+ level. This increase in dependent of the mobilisation of intracellular calcium stores of the endoplasmic reticulum involving the stimulation of IP3-sensitive calcium channels. Mast cells are characterized by the absence of calcium channels in the plasma membrane. Oxatomide has been synthetized as an analog of cinnarizine. However oxatomide is inactive on current calcium channels. In mast cells, oxatomide inhibits the increase of cytosolic calcium elicited during mast cell activation. Consequently mast cell exocytosis is inhibited altogether with the release of newly synthetized mediators. The authors propose several putative targets for oxatomide in mast cells. The therapeutic effect of oxatomide is also related to its property to antagonize the effects of anaphylactic mediators on their selective receptors.

Animals↗
PubMed1989

Resting plasma membrane potential of rat peritoneal mast cells is set predominantly by the sodium pump.

Changes in the plasma membrane potential of two histamine-releasing cells, rat peritoneal mast cells and basophilic leukemia cells 2H3 (RBL 2H3), were recorded with the potential-sensitive dye bis-oxonol. For mast cells, the presence of ouabain or the absence of K+ increased the fluorescence intensity of bis-oxonol; gramicidin had no effect. For RBL 2H3 cells, the presence of ouabain and the absence of K+ also increased bis-oxonol fluorescence but gramicidin also increased it. These results show that the plasma membrane potential of RBL 2H3 cells is set, in part, by the activity of the Na+ pump and in part by the K+ conductance, while that of rat mast cells is set predominantly by the Na+ pump.

Animals↗
PubMed1989

Contractile activity of the N-acylated C-terminal part of substance P7-11 in guinea pig trachea. Effect of epithelium removal.

Substance P, neurokinin A, neurokinin B, and N-acylated pentapeptide X-Phe-Phe-Gly-Leu-Met-NH2 analogs of substance P7-11 were tested for their spasmogenic activities in intact or in epithelium-denuded tracheal strips from guinea pig. Epithelium removal enhanced the efficacies and potencies relative to substance P of all the peptides tested in guinea pig trachea. In epithelium-containing preparations, the presence of a cyclic substituent (o-hydroxyphenyl-acetyl, p-hydroxyphenyl-acetyl, pyroglutamyl) in Phe7 greatly enhanced the potency and efficacy compared to substance P. These substitutions were twice as active as neurokinin A itself. The presence of an aliphatic chain (non-protected and t-butyloxycarbonyl-protected aminopropyl and aminocaproyl) in Phe7 also improved the potency and the efficacy of the synthetic peptides. The aliphatic substituents could favour an increase in local concentration of the peptides in the vicinity of the receptor(s) allowing a more effective ligand-receptor interaction. Thus, lipophilicity could be determinant in the potency of the peptides in intact guinea pig trachea. In epithelium-denuded tracheal strips from guinea pig, all the synthetic peptides were more effective than substance P but less active than neurokinin A which probably reflects the presence of the NK2 receptor subtype, which may be predominant in this type of epithelium-denuded preparation. Our results suggest that hydrophobicity plays a strong role in the interaction of the peptides, namely substance P and its analogues with the membrane and possibly the receptors themselves.

Animals↗
PubMed1989

Nedocromil sodium inhibits IgE- and IgG-related antigen-induced contraction in guinea-pig trachea.

The effects of nedrocromil sodium and disodium cromoglycate were studied on the anaphylactic contraction of guinea-pig trachea in two models of active sensitization (IgE and IgG models). The influence of epithelial removal on the effects of nedocromil sodium and disodium cromoglycate was examined because several studies have shown that the epithelial layer can modulate agonist- or antigen-induced contractile responses. Disodium cromoglycate (10(-4) M) and nedocromil sodium (10(-4) M) provided significant protection against antigen-induced contractions of guinea-pig tracheal smooth muscle in the IgG model. But only nedocromil sodium had an effect at this concentration in the IgG model and was also effective at 10(-5) M in the epithelium-denuded tracheal strips. At this concentration, disodium cromoglycate lost its protective effect. Comparison with the results obtained with FPL-55712, AA-861 and mepyramine suggested that these drugs affect histamine and particularly leukotriene synthesis and/or release by mast cells or other immunocompetent cells. These findings indicate that nedocromil sodium inhibits the IgE- and IgG-related antigen-induced contraction in guinea-pig airways, whereas disodium cromoglycate inhibits only the IgG-related processes. This study supports the hypothesis that these drugs modulate antigen-induced mediator synthesis and/or release from immunocompetent cells.

Airway Resistance↗
PubMed1989

Activation of rat peritoneal mast cells by substance P and mastoparan.

Incubation of rat peritoneal mast cells with substance P resulted in the transient stimulation of phosphoinositol breakdown and histamine secretion through an exocytotic process. These effects were inhibited markedly by a prior 2-hr exposure of the cells to pertussis toxin. Pertussis toxin also inhibited exocytosis induced by substance P, mastoparan and compound 48/80, but did not modify the secretory effect of the ionophore A23187. The transfer of rat peritoneal mast cells from balanced salt solution to calcium-free buffer led to a similar time-dependent decrease in their response to substance P and mastoparan. The concomitant absence of potassium from the calcium-free buffer enabled the mast cells to retain their secretory response. These data demonstrate identical dependency for calcium and monovalent ions of the secretory process elicited by substance P, mastoparan and compound 48/80. Pretreatment of mast cells with neuraminidase decreased the secretagogic effect of substance P, mastoparan and compound 48/80 without modifying the efficiency of the ionophore A23187. Thus, sialic acid residues might be involved in the initial binding of peptides and compound 48/80 to mast cells, which activate a pertussis toxin-sensitive G-protein and allows the increase in phospholipase C activity to induce exocytosis. This sequence of events might characterize the physiological pathway of mast cell activation by peptides, without necessarily requiring selective membrane receptors.

Animals↗
PubMed1989

Characterization of muscarinic receptors in human, guinea pig and rat lung.

Muscarinic receptor subtypes in human, guinea pig and rat lung tissue were characterized by radioligand binding, and functional studies were carried out on guinea pig and rat tissues. Control binding experiments were performed with membranes from human tissues rich in M1 (hippocampus), M2 (pons-medulla) and M3 (salivary gland) receptor subtypes. Competitive binding experiments with atropine and 4-diphenylacetoxy-N-methylpiperidine methobromide did not reveal any tissue selectivity of these ligands. Pirenzepine, a selective M1 antagonist with 11-2[[2-[(diethylamino)methyl]-1-piperidinyl] acetyl]-5, 11-dihydro-6H-pyrido[2,3-b] [1,4]-benzodiazepine-6-one (AF-DX116), a selective M2 antagonist, made it possible to characterize muscarinic subtypes. In hearts from the three species, the low affinity for pirenzepine and the high affinity for AF-DX116 were related to M2 receptors. In rat lung, the high affinity for AF-DX116 and the intermediate affinity for pirenzepine indicate M2 and M3 subtypes. Guinea pig and human lung tissues contain 48 and 67%, respectively, of muscarinic binding sites with high affinity for pirenzepine (M1). The second muscarinic receptor population in human lung might be classified as M3 in view of the cardioselectivity of AF-DX116, but the occurrence of M2 cardiac-type receptors could not be excluded. In guinea pig lung, both M2 and M3 subtypes might occur in addition to M1 receptors. Muscarinic stimulation led to the contraction of guinea pig and rat lung strips but did not significantly affect human lung strips. We suggest that presynaptic M2-muscarinic receptors modulated the M3-induced contraction in the guinea pig lung smooth muscle.

Animals↗
PubMed1988

Sialic acid is selectively involved in the interaction of agonists with M2 muscarinic acetylcholine receptors.

Neuraminidase and slight acid hydrolysis were used to investigate the role of sialic acid residues in the binding of muscarinic agonists and antagonists to membranes from tissues rich in M1 and M2 receptors. Membranes were pretreated with neuraminidase at pH 5 and the binding parameters were determined from competitive experiments with (3H)-quinuclidinylbenzylate. The removal of sialic acid residues reduced the affinity of muscarinic agonists for cerebellum, heart and lung membranes (M2), in contrast to striatum (M1). The affinity of antagonists was not affected. Thus, sialic acid is selectively involved in the interaction of agonists with M2 muscarinic receptors.

Animals↗
PubMed1988

Membrane phospholipid polar heads influence the coupling of M2 muscarinic receptors to G proteins.

Treating membranes from rat heart with phospholipase C (phosphatidylcholine choline phosphohydrolase) from Clostridium perfringens increased the affinity of muscarinic acetylcholine receptors (M2) for the agonists carbachol and oxotremorine. The affinity for antagonists was not affected. Phospholipase C activity, i.e., the cleavage of polar heads of membrane phospholipids, led to the disappearance of the guanine nucleotide-dependent rightward shift of the isotherm for agonist binding. The treatment of tracheal smooth muscle with phospholipase C led to a decrease in the maximum contractile effect of muscarinic (M2) stimulation with no modification of the agonist EC50, i.e., to the uncoupling of the stimulation-contraction process. These results demonstrate that when phospholipid polar heads are hydrolysed by phospholipase C, M2 receptors are uncoupled from G proteins, which enhances their affinity for agonists but prevents information transfer.

Animals↗
PubMed1988

[Not Available].

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Canada↗
PubMed1987

Preservation of the secretory response of peritoneal mast cells in the absence of extracellular calcium.

The transfer of rat peritoneal mast cells from balanced salt solution to calcium-free buffer led to a time-dependent decrease in their response to compound 48/80 and to ionophore A23187. The concomittant absence of potassium from the calcium-free buffer enabled the mast cells to retain their secretory response. The increase in potassium level, with a parallel decrease in sodium to maintain osmolarity, led to a slight potentiation of the response to 48/80 and to a large but transient potentiation of the response to A23187. Mast cells can be considered nonexcitable. The apparent dependency upon extracellular calcium of mast cell secretory responses might be related to the presumed tight equilibrium between endoplasmic reticulum calcium stores and extracellular calcium. The control of this equilibrium by transmembrane gradients of monovalent ions is proposed.

Animals↗
PubMed1987

Compound 48/80 is a potent inhibitor of phospholipase C and a dual modulator of phospholipase A2 from human platelet.

Compound 48/80 inhibited phosphatidylinositol-specific phospholipase C activity from human platelets. Whereas 1 microgram/ml of compound 48/80 slightly stimulated Ca2+-dependent phospholipase A2, higher concentrations led to dose-dependent inhibition of this platelet enzyme. This biphasic effect was confirmed with phospholipases A2 purified from rat liver and human synovial fluid. The aggregation of human platelets induced by ADP and PAF-acether was inhibited by compound 48/80, whereas the aggregation induced by ionophore A23187 was not modified by this compound. These results demonstrate that the inhibition of platelet aggregation by compound 48/80 is not due solely to effects on calmodulin as previously reported, but that inhibition of phospholipases and probably arachidonate mobilization may also be involved.

Animals↗
PubMed1987

Temperature-dependence and heterogeneity of muscarinic agonist and antagonist binding.

The binding parameters of muscarinic agonists and antagonists in rat central (brain, cerebellum and striatum) and peripheral (heart and lung) tissues were determined at 2 degrees and 37 degrees from competitive binding experiments with (3H)-quinuclidinylbenzylate (QNB). Muscarinic ligands binding affinities for cerebellum, heart and lung were tightly correlated. These tissues were also characterized by their low concentration of muscarinic receptors with high affinity for agonists. In contrast, brain and striatum contained a higher concentration of muscarinic receptors with a lower affinity for agonists. The affinity of QNB was lower at 2 degrees whereas that of other ligands was higher. The temperature-dependent shifts of competition curves differed from tissue to tissue and from compound to compound. The shifts were highest with gallamine and carbachol. The binding isotherms of muscarinic ligands were tentatively studied with a two-site binding model. The percentage of high- and low-affinity binding components of agonists differed with the compound. Guanine nucleotides and the temperature increase lowered agonist affinity without changing the proportions of the high- and low-affinity binding components. These results corroborate that the binding heterogeneity of muscarinic ligands does not depend only on the presence of two distinct receptors. Neither guanine nucleotides nor temperature changes allow conversion between the different putative conformational states of the muscarinic receptors.

Animals↗
PubMed1987

Arachidonic acid metabolites and airway epithelium-dependent relaxant factor.

Exogenous arachidonic acid (10(-8) to 10(-4) M) contracted epithelium-free guinea pig tracheal strips. Intact tracheal strips were contracted slightly by low concentrations of arachidonic acid (10(-8) to 10(-5) M), but higher concentrations relaxed them. In contrast, when tracheal strips were precontracted with histamine or carbachol, exogenous arachidonic acid had no effect on epithelium-free preparations but induced concentration-dependent (10(-8) to 10(-4) M) relaxation of intact tracheal strips. The effects of arachidonic acid both in epithelium-free and epithelium-containing trachea were blocked by either indomethacin (10(-6) M) or aspirin (10(-4) M). Studies on the effects of exogenous arachidonic acid, performed with a "sandwich protocol," demonstrated that the postulated airway epithelium-dependent relaxant factor released by an intact tracheal strip relaxes an adjacent epithelium-free strip in the same organ bath. This relaxation is antagonized by indomethacin suggesting the involvement of a cyclooxygenase product in this phenomenon. Comparison of concentration-response curves for contractile agonists in epithelium-free preparations and in one containing epithelium suggests the mobilization of airway epithelium-dependent relaxant factor by histamine but not by carbachol. The effects of cyclooxygenase and lipoxygenase inhibitors indicated that both relaxant and contractile arachidonic acid metabolites are generated by epithelial and nonepithelial cells alike in response to contractile agonists.

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