References of "Landry, Y"
     in
Bookmark and Share    
Peer Reviewed
See detailThe M2 muscarinic receptor antagonist methoctramine activates mast cells via pertussis toxin-sensitive G proteins
Chahdi, A.; Daeffler, L.; Bueb, Jean-Luc UL et al

in Naunyn-Schmiedeberg's Archives of Pharmacology (1998), 357(4), 357-62

Methoctramine, a selective M2 muscarinic cholinergic receptor antagonist, has been reported to activate phosphoinositide breakdown at high concentrations. Its polyamine structure suggests a putative ... [more ▼]

Methoctramine, a selective M2 muscarinic cholinergic receptor antagonist, has been reported to activate phosphoinositide breakdown at high concentrations. Its polyamine structure suggests a putative activation of guanine nucleotide-binding proteins (G proteins). Incubation of methoctramine with rat peritoneal mast cells resulted in a dose-dependent noncytotoxic histamine release, with an EC50 of 20 microM and a maximum effect at 1 mM. Atropine, pirenzepine and HHSiD neither inhibited methoctramine-induced histamine release nor stimulated histamine release. Histamine release and inositol phosphates generation induced by methoctramine were both inhibited by pertussis toxin pretreatment. Benzalkonium chloride, a selective inhibitor of histamine secretion induced by basic secretagogues, inhibited the secretory response to methoctramine. [p-Glu5, D-Trp7,9,l0]-SPs5-11 (GPAnt-2), a well-characterized antagonist of G proteins, blocked the methoctramine-induced histamine release when the antagonist was allowed to reach its intracellular target by streptolysin O-permeabilization. The response to methoctramine was prevented by the hydrolysis of sialic acid residues of the cell surface by neuraminidase. The response of mast cells was restored by permeabilization of the plasma membrane. These results demonstrate that methoctramine, following its entry into the cell and the involvement of pertussis toxin-sensitive G proteins, activates phosphoinositide hydrolysis leading to mast cell exocytosis. [less ▲]

Detailed reference viewed: 99 (0 UL)
Peer Reviewed
See detailStructure-activity studies of bradykinin analogues on rat mast cell histamine release
Bueb, Jean-Luc UL; Mousli, M.; Landry, Y. et al

in Peptides (1993), 14(4), 685-9

Bradykinin (BK), kallidin (KD), and various analogues induced histamine release from rat mast cells. The results obtained with substituted analogues of BK indicated that: 1) the presence of both Arg ... [more ▼]

Bradykinin (BK), kallidin (KD), and various analogues induced histamine release from rat mast cells. The results obtained with substituted analogues of BK indicated that: 1) the presence of both Arg residues at position 1 and 9 of kinins was favorable to confer histamine-releasing activity, 2) acetylation of the N-terminal amino acid residue led to a drastic reduction of this activity, 3) addition of a D-Arg residue at the N-terminus reduced their activity, as well as trans-4-hydroxyproline (Hyp) substitutions at position 2 or 3,4) D-Arg0 addition and Hyp3 substitution were synergistic in lowering activity, and 5) D-Phe7 substitution led to enhanced histamine-releasing activity. [less ▲]

Detailed reference viewed: 83 (0 UL)
Peer Reviewed
See detailAn epithelial-dependent contracting factor induced by calcium influx in guinea-pig trachea
Bertrand, C.; Da Silva, A.; Landry, Y. et al

in Pulmonary Pharmacology (1993), 6(1), 69-76

The effects of epithelium removal were studied on the contraction induced by Ca2+ in K(+)-depolarizing solution, and by the calcium ionophore A 23187 in guinea-pig isolated tracheal strips. Epithelium ... [more ▼]

The effects of epithelium removal were studied on the contraction induced by Ca2+ in K(+)-depolarizing solution, and by the calcium ionophore A 23187 in guinea-pig isolated tracheal strips. Epithelium removal reduced the maximal response to Ca2+ in K(+)-depolarizing solution and caused a significant shift to the right of the Ca2+ concentration-response curves. The contraction induced by the calcium ionophore A 23187 (10(-6) M) was also markedly reduced by epithelium removal. These results suggest the occurrence of an epithelium-derived contracting factor. The effects of hexamethonium, atropine, spantide and thiorphan showed that acetylcholine and neurokinins play a minor role in the Ca(2+)-induced contraction. The epithelium-dependent potentiation of the calcium- and of the A 23187-induced contractions was inhibited by an antibody selective for rat calcitonin gene-related peptide (rCGRP alpha). Therefore, CGRP-like immunoreactive material may be part of the epithelium-dependent contracting factor of guinea-pig trachea. Comparison of concentration-response curves for rCGRP alpha in epithelium-free and in intact guinea-pig tracheal strips suggests that an epithelium-dependent contracting factor may be mobilized by CGRP. [less ▲]

Detailed reference viewed: 62 (2 UL)
Peer Reviewed
See detailNatural polyamines stimulate G-proteins
Bueb, Jean-Luc UL; Da Silva, A.; Mousli, M. et al

in Biochemical Journal (1992), 282 (Pt 2)

The natural polyamines spermine and spermidine, the biosynthetic precursor putrescine and their analogues cadaverine and tyramine stimulate the GTPase activity of purified GTP-binding proteins (Go/Gi ... [more ▼]

The natural polyamines spermine and spermidine, the biosynthetic precursor putrescine and their analogues cadaverine and tyramine stimulate the GTPase activity of purified GTP-binding proteins (Go/Gi) from calf brain reconstituted into phospholipid vesicles. The order of potency was spermine greater than spermidine greater than putrescine = cadaverine greater than tyramine. The physiological relevance of this observation was assessed, showing the same order of potency of polyamines in the stimulation of peritoneal and tracheal rat mast cells. The activation of rat mast cells by polyamines was inhibited by benzalkonium chloride or by a 2 h pretreatment of the cells with pertussis toxin. The increase in inositol phosphates evoked by polyamines was also inhibited by pertussis toxin. Therefore we propose that intracellular polyamines might control the basal level of second messengers and modulate extracellular signals transduced through G-protein-coupled receptors. [less ▲]

Detailed reference viewed: 68 (0 UL)
Peer Reviewed
See detailEpithelial modulation of thromboxane A2 and PAF involvement in IgE- and IgG-mediated guinea pig anaphylaxis
Bertrand, C.; Tschirhart, Eric UL; Landry, Y.

in Immunopharmacology (1992), 22(2), 115-25

The role of prostanoids and platelet-activating factor (PAF) was studied in the in vitro response of guinea pig trachea to immunochallenge according to the presence or the absence of the epithelial layer ... [more ▼]

The role of prostanoids and platelet-activating factor (PAF) was studied in the in vitro response of guinea pig trachea to immunochallenge according to the presence or the absence of the epithelial layer and to the sensitization procedure leading to the preferential synthesis of immunoglobulin E (IgE) or immunoglobulin G (IgG) antibodies. Indomethacin, a cyclooxygenase inhibitor, potentiated the antigen-induced contractions both in IgE and IgG models, suggesting the involvement of relaxant prostaglandins (PGs), independently of the presence of the airway epithelium. UK-38485, a thromboxane synthetase inhibitor, did not modify the tracheal response to antigen in the IgE model. However, this compound enhanced the maximum contractile response to antigen of the intact tracheal strips of IgG-sensitized guinea pig, but reduced the contractile response of the epithelium-free tracheal strips. Two potent non-structurally related PAF antagonists, Ro 19-3704 and BN 52021, reduced antigen-induced contraction of the epithelium-free tracheal strips in the IgE model. In contrast, these compounds did not affect the contractile responses of the preparations in the IgG model. These results suggest the selective implication of thromboxane A2 and PAF, in IgG- and IgE-mediated guinea pig anaphylaxis respectively. Finally, these results indicate that thromboxane A2 (TXA2) and PAF are potent inducers of epithelium-derived mediators. [less ▲]

Detailed reference viewed: 85 (0 UL)
See detailSelective implication of thromboxane A2 and PAF-acether in two guinea pig anaphylactic models
Bertrand, C.; Tschirhart, Eric UL; Landry, Y.

in Agents and Actions. Supplements (1991), 31

In an IgE and an IgG model of anaphylaxis in the guinea pig, we investigated the role of prostanoids and PAF-acether in the tracheal response in vitro to immunochallenge. Indomethacin (10(-6) M ... [more ▼]

In an IgE and an IgG model of anaphylaxis in the guinea pig, we investigated the role of prostanoids and PAF-acether in the tracheal response in vitro to immunochallenge. Indomethacin (10(-6) M) potentiated the antigen-induced contraction in both models suggesting the synthesis of relaxant prostaglandins during the anaphylactic phenomenon. UK-38,485 (10(-5) M), a thromboxane (TxA2) synthetase inhibitor, did not modify the tracheal response in the IgE model. In the IgG model, this drug reduced the response of the tracheal strips to antigen. Ro 19-3704 (10(-6) M) and BN 52021 (10(-5) M), two potent PAF antagonists, reduced antigen-induced contraction of the tracheal strips in the IgE model. These two drugs did not modify the contractile response in the IgG model. These results indicate that PAF-acether and TxA2 play a role in the IgE and IgG model of anaphylaxis, respectively. [less ▲]

Detailed reference viewed: 64 (0 UL)
Peer Reviewed
See detailEvidence for the interaction of mast cell-degranulating peptide with pertussis toxin-sensitive G proteins in mast cells
Mousli, M.; Bronner, C.; Bueb, Jean-Luc UL et al

in European Journal of Pharmacology (1991), 207(3), 249-55

K(+)-channel blocker properties have been reported for mast cell-degranulating peptide (MCD) in the central nervous system, but its action mechanism in mast cells remains unknown. We studied the effect of ... [more ▼]

K(+)-channel blocker properties have been reported for mast cell-degranulating peptide (MCD) in the central nervous system, but its action mechanism in mast cells remains unknown. We studied the effect of MCD on the membrane potential of rat peritoneal mast cells using the fluorescent probe bis-oxonol. Unexpectedly, MCD induced a decrease in bis-oxonol fluorescence, in a rapid and then a slower phase, suggesting hyperpolarization of mast cells. Other K(+)-channel blockers, tetraethylammonium and 4-aminopyridine, did not significantly modify the bis-oxonol fluorescence and did not alter the effect of MCD. The late phase of bis-oxonol fluorescence decrease was inhibited by ouabain and by potassium deprivation, whereas histamine release was not affected. The first phase of putative hyperpolarization induced by MCD coincided with histamine release and with the generation of inositol polyphosphates. Prior treatment of the cells with pertussis toxin inhibited these effects of MCD. MCD stimulated the GTPase activity of purified G proteins (G0/Gi) in a concentration-dependent manner. These results indicate that the effect of MCD on mast cells is unrelated to K+ channels but that it is relevant to the activation of pertussis toxin-sensitive G proteins leading to the activation of phospholipase C. A direct interaction of MCD with G proteins is proposed, which, unlike mastoparan, does not require positive cooperativity. [less ▲]

Detailed reference viewed: 79 (0 UL)
Peer Reviewed
See detailMolecular basis for cellular effects of naturally occurring polyamines
Bueb, Jean-Luc UL; Mousli, M.; Landry, Y.

in Agents and Actions (1991), 33(1-2), 84-7

The naturally occurring polyamines, putrescine, spermidine and spermine, and the analogue cadaverine, induce a dose-dependent histamine release from rat peritoneal mast cells. Spermine was the most active ... [more ▼]

The naturally occurring polyamines, putrescine, spermidine and spermine, and the analogue cadaverine, induce a dose-dependent histamine release from rat peritoneal mast cells. Spermine was the most active among these polycationic metabolites, followed by spermidine and putrescine. The histamine release was inhibited by a 2 h pretreatment of the cells with pertussis toxin (100 ng/ml), demonstrating the involvement of a pertussis toxin-sensitive GTP-binding regulatory protein during the exocytotic process. Experiments performed with purified Go/Gi proteins reconstituted into phospholipid vesicles showed a direct stimulation of GTPase activity by the polyamines. This direct stimulation of G proteins and the consequent activation of the coupled effectors may represent a new mechanism of action for natural polyamines controlling receptor-dependent processes. [less ▲]

Detailed reference viewed: 71 (0 UL)
Peer Reviewed
See detailActivation of Gi-like proteins, a receptor-independent effect of kinins in mast cells
Bueb, Jean-Luc UL; Mousli, M.; Bronner, C. et al

in Molecular Pharmacology (1991), 38(6), 816-22

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 ... [more ▼]

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. [less ▲]

Detailed reference viewed: 51 (0 UL)
Peer Reviewed
See detailG-proteins as targets for non-immunological histamine releasers
Mousli, M.; Bueb, Jean-Luc UL; Rouot, B. et al

in Agents and Actions (1991), 33(1-2), 81-3

The molecular mechanism of action of several non-immunological histamine releasers has been investigated using pertussis toxin which interfers, via ADP-ribosylation, with some G-proteins. Pertussis toxin ... [more ▼]

The molecular mechanism of action of several non-immunological histamine releasers has been investigated using pertussis toxin which interfers, via ADP-ribosylation, with some G-proteins. Pertussis toxin (100 ng/ml) inhibited histamine release induced by compound 48/80, substance P, mastoparan, peptide 401, bradykinin and spermine showing that a G-protein sensitive to pertussis toxin was involved in the non-immunological histamine release. All these compounds directly activate purified G-proteins. The sensitivity to pertussis toxin of this direct stimulatory effect was demonstrated for compound 48/80, mastoparan and substance P. Altogether these results suggest that a direct activation of G-protein might be the molecular mechanism of action of histamine secretagogues acting through a pertussis toxin sensitive G-protein and in this way mimic agonist-ligand receptor interaction. [less ▲]

Detailed reference viewed: 74 (1 UL)
Peer Reviewed
See detailA pertussis toxin-sensitive G protein is required to induce histamine release from rat peritoneal mast cells by bradykinin
Bueb, Jean-Luc UL; Mousli, M.; Landry, Y. et al

in Agents and Actions (1990), 30(1-2), 98-101

Bradykinin, kallidin (Lys-bradykinin) and [Thi 5,8, D-Phe7]-bradykinin, a functional B2 antagonist, induce histamine release from rat peritoneal mast cells. The histamine release is dependent upon added ... [more ▼]

Bradykinin, kallidin (Lys-bradykinin) and [Thi 5,8, D-Phe7]-bradykinin, a functional B2 antagonist, induce histamine release from rat peritoneal mast cells. The histamine release is dependent upon added calcium when mast cells are placed in calcium-free medium 30 min before being triggered with the kinins. Histamine release was dose-dependently inhibited by pertussis toxin (1-100 ng/ml) and by benzalkonium chloride (0.1-3 micrograms/ml). The efficiency of ionophore A23187 on histamine release was affected neither by pertussis toxin nor by benzalkonium chloride. The parallel response of rat peritoneal mast cells to kinins and to substance P suggest that these peptides have the same mechanisms of action i.e. activation of a pertussis toxin-sensitive G protein and of phospholipase C defining a peptidergic triggering pathway of mast cells. [less ▲]

Detailed reference viewed: 74 (0 UL)
Peer Reviewed
See detailOxatomide and calcium: mechanisms involved in the secretion of mast cell mediators
Bueb, Jean-Luc UL; Landry, Y.

in Annales de Dermatologie et de Vénéréologie (1990), 117 Suppl 1

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 ... [more ▼]

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. [less ▲]

Detailed reference viewed: 59 (0 UL)
Peer Reviewed
See detailNeuropeptides and inflammation: presumed mechanisms in neurogenic inflammation
Landry, Y.; Bloch, J. G.; Mousli, M. et al

in Pathologie et Biologie (1990), 38(1), 53-6

Neuropeptides, among which substance P, VIP (Vasoactive intestinal peptide), somatostatin, neurotensin, dynorphin and enkephalins, are able to modulate inflammatory processes. Increasing interest is now ... [more ▼]

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. [less ▲]

Detailed reference viewed: 59 (0 UL)
Peer Reviewed
See detailG protein activation: a receptor-independent mode of action for cationic amphiphilic neuropeptides and venom peptides
Mousli, M.; Bueb, Jean-Luc UL; Bronner, C. et al

in Trends in Pharmacological Sciences (1990), 11(9), 358-62

The neuropeptide substance P, the venom peptide mastoparan and the synthetic polyamine compound 48/80 activate rat peritoneal mast cells, leading to rapid histamine release by exocytosis. Although these ... [more ▼]

The neuropeptide substance P, the venom peptide mastoparan and the synthetic polyamine compound 48/80 activate rat peritoneal mast cells, leading to rapid histamine release by exocytosis. Although these effects are inhibited by pertussis toxin and involve a transient increase in IP3, no selective membrane receptors have been identified. However, it has recently been shown that these compounds activate G proteins in vitro. Here Yves Landry and colleagues discuss the proposal that direct activation of G protein is the physiological mechanism of action of substance P on rat peritoneal mast cells, this mechanism being mimicked by mastoparan and 48/80, and possibly by other cationic amphiphilic peptides such as kinins. These compounds might be of help in defining the interaction between membrane receptors and G proteins. [less ▲]

Detailed reference viewed: 86 (0 UL)
Peer Reviewed
See detailEvidence for the involvement of calcitonin gene-related peptide in the epithelium-dependent contraction of guinea-pig trachea in response to capsaicin
Tschirhart, Eric UL; Bertrand, C.; Theodorsson, E. et al

in Naunyn-Schmiedeberg's Archives of Pharmacology (1990), 342(2), 177-81

Capsaicin (10(-9) to 10(-5) M) contracted guinea-pig tracheal strips. Epithelium-containing tracheal strips developed a maximum active tension which was significantly higher than that observed in ... [more ▼]

Capsaicin (10(-9) to 10(-5) M) contracted guinea-pig tracheal strips. Epithelium-containing tracheal strips developed a maximum active tension which was significantly higher than that observed in epithelium-free strips. Anti-CGRP (calcitonin gene-related peptide) serum blocked the epithelium-dependent potentiation of the capsaicin-induced contraction in the intact tracheal strips, without affecting the response of the epithelium-free strips. This result suggests the occurrence of an epithelium-dependent release of CGRP. This same serum markedly reduced the contraction induced by exogenous rat CGRP in both intact and epithelium-free tracheal strips. In epithelium-free tracheal strips, capsaicin-induced contraction was abolished by spantide (10(-6) and 10(-5) M), a substance P antagonist, but, in intact tracheal strips, spantide did not abolish the capsaicin-induced contraction, showing that both CGRP and substance P release are directly induced by capsaicin. Moreover, the contractile responses to rat CGRP of intact tracheal strips from guinea pig suggest that CGRP itself might be able to release a contracting factor from the airway epithelium. Therefore, CGRP originating from the airway epithelium may play a major role in the control of airway smooth muscle tone. [less ▲]

Detailed reference viewed: 82 (0 UL)
Peer Reviewed
See detailActivation of rat peritoneal mast cells by substance P and mastoparan
Mousli, M.; Bronner, C.; Bueb, Jean-Luc UL et al

in Journal of Pharmacology and Experimental Therapeutics (1989), 250(1), 329-35

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 ... [more ▼]

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. [less ▲]

Detailed reference viewed: 101 (0 UL)
Peer Reviewed
See detailContractile activity of the N-acylated C-terminal part of substance P7-11 in guinea pig trachea. Effect of epithelium removal
Tschirhart, Eric UL; Schmitt, P.; Bertrand, C. et al

in Naunyn-Schmiedeberg's Archives of Pharmacology (1989), 340(1), 107-10

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 ... [more ▼]

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. [less ▲]

Detailed reference viewed: 72 (0 UL)
Peer Reviewed
See detailNedocromil sodium inhibits IgE- and IgG-related antigen-induced contraction in guinea-pig trachea
Bertrand, C.; Tschirhart, Eric UL; Landry, Y.

in International Archives of Allergy and Applied Immunology (1989), 88(4), 439-46

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 ... [more ▼]

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. [less ▲]

Detailed reference viewed: 124 (2 UL)
Peer Reviewed
See detailArachidonic acid metabolites and airway epithelium-dependent relaxant factor
Tschirhart, Eric UL; Frossard, N.; Bertrand, C. et al

in Journal of Pharmacology and Experimental Therapeutics (1987), 243(1), 310-6

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 ... [more ▼]

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. [less ▲]

Detailed reference viewed: 91 (0 UL)
Peer Reviewed
See detailAirway epithelium releases a relaxant factor: demonstration with substance P
Tschirhart, Eric UL; Landry, Y.

in European Journal of Pharmacology (1987), 132(1), 103-4

Detailed reference viewed: 92 (1 UL)