Search PubMed⌕ Search

Biomedical subjects

P Devillier

Publications and source records attributed to P Devillier.

At least 91 records · Page 5Linked to original sources
PubMed1989

Characterization of neurokinin effects and receptor selectivity in human isolated bronchi.

Sensitive afferent nerves and the neurokinins they release upon activation are considered to be important in controlling bronchomotor tone. Human isolated bronchi respond to neurokinin A (NKA), substance P (SP), and neurokinin B (NKB) with dose-dependent contractions. The order of potency of the three natural neurokinins is NKA greater than SP greater than NKB, suggesting the presence of NK-2 receptors. To further characterize the neurokinin receptors in human bronchi, we used selective agonists for each receptor type (i.e., NK-1, NK-2, and NK-3). In fact, NK-1 selective compounds, [Pro9]SP(1-11) sulfone and [beta-ala4,Sar9]SP(4-11) sulfone, did not induce significant contractions up to 10(-5) M. Similarly, the selective agonist for the NK-3 receptor, [MePhe7]NKB(4-10), was almost inactive. However, the NK-2 selective fragment [Nle]NKA(4-10) was a potent stimulant. The negative log of the peptide concentration that caused 50% of maximal effect (pD2) was 6.99 for NKA and 6.12 for [Nle10]NKA(4-10). Removal of the epithelium significantly enhanced the contractile responses to the three neurokinins and also to the NK-2 selective agonist. Phosphoramidon, an enkephalinase inhibitor, was more potent than epithelium removal in enhancing the contractile responses to these agonists. However, epithelium removal and phosphoramidon did not increase the weak responses to the NK-1 and NK-3 selective compounds. In the presence of phosphoramidon, removal of the epithelium slightly enhanced the contractile responses to NKA and [Nle]NKA(4-10) but not to SP and NKB.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1988

Histamine release from rat peritoneal mast cells by kinin antagonists.

Kinins are known to be potent releasers of histamine. In the present study, the B2 antagonist analogues of bradykinin (BK) and kallidin (KD): [( Thi6,9,D-Phe8]KD, [Thi5,8,D-Phe7]BK) were also found to be potent releasers of histamine from rat mast cells and not to exert any antagonistic effect. Similarly, two B1 receptor antagonists, des-Arg10-[Leu9]KD and des-Arg9-[Leu8]BK, were shown to promote histamine release and acted only as agonists. The order of potency of these analogues was the following: [Thi6,9,D-Phe8]KD greater than [Thi5,8,D-Phe7]BK greater than des-Arg10- [Leu9]KD greater than des-Arg9-[Leu8]BK. The high activity of some of these compounds suggests that (1) the potency of kinins for histamine release from rat mast cells not only increases in parallel with the number of positively charged amino acids (Lys, Arg) but also, because of others factors such as peptide conformation, receptor binding affinity or receptor accessibility, (2) the histamine release by kinins is either a non-specific effect not mediated by receptors or, if receptors are involved, these sites may be different from other kinin receptors (i.e. B1 or B2).

Animals↗
PubMed1988

Influence of epithelium on the responsiveness of guinea-pig isolated trachea to adenosine.

1. The influence of epithelium removal on the effects of adenosine on airway contractility was investigated on the guinea-pig isolated trachea. 2. In preparations under resting tone or precontracted with histamine 10(-5) M, removal of the tracheal epithelium resulted in similar shifts to the left of the adenosine concentration-response curves (0.61 +/- 0.18 (P less than 0.05) and 0.80 +/- 0.09 (P less than 0.001) log units; n = 5), corresponding to 4.07 and 6.31 fold potentiations of the relaxant effect of adenosine. 3. In the presence of dipyridamole 10(-5) M the relaxant effects of adenosine were potentiated 85.1 fold on tracheae with epithelium; removal of the epithelium did not produce a significant additional shift to the left of the adenosine concentration-response curves (0.07 +/- 0.03 log units; n = 5; NS). 4. In the absence of dipyridamole, the theophylline-adenosine antagonism was not of the competitive type, irrespective of whether the tracheae were with or without epithelium. 5. In the presence of dipyridamole, this antagonism was likely to be of the competitive type and its characteristics were the same when the epithelium was present or absent. Regression slope and pA2 values were 0.84 and 5.07, respectively, in the presence of epithelium and 0.76 and 4.89, respectively, in its absence. 6. It is suggested that, at least in the guinea-pig isolated trachea model, the airway epithelium seems to be involved only in the uptake and metabolism of adenosine.

Adenosine↗
PubMed1988

Comparison of the effects of epithelium removal and of an enkephalinase inhibitor on the neurokinin-induced contractions of guinea-pig isolated trachea.

1. The influence of epithelium removal and/or thiorphan on the effects of neurokinins (substance P (SP), neurokinin A (NKA), neurokinin B (NKB)) and related peptides on airway contractility was investigated on the guinea-pig isolated trachea. 2. Removing the tracheal epithelium significantly enhanced the sensitivity but not the maximum contractile responses to the peptides. 3. After removal of the epithelial layer, the shifts to the left of the log concentration response curves were greater for SP and SP-OMe (1.62 and 1.94 log units, respectively) than for two SP analogues substituted in position 9 namely [Pro9]SP sulfone and [beta-Ala4, Sar9]SP(4-11) sulfone (0.66 and 0.68 log units, respectively). The leftward shifts for compounds related to NKA or NKB lay between 0.58 and 0.73 log units. 4. The leftward shifts of the log concentration-response curves for SP, SP-OMe, [Pro9]SP sulfone, [beta-Ala4, Sar9]SP(4-11) sulfone and NKA were of similar magnitude after removal of the epithelium or after pretreatment with thiorphan (10(-5) M), an enkephalinase inhibitor, in the presence of epithelium. No significant additional shift of the curves to the left was observed with thiorphan plus epithelium removal. 5. The results obtained with the selective agonists for each of the three classes of neurokinin receptor (i.e NK1, NK2, NK3) suggest that the guinea-pig trachea contains receptors for SP and NKA but few if any for NKB. 6. It was concluded that neurokinins and related peptides (especially SP and analogues not substituted in position 9) are degraded by enkephalinase mainly located in the tracheal epithelium and that the addition of thiorphan or epithelium removal results in an inhibition or loss of enkephalinase activity, thereby increasing similarly the potencies of these peptides. It was, therefore, suggested that the supersensitivity to neurokinins produced by epithelium removal was due neither to the elimination of a permeability barrier nor to reduced production of a relaxant factor, but mainly to reduced peptide degradation.

Airway Resistance↗
PubMed1988

Local cellular and humoral responses to antigenic and distilled water challenge in subjects with allergic rhinitis.

We studied nasal responses to allergen, saline, and distilled water aerosol in 7 subjects with allergic rhinitis to determine whether they caused a similar release of mediators and influx of inflammatory cells into the nasal lumen. The subjects were challenged first with allergen and then with aerosols of distilled water and of normal saline in random order on separate days. We measured nasal airway resistance (Rn) by posterior rhinomanometry, measured the concentrations of protein, histamine, leukotrienes (LT) B4, C4, and D4, and platelet-activating factor (PAF-acether) and performed total and differential cell counts in nasal lavage fluid obtained before and after each challenge. Allergen challenge provoked a 2-fold or greater increase in nasal airway resistance in all subjects (mean increase = 12.2-fold). This response was associated with significant increases in protein, histamine, LTB4, and sulfidopeptide leukotrienes. 2-lyso-PAF-acether increased significantly, indicating activation of phospholipase A2, but PAF-acether was detected in only one subject. The total cell count increased from 55 +/- 44 x 10(3)/ml to 200 +/- 168 x 10(3)/ml; polymorphonuclear neutrophils increased from 11 +/- 22 x 10(3)/ml to 108 +/- 96 x 10(3)/ml, and eosinophils increased from 1.3 +/- 1.8 x 10(3)/ml to 10.6 +/- 15.3 x 10(3)/ml (p less than 0.05). Saline insufflation provoked insignificant changes in mean Rn, in the levels of protein and all inflammatory mediators, and in the number and types of cells in nasal lavage fluid. Distilled water insufflation also provoked an insignificant increase in mean Rn, but there was a 14-fold increase in one subject.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Nasal response to substance P and methacholine in subjects with and without allergic rhinitis.

We compared the rise in nasal airway resistance (NAR) provoked by topical application of substance P (SP) and of methacholine (MCH) in seventeen patients suffering from rhinitis and fourteen control subjects. Challenges with SP or MCH were separated by a week or more. NAR was measured by posterior rhinomanometry before and 10 min after intranasal administration of SP (10-40 nmol) or MCH (3-12 mumol). The two groups of subjects had similar baseline levels of NAR and similar small responses to buffered saline. Substance P but not MCH provoked cutaneous flushing in all subjects. Both SP and MCH provoked a significantly greater increase in NAR in patients suffering from rhinitis than in control subjects. The increase in NAR was dose-dependent, and on a molar basis, SP was 375-500-fold more potent than MCH. Pretreatment with 200 micrograms of a topically active anticholinergic agent, oxytropium bromide, prevented the rise in NAR caused by 12 mumol of MCH but not that caused by 40 nmol of SP in six patients suffering from rhinitis. We conclude that SP is absorbed across the nasal mucosa and causes cutaneous vasodilation, that MCH and SP cause a greater rise in NAR in patients suffering from rhinitis than in control subjects, that SP is about 500-fold more potent than MCH in increasing NAR, and that the rise in NAR caused by SP is not mediated by postganglionic parasympathetic mechanisms.

Administration, Intranasal↗
PubMed1988

[The nonadrenergic, noncholinergic neuropeptide system and asthma].

An understanding of the non adrenergic non cholinergic nervous system and its implication in the pathogenesis of asthma would benefit by the identification and localisation of the numerous natural bioactive peptides at the pulmonary level. In the past few years two components of the non adrenergic non cholinergic nervous system have been characterised. A bronchodilator component which would be mediated by "vaso-active intestinal peptide" (VIP) and the "peptide histidine methionine" (PHM). A broncho-constrictor component which would be mediated by the neurokinins (substance P (SP), neurokinin A (NKA) and the "calcitonin gene related peptide" (CGRP)). These neuropeptides, in vitro as well as in vivo, have effects which are not limited to the regulation of bronchial smooth muscle tone. In effect, they may intervene in the regulation of vascular tone, in the production of mucous and in the expression of immediate hypersensitivity reactions at pulmonary level. Several neuropeptides are present or co-exist with classical neurotransmitter in the afferent nerve endings of the pulmonary efferents. This co-existence of several neurotransmitters in the same nervous fibres raised the questions as to their interactions at the pre or post synaptic level. The implication of these neuropeptides in the pathogenesis of asthma rests on numerous experimental arguments. This recent aspect in the pathophysiology of asthma allows us to hope for new therapeutic approaches.

Asthma↗
PubMed1986

A simple indirect immunofluorescence micromethod for cell typing.

We describe a simple indirect immunofluorescence micromethod for cell typing. Cells are layered on 18-well immunofluorescence slides coated with high polymer poly-L-lysine. Expressed cell surface membrane markers are detected by indirect immunofluorescence using monoclonal antibodies and the cells are stained with Evans blue dye to permit easy morphological identification under fluorescence and light microscopy. We compared this method with a conventional method for lymphocyte typing in 16 blood samples and 10 bronchoalveolar lavage samples. The results of the two methods did not differ and correlated closely (r = 0.988 for blood samples; r = 0.995 for bronchoalveolar lavage samples). The principal advantages of this micromethod are: the small amounts of cells (10(4) cells) and reagents needed, the ease with which numerous antibodies can be tested and the convenience offered by fixation and staining of cell preparations for reading.

Animals↗
PubMed1986

Histamine release and local responses of rat and human skin to substance P and other mammalian tachykinins.

Substance P and two recently identified neurokinins, substance K and neuromedin K as well as the nonmammalian tachykinin kassinin were compared for histamine-releasing abilities from rat mast cells, plasma extravasation effects on rat skin, and wheal and flare responses on human skin. Among the four tachykinins, a significantly dose-dependent histamine release from rat mast cells and a flare response in human skin was observed only with substance P, indicating the possible implication of histamine in this response. On the other hand, the four peptides were similarly active on the wheal response (plasma extravasation produced by increased permeability of capillaries and venules) in human skin and on the plasma extravasation in the rat skin, suggesting a dissociation of effects and possibly of receptors.

Animals↗
PubMed1986

[Culture of murine mastocytes: heterogeneity of the ultrastructural aspects].

In cultures of normal mouse hematopoietic cells containing mast cell growth factor develop cells with many features of mast cells. These cells seem heterogeneous with respect to size, cell surface, granules maturity and morphology of nucleus using transmission and scanning electron microscopy. Alcian blue-safranin staining shows that most of the proteoglycan synthesized by cultured mast cells is weakly sulfated and non heparin-mucopolysaccharides. These results support the view that cultured mast cells resemble to mucosal mast cells, and are clearly different from serosal mast cells.

Animals↗
PubMed1985

Peptides and histamine release from rat peritoneal mast cells.

Various vasoactive peptides were compared for their histamine releasing effects on rat mast cells. Neurotensin, substance P (SP), and kallidin were the most active natural peptides, followed by bradykinin; neurokinin A and B, bombesin, angiotensin and tuftsin were practically inactive. Several kinins and tachykinin-related peptides were tested in an attempt to characterize the receptors mediating histamine liberation. The order of potency of the kinins was the following: kallidin greater than [Tyr(Me)8]bradykinin = bradykinin greater than [desArg10]kallidin greater than desArg9-bradykinin, the same as that found in smooth muscle possessing receptors of the B2 type. Tachykinin-related peptides were potent stimulants and followed the order: [D-Tryp7,9,10]SP-(1-11) greater than [D-Pro2,D-Tryp7,9,10]SP-(1-11) greater than SP-(1-11) greater than SP-(1-9) greater than [D-Pro4,D-Tryp7,9,Leu11]SP-(4-11) greater than SP-(1-7) greater than SP-(4-11) greater than neurokinin A = neurokinin B, indicating that: (a) undecapeptide antagonists of SP behave as superagonists; (b) both N- and C-terminal portions of SP-(1-11) are essential for activity; and (c) receptors for the tachykinins mediating histamine release appear to be of the SP-P type.

Animals↗
PubMedDate not supplied

Vascular biology of the isoprostanes.

Isoprostanes are a family of compounds produced from polyunsaturated fatty acids via a free-radical-catalysed mechanism. F(2)-isoprostanes are prostaglandin F(2alpha) isomers derived from arachidonic acid. These compounds induce potent vasoconstriction, mediated primarily by TP receptor stimulation, and in some vessels by the release of cyclooxygenase products. This vasoconstriction may be modulated by the endothelium through the release of NO. Potent vasoconstriction is also observed with E(2)-isoprostanes. Experimental and clinical data suggest a role for F(2)-isoprostanes in atherogenesis. These compounds can be detected in free forms in biological fluids as well as esterified in low-density lipoproteins or cell membranes. Their quantification represents a reliable marker of lipid peroxidation. Elevated levels of F(2)-isoprostanes in biological fluids in pathological conditions including atherosclerosis, ischaemia-reperfusion injury, and inflammatory vascular diseases, suggest a relationship between lipid peroxidation and such diseases. F(2)-isoprostanes are currently being investigated as non-invasive quantitative markers to monitor the response to anti-oxidant treatment.

Dinoprost↗
PubMedDate not supplied

[Research on inflammatory mediators in asthma: new therapeutic approaches].

During the National Meeting of Clinical Pharmacology (Giens 1998), the working group exchanged information and examined the new therapeutic approaches to inflammation in asthma. The group performed a state of the art review of the current research on mediators of bronchial inflammation to determine new pharmacological targets of therapeutic interest. An update on the development of potential drugs acting on these targets was established. Specificities related to asthma in terms of evaluation and development of anti-inflammatory drugs were discussed. The place of pharmaco-economy in the development of anti-asthmatic drugs was specified.

Anti-Asthmatic Agents↗
PubMedDate not supplied

[In vitro study of of the effects of cysteinyl leukotrienes on human vascular preparations].

Leukotrienes are 5-lipoxygenase-derived arachidonic acid metabolites. In addition to their bronchoconstrictor effects, leukotrienes are also important modulators of the vascular tone which may exert paradoxical effects. Indeed, depending on the vascular tone (in either the basal or norepinephrine-precontracted state), leukotrienes are capable of inducing either contraction or relaxation. These paradoxical effects of leukotrienes depend on the vascular bed and the species investigated. Since urinary LTE4 excretion is increased in various cardiovascular diseases, including arterial pulmonary hypertension or cardiac ischaemia, the study of the effects of leukotrienes on human vascular preparations is of interest. This article reviews the in vitro evidence linking cysteinyl leukotrienes to the modulation of the vascular tone on human vascular preparations.

Blood Vessels↗
PubMedDate not supplied

Inflammatory cytokine production in interferon-gamma-primed mice, challenged with lipopolysaccharide. Inhibition by SK&F 86002 and interleukin-1 beta-converting enzyme inhibitor.

Mice challenged with lipopolysaccharide (LPS) produce variable serum levels of pro-inflammatory cytokines, and particularly low levels of interleukin-1 beta (IL-1 beta). Interferon-gamma (IFN-gamma) has been shown to be an important mediator of bacteria-induced hypersensitivity to LPS in mice. In the present study, we show that mice pretreated with IFN-gamma exhibit an enhanced capacity to produce serum IL-1 beta, IL-1 alpha, tumour necrosis factor (TNF-alpha) as well as IL-6 in response to LPS. Priming with intraperitoneal (i.p.) injection of 15 mg rat recombinant IFN-gamma, 18 hours prior to the i.p. LPS (300 mg) challenge resulted in a 4-fold increase in the LPS-stimulated release of IL-1 beta and a 2- to 7-fold increase in the release of IL-1 alpha, TNF-alpha, as well as IL-6 into the serum. LPS induced a concentration-dependent increase in the release of IL-1 beta in isolated peritoneal macrophages from IFN-gamma-primed mice whereas macrophages from unprimed mice released minute amounts of IL-1 beta. In addition, nigericin markedly enhanced the release of IL-1 beta in unprimed mice but not in macrophages from IFN-gamma primed mice. The cytokine synthesis inhibitor SK&F 86002, administered per os (100 mg/kg), 1 hour prior to LPS challenge, strongly inhibited the rise in serum levels of the four cytokines. Furthermore, treatment with the IL-1 beta converting enzyme (ICE) specific reversible inhibitor YVAD-CHO resulted in a sharp dose- and time-dependent inhibition of IL-1 beta secretion in the serum, whereas the other cytokines were not affected. In conclusion, IFN-gamma priming strongly potentiates the release of proinflammatory cytokines in the serum of mice as compared to LPS stimulation alone, and provides therefore a useful way to test the in vivo potency and selectivity of cytokine synthesis inhibitors.

Animals↗
PubMedDate not supplied

[Vascular effects of neurokinins in humans].

Neurokinins (mainly substance P and neurokinin A) are released by sensitive nerve fibres. These fibres have been found in the vascular wall of arteries and veins of many vascular regions, particularly in nasal mucosa vessels, temporal and coronary arteries and saphenous veins. Substance P causes vascular relaxation by stimulating NK1 endothelial receptors. This relaxant effect is mediated, according to the vessels, by nitric oxide (NO), prostanoids or endothelium-dependent hyperpolarizing factor (EDHF). Capsaïcin, which induces the release of neurokinins, and neurokinin A can cause contractions of some vascular preparations, suggesting the existence of smooth muscle NK2 receptor associated with contraction. The vasodilatation induced by substance P injection appears reduced in patients with cardiovascular risk factors. The clinical development of specific neurokinin receptor antagonists may give the opportunity to specify the role of neurokinins in systemic vascular diseases. The results already obtained after repeated local applications of capsaïcin (to reduce local levels of neurokinins) in vasomotor rhinitis and urticaria suggest that the vascular effects of neurokinins may participate in the clinical expression of these diseases.

Blood Vessels↗
PubMedDate not supplied

[Pharmacology of glucocorticoids and ENT pathology].

UNLABELLED: 1. NATURAL AND SYNTHETIC HORMONES: Glucocorticoids are indispensable circulating hormones implicated in carbohydrate and protein metabolism. They also have strong antiinflammatory effects used in therapy. This antiinflammatory activity has led to the development of synthetic compounds with an antiinflammatory action that is much greater than that of the natural hormones (cortisol, cortisone) with reduced mineralocorticoid activity. 2. ANTIINFLAMMATORY EFFICACY OF GLUCOCORTICOIDS: The action of glucocorticoids on the majority of the cells involved in inflammatory reactions, particularly in allergy, and their induction of synthesis of new inflammation mediators explains their antiinflammatory effect. 3. MECHANISMS OF ACTION: The antiinflammatory properties of glucocorticoids result basically from their inhibitory effect on synthesis of proinflammatory proteins, in particular many cytokines. Corticoids reduce the production of prostanoids by inhibiting the expression of COX-2, but are much less effective on the production of leukotrienes. Corticoids inhibit the degranulation of human basophils (histamine release) but have no effect on mast cells. 4. ACTIVATION OF A CYTOPLASMIC RECEPTOR: The antiinflammatory effect of glucocorticoids is mediated by binding to a cytoplasmic receptor which, when activated, migrates to the nucleus. The activated receptor can interact with transcription factors (NF-kappa B, AP-1) inhibiting the synthesis of proinflammatory proteins (cytokines, COX-2...). This "transrepressive" activity explains most of the antiinflammatory effects of glucocorticoids. 5. ACTION OF THE ACTIVATED RECEPTOR: The activated receptor can bind to specific sites present on the regulator region of target genes, inducing their transcription (or transactivation). This induction effect on protein synthesis concerns the renin-angiotensin system, neoglucogenesis, and bone metabolism. Increased production of these proteins explain the metabolic and endocrine effects of glucocorticoids which, when exaggerated, particularly with general administration, can lead to undesirable effects. At the present time, our knowledge suggests it would be best to have molecules with a predominant transrepressive activity (antiinflammatory activity) since the transactivator effects appeared to be associated with the undesirable metabolic effects of glucocorticoids. 6. OTHER PHARMACEUTICAL PROPERTIES: Glucocorticoids also have properties that do not require gene expression. These "non-genomic" effects could occur at high dosage "pulse" therapy. We will have to wait for more pertinent clinical information on these effects to use the power of these non-genomic effects to guide our choice of the appropriate glucocorticoid in given clinical situations. 7. LOCAL TREATMENT FOR ALLERGIC RHINITIS: Given locally glucocorticoids reduce the concentration of many inflammatory mediators and the number of inflammatory cells in secretions and nasal biopsies. The efficacy of glucocorticoids is perfectly established in this indication as well as in nasal polyposis. 8. LOCAL TOLERANCE: During the first days of treatment, local application of corticoids on the inflammatory mucosal surface can cause irritation and/or sneezing. These manifestations generally subside in a few days and are more frequent with solutions containing glycol. The dry nose sensation, sometimes associated with minimal epistaxis, is classically reported, though at a low frequency. A few rare cases of ulceration of perforation of the septum have been report and it would be difficult to exclude a mechanical cause related to administration route. It is clear that the risk of mucosal atrophy has been eliminated with the use of nasal corticosteroids. 9. EVALUATION OF THE SYSTEMIC EFFECT OF NASAL CORTICOSTEROIDS: Most of the studies have examined the hypothalamo-pituitary-adrenal axis. These studies have rarely demonstrated, an then in isolated cases, any significant modification at recommended doses. Likewise for other markers of passage into the systemic circulation such as osteocalcine or the number of circulating eosinophils. There is also very little risk of growth impairment in children or cataracts in adults. 10. SHORT-COURSE GENERAL CORTICOSTEROID THERAPY: Short periods are sometimes recommended for rhinitis, sinusitis, polyposis or laryngitis. Use of a short duration treatment (about one week) at doses in the 1 mg/kg/d range, induce a transient inhibition of the corticoadrenal axis in about half the patients; this inhibition disappears in most all cases in two weeks. The clinical risk associated with this alteration in patients under stress (infection, trauma...) remains hypothetical. In any case, it would be advisable to avoid repeating short-course general corticosteroid therapy at close intervals.

Adult↗