A substance P antagonist not containing D-tryptophan.
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Animals↗
Biomedical subjects
G Drapeau
Publications and source records attributed to G Drapeau.
Partial agonists and antagonists for substance P.
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Animals↗
Receptors for substance P. III. Classification by competitive antagonists.
A series of ten octa- and five undecapeptide antagonists of SP have been tested in four isolated smooth muscle preparations in order to characterise the receptors mediating the SP-induced contractions of the guinea pig ileum (G.P.I.), the guinea pig trachea (G.P.T.) and the rabbit mesenteric vein (R.M.V.) and the relaxation of the dog carotid artery (D.C.A.). It has been shown that: (a) Indirect effects by substance P and related peptides, mediated by acetylcholine or prostaglandins reduce the affinity of [pro4,trp7,9,10]SP (4-11) (an SP-antagonist) only in the G.P.I. (b) Octapeptide antagonists are specific for SP, have no agonistic activities and exert a competitive antagonism against SP, its homologues and fragments. (c) Undecapeptide antagonists are weaker than the octapeptides in the G.P.I. and G.P.T. and slightly stronger in the D.C.A. and R.M.V. However these compounds still have variable degrees of agonistic activity in some tissues. Affinity of octapeptide antagonists bearing the basic structure [pro4,trp7,9]SP-(4-11) is increased by the additional replacement of Leu10 with trp, Met11 with Leu, Nle or Phe, but it is slightly reduced by substituting Phe8 with Val. Antagonists containing aliphatic residues at the C-terminal end, for instance [pro4,trp7,9,Nle11]SP-(4-11) are more potent than others in the R.M.V., while those with aromatic residues, for instance [pro4,trp7,9,10]SP-(4-11) are weak on the R.M.V. but fairly active on the G.P.T. These antagonists do not show any selectivity on the G.P.I. and the D.C.A. Comparison of antagonists affinities for receptor characterisation suggest the existence of three different functional sites for SP-related peptides. The site of the G.P.I. and D.C.A., which accepts both the antagonists containing aromatic or aliphatic groups at the C-terminal end; the site of the G.P.T. which prefers the aromatic and that of the R.M.V. which shows high affinity for aliphatic residues. The receptor classification emerging from data obtained with antagonists is compared with the classifications of the literature and with those based on the order of potencies of SP homologues and fragments.
Animals↗
Features of bronchoalveolar lavage differentiating hypersensitivity pneumonitis and pulmonary sarcoidosis at time of initial presentation.
To evaluate the usefulness of bronchoalveolar lavage (BAL) as an aid in differentiating hypersensitivity pneumonitis (HP) and pulmonary sarcoidosis (S), we studied the cellular and protein components of BAL and pulmonary function tests (PFT) in 11 patients with acute HP and 23 patients with S at the time of initial presentation and compared the findings with those of normals. The only significant difference between the two groups of patients, on the basis of all the PFT performed, was an exercise-induced hypoxemia PaO2 = 75 +/- 4 torr) in patients with HP that, on average, was not found in patients with S (PaO2 = 88 +/- 3 torr) at the same 1.6 l min-1 O2 consumption. In patients with HP, the total cellular yield of BAL was, on average, 4 times that of patients with S and 6 times that of normals (p less than 0.01 for both). Macrophages, as % of total cells, were reduced in both groups of patients but increased in terms of cells ml-1. Lymphocytes in patients with HP averaged 61.4 +/- 6.5%, in patients with S, 32.6 +/- 4.2%, both values being significantly higher than normal (3.2 +/- 0.9%). However the percentages of lymphocytes in BAL did not clearly separate individual patients with HP from those with S.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Partial agonists and antagonists for substance P.
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Animals↗
Asbestos-induced lung injury in the sheep model: the initial alveolitis.
In order to study the cellular and biochemical changes in early asbestosis, three groups of sheep were repeatedly exposed to intratracheal instillations of either saline (controls), low doses of UICC chrysotile asbestos (LD), or high doses of the fibers (HD) until an alveolitis was observed in all HD sheep during the twelfth month of exposure. All sheep were studied bimonthly by transbronchial lung biopsy (LB), bronchoalveolar lavage (BAL), pulmonary function tests (PFT), and chest roentgenograms (CXR). While LBs of the HD sheep demonstrated large accumulations of monocyte-macrophages in the alveolar and interstitial spaces, those of controls and LD sheep did not. In BAL, there was no difference in total and differential cell counts between groups, but the BAL lymphocyte proliferative capacity was clearly depressed in all asbestos-exposed sheep. In the BAL supernatant, total proteins (mainly albumin, beta + gamma globulins) and lactate dehydrogenase were significantly elevated in the HD group only. This alveolitis was associated with a fall in vital capacity, lung compliance, diffusing capacity, and arterial PO2. Abnormalities on CXR appeared 3 months later. Thus, the cellular and biochemical features of early asbestosis are clearly distinct from those reported in idiopathic pulmonary fibrosis.
Alveolitis, Extrinsic Allergic↗
Assessment of progression of asbestosis in the sheep model by bronchoalveolar lavage and pulmonary function tests.
To study the relationship between the results of bronchoalveolar lavage and pulmonary function tests during induction and progression of asbestosis, three groups of six sheep were exposed repeatedly by intratracheal injection to either saline (controls), low doses of Canadian chrysotile UICC asbestos (cumulative exposure 328 mg) (low-dose group), or high doses of the same fibres (cumulative dose 2282 mg) (high-dose group) until there was clear evidence of alveolitis from the lung biopsy specimens of all sheep of the high-dose group. During the course of this induction and for the following eight months lung biopsies, bronchoalveolar lavage and pulmonary function tests were performed at two-month intervals. At the time of initial alveolitis in the high-dose group there was no significant change in the cellularity of the bronchoalveolar lavage fluid, but static lung compliance (Cst), vital capacity (VC), arterial oxygen tension (Pao2), and diffusion capacity (DL/VA) were significantly lower than in the other groups. In the following months, as the alveolitis evolved into a fibrosing process, macrophages and neutrophils from the bronchoalveolar lavage fluid increased significantly and pulmonary function deteriorated. Proteins and enzymes in the bronchoalveolar lavage fluid also increased significantly in the high-dose group. These data show that in the sheep model of asbestosis simple tests of pulmonary function correlate well with histological changes and changes in the bronchoalveolar lavage fluid in the course of the disease and can be used to assess progression of asbestosis.
Animals↗
Pulmonary uptake of gallium-67 in asbestos-exposed humans and sheep.
To evaluate the 67Ga lung uptake as an indicator of inflammatory activity in asbestosis, we obtained 67Ga lung scans in 58 long-term asbestos workers. The 67Ga localized excessively in the lungs of 17 of the 21 workers with asbestosis. Among workers without sufficient criteria for the diagnosis of asbestosis, the 67Ga scan index was significantly increased in 43% (16 of 37). Among the 16 with positive 67Ga scan, abnormal pressure-volume curve and/or gas exchange data were found in 87%, whereas in the 21 workers with negative 67Ga scan, similar abnormalities were found in only 29%. In the sheep model of the disease, bronchoalveolar analysis after 67Ga scan demonstrated that the excessive uptake of 67Ga in asbestosis is caused by enhanced serum protein leakage and macrophage accumulation in the lung. Thus, 67Ga scanning in asbestos workers may be a useful indicator of early lung damage.
Acquired Immunodeficiency Syndrome↗
Biochemical components of bronchoalveolar lavage in early experimental asbestosis of the sheep: phospholipase A2 activity, prostaglandin E2 and proteins.
Biochemical analyses of bronchoalveolar lavage (BAL) supernatants of sheep treated with weekly intratracheal instillations (for 6 months) of saline, 2 mg, or 128 mg of asbestos (chrysotile B; UICC) were performed. Our results showed that proteins (either total or its various components) and phospholipase A2 activity were unchanged in the low exposure group as compared to controls. However, in the high exposure group, with histopathological evidence of early asbestosis, there were significant increases in total proteins, albumin, alpha 2-globulin, beta- and gamma-globulins as well as phospholipase A2 activity of BAL fluid. Prostaglandin E2 activity was significantly increased in both low and high dose groups. These changes in protein and lipid components of BAL following asbestos exposure constitute early indices of lung inflammatory reactions which may contribute to the development of asbestosis.
Animals↗
Computer-based quantitative analysis of gallium-67 uptake in normal and diseased lungs.
To study the 67Ga lung uptake as an index of inflammatory activity, we developed a computer-based method to process the data obtained from the 67Ga scan. Background radioactivity below the kidneys was subtracted from counts in all areas and given a score of 0; the maximal liver uptake was scored as 16. Radioactivity over six lung fields was scored by the computer between 0 and 16 and averaged to yield a mean 67Ga lung uptake index. This index of 67Ga lung accumulation correlates with histopathologic scores of inflammation in lung tissue and with bronchoalveolar lavage (BAL) levels of 67Ga radioactivity retrieval. This study reports the quantitative analysis of 67Ga lung uptake in normal subjects and patients with various pulmonary diseases. This method provides an objective index of inflammatory activity in lung tissues, and it is simple, sensitive, and discriminative.
Adult↗
Rapid in vivo assessment of toxicity of respirable particles: a concise report.
To study the in vivo toxicity of respirable particles, bronchoscopic catheterization of the sheep tracheal lobe was used to expose a limited area of the lung. After control studies, 3 groups of 6 sheep received one exposure to either 100 ml saline, 100 mg of latex beads (1.0 mu diam.) in saline or 100 mg of UICC Canadian chrysotile asbestos in saline. The animals were studied at day 1, 8, 15, 22 and 29 by pulmonary function tests (PFT) and bronchoalveolar lavage (BAL). At day 29, the sheep had chest roentgenograms (CR) and were autopsied. In all sheep, PFT did not changed and CR showed minimal infiltrates only in the asbestos-exposed sheep. In the saline sheep, BAL and lung histology did not change. In the latex sheep, at day 1 total BAL cells increased to 370%, macrophages to 215% and neutrophils to 650% (P less than 0.01) without change in BAL proteins or enzymes. These returned to control levels at day 8 and after except for a slight increase in BAL neutrophils. The lung histology showed inflammatory changes without architectural distortion. In the asbestos sheep, the day 1 response was comparable to latex group in terms of BAL cellularity but BAL neutrophils remained significantly elevated at 40% total BAL cells at day 8, 15, 22 and 29. Also lactate dehydrogenase (LDH) and beta-glucuronidase in BAL were significantly elevated from day 1 to day 29. At autopsy, the tracheal lobe of asbestos sheep had pneumonia-like neutrophilic infiltrates in the surroundings of the peripheral airways with early peribronchiolar fibrosis. This new in vivo model can clearly and rapidly differentiate the relative toxicity of respirable particles in the lung tissue and thus should be a useful tool in environmental lung research.
Animals↗
[Monoclonal gammopathies: a study of 61 cases].
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Aged↗
Trace elements and acute phase reactants in gold treated rheumatoid arthritis patients.
Abnormal concentrations of trace elements, sulfhydryl groups, amino-acids and serum proteins were found in patients with rheumatoid arthritis similar to other chronic inflammatory conditions. These changes have been called the phase reaction. In this study, a systematic profile of the phase reactants was established in rheumatoid arthritis at the onset and during its modulation by chrysotherapy (gold sodium thiomalate 25 mg i.m. weekly). It was shown that this treatment, if successful, is capable of reverting to normal measures of the phase reaction. It was also found that the pattern of the profile varied in individuhe eventual beneficial or toxic effects. In these preliminary studies, no parameters or group of parameters of the phase reaction were predictive of the therapeutic outcome. Extended observations (over 6 months) and more individual profiles are being analyzed to gain insight into these features of inflammation and their modulation by chrysotherapy.
Adult↗
[Effects of short and strenuous exercise on serum constituents in young athletes].
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Adolescent↗
Characterization of pre- and postjunctional receptors for neurokinins and kinins in the rat vas deferens.
Neurokinins and kinins are potent stimulants of the rat vas deferens: they increase both the twitch response to electrical stimulation by facilitating transmitter release and the basal tone of the preparation by activating smooth muscle receptors. The two sites of action have been studied separately in the present experiments by using the prostatic for the prejunction site and the epididymal section of the vas deferens for the postjunction site. Receptors for neurokinins, characterized by the order of potency of agonists, appear to be of the NK-A type both at the pre- and postjunction level. Receptors for kinins are present also at both sites and are probably of the B2 type: they have been characterized by the use of agonists and, the B2 postjunction type has been convalidated with antagonists. These compounds could not be used for the prejunction receptor characterization, because they act as agonists. Receptor for angiotensin at the prejunction level are of the same type as in the cardiovascular and other systems.
Animals↗
Substance P and neurokinins as stimulants of the human isolated urinary bladder.
Neurokinins are active stimulants of the human isolated urinary bladder. In a preliminary study, performed on bladders taken from four donors, we attempted the characterization of neurokinin receptors. It was shown that neurokinin A is more active than neurokinin B and substance P. Neurokinin receptors selective agonists were also tested and it was found that the most active compound was the NK-A selective agonist, [Nle10]NKA 4-10: A substance P antagonist was able to reduce the effect of neurokinin A but its affinity was rather low. This suggests that the receptor mediating the contraction of the human urinary bladder to neurokinins is of the NK-A (NK2) type. The action of neurokinins on the human urinary bladder appears to be a direct one and mediated by specific receptors different from those of other agents. On the contrary, kinins were found to be active through a new mechanism which was not influenced by either anti-B1 or anti-B2 receptor antagonists.
Adult↗
Comparison of binding assay and biological activity on a NK-1 system with new selective agonists.
Binding sites for the [125I]Bolton-Hunter labeled substance P (BH.SP) were studied in homogenates of rat brain. Binding at 4 degrees C was much lower than at 25 degree C or 37 degrees C, but degradation of the peptide was very important at 37 degrees C. A mixture of peptidases inhibitors (bacitracin 4 x 10(-5) M), chymostatin (2 x 10(-6) M), leupeptin (4 x 10(-6) M), phosphoramidon (4 x 10(-6) M) was needed to stabilize the binding conditions, which were established as follows: BH.SP 40 pM, membrane preparation 1.25 mg/ml, incubation 20 min, temperature 25 degrees C and pH 7.4, in the presence of peptidase inhibitors. Binding occurred rapidly and was maximum at 20 min: it increased linearly with the amount of membranes added. It was saturable and readily reversible. Kd and receptor concentration were respectively 0.4 +/- 0.2 nM and 17 +/- 1 fmol/mg protein. Kd value measured in kinetic studies (0.2 nM) was similar to the one measured by saturation experiments (0.6 nM). Several analogues, homologues or fragments of SP were shown to inhibit BH.SP binding: their relative affinities were compatible with an interaction on a binding site of the type NK-1. This was confirmed with new selective agonists. [Sar9,Met(O2)11]SP, the NK-1 selective ligand was very potent, while [Nle10]NKA (4-10) (NK-2 selective) and [MePhe7]NKB (NK-3 selective) were nearly inactive. The present results confirm the findings of other similar studies and stress the importance of using (a) peptidase inhibitors for obtaining stable binding conditions and (b) selective agonists for characterizing NK-1 receptor sites in rat brain.
Animals↗
Structure-activity studies of neurokinin A.
A structure-activity study on neurokinin A and its C-terminal fragment NKA (4-10) has been performed in order to find selective agonists for the NK-2 receptor and identify chemical modifications suitable for protecting the peptides from degradation, while maintaining activity. Five series of compounds have been prepared and tested: 1. the complete series of the L-Ala monosubstituted analogues of NKA; 2. a series of NKA fragments from the C- or N-terminal; 3. the complete series of NKA (4-10) analogues monosubstituted with beta-Ala; 4. a series of NKA (4-10) analogues with monosubstitutions in pos. 4, 8, 10 or multisubstitutions in two or more of the same positions; and 5. a series of 6 NKA (4-10) analogues monosubstituted with 1-amino,1-cyclohexane carboxylic acid residue. It has been found that the most selective agonists for the NK-2 receptor system are [beta Ala8]NKA (4-10) and [Nle10]NKA (4-10). Protection from aminopeptidase may be obtained by acetylation of the N-terminal amide of NKA (4-10), while partial protection from endopeptidases should be expected from the presence of beta-Ala in position 8. Conformational constraints induced with 1,amino,1-cyclohexane carboxylic acid residue gave weakly active compounds. Multiple substitutions reduce rather than potentiating the favorable effects of the corresponding monosubstituted compounds.
Animals↗