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G Drapeau

Publications and source records attributed to G Drapeau.

At least 91 records · Page 5Linked to original sources
PubMed1987

Receptors for substance P and neurokinins. Correlation between binding and biological activities.

The biological activities of neurokinin-related peptides were compared with their binding affinities measured in various laboratories. A positive significant correlation was demonstrated between the relaxation of the dog carotid artery and the binding of Bolton-Hunter [125I]substance P to rat brain synaptosomes, the contractions of the rat duodenum and the rabbit pulmonary artery and the binding of Bolton-Hunter [125I]neurokinin A to duodenum smooth muscle plasma membranes, and the contraction of the rat portal vein and the binding of [125I]Bolton-Hunter NH-senktide to rat cerebral cortex membranes.

Animals↗
PubMed1987

Specific agonists for neurokinin B receptors.

A series of analogues of the partial sequence NKB-(4-10) (H-Asp-Phe-Phe-Val-Gly-Leu-Met.NH2) was prepared in an attempt to identify selective agonists for the neurokinin B receptor type. The compounds were tested in the dog carotid artery, the rabbit pulmonary artery and the rat portal vein to evaluate their affinity for the receptors of substance P, neurokinin A and neurokinin B respectively. It has been shown that the replacement of Val7 with MePhe increased significantly the affinity of NKB-(4-10) for the neurokinin B receptor and confered marked selectivity. [MePhe7]NKB-(4-10) was practically inactive as stimulant of the receptor for NKA and was a weak agonist on the receptor for SP. Such significant changes in the pharmacological spectrum of [MePhe7]NKB-(4-10) cannot be attributed to protection from metabolism and appear to be due to changes in the peptide conformation.

Animals↗
PubMed1987

The rat isolated portal vein: a preparation sensitive to neurokinins, particularly neurokinin B.

The rat isolated portal vein is a pharmacological preparation more sensitive to neurokinin B than to any other neurokinin or tachykinin. The preparation is more sensitive to C-terminal partial sequences of substance P (SP) particularly SP-(6-11) than to the whole undecapeptide. The order of potency of neurokinins is as follows: neurokinin B greater than neurokinin A greater than substance P. The preparation shows high sensitivity also to kassinin and eledoisin. Comparative tests performed with strips of the rat portal vein suspended in a microbath under continuous perfusion (system 1) or in ordinary baths for isolated smooth muscles (system 2) have given similar results and have shown that the myotropic effect of neurokinin B is not modified by a variety of antagonists of endogenous agents as well as by inhibitors of the arachidonic acid cascade. The present results suggest that neurokinin B contracts the rat portal vein by activating specific receptors, presumably located on the smooth muscle membrane, different from those of biologically active amines and peptides which are active stimulants of the vein. Neurokinin B is ten times more active than neurokinin A and at least 100 times more than substance P. Such an order of potency of agonists suggests the existence of a new neurokinin receptor type, particularly sensitive to neurokinin B.

Animals↗
PubMed1987

Pharmacological receptors for substance P and neurokinins.

The three neurokinins identified in mammals, substance P, neurokinin A and neurokinin B, as well as their C-terminal biologically active fragments, have been used to characterize the responses of a variety of isolated organs. Three preparations selective either for substance P (the dog carotid artery), or for neurokinin A (the rabbit pulmonary artery) or for neurokinin B (the rat portal vein) are described. A neurokinin receptor classification is attempted using the neurokinins and their fragments to determine the order of potency of agonists. Three receptor subtypes have been identified: the NK-P, on which substance P (SP) is more active than neurokinin A (NKA) and neurokinin B (NKB), and the neurokinins are more active than their respective fragments; the NK-A on which NKA greater than NKB greater than SP, and some NKA fragments are more discriminative than their precursor; the NK-B on which NKB greater than NKA greater than SP, and fragments of NKB are less active than their precursor. Among the peptides studied, some potent compounds have been identified that could provide selective receptor ligands.

Animals↗
PubMed1987

Selective agonists for substance P and neurokinin receptors.

A series of neurokinin analogues and fragments have been prepared in an attempt to identify selective agonists for NK-P, NK-A and NK-B receptors. The compounds have been tested on the dog carotid artery (NK-P receptor system), the rabbit pulmonary artery (NK-A) and the rat portal vein (NK-B). C-terminal substituted analogues of the three neurokinins have provided indication that NK-P receptor selectivity is improved by the oxidation of methionine to Met(O2), while selectivity for NK-A is favoured by replacing Met with NIe. Selectivity for NK-P receptors is further improved by the replacement of Gly9 with Sar. Selectivity and affinity for NK-B receptors is markedly increased when Val7 is replaced with MePhe in both the fragment NKB (4-10) and NKB. The results of the present study indicate that a) [Sar9,Met(O2)11]SP is a potent and selective agonist for the NK-P receptors of the dog carotid artery; b) [MePhe7]NKB is a very potent and selective stimulant of receptors for neurokinin B and c) [Nle10]NKA (4-10) is a promising compound, showing some selectivity for NK-A receptor; further modifications are however needed to improve its affinity.

Animals↗
PubMed1987

Monoclonal antibodies to substance P: production, characterization of their fine specificities, and use in immunocytochemistry.

Five hybrid clones secreting antibodies to the neuropeptide substance P have been obtained by somatic cell fusion of mouse myeloma cells with splenocytes from immunized mice of the Biozzi strain. To perform rapid and sensitive screening tests as well as to study the fine specificities of each monoclonal antibody, we developed a new enzyme immunoassay of substance P using acetylcholinesterase as label. All five monoclonal antibodies were directed to the C-terminal pentapeptide of substance P, especially to the Phe7 residue. They cross-reacted with neurokinin A and to some extent with neurokinin B but not with other nontachykinin mammalian peptides. One monoclonal antibody (SP 14) was used for immunocytochemical experiments in the rat spinal cord and spinal ganglion, both at the light and electron microscopic levels. A strong specific neurokinin-like immunoreactivity was observed in cell bodies, nerve fibers, and terminals, with a very low background staining. Finally, the affinities of several analogues of substance P for SP 14 monoclonal antibody were shown to be correlated with their biological activities, as measured by their hypotensive effects in vivo. These findings suggested a strong structural resemblance between the combining site of the antibody and that of the physiological substance P receptor.

Animals↗
PubMed1987

Asbestos exposure dose-bronchoalveolar milieu response in asbestos workers and the sheep model: evidences of a threshold for chrysotile-induced fibrosis.

Epidemiological studies of asbestos workers have proposed a linear dose-response relationship between asbestos cumulative exposure indices and the incidence of asbestos-related lung diseases. However, for chrysotile, several studies have not observed such a linear relationship in low exposure workers. To further study the relationship of chrysotile exposure dose - lung tissue response, we designed in the sheep model one experiment of one exposure at variable intensity and one experiment with variable rates of individual exposures. In the first study, 6 groups of 6 sheep were exposed to either 0, 1, 10, 25, 50 or 100 mg chrysotile in 100 ml saline and lung lavage analyses carried out at day 0, 12, 24, 40 and 60 after. Histopathology was done at day 60. In the second experiment, 4 groups of 12 sheep were exposed to 100 ml saline every week or every two weeks, 100 mg chrysotile in 100 ml saline every week or every two weeks. In the second experiment, lung damage was assessed by changes in vital capacity (VC), lung compliance (Cst) and profusion of chest radiographic opacities (PO). On BAL in the control sheep, there were small and transient early increases in total cells/ml, macrophages/ml, neutrophils/ml, lactate dehydrogenase (LDH)/ml, alkaline phosphatase (AK)/ml, beta-glucuronidase (beta G)/ml and procollagen lll/ml. In the 1, 10, 25, and 50 mg asbestos sheep groups, there were no significant differences. However, in the 100 mg asbestos sheep, there were significant sustained increases in total cells/ml (3-6 times controls), macrophages/ml (2-6 times controls), neutrophils/ml (60-600 times controls), LDH/ml (5-10 times controls), AK/ml (1.5-2 times controls), beta G/ml (3-5 times controls), procollagen lll/ml (2 times controls) and IgG (1.5-3 times controls). These data were correlated with histopathological findings. In the sheep exposed weekly to chrysotile, significant changes in VC, Cst and PO occurred at mean cumulative exposure dose of 1.2 g whereas in the sheep exposed every 2 weeks, similar changes in VC, Cst and PO occurred at the cumulative exposure dose of 3.6 g (P less than 0.05). In conclusion, our data suggest that there is a threshold for chrysotile-induced fibrosis. This level cannot be considered adequately in term of cumulative exposure dose but must take into account intensity and rate of individual exposures.

Animals↗
PubMed1986

Conversion of kinins and their antagonists into B1 receptor activators and blockers in isolated vessels.

A carboxypeptidase inhibitor (DL-2-mercaptomethyl-3-guanidoethylthiopropranoic acid) (mergetpa) was used to block the conversion of kinins and B2 receptor antagonists into metabolites devoid of the C-terminal Arg. Experiments were carried out on rabbit isolated aortae (a B1 receptor system) or rabbit jugular veins and dog carotid arteries (two B2 receptor systems). The contractile effect of bradykinin in the rabbit aorta was significantly reduced by mergetpa while that of desArg9-BK was not modified. pA2 values of B2 receptor antagonists, [Thi5,8,D-Phe7]bradykinin and [Thi6,9,D-Phe8]kallidin were markedly reduced by mergetpa. The apparent affinity (pA2) of a B1 receptor antagonist, [Leu9]desArg10-kallidin was not affected. Carboxypeptidases inhibition did not modify the activities of bradykinin or the affinities of B2 receptor antagonists in the rabbit jugular vein and the dog carotid artery. An inhibitor of kininase II (D-3-mercapto-2-methylpropranoyl-L-proline (S,S] (captopril) reduced the contractile effects of angiotensin I in the three preparations and potentiated the stimulatory or inhibitory effects of bradykinin: captopril did not have effect on the affinities of B2 receptor antagonists and did not modify the effects of angiotensin II. Comparative experiments performed in tissues with or without endothelium gave the same results with both mergetpa and captopril. The present findings suggest that bradykinin and B2 receptor antagonists are converted by carboxypeptidases into biologically active B1 receptor agonist or antagonists. This is the reason why B2 receptor antagonists are not selective.

3-Mercaptopropionic Acid↗
PubMed1986

Different receptors are involved in the endothelium-mediated relaxation and the smooth muscle contraction of the rabbit pulmonary artery in response to substance P and related neurokinins.

Four neurokinins, substance P (SP), neurokinin A (NKA) neurokinin B (NKB) and kassinin (Kass) were used in the present study together with other peptides and nonpeptide agents to demonstrate the existence of two different neurokinin receptor types in the rabbit isolated pulmonary artery. Similar to other arterial vessels, the endothelium-dependent relaxation of the pulmonary artery in response to neurokinins is due to the activation of a SP-P receptor more sensitive to SP than to the other neurokinins. The endothelium-dependent relaxation is an indirect phenomenon, mediated by an unknown endothelial agent, similar to that released by acetylcholine. The contraction of the pulmonary artery in response to neurokinins is due to receptors of the NK-A type, particularly sensitive to NKA and NKB, and much less sensitive to SP. The contraction is a direct phenomenon, apparently not involving any of the known endogenous autacoids and neurotransmitters or metabolites of arachidonic acid. Contraction appears to be due to stimulation by the neurokinins of receptors located in the arterial smooth muscle. The results presented in this paper indicate that NK-A receptors for neurokinins (which are present in the tracheo-bronchial tree) are also to be found in pulmonary vessels and mediate contraction of arterial vascular smooth muscle, an interesting property of neurokinins.

Animals↗
PubMed1986

The actions of kinin antagonists on B1 and B2 receptor systems.

The newly discovered bradykinin antagonist [Thi5,8,D-Phe7]Bradykinin, supplied by J.-M. Stewart and three other compounds, [D-Phe7]BK, [Thi5,8,D-Phe7]Bradykinin and [Thi6,9,D-Phe8]Kallidin synthesized in our laboratory, were tested for their ability to antagonize bradykinin in four B2 receptor systems, the guinea-pig ileum, the rabbit jugular vein, the dog carotid artery and the dog urinary bladder as well as against desArg9-bradykinin in the rabbit aorta (a B1 receptor system). [D-Phe7]Bradykinin is a partial agonist, while [Thi5,8,D-Phe7]Bradykinin and [Thi6,9,D-Phe8]Kallidin are pure antagonists, the second one showing little BK-like activity on three of the four preparations. The kallidin analogue is more potent in all preparations than the bradykinin one. The two [Thi5,8,D-Phe7]BK (that supplied by J.-M. Stewart and that prepared in our laboratory) show very similar affinities in all preparations. The bradykinin analogue as well as the kallidin one are also active against desArg9-bradykinin in the rabbit aorta, at concentrations similar to those active on B2 receptor systems. The kinin antagonists are however specific for the kinins, since they do not interfere with the myotropic effects of angiotensin or substance P (SP) in the various preparations.

Animals↗
PubMed1986

Enzyme activities of lung lavage in asbestosis.

We analyzed lung lavage supernatant for amylase, lactate dehydrogenase (LD), alkaline phosphatase (ALP), beta-glucuronidase (beta G), and albumin, and a differential count was made of the cellular component of lung lavage in 18 normal controls and 36 long-term asbestos workers of the mines and mills of Québec. The men were concomitantly evaluated by the usual clinical, radiological, functional parameters and 67Ga lung scan. In 7 workers without asbestosis and normal 67Ga scan, lavage enzyme activities, albumin and cell counts were comparable to those of controls. Of 9 without sufficient criteria for asbestosis but increased 67Ga lung uptake, cell counts documented significant increases in the mean number of macrophages (X 2), lymphocytes (X 2) and neutrophils (X 3). Supernatant analyses showed significant increases in amylase (X 4-5), LD (X 2.5), ALP (X 1.5) and beta G (X 2-4). These changes were comparable to those in the lavage of workers with well established asbestosis except that in the latter, the lymphocyte count was slightly lower but the neutrophil count higher (p less than 0.05). These data document that enzyme activities of lung lavage can differentiate asbestos workers with early or late asbestosis from controls and asbestos workers without disease.

Adult↗
PubMed1986

Fibronectin and procollagen 3 levels in bronchoalveolar lavage of asbestos-exposed human subjects and sheep.

To evaluate the potential interest of levels of fibronectin and procollagen 3 in bronchoalveolar lavage fluid as markers of fibrogenic activity, we characterized the time course of changes in fibronectin and procollagen 3 levels in the tracheal lobe of sheep exposed to nonfibrogenic and fibrogenic materials. We correlated these observations with those of bronchoalveolar lavage in long-term asbestos workers in various stages of disease activity. Following studies before exposure, the tracheal lobe of three groups of 24 sheep were exposed once to 100 ml of phosphate-buffered saline solution (PBS), to 100 mg of latex beads in 100 ml of PBS, or to 100 mg of chrysotile fibers in 100 ml of PBS. Bronchoalveolar lavages were obtained at 0, 1, 2, 4, 8, and 12 months after exposure, and four or five sheep per group were killed after each lavage for histopathologic analysis. Fibronectin in bronchoalveolar lavage fluid increased significantly only in the asbestos-exposed sheep to values two to three times above controls or latex-exposed sheep and remained elevated during the 12 months of the study. Levels of procollagen 3 in bronchoalveolar lavage fluid were increased significantly only during the first two months following exposure in the asbestos-exposed sheep only. In the asbestos workers without disease, levels of fibronectin and procollagen 3 in bronchoalveolar lavage fluid were comparable to controls, but these levels were significantly elevated in those with asbestos-associated alveolitis or asbestosis. This study documents that the measurement of levels of fibronectin and procollagen 3 in bronchoalveolar lavage fluid assesses fibrogenic activity of alveolitis and should be useful to predict its progression in a fibrotic process. In asbestos workers the potential use of these markers is primarily related to early detection of asbestos-induced pulmonary injury.

Adult↗
PubMed1985

Tachykinin receptors in smooth muscles: a study with agonists (substance P, neurokinin A) and antagonists.

Four preparations, sensitive to tachykinins, the guinea-pig urinary bladder, the rat duodenum, the hamster and dog urinary bladders have been investigated and compared with four other preparations described before: the guinea-pig ileum and trachea, the dog carotid artery and the rabbit mesenteric vein. On the basis of the order of potency of agonists, evaluated with substance P, physalaemin, eledoisin, kassinin and neurokinin A, the preparations can be separated into three groups, the guinea-pig urinary bladder and the dog carotid artery, in which substance P is the most potent and neurokinin A the weakest tachykinin, the rabbit mesenteric vein, the guinea-pig trachea and the rat duodenum, in which the opposite order is observed and the hamster and dog urinary bladders, in which kassinin is the most potent agonist. The guinea-pig ileum shows similar sensitivity to the five tachykinins. C-terminal partial sequences appear to be weaker than SP-(1-11) in three of the four new preparations, SP-(6-11) being first in the rat duodenum and slightly weaker than SP-(1-11) in the hamster and dog urinary bladders. Studies performed with antagonists or inhibitors of endogenous agents suggest that substance P and neurokinin A act directly on specific receptors. The effects of the two peptides are reduced by antagonists analogues of the sequence SP-(4-11). One of the antagonists, [D-Pro4,Lys6,D-Trp7,9,10, Phe11]SP-(4-11) has been shown to be competitive against substance P and neurokinin A in the guinea-pig ileum, the guinea-pig urinary bladder and the rat duodenum. This compound, shows definitely higher activity against neurokinin A and kassinin, compared to substance P in various preparations. [D-Tyr4,D-Trp7,9,Nle11]SP-(4-11) is the most potent tachykinin antagonist in the hamster and dog urinary bladders. In these preparations, the antagonists act also against substance P, but with lower affinity. These findings with antagonists support the indication, emerged from the order of potency of agonists, that tachykinins may act on two and possibly three different receptor types.

Animals↗
PubMed1985

Substance P antagonists showing some selectivity for different receptor types.

Five antagonists have been used against substance P (SP) and neurokinin A (NA) in isolated smooth muscle preparations containing either SP-P (the guinea pig ileum (G.P.I.), the dog carotid artery (D.C.A.) or SP-E receptors (the rat duodenum (R.D.), the dog (D.U.B.) and hamster urinary bladders (H.U.B.]. [D-Pro4,D-Trp7,9,10, Phe11]SP-(4-11) was found to be selective for SP-P receptors, since it showed high affinity both against SP and NA, on the G.P.I. and D.C.A., while it was found to be inactive on some SP-E receptor systems (D.U.B., H.U.B.) and very weak in others (R.D.). Two octapeptide antagonists, modified in position 6, [D-Pro4,Ala6,D-Trp7,9,10,Phe11]SP-(4-11) and [D-Pro4,Lys6,D-Trp7,9,10,Phe11]SP-(4-11) showed some selectivity for SP-E receptors since they acted as full agonists on one SP-P preparation (the D.C.A.) and the first compound contracted also the G.P.I. In addition to being pure antagonists on the D.U.B., H.U.B. and on the R.D., the two octapeptides showed a higher potency against the SP-E stimulant NA, compared to SP, in the R.D. Two undecapeptide antagonists were active against SP and NA on both SP-P and SP-E receptor preparations and therefore were less discriminative than the octapeptides. They were however more active against NA on the R.D., similar to the octapeptides modified in position 6. It is concluded that: (a) both agonists and antagonists appear to be useful for the characterization of tachykinins receptors; (b) either the whole N-terminal portion of SP or a shorter sequence, modified in position 6, increase the antagonist affinity against NA in the SP-E receptor system of the rat duodenum.

Angiotensin II↗
PubMed1985

Clinical features to stage alveolitis in asbestos workers.

To analyze the clinical features of asbestos-induced alveolitis and stage its activity, we evaluated 217 asbestos workers by the usual clinical, radiological, and functional parameters and computerized gallium 67(Ga) lung scan; we obtained bronchoalveolar lavage (BAL) in 33 and lung biopsy in 6. In addition, we scored the profusion of lung rales and correlated it with other parameters of severity of asbestosis. In the 55 workers without asbestosis and normal 67Ga scan, BAL analyses were comparable to those of controls. Of the 56 without asbestosis but increased 67Ga lung uptake, BAL analyses in 8 documented a predominantly macrophagic alveolitis (confirmed on lung biopsy in 3), with the highest levels of BAL fibronectin. In the 106 workers with asbestosis, 67Ga lung uptake was increased in 75; BAL in 17 demonstrated a macrophagic and neutrophilic alveolitis with elevated fibronectin levels. Lung biopsy in 3 of the latter workers documented peribronchiolar fibrosing alveolitis. Rale scores in all workers or in those without asbestosis did not correlate with 67Ga scores; they correlated fairly well with profusion of parenchymal opacities (Rs = 0.42) and rigidity of the lung pressure-volume curve (Rs = 0.39). Thus, 67Ga lung uptake is an early indicator of chronic macrophagic alveolitis in asbestos workers, which usually progresses to asbestosis. In the disease, profusion of lung rales constitutes a simple clinical mode of assessment of disease severity that correlates better with radiological and functional parameters than with parameters of alveolitis.

Adult↗
PubMed1985

Selective exposure and analysis of the sheep tracheal lobe as a model for toxicological studies of respirable particles.

A conscious sheep model, recently developed to study sequentially the bronchoalveolar milieu, was further refined to use in the rapid in vivo assessment of the biological effects of respirable particles. In this model, the anatomically isolated tracheal lobe was selectively exposed to either 100 ml phosphate buffered saline (PBS) (control group of 12 sheep), 100 mg of 0.1-micron latex beads in 100 ml PBS (latex group of 12 sheep), or 100 mg of UICC Canadian chrysotile fibers in 100 ml PBS (asbestos group of 12 sheep). Bronchoalveolar lavages (BAL) of the tracheal lobe were obtained prior to exposure and at Days 1, 8, 15, 21, 29, 45, and 60 after exposure. Whole-lung detailed pulmonary function tests (PFT) were performed at the same times and the histopathology of the lobe was examined in six sheep in each group at Days 29 and 60. In the control sheep, there were no significant changes over time in any of the measures, and lung morphology remained normal. In the latex group, there was no significant change in PFT, the BAL analyses documented early transient increase in cellularity (macrophages and neutrophils at Day 1) and only macrophages after; lung histology documented an early macrophagic alveolitis which decreased to less than 10% of the initial inflammatory reaction at Day 60, without other distortion of the lung and airway architecture. In the asbestos sheep, the only change in whole-lung PFT was a 10-torr fall in arterial O2 pressure. BAL analyses documented persistent increases in macrophages, neutrophils, and lactate dehydrogenase as well as increasing gamma-globulins. Lung histology revealed a macrophagic and neutrophilic peribronchiolar alveolitis at Day 30, which regressed substantially by Day 60, but persistent peribronchiolar alveolitis, early fibrosis, and severe distortion of the small airways, lesions comparable to those of early asbestosis in sheep or humans. Thus selective exposure and sequential analyses of the sheep tracheal lobe in terms of BAL histomorphology should be valuable for rapid in vivo assessment of toxicity of respirable particles.

Air Pollutants↗
PubMed1985

[Spinal hyperostosis and disorders of retinol metabolism].

Vitamin A or its acid derivatives can be responsible for bony lesions similar to those in ankylosing hyperostosis in animals and in man. We performed a controlled, prospective study on vitamin A metabolism in 23 patients with ankylosing hyperostosis and in 17 normal controls. Beta-carotene serum levels were determined by spectrophotometry, and retinol serum levels by inverse phase high performance liquid chromatography, and retinol binding protein (RBP) by radial immunodiffusion. After eliminating the causes which disturb vitamin A metabolism or RBP, we found a significant increase in retinol (p less than 0.02), in the molar relationship, retinol/RBP (p less than 0.05), without zinc deficiency. The association of diabetes with ankylosing hyperostosis normalizes in a statistically significant manner serum retinol levels (p less than 0.05), but apparently does not modify the increased molar relationship, retinol/RBP. These findings suggest a toxic effect of retinol due to the increased amount of free retinol or by nonspecific transport by proteins other than RBP.

Aged↗