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Biomedical subjects

S St-Pierre

Publications and source records attributed to S St-Pierre.

At least 127 records · Page 7Linked to original sources
PubMed1985

The effects of vasoactive intestinal peptide on human natural killer cell function.

Vasoactive intestinal peptide (VIP) can be found at nerve endings in various tissues and has recently been shown to interact with human lymphocytes through an adenylate cyclase-linked receptor. Because various neuroendocrine factors are thought to influence immune responsiveness, we studied the effect of VIP on natural killer (NK) effector function. Human lymphocytes were incubated with 51Cr-labeled K562 target cells in a 4-hr cytotoxicity assay in the absence or presence of increasing concentrations of VIP. As expected from its activation of adenylate cyclase, VIP was inhibitory at 10(-6) to 10(-10) M. Interestingly, however, when lymphocytes were preincubated with VIP for 30 or 60 min, then washed and added to target cells, a significant augmentation of NK activity ensued. Binding studies revealed that preincubation with VIP resulted in increased numbers of effector-target conjugates, whereas cytotoxic activity in agarose was not affected at the single cell level. Studies with synthetic analogs of VIP revealed that the integrity of the 14-28 C-terminal amino acid sequence was essential for its activity in cytotoxicity. These data strongly suggest a functional role for VIP in modulating immune responses during neuroendocrine interactions with the immune system.

Cell Line↗
PubMed1984

Neurotensin stimulates histamine release from the isolated, spontaneously beating heart of rats.

Neurotensin (NT) evoked a transient, dose-dependent histamine release (ED50 170 ng ml-1) from the rat perfused heart. Histamine release by NT occurred within seconds and lasted less than 2 min. The histamine releasing effect of NT was followed by a dose-dependent increase of the perfusion pressure and a slight tachycardia. The histamine releasing effect of NT was completely abolished in hearts derived from rats pretreated for 3 days with high doses of compound 48/80. The coronary vasoconstrictor effect of NT was increased in hearts derived from compound 48/80-pretreated rats. The mast cell inhibitor cromoglycate markedly inhibited NT-induced histamine release without affecting the coronary vasoconstrictor effect of NT. The histamine releasing effect of NT was inhibited, while its coronary vasoconstrictor effect was markedly potentiated, in hearts derived from rats pretreated with the antiallergic and antiinflammatory steroid dexamethasone. The increase of perfusion pressure evoked by NT was not modified by antihistamine drugs. Infusions of exogenous histamine (10(-6)-10(-5) g ml-1) caused a dose-dependent coronary vasodilation in the rat perfused heart. The results suggest that NT stimulates histamine release from cardiac mast cells. These results together with those obtained in previous studies suggest that mast cell mediators (particularly histamine and serotonin) are unlikely to be responsible for the coronary vasoconstrictor effect of NT in the rat perfused heart.

Animals↗
PubMed1984

The contractile effect of bombesin, gastrin releasing peptide and various fragments in the rat stomach strip.

The contractile activity of bombesin (BB) and related peptides including the gastrin releasing peptide (GRP) was evaluated in the rat stomach strip. BB and GRP were found to elicit concentration-dependent contractile effects in concentrations varying between 5.0 X 10(-10) and 5.0 X 10(-7) M. EC50 values of BB and GRP were 6.5 X 10(-9) and 10(-8) M, respectively. The contractile effect of BB (1.5 X 10(-8) M) was not modified by a mixture of antagonists containing atropine (1.7 X 10(-6) M), mepyramine (1.2 X 10(-6) M), methysergide (1.4 X 10(-6) M), phentolamine (1.8 X 10(-6) M), propranolol (1.9 X 10(-6) M) and indomethacin (7.0 X 10(-6) M), nor by the nerve paralyzing drug tetrodotoxin (1.6 X 10(-6) M). These results suggest the existence of BB receptors in the rat stomach strip. The results also suggest that the contractile effects of BB in this tissue result from a direct effect on the smooth muscle cell. The data derived from our structure-activity study indicate that deletion of the N-terminal sequence pGlu1-Gln2-Arg3-Leu4-Gly5- from the BB molecule causes practically no loss of affinity and intrinsic activity. Further shortening of BB gives rise to a gradual reduction of both parameters. Residual contractile activity could still be observed with the tetra- and pentapeptide BB-(11-14) and BB-(10-14) at 10(-5) M.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Evidence for biological activity of two N-terminal fragments of neurotensin, neurotensin1-8 and neurotensin1-10.

Intracisternal (i.c.) administration of the endogenous tridecapeptide neurotensin (NT) has been previously shown to significantly reduce the incidence of cold-restraint stress (CRS)-induced gastric ulcers in rats. In this study we confirm the cytoprotective activity of central NT, and document structure-activity relationships for this effect of NT. When tested in a dose equimolar to 17.9 nmol of NT the NT analogs [Gln4]NT, D-Trp11-NT, and D-Arg8-NT were cytoprotective, whereas D-Arg9-NT was not. Gonadotropin-releasing hormone (Gn-RH) and melanocyte-stimulating hormone-release inhibiting factor (MIF-1), two oligopeptides structurally unrelated to NT exhibited no cytoprotective efficacy in this paradigm. The C-terminal fragments of NT, xenopsin and NT8-13, and the N-terminal fragment NT1-6 were completely ineffective. Finally, NT1-8 and NT1-10, two N-terminal fragments of NT produced significant cytoprotective activity at this dose level. The cytoprotection afforded by NT1-8 and NT1-10, like that of NT, was dose-dependent with ED50's similar to that of NT (NT = 16.2 nmol, NT1-8 = 17.8 nmol and NT1-10 = 19.9 nmol). In conclusion, we demonstrate that smaller molecular weight forms of NT thought to be degradation products of NT can effectively exert biological effects.

Animals↗
PubMed1984

Participation of mast cell 5-hydroxytryptamine in the vasoconstrictor effect of neurotensin in the rat perfused hindquarter.

Neurotensin (NT) (1 X 10(-8) - 1.5 X 10(-6) g ml-1) caused a transient, dose-dependent increase in perfusion pressure in the rat perfused hindquarter. The vasoconstrictor effect of NT was associated with a short-lived, dose-dependent release of histamine and 5-hydroxytryptamine (5-HT) in the hindquarter effluent. Compound 48/80, a classical mast cell secretagogue, also elicited a vasoconstrictor effect in, and release of histamine from, the rat hindquarter. The vasoconstrictor effect and the release of histamine and 5-HT evoked by NT were much smaller in hindquarters derived from rats pretreated with compound 48/80 for 4 days to cause mast cell depletion than in hindquarters derived from control rats. The mast cell inhibitor cromoglycate (4 mg ml-1) inhibited by about 50% the histamine releasing effect and vasoconstriction produced by the lowest concentrations of NT utilized. The histamine releasing effect of compound 48/80 was more sensitive to blockade by cromoglycate than that of NT. The steroidal antiinflammatory and antiallergic drug dexamethasone did not affect the histamine and 5-HT releasing effect of NT. The vasoconstrictor effects of NT, compound 48/80 and 5-HT were markedly reduced by the 5-HT receptor antagonist methysergide (1 X 10(-7) g ml-1). Histamine (1 X 10(-6) - 10(-4) g ml-1) evoked a decrease in perfusion pressure in hindquarters pre-exposed to noradrenaline. The results suggest the participation of mast cell 5-HT in the vasoconstrictor effect of NT in the rat perfused hindquarter.

Animals↗
PubMed1984

Relationships between structure and duration of neurotensin's central action: emergence of long acting analogs.

Relationships between structure and duration of neurotensin's central action were examined. Included in the study were analogs containing amino acid substitutions at purported enzymatic cleavage sites of neurotensin: the arg8-arg9, the Pro10-Tyr11, and the Tyr11-Ile12 peptide bonds. Peptides were administered in rats via the cerebro-ventricular route and the ensuing hypothermia was monitored repeatedly until the effect dissipated. Results indicate that substitutions of the Tyr11 residue of the neurotensin molecule with either Dopa, Trp, D-Trp, or D-Tyr yielded analogs displaying markedly increased durations of action. Substitutions at other sites did not alter the time course of neurotensin's hypothermic effect. The longest acting analog was [Dopa11]-NT. At a dose of 7.5 micrograms the hypothermia induced by this analog persisted for 660 min while the effect of a same dose of neurotensin endured for only 90 min after injection. No clear correlation was found between the relative potency of analogs and their duration of action. Taken together, the results confirm the predominant role of Tyr11 in the inactivation of neurotensin by the brain, but do not support the hypothesis that relative potencies of structural analogs are solely dependent on differing susceptibilities to enzymatic degradation.

Animals↗
PubMed1984

Selective induction of cardiovascular responses to des-Arg9-bradykinin by bacterial endotoxin.

Bacterial lipopolysaccharide (LPS) induces in 5 h a hypotensive response mediated by the B1-receptor for kinins in the rabbit, an effect which is not observed in untreated animals. The present study is intended to evaluate the capacity of other acute toxic treatments to induce such a response and to analyze the mechanism of induction. Intravenous injections of inulin (20 mg), Naja venom (50 micrograms), compound 48/80 (1 mg), and etiocholanolone (6 mg) failed to induce hypotensive response to des-Arg9-bradykinin (the selective agonist of the B1-receptor) in 5 h. LPS from Salmonella (100 micrograms) and E. coli (10 micrograms) were highly effective, whereas trypsin (2 mg) gave doubtful responses. White blood cell counts revealed a profound and rapid neutropenic effect of the 2 LPS and a less marked one for trypsin. It is concluded that (1) LPS is a selective inducer of a new cardiovascular response to kinins mediated by the B1-receptor, and (2) that the mechanism of induction may include an intimate interaction between neutrophil leukocytes and blood vessel walls.

Adrenergic beta-Agonists↗
PubMed1984

Characterization and localization of vasoactive intestinal peptide receptors in the rat lung.

Experiments were performed to characterize vasoactive intestinal peptide (VIP) receptors in rat lung and to study their localization by means of light and electron microscope autoradiography. [125I]Iodo-VIP binding to lung homogenate was inhibited by synthetic VIP, [Val5]secretin, secretin, and 7-27 secretin with half-maximal inhibition (ID50) values of 1.62, 13, 121 nmol/liter and up to 0.1 mmol/liter, respectively. The relative potency of [Val5]secretin and 7-27 secretin to displace the tracer indicated that [125I]iodo-VIP binds to specific VIP receptors. Kinetic studies showed two sites of binding, a site of high affinity with equilibrium dissociation constant (KD) values of 0.32 +/- 0.09 nM and Bmax of 88.7 +/- 28.6 fmol/mg protein and a lower affinity binding site with a KD value of 23.0 +/- 2.9 mM and Bmax of 584 +/- 136.9 fmol/mg protein. The localization of VIP receptors was performed by radioautography both in vivo after iv injection of [125I]iodo-VIP and in vitro by the direct application of the radiolabeled peptide to cryostat sections of unfixed lung tissue. After iv injection of label, silver grains were detected only over alveoli. Electron microscopy indicated that radioactivity was mostly associated with alveolar capillaries. In vitro localization studies showed specific binding not only to alveoli but also to bronchi. These studies suggest that VIP can act at different sites and that the peptide could gain access to alveoli via the general circulation.

Animals↗
PubMed1984

Analysis of the behavioral activity of C- and N-terminal fragments of cholecystokinin octapeptide.

Cholecystokinin (CCK) is a gut peptide which induces a syndrome of satiety, including reduced food intake and reduced exploratory behaviors. To investigate the minimal active sequence within the octapeptide molecule for reducing exploratory behavior, all C- and N-terminal fragments of CCK 26-33 (CCK8) were synthesized. Only CCK26-33 [H-Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2] and CCK 27-33 [H-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2] induced the behavioral effects within a physiological dose range. Smaller fragments as well as unsulfated CCK26-33 and CCK27-33 were inactive in doses as high as 10(-3) mol/kg. The requirement of the entire C-terminal heptapeptide for the behavioral effects of CCK is contrasted against the activity of smaller fragments at pancreatic, gastrointestinal and brain CCK receptors.

Amino Acid Sequence↗
PubMed1984

Evidence for the activation of the kallikrein-kinin system in experimental asbestosis.

Immunoreactive bradykinin (BK) and its metabolites, namely des-Arg9-BK and des (Phe8,Arg9)-BK, were measured in acidic extracts of lungs from normal and asbestos-treated guinea pigs. The development of experimental asbestosis did not change the levels of BK (0.67 ng/mg and 0.72 ng/mg) while the levels of des-Arg9-BK increased from 0.06 to 0.57 ng/mg (P less than 0.01) and those of des (Phe8,Arg9)-BK, from 0.09 to 1.48 ng/mg (P less than 0.01). These increases in the amount of the BK metabolites suggest the participation of the kallikrein-kinin system in the inflammatory reaction induced by the intratracheal administration of asbestos into guinea pigs.

Animals↗
PubMed1984

Forskolin inhibits histamine release by neurotensin in the rat perfused hind limb.

We have assessed the influence of forskolin, a potent activator of adenylate cyclase, on histamine release by neurotensin (NT) in the rat perfused hind limb. The results indicate that forskolin, in concentrations known to increase the cyclic AMP content of various tissues, markedly inhibits the histamine releasing effect of NT. The inhibitory action of forskolin was mimicked by a synthetic cyclic AMP derivative and by 3-isobutyl-1-methyl-xanthine (IBMX), a potent phosphodiesterase inhibitor. Our results suggest that the inhibitory action of forskolin toward histamine release by NT in the rat hind limb mast cells results from the activation of a cyclic AMP-generating system in mast cells.

1-Methyl-3-isobutylxanthine↗
PubMed1984

Dynorphin-(1-13). I. Structure-function relationships of Ala-containing analogs.

Dynorphin-(1-13) (Dyn-(1-13] and its analogs substituted by single introduction of Ala in positions 1-11 were synthesized by the solid-phase method and purified by high pressure liquid chromatography. Relative potencies of the synthetic compounds were determined by their ability to inhibit electrically-evoked contractions of the guinea pig ileum (GPI) and of the mouse vas deferens (MVD) and to compete with [3H]-etorphine for opiate receptors in rat brain homogenates. Introduction of Ala in positions 1 and 4 of Dyn-(1-13) provoked most important decreases in the activity of the molecule in the three assays (relative potency of 0.2% or less). Substitution of Ala in positions 2 or 5, but not 3, also severely decreased the potency of the peptide in the smooth muscle preparations (0.6-5.0% activity). However, the opiate receptor binding assay was less sensitive to the replacement of residue in position 2 (20% activity) than that in positions 3 or 5 (12% and 6% relative potencies, respectively). In the GPI assay and the opiate binding test, the other substitutions which greatly lowered the potency of the molecule were seen in positions 6, 7, 9 and 11, four basic residues. Among these, Arg6 and Arg7 were demonstrated to be the most important in the three biological tests. Finally, the replacement of Ile8 by Ala increased the relative potency of Dyn-(1-13) up to 191% and 900% in the MVD and the opiate binding tests, respectively.

Amino Acids↗
PubMed1984

Polymer resins with amino acid containing pendants for sorption of bilirubin. I. Comparison of Merrifield and polyamide resins.

Merrifield resins with various amino acid containing pendants and a water swellable polyamide resin with the peptide alanine-alanine-alanine-arginine as the pendant group have been prepared by solid phase peptide synthesis. Merrifield resins with either arginine or lysine pendants are capable of sorbing bilirubin from aqueous solution (pH = 7.8) but those with other amino acid pendants gave no indication of sorption. The polyamide-arginine resin showed, on a functional group basis, a higher capacity for bilirubin than does cholestyramine. It is proposed that the formation of salt linkages causes a strong interaction of bilirubin with arginine and lysine.

Adsorption↗
PubMed1984

[Separation of the virotoxins of the mushroom Amanita virosa and comparative study of their interaction on actin in vitro].

Cyclic peptides have been extracted with methanol from Amanita virosa and separated by preparative HPLC. Six peptides were obtained: phalloidin and five new peptides recently identified by Faulstich as virotoxins. We have compared the interaction of these six peptides with actin in vitro. They increased the rate of polymerization of actin and protected F-actin against several denaturating agents: proteases, heat, chaotropic ions, cytochalasin B, and DNAse I. The five virotoxins have therefore the same biological properties as phalloidin. However, the differential spectra of interaction between actin and the five virotoxins are different than the differential spectra between actin and phalloidin, thus it appears that the molecular interaction of actin with virotoxins is different than with phalloidin. The five virotoxins have the same activity. Although these virotoxins have different functional groups on amino acids 1 and 7, it is concluded that these two amino acids are of minor importance in the interaction of these peptides with actin.

Actins↗
PubMed1983

Rapid assay of human plasma carboxypeptidase N by high-performance liquid chromatographic separation of hippuryl-lysine and its product.

A rapid and sensitive method for measuring carboxypeptidase N (CPN) activity in human plasma is described. The procedure is based on the hydrolysis of a high-specificity/low-affinity substrate, hippuryl-L-lysine, to its products hippuric acid and lysine. The substrate and product are separated quantitatively by high-performance liquid chromatography in less than 10 min following a minimal sample preparation time. The advantages of this method over previous ones are discussed and data are presented demonstrating the reliability of this method for the routine clinical determination of CPN activity.

Carboxypeptidases↗
PubMed1983

Cellular immune function in uremia: altered cytotoxic and suppressor cell responses to an immunomodulating heptapeptide.

Hemodialysates of uremic patients have been shown by T. Abiko, M. Kumikawa, and H. Sekimo (Biochem. Biophys. Res. Commun. 86, 945, 1979) to contain a heptapeptide which inhibits E-rosette formation by human T cells. This heptapeptide also corresponds to a fragment of beta 2-microglobulin and may play an immunoregulatory role in uremia. We investigated the potential for induction of cytotoxic and suppressor cells by the synthetic heptapeptide (HP) in blood lymphocytes of normal donors and uremic patients. Cytotoxic activity of normal lymphocytes was significantly enhanced by low concentrations of HP while high concentrations depressed it. Two patterns of responsiveness were observed among uremic patients: a high responder group reacted similarly to normals, whereas a low responder group showed little reactivity to HP. Removal of the NH2-terminal histidine of the heptapeptide strongly diminished its enhancing activity on normal cytotoxic cells while maintaining activity on uremic lymphocytes. When HP and des-His-HP were studied as possible inducers of suppressor cell activity, only the latter was found to be active on normal cells. Lymphocytes from uremic patients failed to respond to either HP or des-His-HP in suppressor cell generation. It is suggested that continuous interaction between lymphocytes and high concentrations of HP or des-His-HP in uremia may have altered their sensitivity to the immunomodulatory effects of the peptides and may be instrumental in the immune deficiency associated with renal failure.

Adjuvants, Immunologic↗
PubMed1983

Characterization of the inhibitory effect of [D-Trp11]-NT toward some biological actions of neurotensin in rats.

We assessed the influence of various doses of [D-Trp11]-NT on the increase of histaminemia and hematocrit, and decrease of blood pressure, caused by intravenous injections of neurotensin (NT), substance P (SP) and compound 48/80 (C48/80) in anesthetized rats. [D-Trp11]-NT was found to inhibit dose-dependently and selectively the changes of histaminemia, hematocrit and blood pressure caused by NT. Since the highest dose of [D-Trp11]-NT utilized exhibited slight NT-like activity, we tested the possibility that desensitization rather than true pharmacological antagonism was responsible for the inhibitory action of [D-Trp11]-NT toward NT. This hypothesis was verified by evaluating the influence of intravenous infusions of sub-stimulatory and slightly active doses of NT on NT-induced effects. The sub-stimulatory dose (0.1 nmoles kg-1 min-1) as well as a higher dose rate (0.2 nmole kg-1 min-1) of NT were found to inhibit markedly the changes of histaminemia, hematocrit and blood pressure evoked by bolus doses of NT, without altering the effects of C48/80 on the same parameters. These results suggest that the inhibitory action of [D-Trp11]-NT toward NT-induced changes of histaminemia, hematocrit and blood pressure could be the result of receptor desensitization rather than to a true pharmacological antagonism. The results also suggest that the sensitivity of target tissues to exogenous NT could be modulated to some extent by endogenous circulating levels of NT.

Animals↗