Biomedical subjects

S St-Pierre

Publications and source records attributed to S St-Pierre.

At least 37 records · Page 2Linked to original sources

PubMed1998

Human syncytiotrophoblast NPY receptors are located on BBM and activate PLC-to-PKC axis.

Neuropeptide Y (NPY) is abundant in plasma and amniotic fluid of women throughout pregnancy, during which its involvement in placental hormonogenesis has been proposed. In accordance with its putative role, the aim of this study was to characterize the human placental syncytiotrophoblast receptivity to NPY. Thus we performed this study on brush-border membranes (BBM) and basal plasma membranes (BPM). Specific 125I-labeled NPY (125I-NPY) binding to BBM was rapid (20 min), saturable, with a maximum binding capacity of 604 +/- 100 fmol/mg protein, and of high affinity, with a dissociation constant of 11 +/- 3 nM. No saturable binding could be shown in BPM. The rank order of affinity of NPY and related peptides to compete for 125I-NPY binding sites was peptides YY (PYY) > NPY = [Leu31,Pro34]NPY > 13-36NPY >> pancreatic polypeptide (PP). It is noteworthy that PYY displaced only 45% of the binding sites. In BBM, both NPY and PYY were potent phospholipase C (PLC) stimulators, leading to a four- to fivefold increase of control phosphodiesterase activity. The latter effect could be prevented by preincubation of membranes with 5 microM U-73122, a known inhibitor of G protein-linked receptor activation of PLC-beta. Furthermore, 5 microM BIBP-3226, a Y1-receptor antagonist, shifted both dose-response curves to the right in a similar fashion for both peptides. In accordance with the PLC stimulation, both peptides also induced stimulation of protein kinase C (PKC) activity, which could be partially but additively prevented by U-73122 and LY-294002, a selective inhibitor of phosphatidyl-inositol-3 kinase (PI3K). Taken together, these data suggest that placental and blood-derived NPY binds to a mixed population of receptors composed of Y1 and Y3 subtypes on the maternal side of the syncytiotrophoblast, where it can mediate its physiological purposes via PLC-beta and PI3K activation, both of which lead to PKC activation. However, because BIBP-3226 antagonized both effects, the physiological relevance of the apparent Y3 fraction is still unsolved.

Adenylyl Cyclases↗

PubMed1997

Solution structure of neuropeptide tyrosine 13-36, a Y2 receptor agonist, as determined by NMR.

The three-dimensional structure of neuropeptide tyrosine (NPY) 13-36, a specific Y2 receptor agonist, has been investigated by two-dimensional 1H-NMR spectroscopy in solution. Analysis of the double-quantum-filtered correlation spectroscopy (DQFCOSY), total correlation spectroscopy (TOCSY) and nuclear Overhauser enhancement spectroscopy (NOESY) spectra provided a complete assignment of the proton signals. The interproton connectivities observed in the NOESY spectra comprised 166 intraresidue and 95 interresidue distance ranges which were used as constraints for molecular modeling by distance geometry, simulated annealing and energy minimization. The optimal structures are characterized by a helical C-terminal fragment Leu30-Tyr36 and a wide loop from Leu17 to Ser22. The structure of NPY 13-36 is analogous to the structure of NPY under the same solvent conditions. Comparison with other reported Y2 agonists suggests that the helical Leu30-Tyr36 fragment is the most critical for activity.

Animals↗

PubMed1997

Upper esophageal sphincter myotomy in oculopharyngeal muscular dystrophy: long-term clinical results.

From 1980 to 1995, 53 patients with oculopharyngeal muscular dystrophy (OPMD) underwent an upper esophageal sphincter (UES) myotomy for the control of marked dysphagia. From this number, a group of 21 patients had been evaluated for preoperative and postoperative symptoms in 1987. The same clinical assessment was performed in 1995 by an independent evaluator for a total of 37 patients including 12 patients from the first group. As a whole, after a mean follow-up of 6.2 years, surgery succeeded in 18 patients (49%), gave a partial improvement in 12 (32%) and failed in seven (19%). The 12 patients evaluated twice (in 1987 and 1995) have had very good early results, 8-69 months after UES myotomy: dysphagia was totally relieved in eight patients, occurred rarely in three and was moderate in one. Nevertheless, the very long-term follow-up (8 years later) has shown a recurrence of the swallowing and tracheobronchial symptoms in many cases.

Adult↗

PubMed1997

Acute effect of exercise and low-fat diet on energy balance in heavy men.

OBJECTIVE: To quantify the acute effect of the exercise-low-fat diet combination on energy balance compared with sedentarity and a high fat diet in overweight individuals. DESIGN AND MEASUREMENTS: We assessed the acute effect of exercise and ad libitum intake of low-fat foods on daily energy balance. Six heavy men participated in two randomly assigned sessions which required a 24 h stay in a whole body indirect calorimeter. Sessions were preceded by either a 60 min aerobic exercise at 50% VO2 max or a 60 min rest. Subjects were fed a low-fat diet (mean FO = 0.89) after exercise and a mixed diet (mean FQ = 0.85) after the resting period. RESULTS: The difference in energy balance between the two conditions was 7.3 MJ. About half of the effect was attributable to the energy surplus expended during exercise whereas the remaining fraction was explained by the difference in post-exercise energy balance. CONCLUSION: In heavy men, the combination of a low-fat diet and exercise has a strong acute effect on energy balance compared to a rest-mixed diet condition.

Adult↗

PubMed1997

Neuropeptide Y and the calcitonin gene-related peptide attenuate learning impairments induced by MK-801 via a sigma receptor-related mechanism.

It has been shown recently that low doses of sigma (sigma) receptor ligands like 1,3-di-(2-tolyl)guanidine (DTG), (+)N-allylnormetazocine [(+)SKF 10,047] and (+)pentazocine can antagonize learning impairments induced by dizocilpine (MK-801), a non-competitive antagonist at the NMDA receptor channel. This antagonism has been proposed to involve sigma receptor sites since it is blocked by the administration of purported sigma antagonists such as NE-100 and BMY-14802. It has also been demonstrated that peptides of the neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) families modulate, in vivo, sigma labelling and electrophysiological effects in the hippocampal formation. Accordingly, we investigated if NPY- and CGRP-related peptides modulate cognitive processes by interacting with sigma sites in mice. In order to test this hypothesis, a step-down passive avoidance task was used. Interestingly, similarly to various sigma agonists, NPY, peptide YY (PYY) and the Y1 agonist [Leu31Pro34]NPY (but not NPY[13-36], a purported Y2 agonist), as well as hCGRPalpha and the purported CGRP2 agonist [Cys(ACM)2-7]hCGRPalpha (but not CGRP[8-37], a CGRP1 receptor antagonist), significantly attenuated learning impairments induced by MK-801. Furthermore, the effects of NPY, [Leu31Pro34]NPY, hCGRPalpha and [Cys(ACM)2-7]hCGRPalpha were blocked by the administration of the sigma antagonist, BMY-14802. The present data suggest that NPY- and CGRP-related peptides can indirectly interact in vivo with sigma receptors to modulate cognitive processes associated with NMDA receptor function.

Animals↗

PubMed1997

Neural mediation of the motilin motor effect on the human antrum.

To elucidate the mode of action of motilin on the stimulation of human gastrointestinal motility, we studied the effect of exogenous motilin during muscarinic or serotoninergic pharmacological blockade. Manometric recording of the interdigestive antroduodenal motility was carried out in 27 healthy volunteers until the appearance of a spontaneous antral phase III. The tested blocker was then administered intravenously and was followed 30 min later by a 10-min infusion of synthetic human motilin (50 ng/kg). Motilin administered on a background of saline induced a premature phase III migrating from the antrum to the duodenum in every tested subject (n = 5). A low dose of atropine (5 micrograms.kg-1.h-1 for 90 min) inhibited the motilin effect in two of five subjects [not significant (NS)], whereas a high dose of atropine (15 micrograms/kg given in 30 min) blocked the motilin-induced premature antral phase III in all instances (n = 5, P < 0.01). Exogenous motilin given with low-dose ondanseton (8 mg given in 15 min followed by 1 mg/h for 90 min) or high-dose ondansetron (32 mg given in 30 min) was without effect in three of seven (NS) or in two of five (NS) subjects, respectively. During the administration of 15 micrograms/kg atropine, when exogenous motilin always failed to induce a premature antral phase III motor, a phase III-type activity was generated at the duodenum in four of five subjects. We conclude that the induction by motilin of phase III activity in human antrum is dependent on muscarinic mediation and that the contractile effect of motilin on human duodenum involves a noncholinergic mechanism, different therefore from the antral pathway.

Adolescent↗

PubMed1997

Calcitonin gene-related peptide in viscerosensitive response to colorectal distension in rats.

The role of calcitonin gene-related peptide (CGRP) on colorectal distension-induced visceral pain was investigated in conscious rats. Intracolonic administration of acetic acid (0.6%) resulted in a significantly increased number of abdominal contractions in response to colorectal balloon distension from 5.8 +/- 1.2 in controls to 16.6 +/- 1.0 in acetic acid-treated animals (P < 0.05), evidencing sensitization of visceral afferent pathways and subsequently visceral hyperalgesia. This sensitization phenomenon was not observed in animals previously treated with systemic capsaicin. Likewise, in animals not treated with capsaicin, use of an intravenous antagonist for CGRP [human CGRP-(8-37)], completely reversed the sensitizing effects of acetic acid. Furthermore, intravenous administration of CGRP dose dependently increased the number of abdominal contractions in response to colorectal distension from 3.0 +/- 1.1 (CGRP 250 ng) to 17.0 +/- 1.2 (CGRP 500 ng, P < 0.05), as previously observed in acetic acid-treated animals. Finally, intrathecal administration of hCGRP-(8-37) (mid-lumbar) also resulted in a total dose-dependent reversal of CGRP (500 ng) or acetic acid-induced visceral hypersensitivity. These results demonstrate that CGRP plays a major role in this model of visceral afferent nerve sensitization from gastrointestinal origin.

Abdomen↗

PubMed1997

A potent and selective CGRP2 agonist, [Cys(Et)2,7]hCGRP alpha: comparison in prototypical CGRP1 and CGRP2 in vitro bioassays.

The development of highly selective and potent agonists and antagonists is critical in evaluating the physiological role(s) of each receptor subtype in a peptide family. The existence of at least two calcitonin gene related peptide (CGRP) receptor subtypes has been proposed based on the potency of CGRP8-37 to antagonize the effect of hCGRP alpha in the guinea pig atrium and the agonistic properties of the linear analogue [Cys(Acm)2,7]hCGRP alpha to mimic the effect of hCGRP alpha in the rat vas deferens. However, the rather low potency of [Cys(Acm)2,7]hCGRP alpha (ED50 = 82 +/- 7.5 nM) to activate the CGRP2 receptor subtype limits its usefulness. Accordingly, we investigated various structural modifications of this linear analogue in prototypical CGRP1 and CGRP2 in vitro bioassays. Among them, replacing the acetaminomethyl moiety (Acm) by an ethylamide group, [Cys(Et)2,7]hCGRP alpha demonstrated a high potency to inhibit the rat vas deferens twitch response (ED50 = 3.4 +/- 1.2 nM), whereas in the guinea pig atrium, this analogue induced only a slight inotropic effect at very high concentrations (1 microM). Moreover, [Cys(Et)2,7]hCGRP alpha as well as the addition of a tyrosine residue at the N-terminal, [Tyr0,Cys(Et)2,7]hCGRP alpha, competed with high affinities for [125I]hCGRP binding in rat brain homogenates (IC50 = 0.3 and 0.1 nM, respectively). Taken together, these results suggest that [Cys(Et)2,7]hCGRP alpha is a new potent analogue that could prove valuable in addressing the functional relevance of the CGRP2 receptor class.

Animals↗

PubMed1996

Autoradiographic distribution of [125I]Leu31,Pro34]PYY and [125I]PYY3-36 binding sites in the rat brain evaluated with two newly developed Y1 and Y2 receptor radioligands.

The peptide YY derivatives [Leu31,Pro34]PYY and PYY3-36 are highly selective Y1 and Y2 agonists, devoid of activity on the Y3 receptor subtype [Dumont et al. (1994) Molec. Brain Res., 26:3220-3324]. These selective ligands were iodinated and used to evaluate the respective quantitative autoradiographic distribution of the Y1 and Y2 receptor subtypes in the rat brain, excluding a potential contamination from Y3 receptor. Specific [125I][Leu31,Pro34]PYY (Y1), and [125I]PYY3-36 (Y2) binding sites are detected in various brain regions, but each showed a differential distribution profile. Y1/[125I][Leu31,Pro34]PYY sites are especially concentrated in superficial layers of the cortex, the olfactory tubercle, islands of Calleja, tenia tecta, molecular layer of the dentate gyrus, several thalamic nuclei, and the posterior part of the medial mammaliary nucleus. These areas generally contained only low densities of Y2/[125I]PYY3-36 binding sites. In contrast, [125I]PYY3-36 binding is most abundant in multiple other regions including the lateral septum, piriform cortex, triangular septal nucleus, bed nucleus of the stria terminalis, oriens layer and stratum radiatum of the dorsal hippocampus, ventral tegmental area, substantia nigra, dorsal raphe nucleus, and the granular cell layer of the cerebellum. Few areas of the rat brain contained significant amounts of both [125I][Leu31,Pro34]PYY and [125I]PYY3-36 binding sites such as the anterior olfactory nuclei, oriens layer and stratum radiatum of the ventral hippocampus, nucleus tractus solitarius, area postrema, and inferior olive. Taken together, these results and the use of two selective radioligands demonstrate further the discrete, differential distribution of the Y1 and Y2 receptor subtypes in the rat brain.

Animals↗

PubMed1996

Locations and molecular forms of gastrin-releasing peptide-like immunoreactive entities in ovine pregnancy.

Large quantities of gastrin-releasing peptide-like immunoreactivity (GRP-LI) are present in ovine pregnancy fluids (allantoic fluid > fetal plasma > esophageal fluid = amniotic fluid = urine > maternal plasma) and in term endometrium (60 +/- 29 pmol.g-1) and myometrium (4.5 +/- 1.2 pmol.g-1). The larger molecular size [greater than GRP (1-27)] of this GRP-LI entity is not due to a GRP binding protein nor to a C-terminal extension of GRP. In contrast, ovine fetal colon extracts appear to contain the usual GRP (1-27) and GRP (18-27) forms. Hence, the uterus, not the fetus, is the probable source of this novel GRP-like peptide. It apparently acts as a hormone in ovine pregnancy and may play an important role in fetal-placental development.

Amino Acid Sequence↗

PubMed1996

Heterogeneity of motilin receptors in the gastrointestinal tract of the rabbit.

Motilin, a 22-amino acid peptide synthesized in endocrine cells of intestinal mucosa, stimulates GI smooth muscle contractility. To elucidate the mode of action of motilin, we attempted to determine whether motilin receptors are localized on nerve cells or on smooth muscle cells of the GI tract. Mucosa-free tissues from rabbit antrum and duodenum were homogenized separately with a Polytron prior to differential centrifugation to obtain synaptosome or plasma membrane-enriched fractions, as determined by the distribution of [3H]saxitoxin (SAX) binding (neural membranes) and 5' nucleotidase (5'N) activity (smooth muscle plasma membranes). Motilin binding was evaluated by the displacement of [125I]motilin by motilin (1-22) on the various membrane fractions. In the antrum, motilin binding was highly correlated with SAX binding (r = 0.81, p < 0.0005), and also significantly with 5'N activity (r = 0.54, p < 0.05). In the duodenum, motilin binding correlated significantly with 5'N activity (r = 0.67, p < 0.005), but not with SAX binding (r = -0.11, NS). Receptor affinity, for the motilin antagonist MOT(1-12)[CH2NH]10-11, for motilin(1-22), and for the motilin agonist erythromycin lactobionate was significantly (p < 0.001, p < 0.001, and p < 0.05, respectively) higher in SAX-enriched fractions from the antrum than in 5'N-enriched fractions from the duodenum. Therefore, in the rabbit: 1) motilin receptors appear to be predominantly located on nerve tissues in the antrum and restricted to smooth muscle cells in the duodenum, and 2) antral receptors and duodenal receptors displayed different pharmacological characteristics, probably corresponding to two specific and heterogeneous motilin receptor subtypes.

5'-Nucleotidase↗

PubMed1996

The hyperphagic effect of a high-fat diet and alcohol intake persists after control for energy density.

This study was performed to investigate the effect of a high-fat diet and alcohol (high-fat, alcohol) intake on subsequent spontaneous energy intake when controlling for food energy density. Twelve adults males participated in two 1-d randomly assigned sessions that only differed by the macronutrient composition of the appetizer served at lunchtime. Dietary energy was mainly provided by lipid and alcohol in one appetizer whereas carbohydrate was the main source of energy in the other appetizer. The energy density, content, and weight of the foods were comparable in the two appetizers. Ad libitum energy intake measured at lunchtime after ingestion of the high-fat, alcohol appetizer exceeded that observed after the high-carbohydrate appetizer by >812kJ (P<0.01). This overfeeding had no detectable effect on postprandial hunger and was not compensated by changes in energy intake at dinnertime. In conclusion, this study demonstrates that a high-fat diet and alcohol favor subsequent overfeeding, which is not due to their higher energy density.

Adult↗

PubMed1996

Structural comparison of alanine-substituted analogues of the calcitonin gene-related peptide 8-37. Importance of the C-terminal segment for antagonistic activity.

Replacement of specific residues of the antagonistic fragment human calcitonin gene-related peptide 8-37 (hCGRP 8-37) by alanine residues produces good antagonists to CGRP1 receptors when the replacement is made at positions 17 and 20 but a poor antagonist when the replacement is made at position 21. The solution structures of hCGRP 8-37 and of the three alanine analogues have been determined by two-dimensional 1H NMR spectroscopy and molecular modeling. Following the complete assignment of the NMR spectra, a comparison of the chemical shifts and of the temperature dependence of the amide chemical shifts showed that these parameters differed for [Ala17]-hCGRP 8-37 and [Ala20]-hCGRP 8-37 relative to hCGRP 8-37 in the N-terminal and central segments but not in the C-terminal segment (residues 31-37). In the case of [Ala21]-hCGRP 8-37, differences were observed all along the chain. Molecular modeling calculations were performed by distance geometry, simulated annealing and energy minimization using NOE distance constraints. Molecular models showed a structural homology between [Ala17]-hCGRP 8-37, [Ala20]-hCGRP 8-37 and hCGRP 8-37 in the C-terminal segment Asn31-Phe37 as well as hydrogen bonding between Val28 and Asn31. These structural similarities are not observed with [Ala21]-hCGRP 8-37. Therefore, the structure of the C-terminal segment of hCGRP 8-37 appears to be critical for antagonistic activity at CGRP1 receptors.

Alanine↗

PubMed1996

Neuropeptide Y Y2 receptors in hypothalamic neuroendocrine areas are up-regulated by estradiol and decreased by progesterone cotreatment in the ovariectomized rat.

Central neuropeptide Y (NPY) systems are known to stimulate, via the Y1 subtype of NPY receptor, the release of LHRH that leads to surges of LH. Levels of NPY receptors in relation to the above modulation have not been assessed. This study, therefore, examined profiles of NPY receptors in ovariectomized (Ovx) rats and in Ovx rat treated with estradiol (E2) with or without cotreatment with progesterone (P4). [125I]Human PYY containing proline in position 34 [(Pro 34 )hPYY] was used as the Y1 receptor ligand, and [125 I]human peptide YY-(3-36) [hPYY-(3-36)] was used as the Y2 site ligand. Treatment with E2 over 3 days increased Y2 binding in the preoptic hypothalamus and the medial basal hypothalamus, whereas no changes were found in the lateral anterior hypothalamus or the piriform cortex. Administration of P4 (1.5 mg/animal) on the third day of E2 treatment reduced Y2 binding in both the preoptic hypothalamus and the medial basal hypothalamus to or below the density found in Ovx controls. The Y1 receptor levels and the affinity of either Y1 or Y2 binding did not change appreciably with any of the treatments. No significant changes in the binding of wheat germ agglutinin were found at the time of the largest reduction in Y2 receptor numbers by P4, indicating the absence of a major membrane receptor reduction in response to the progestin. The down-regulation of Y2 sites by P4 preceded and accompanied the surge of serum LH induced by the progestin in E2-treated animals. A short term P4 treatment thus appears to reduce the Y2 tone in hypothalamic areas involved in LHRH secretion. This reduction might reinforce Y1 drives known to stimulate the output of LHRH, and thus contribute to LH release.

Analysis of Variance↗

PubMed1996

A case study on energy balance during an expedition through Greenland.

A 59-year-old man who had always been lean was submitted to overfeeding for two months in preparation for a 3-week expedition through Greenland, during which a considerable negative energy balance was expected. The overfeeding protocol consisted of an estimated energy surplus of 2000 kJ per day and this induced body weight and fat gains of 4.7 and 3.6 kg, respectively. Whole-body indirect calorimetry measurements following 4 and 8 weeks of overfeeding showed that there was no change in the subject's daily energy expenditure. Ad libitum energy intake measured during a buffet-type meal was substantially increased during overfeeding. As expected, the expedition induced a negative energy balance which reduced body weight below the pre-overfeeding level. Daily energy expenditure measured 12 days after the expedition, when the subject had recovered his initial body weight, was decreased by 1.4 MJ/day. The increase in ad libitum energy intake observed during the pre-expedition overfeeding persisted after the expedition. These adaptations tended to persist three weeks and four months after the end of the expedition. These results suggest that both energy expenditure and intake were modified after the expedition to prevent a subsequent body energy deficit.

Body Composition↗

PubMed1995

Involvement of the Y2 receptor subtype in the regulation of prolactin gene expression by neuropeptide Y in the male rat.

In order to determine the influence of neuropeptide Y (NPY) on the biosynthesis of prolactin (PRL), we have studied the effects of NPY and some NPY analogs on PRL gene expression in the male rat anterior pituitary gland. The following peptides (4 micrograms/100 g body wt): NPY, peptide YY (PYY), NPY13-36 (a Y2 receptor agonist) and [Leu31,Pro34]NPY (a Y1 receptor agonist) were injected into the left lateral ventricle of adult male rats. Control animals received only the vehicle (0.9% NaCl). All the animals were perfused with 4% paraformaldehyde 4 h after injection and processed for in situ hybridization. The intracerebroventricular injection of NPY, PYY, and NPY13-36 induced a significant increase in the hybridization signal (22-40% over control). On the other hand, the Y1 receptor agonist [Leu31,Pro34]NPY did not influence PRL mRNA levels. These data then suggest that activation of the Y2 NPY receptor subtype at the central level can positively regulate PRL gene expression.

Animals↗

PubMed1995

Regulation of proopiomelanocortin gene expression by neuropeptide Y in the rat arcuate nucleus.

In the arcuate nucleus which is richly innervated by both proopiomelanocortin (POMC) and neuropeptide Y (NPY) neurons, it has been shown that NPY fibers are in synaptic contact with POMC cell bodies. In order to determine whether NPY could influence POMC neuronal activity, we have studied the effects of NPY and some NPY analogs on POMC gene expression using quantitative in situ hybridization. The following peptides NPY, [Leu31,Pro34]-NPY (a Y1 receptor agonist), and NPY13-36 (a Y2 receptor agonist) were injected into the left lateral cerebral ventricle of adult male rats 4 h before being perfused for histological procedures. The intracerebroventricular injection of NPY and NPY13-36 induced a significant decrease in the number of grains overlying the labelled neurons. On the other hand, the Y1 receptor agonist [Leu31,Pro34]-NPY did not modify POMC mRNA levels. These data then strongly suggest that NPY negatively regulates the genetic expression of POMC neurons via the Y2 NPY receptor subtype.

Animals↗

PubMed1995

Influence of ambient temperature on the effects of NPY on body temperature and food intake.

Because thermoregulation and food consumption are interrelated, and because thermoregulation processes are influenced by ambient temperature, we examined the effects of neuropeptide Y (NPY) on both body temperature and food intake in various thermal environments after intracerebroventricular administration of 20 micrograms. Results reveal that the prominent effects of NPY on body temperature and food intake in relatively thermoneutral environments are drastically altered at more extreme ambient temperatures. NPY produced hypothermia in animals placed at 4, 12, and 21 degrees C, and actually increased body temperature in animals subjected to 30 and 38 degrees C temperature. On the other hand, in comparison with ambient temperatures of 12 and 21 degrees C, ambient temperatures of 4 and 30 degrees C significantly reduced the stimulatory effect of NPY on food consumption. Moreover, at 38 degrees C the effect of NPY on food intake was totally abolished. These data demonstrate that ambient temperature has a critical influence on central actions of NPY.

Animals↗