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Biomedical subjects

A Fournier

Publications and source records attributed to A Fournier.

At least 163 records · Page 9Linked to original sources
PubMed1998

[Pituitary adenylate cyclase-activating polypeptide].

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been originally isolated from the sheep hypothalamus on the basis of its ability to stimulate cAMP formation in anterior pituitary cells. Post-translational processing of the PACAP precursor generates two biologically active molecular forms, PACAP38 and PACAP27, and a novel peptide called PACAP-related peptide whose activity remains unknown. The primary structure of PACAP has been remarkably conserved during evolution, from protochordates to mammals, suggesting that the peptide exerts important activities throughout the vertebrate phylum. The sequence of PACAP27 exhibits substantial similarities with those of vasoactive intestinal polypeptide (VIP), glucagon and secretin. The gene encoding the PACAP precursor is widely expressed in the brain and in various peripheral organs, notably in endocrine glands, the gastro-intestinal and uro-genital tracts and the respiratory system. In vivo and in vitro studies have shown that PACAP exerts multiple activities as a hormone, neurohormone, neurotransmitter or trophic factor. For instance, PACAP triggers the release of insulin and glucagon, activates steroidogenesis in the adrenal gland and gonads, and stimulates the secretion of most hypophysial cells. PACAP exerts a potent relaxant activity on smooth muscle fibers in blood vessels, lung and gut. In the brain, PACAP stimulates the electrical activity of various populations of neurons and increases tyrosine hydroxylase gene expression. Recent studies have shown that PACAP exerts a trophic activity during ontogenesis, notably in the adrenal medulla and in the central nervous system. The biological effects of PACAP are mediated through three distinct receptor subtypes which exhibit differential affinities for PACAP and VIP. The PAC1 receptor, which shows high selectivity for PACAP, is coupled to several transduction systems. In contrast, VPAC1 and VPAC2, which bind with the same affinity PACAP and VIP, are mainly coupled to the adenylyl cyclase pathway. The bronchodilatator and vasorelaxant effects of PACAP, as well as the antiproliferative and neuroprotective actions of the peptide, make it a valuable target for new drug development.

Adenylyl Cyclases↗
PubMed1997

Effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on corticotropin-releasing hormone (CRH) gene expression in the rat hypothalamic paraventricular nucleus.

Pituitary adenylate cyclase-activating peptide (PACAP) is a 38-amino-acid polypeptide, first isolated from hypothalamus, which directly stimulates in vitro the production of cAMP as well as the release of several pituitary hormones, such as growth hormone and luteinizing hormone. In vivo, PACAP has been shown to stimulate ACTH release. The presence of PACAP receptors in several brain areas, including the hypothalamus, suggests that this peptide might play a role as a neurotransmitter/neuromodulator and might be involved in the regulation of hypophysiotropic neurohormones. In order to study the role of PACAP on corticotropin-releasing hormone (CRH) neuron, we have investigated the effects of intracerebroventricular (i.c.v.) and intravenous (i.v.) injections of PACAP and the potent PACAP antagonist PACAP(6-38) on CRH gene expression in the hypothalamic paraventricular nucleus (PVN) in the male rat. The levels of CRH mRNA were evaluated by quantitative in situ hybridization. The i.c.v. injection of PACAP (4 microg/kg b.wt.) produced a 22% increase in the hybridization signal, an effect which was completely prevented by the concomitant injection of the PACAP antagonist (4 microg/kg b.wt.). On the other hand, the administration of the PACAP antagonist induced by itself a 40% decrease in the amounts of CRH mRNA. The i.v. injection of the same peptides (100 microg/kg. b.wt.) produced very similar results. These data strongly suggest that PACAP is involved in the positive regulation of CRH gene expression via specific central receptors and then can play a role as a neurotransmitter/neuromodulator. The effect observed after i.v. injection of PACAP also suggests that the circulating levels of PACAP can play a role in the modulation of CRH gene expression. PACAP might then be involved in the regulation of the HPA axis by a double mechanism: stimulation of CRH gene expression at the central level and direct effect on pituitary corticotrophs.

Analysis of Variance↗
PubMed1997

The rabbit ileum: a sensitive and selective preparation for the neuropeptide Y Y5 receptor.

The rabbit ileum shows high sensitivity to neuropeptide Y. Relaxations are obtained in this tissue with human pancreatic polypeptide > peptide YY > > [Leu31,Pro34]neuropeptide Y > rat pancreatic polypeptide > human neuropeptide Y in this order of potency that is indicative of a Y5 receptor. Effects of neuropeptide Y and congeners are not affected by neuropeptide Y Y1 receptor antagonist (BIBP 3226), but are reduced by the neuropeptide Y Y5 receptor antagonist JCF 104 (2-(naphtalen-1-yl)-3-phenylpropane-1,2-diamine). Rabbit ilea provide sensitive and selective neuropeptide Y Y5 receptor preparations.

Animals↗
PubMed1997

The dog saphenous vein: a sensitive and selective preparation for the Y2 receptor of neuropeptide Y.

The dog saphenous vein responds to neuropeptide Y with a dose-dependent contraction and this vasopressor effect is not altered by the removal of the endothelium nor by the neuropeptide Y Y1 receptor antagonist, BIBP 3226 ((R)-N2-(diphenylacetyl)-N-[(n-hydroxyphenyl)methyl]-argininami de). The dose-response curves obtained with neuropeptide Y, peptide YY and with C-terminal fragments such as neuropeptide Y-(2-26), neuropeptide Y-(13-36) and peptide YY-(3-36) have similar slopes and maxima. EC50 values of these compounds vary between 30 +/- 10 and 89 +/- 47 nM. The neuropeptide Y Y1 receptor-selective agonist [Leu31,Pro34]neuropeptide Y and human pancreatic polypeptide are inactive up to 1 microM. This pharmacological profile suggests that the contraction of the dog saphenous vein induced by neuropeptide Y and its homologues or fragments is mediated by a neuropeptide Y Y2 receptor type. Moreover, this neuropeptide Y Y2 receptor appears to be localized in the venous smooth muscle, where it exerts a direct myotropic effect that may be useful for the pharmacological characterization of new compounds acting as agonists or antagonists of the neuropeptide Y Y2 receptor.

Animals↗
PubMed1997

Hydrophobic forces are responsible for the folding of a highly potent natriuretic peptide analogue at a membrane mimetic surface: an NMR study.

A conformational study by nmr spectroscopy was performed with the highly active 28 residue hybrid natriuretic peptide analogue pBNP1 [M. Mimeault, A. De Léan, M. Lafleur, D. Bonenfant, and A. Fournier (1995) Biochemistry, Vol. 34, pp. 955-964], which consists of the cyclic peptide core of pBNP32 and the N- and C-terminal exocyclic segments of rANP (99-126). In purely aqueous solution pBNP1 exhibits random coil behavior as evidenced by the almost complete absence of structurally significant nmr observables. By contrast, elements of secondary structure emerged upon the addition of dodecylphosphocholine micelles to the aqueous sample. Nuclear Overhauser effect distance-restrained molecular dynamics simulations in conjunction with torsional angle determinations permitted the generation of reasonable model of the lipid-bound conformation of pBNP1. According to this model, pBNP1 adopts turn-like features in the cyclic and C-terminal regions of the peptide, but remains quite flexible in the N-terminal segment. Two hydrophobic cores separated by a hydrophilic cleft were also evident in the generated structure. A mechanism is proposed whereby the hydrophobic interactions necessary to stabilize a folded structure of pBNP1 are facilitated by the presence of the membrane-like polar/apolar interface provided by the phospholipid micelles.

Amino Acid Sequence↗
PubMed1997

Steady-state captopril renography: continuous monitoring of the captopril-induced increase in 99mTc-MAG3 mean parenchymal transit time in renovascular hypertension.

Steady-state captopril renography (SSCR) is an original technique for assessing the captopril-induced increase in technetium-99m mercaptoacetyltriglycine (99mTc-MAG3) mean parenchymal transit time (MPTT) in kidneys affected with functional renal artery stenosis (RAS). The steady-state parenchymal activity achieved by constant infusion of 99mTc-MAG3 is directly linked to the MPTT of the radiopharmaceutical. This steady-state parenchymal activity was continuously monitored from 15 min before to 60 min after a single dose of captopril in order to detect possible disruption of the steady state. SSCR was performed in 11 hypertensive patients with unilateral RAS and in two with RAS of a solitary kidney before renal revascularization (RR). In four of these patients, an additional SSCR was performed after RR. Of the ten patients whose hypertension was cured or improved by RR, one presented an uninterpretable SSCR and six presented a positive SSCR on the affected side. Control SSCR performed in four of these six patients was bilaterally negative. SSCR was also bilaterally negative in the three patients who showed no blood pressure response to RR. These preliminary results tend to indicate that, in spite of the stability of pre- and post-captopril hydration and data acquisition conditions allowed by this steady-state technique, the sensitivity is lower than expected. However, the reason for the false-negative results does not seem to be inherent to SSCR.

Adult↗
PubMed1997

Cardiovascular responses to dynamic submaximal exercise in children previously treated with anthracycline.

This study assessed the long-term (5-year) outcome of pediatric low-dose anthracycline therapy on the circulatory response to moderate exercise. Thirteen patients (13 +/- 4 years old) and 15 age-matched control subjects completed a maximal cycle ergometer protocol as well as two 5-minute cycling tests at 33% and 66% maximal oxygen uptake (V(O2)max) for determination of cardiac index (carbon dioxide rebreathing). V(O2)max was lower in patients than in control subjects (1.3 +/- 0.5 L/min vs 2.3 +/- 0.6 L/min) (p< 0.05). Smaller relative increases in cardiac index for similar increases in relative exercise intensities were found in patients (33% V(O2)max, 73% vs 116%; 66% V(O2)max, 115% vs 192%), as a result of smaller increases in stroke index from rest (33% V(O2)max, 33% vs 54%; 66% V(O2)max, 33% vs 69%; p< 0.05). Similarly, despite normal resting systolic function, patients exhibited a lower stroke index and higher heart rate for any given value of oxygen uptake (milliliters per minute per square meter). Children who had survived cancer exhibited stroke index impairment during exercise similar in intensity to that of recreational activities or play, attesting to a limited inotropic reserve.

Adolescent↗
PubMed1997

Tissue-specific regulation of fat cell lipolysis by NPY in 6-OHDA-treated rats.

The effects of neuropeptide Y (NPY), peptide YY (PYY), [Leu31, Pro34]NPY, and NPY (13-36) on adipocyte lipolysis have been studied in subcutaneous (inguinal) and visceral (parametrial) rat adipose tissues. A 48-h fasting period and chemical sympathectomy were used to evaluate the regulation of Y1 and Y2 pathways in rat adipocytes. NPY, PYY, and [Leu31, Pro34]NPY significantly inhibited fat cell lipolysis by about 25% in both tissues (p < or = 0.05). This inhibition was achieved mainly through the Y1 pathway. No significant response to NPY (13-36) was observed, suggesting a lack of involvement of the Y2 pathway in the antilipolytic effect of NPY and PYY. The 48-h fasting period led to the loss of the Y1 inhibitory effect previously observed in control rats. On the other hand, the chemical sympathectomy induced a 35% increase of fat cell lipolysis (p < or = 0.05). The latter involved the Y2 pathway as stimulated by NPY (13-36), and was observed in the parametrial tissue exclusively. These results suggest that: a) rat Y receptors reported to exhibit Gi responses can also express Gs-like responses, and b) visceral and subcutaneous adipose tissues exhibit specific regulation of fat cell lipolysis.

Adipocytes↗
PubMed1997

Pituitary adenylate cyclase-activating polypeptide promotes cell survival and neurite outgrowth in rat cerebellar neuroblasts.

High concentrations of pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors have been detected in the rat cerebellum during ontogenesis. In particular, PACAP receptors are actively expressed in immature granule cells, suggesting that PACAP may act as a neurotrophic factor in the developing rat cerebellum. In the present study, we have investigated the effect of PACAP on cell survival and neurite outgrowth in cultured immature cerebellar granule cells. In control conditions, cultured granule cells undergo programmed cell death. Exposure of cultured cells to PACAP for 24 and 48 h provoked a significant increase in the number of living cells. The effect of PACAP on cell survival was inhibited by the PACAP antagonist PACAP(6-38). Vasoactive intestinal polypeptide was approximately 1000 times less potent than PACAP in promoting cell survival. PACAP also induced a significant increase in the number of processes and in the cumulated length of neurites borne by cultured neuroblasts. The present results demonstrate that PACAP promotes cell survival and neurite outgrowth in cultured immature granule cells. Since PACAP and its receptors are expressed in situ in the rat cerebellar cortex, these data strongly suggest that PACAP plays a physiological role in the survival and differentiation of cerebellar granule cells.

Animals↗
PubMed1997

Characterization of neuropeptide Y receptor subtypes in the normal human brain, including the hypothalamus.

The aim of the present study was to investigate the existence and distribution of neuropeptide Y receptor subtypes in various regions of the normal human brain using the peptide YY derivative receptor probes, [125I][Leu31,Pro34]polypeptide YY/Y1 and [125I]polypeptide YY(3-36)/Y2, in addition to the non-selective ligand [125I]polypeptide YY. Membrane binding assays performed with post mortem frontal cortex homogenates revealed that [125I]polypeptide YY and [125I]polypeptide YY(3-36) bound in a time- and protein concentration-dependent manner. Very low amounts of specific [125I][Leu31,Pro34]polypeptide YY binding could be detected even in the presence of high amounts of protein, contrasting with results obtained with [125I]polypeptide YY and [125I]polypeptide YY(3-36), a preferential Y2 receptor probe. Analysis of saturation isotherms revealed that [125I]polypeptide YY(3-36) bound to a single class of high-affinity sites (0.5-2 nM). Significantly higher binding capacities were evident for [125I]polypeptide YY(3-36) as compared to [125I][Leu31,Pro34]polypeptide YY, suggesting that the human frontal cortex, in contrast to the rat, is mostly enriched with Y2 receptors. Ligand selectivity profile confirmed the hypothesis that polypeptide YY(3-36), neuropeptide Y and polypeptide YY but not the [Leu31,Pro34] derivatives are potent competitors of [125I]polypeptide YY and [125I]polypeptide YY(3-36) binding sites. Autoradiographic studies demonstrated further that cortical areas, as well as most other regions of the human brain, are particularly enriched with Y2/[125I]polypeptide YY(3-36) sites, while only low to very low amounts of Y1 binding were detected except in the dentate gyrus of the hippocampal formation. In the human hypothalamus, a preponderance of Y2 binding sites was also noted. Taken together, these results clearly establish that the distribution of the Y1 and Y2 receptor subtypes in human is different from the rodent brain, the Y2 subtype being most abundant in the human brain.

Aged↗
PubMed1997

Percutaneous recanalization of occlusion of central and proximal veins in chronic hemodialysis. Technical note.

Occlusion of the central and proximal veins in chronic hemodialysis patients results in considerable edema of the arm of the vascular access that is unable to drain normally. This is a formidable problem because it is very often necessary to close the vascular access, which is sometimes the last available one. To avoid resorting to this disastrous solution, recanalization of the occluded vein by percutaneous recanalization followed by endoluminal angioplasty was successfully performed in five patients (4 innominate veins and one axillary vein). Immediate failure occurred in a sixth patient, and delayed failure after two months of patency (innominate vein) in another patient for whom there had been no systematic stent placement. Recanalization was still patent in four other patients at 3, 6, 12 and 26 months. These results are an encouragement to attempt percutaneous recanalization by angioplasty of occluded central veins because, when successful, this technique makes it possible to preserve the vascular access and to avoid onerous surgery. We believe that this technique should therefore become better known.

Adult↗
PubMed1997

Stimulation of the sympathetic perimesenteric arterial nerves releases neuropeptide Y potentiating the vasomotor activity of noradrenaline: involvement of neuropeptide Y-Y1 receptors.

Neuropeptide Y (NPY) appears to be involved in the sympathetic regulation of vascular tone. To assess the putative role of NPY in mesenteric circulation, the release and biological effect of NPY were examined after electrical stimulation of perimesenteric arterial nerves. Nerve stimulation with trains of 2-30 Hz increased the perfusion pressure of the arterially perfused rat mesenteric bed in a frequency- and time-dependent fashion. Trains of 15-30 Hz significantly displaced to the left, approximately threefold, the noradrenaline (NA)-induced pressor concentration-response curve, in addition to increasing significantly its efficacy. Perfusion with 10 nM exogenous NPY mimicked the electrical stimulation effect, causing a threefold leftward shift of the NA concentration-response curve and increasing the maximal NA response. These effects were antagonized by 100 nM BIBP 3226, indicating the activity of NPY-Y1 receptors. Electrical stimulation of the perimesenteric nerves released immunoreactive NPY (ir-NPY) in a frequency-dependent fashion; the ir-NPY coelutes with synthetic NPY as confirmed by HPLC. Both the electrically induced pressor response and the calcium-dependent release of NPY were obliterated in preparations perfused with 1 microM guanethidine or in rats pretreated intravenously for 48 h with 6-hydroxydopamine, thus revealing the sympathetic origin of these phenomena. Only a small proportion of the total NPY content in the perimesenteric arterial nerves is released after electrical stimulation. Chromatographic studies of the physiological sources of the ir-NPY support that NPY fragments are generated via peptidase degradation. The present findings demonstrate that NPY is released from the perimesenteric arterial sympathetic nerves and acts, via the activation of NPY-Y1 receptors, as the mediator responsible for the potentiation of NA's effect on perfusion pressure in the isolated rat mesenteric bed.

Animals↗
PubMed1997

Mouse aorta: a preparation highly sensitive to the vasodilatory action of CGRP.

Calcitonin gene-related peptide (CGRP), carbamylcholine, and vasoactive intestinal peptide (VIP) caused a concentration-related relaxation in mouse aorta precontracted to noradrenaline. Maximal relaxations obtained were 110, 44, and 46% with median effective concentrations (EC50) values of 7.8, 813.7, and 24.5 nM for CGRP, carbamylcholine, and VIP, respectively. The carbamylcholine- and VIP-induced relaxations were exclusively mediated by endothelial cell-derived factors, whereas CGRP maintained a full vasodilatory action in denuded aorta. However, its concentration-response curve was slightly shifted to the right in the absence of endothelium. The relaxation caused by CGRP was also slightly inhibited at 2 x 10(-8) M by removal of endothelium and in the presence of methylene blue, NG-nitro-L-arginine methylester (L-NAME), or glibenclamide but was not affected by atropine, propranolol, indomethacin, or tetrodotoxin. Moreover, the absence of Ca2+ in the bathing solution had no inhibitory effect on CGRP-induced relaxation in noradrenaline-precontracted aorta. It is concluded that the relaxation evoked by CGRP in the mouse aorta does not mainly depend on an endothelium-derived factor or on the activation of ATP-sensitive K+ (KATP) channels but rather is caused by a mechanism primarily associated with the inhibition of the mobilization of intracellular Ca2+.

Animals↗
PubMed1997

Invasive versus non-invasive diagnosis of renal bone disease.

At present, bone histomorphometry remains the gold standard for the diagnosis of the various types of renal bone disease. In the search for a non-invasive method of diagnosis, biochemical serum markers of bone remodelling, in addition to serum intact parathyroid hormone and aluminium determinations, have been proposed as the most reliable tools and are at present widely used in clinical practice. Their respective diagnostic values, as separate items and in combined analysis, are thoroughly discussed in the present review.

Aluminum↗