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Biomedical subjects

A Fournier

Publications and source records attributed to A Fournier.

At least 253 records · Page 14Linked to original sources
PubMed1995

Structure-activity studies of the C-terminal segment of structurally reduced analogues of ET-1.

Structurally reduced analogues of endothelin-1 (ET-1) were synthesized by linking via aminocaproic acid (Aca) the segment 3-11 of ET-1 to C-terminal fragments of various lengths [16-21, 17-21,...,21]. Analogues were studied in their linear or cyclic form in the absence or presence of a formyl group on the Trp21 side-chain, and their biologic activities were tested using guinea pig lung parenchymal strips. The absence of the first disulfide bridge and the presence of the Aca spacer caused a slight decrease in activity. The presence of His16 is essential for the contractile activity of the monocyclic peptides. Formylation of these monocyclic analogues did not modify this behavior. Similarly, linear analogues carrying S-acetamidomethyl (Acm) functions and an Aca linker were still active. However, most formylated linear derivatives were partial agonists, whereas the addition of His16 caused a decrease in contractile activity. In these latter analogues, molecular modeling studies suggested that formylation produces different conformations.

Animals↗
PubMed1995

Characterization of the endothelin-converting enzyme in guinea pig upper bronchus.

We studied the pharmacologic effects of big endothelin-1 (big ET-1), big endothelin-2 (big ET-2), and big endothelin-3 (big ET-3), and characterized the enzyme involved in the conversion of the three peptides in guinea pig upper bronchus (GPUB). ET-1, ET-2 and ET-3 (0.1-300 nM) elicited similar concentration-dependent contractions of GPUB. Big ET-1 and big ET-2, but not big ET-3, also elicited potent concentration-dependent contractions of GPUB. The conversion of big ET-1 to ET-1 in the GPUB is sensitive to phosphoramidon but not to thiorphan or captopril. Phosphoramidon inhibited the conversion of big ET-2 to ET-2, thiorphan had minimal effect, and captopril was without effect. These results suggest that the putative endothelin-converting enzyme (ECE) is involved in the conversion of big ET-1 to ET-1 in GPUB and the conversion of big ET-2 to ET-2 by a nonselective enzymatic process.

Animals↗
PubMed1994

Differential effects of pertussis toxin on body temperature changes induced by neuropeptide Y and NPY2-36.

Many effects of NPY have been attributed to a decrease in the activity of adenylate cyclase. Pre-treatment with pertussis toxin (PTx) has been shown to inhibit many pharmacological effects of NPY including increased feeding following administration in the paraventricular nucleus (PVN). In the present study, we examined the influence of PTx pretreatment on the effects of NPY on body temperature following administration in the preoptic area (POA), a region which seems to be the most sensitive to the effects of the peptide on body temperature. The effects of the same pre-treatment on the action of NPY2-36 was also studied since we have found previously that this fragment produced opposite effects on body temperature to that of NPY when injected in the POA. PTx was administered 3 days prior to the injection of NPY or NPY2-36. Results indicate that the hypothermic effect of NPY produced in the POA was blocked by PTx whereas the hyperthermic effect of NPY2-36 was not affected. These results are important as they provide evidence that, in the POA at least, the receptors mediating the hypothermic effect of NPY might be biochemically different from those mediating the hyperthermic effect of NPY2-36.

Adenylate Cyclase Toxin↗
PubMed1994

A specific binding site recognizing a fragment of angiotensin II in bovine adrenal cortex membranes.

We have characterized a specific binding site for angiotensin IV in bovine adrenal cortex membranes. Pseudo-equilibrium studies at 37 degrees C for 2 h have shown that this binding site recognizes angiotensin IV with a high affinity (Kd = 0.24 +/- 0.03 nM). The binding site is saturable and relatively abundant (maximal binding capacity around 0.5 pmol/mg protein). Non-equilibrium kinetic analyses at 37 degrees C revealed a calculated kinetic Kd of 47 pM. The binding site is pharmacologically distinct from the classic angiotensin receptors AT1 or AT2. Competitive binding studies with bovine adrenal cortex membranes demonstrated the following rank order of effectiveness: angiotensin IV (Val-Tyr-Ile-His-Pro-Phe) = angiotensin II-(3-7) (Val-Tyr-Ile-His-Pro) > angiotensin III (Arg-Val-Tyr-Ile-His-Pro-Phe) > or = angiotensin II-(4-7) (Tyr-Ile-His-Pro) > angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) > angiotensin II-(1-6) (Asp-Arg-Val-Tyr-Ile-His) > angiotensin II-(4-8) (Tyr-Ile-His-Pro-Phe) > > > angiotensin II-(3-6) (Val-Tyr-Ile-His), angiotensin II-(4-6) (Tyr-Ile-His), L-158,809 (5,7-dimethyl-2-ethyl-3-[(2'(1-H-tetrazol-5-yl)[1,1'-biphenyl]-4-y l) methyl]-3-H-imidazo[4,5-beta]pyridine H2O) and PD 123319 (1-[4-(dimethylamino)3-methylphenyl]methyl-5-(diphenylacetyl)4,5,6 ,7- tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid). The divalent cations Mg2+ and Ca2+ were shown to diminish the binding of 125I-angiotensioffn IV to bovine adrenal cortex membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗
PubMed1994

Ontogeny of pituitary adenylate cyclase-activating polypeptide (PACAP) receptors in the rat cerebellum: a quantitative autoradiographic study.

Pituitary adenylate cyclase-activating polypeptide and PACAP receptors are both present in the rat cerebellar cortex, suggesting that PACAP may play an important role in the cerebellum. In the present study, the variation of the concentration of PACAP binding sites in the rat cerebellum was investigated during postnatal development by means of quantitative autoradiography, using [125I]PACAP27 as a radioligand. In the external granule cell layer and the medulla, the density of PACAP binding sites was high at birth, markedly decreased from postnatal day 8 (P8) to P25 and finally vanished at the end of the third postnatal week. In the internal granule cell layer and molecular layer, PACAP binding sites were first detected at P8. In the internal granule cell layer, the density of binding sites slightly decreased during development but remained elevated in adults. Conversely, in the molecular layer, PACAP binding sites rapidly decreased during the second and third postnatal weeks and virtually disappeared after P25. In all four layers of the cerebellar cortex, the autoradiographic labeling was displaced by PACAP27 (IC50 close to 10(-8) M), but was not affected by VIP. No significant changes in IC50 and Hill coefficient were noticed in the various layers throughout development. The present study shows that all four layers of the cerebellar cortex express PACAP binding sites during development. The evolution of the receptor concentration exhibited differential profiles in the various layers but the specificity characteristics of the recognition sites were identical in all four structures.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1994

Randomised controlled trial of enalapril and beta blockers in non-diabetic chronic renal failure.

OBJECTIVE: To compare the ability of angiotensin converting enzyme inhibitors and beta blockers to slow the development of end stage renal failure in non-diabetic patients with chronic renal failure. DESIGN: Open randomised multicentre trial with three year follow up. SETTING: Outpatient departments of six French hospitals. PATIENTS: 100 hypertensive patients with chronic renal failure (initial serum creatinine 200-400 mumol/l. 52 randomised to enalapril and 48 to beta blockers (conventional treatment). INTERVENTIONS: Enalapril or beta blocker was combined with frusemide and, if necessary, a calcium blocker or centrally acting drug in patients whose diastolic pressure remained above 90 mm Hg. RESULTS: 17 patients receiving conventional treatment and 10 receiving enalapril developed end stage renal failure. The cumulative renal survival rate was significantly better in the enalapril group than in the conventional group (P < 0.05). The slope of the reciprocal serum creatinine concentration was steeper in the conventionally treated patients (-6.89 x 10(-5)l/mumol/month) than in the enalapril group (-4.17 x 10(-5)l/mumol/month; P < 0.05). No difference in blood pressure was found between groups. CONCLUSION: In hypertensive patients with chronic renal failure enalapril slows progression towards end stage renal failure compared with beta blockers. This effect was probably not mediated through controlling blood pressure.

Acebutolol↗
PubMed1994

Comparison of PD 145065 and Ro 46-2005 as antagonists of contractions of guinea-pig airways induced by endothelin-1 or IRL 1620.

Cumulative concentrations of endothelin-1 or IRL 1620 (Suc-[Glu9,Ala11,15]endothelin-1-(8-21)), and endothelin ETB receptor selective agonist were similarly potent in contracting guinea-pig upper bronchi, whereas endothelin-1 was more potent than IRL 1620 in contracting lung parenchymal strips. PD 145065 (10(-5) M and 10(-4) M), a non-selective endothelin ETA/ETB receptor antagonist (Ac-D-Bhg-L-Leu-L-Asp-L-Ile-L-Ile-L-Trp), significantly attenuated the contractions induced by endothelin-1 in either preparation whereas Ro 46-2005 (3 x 10(-5) M and 10(-4) M), a non-peptide non-selective receptor antagonist (4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-3-methoxy-phenoxy)-4-pyrimidinyl (benzenesulfonamide)), was without effect. PD 145065 (10(-6) M and 10(-5) M) also strongly inhibited contractions induced by IRL 1620, whereas Ro 46-2005 caused much less antagonism. Thus, PD 145065 is a more potent antagonist than Ro 46-2005 of contractions induced by endothelin-1 or IRL 1620 and mediated by endothelin ETB receptors in these guinea-pig airway preparations.

Animals↗
PubMed1994

Catheter ablation using radiofrequency or low-energy direct current in pediatric patients with the Wolff-Parkinson-White syndrome.

Percutaneous ablation of accessory pathways was performed in 22 consecutive children and adolescents (9 boys and 13 girls, age range 8 to 18 years). Low-energy direct current (DC) was used exclusively in the first 6 patients, whereas ablation was performed with radiofrequency energy in the following 16. Accessory pathways were located in the left free wall in 15 patients, were posteroseptal in 3, were in the right free wall in 3 and were anteroseptal in 1. A concealed accessory pathway was present in 7 patients (32%). There was no significant difference in clinical or electrophysiologic variables between both groups. Catheter ablation was successful in the initial 6 patients using low-energy DC, as compared with 13 of 16 patients using radiofrequency ablation. Low-energy DC was successful as a backup power source in all 3 patients who had unsuccessful radiofrequency ablation. There was no complication. The median procedural and fluoroscopic times for successful ablation were 2.5 hours and 49 minutes, respectively (p = NS between both power sources). Accessory pathway conduction recurred in 2 patients (33%) who had low-energy DC as compared with 1 (6%) who had radiofrequency ablation (p = NS). These 3 patients had successful reablation of their accessory pathways. In children and adolescents with accessory pathways, both new power sources compare favorably, with an overall success rate of ablation of 100% (22 of 22 patients). Radiofrequency ablation should be used initially because it does not require general anesthesia and is associated with a lower rate of recurrence of accessory pathway conduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Neurochemical effects of neuropeptide Y (NPY) and NPY2-36.

Our previous in vivo structure-activity studies suggested that the putative receptors mediating the effects of NPY and NPY2-36 on food intake and body temperature following ICV administration are pharmacologically different. In the present study, we examined and compared dose related effects of NPY and NPY2-36 on levels of norepinephrine (NE), dopamine (DA) and its main metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA), as well as serotonin (5-HT) and its metabolite, 5-hydroxyindolacetic acid (5-HIAA), in several brain regions of the rat, including: frontal cortex, hypothalamus, amygdala, septum, nucleus accumbens, corpus striatum, globus pallidus, substantia nigra and hippocampus. NPY and NPY2-36 (10 or 20 micrograms) were administered intraventricularly and the regional levels of the amines and metabolites were assessed 30 min following administration. Results indicate that both doses of NPY decreased NE levels within the hypothalamus. Furthermore, DOPAC concentrations were increased in this region while DA and HVA remained unchanged. The most pronounced neurochemical effects of NPY were found in the hippocampus, where the peptide produced dose related increases in DA, DOPAC and HVA. On the other hand, NPY2-36 significantly increased NE, DA and its metabolite DOPAC in both the amygdala and septum. The metabolism of DA was most obviously affected in the hippocampus and frontal cortex where levels of DA and DOPAC were significantly increased. 5-HT was affected in both the hypothalamus and globus pallidus where DA and its metabolite HVA were also increased.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Role of neuropeptide Y in the regulation of gonadotropin-releasing hormone gene expression in the rat preoptic area.

It is well documented that neuropeptide Y (NPY) is involved in the regulation of the hypothalamo-pituitary gonadal axis. In order to determine the influence of NPY on the biosynthesis of GnRH, we have studied the effects of NPY and some NPY analogs on GnRH gene expression in neurons in the male rat preoptic area (POA). The following peptides NPY, peptide YY (PYY), [Leu31,Pro34]NPY (a Y1 receptor agonist) and NPY13-36 (a Y2 receptor agonist) were injected into the left lateral ventricle of adult castrated male rats. In another series of experiments, the same peptides were administered intravenously (IV). All the animals were perfused with 4% paraformaldehyde 4 hours after injection. Cryostat sections through the POA were processed for quantitative in situ hybridization. The intracerebroventricular injection of PYY, NPY and [Leu31,Pro34]NPY induced a marked increase in the number of grains overlying the labelled neurons (20 to 45% over control). On the other hand, the Y2 receptor agonist NPY13-36 did not influence mRNA levels. Similar results were obtained following the i.v. administration although the magnitude of the stimulating effect was less important (12 to 20% over control). These data then strongly suggest that NPY positively regulates the genetic expression of GnRH in neurons via the Y1 NPY receptor subtype.

Animals↗
PubMed1994

Peptide YY derivatives as selective neuropeptide Y/peptide YY Y1 and Y2 agonists devoided of activity for the Y3 receptor sub-type.

Peptide YY derivatives were evaluated for their respective ability to bind and activate the NPY/PYY receptor sub-types (Y1, Y2 and Y3) present in various preparations. The analogue [Leu31,Pro34]PYY demonstrated high (nM) affinity in rat frontoparietal cortical membrane preparations (Y1-enriched tissue) and the rabbit saphenous vein (Y1 in vitro bioassay) but only low affinity in a Y2-enriched preparation (rat hippocampus). In contrast, PYY C-terminal fragments such as PYY3-36 and PYY13-36 were more potent in Y2 than Y1 assays. Interestingly, and in contrast to [Leu31,Pro34]NPY and NPY13-36, the PYY derivatives [Leu31,Pro34]PYY and PYY3-36 were inactive in a purported Y3 bioassay (rat colon). These results suggest that [Leu31,Pro34]PYY and PYY3-36 respectively represent the first selective and potent Y1 and Y2 agonists, devoided of significant affinity/activity for the Y3 receptor class.

Animals↗
PubMed1994

In vivo central actions of NPY(1-30), an N-terminal fragment of neuropeptide Y.

The purpose of the present study was to examine the possible central actions of a N-terminal fragment of NPY, NPY(1-30), on five measures typically influenced by the native peptide: decreased spontaneous activity, enhancement of muscle tone (increased grasping response), catalepsy, hypothermia, and stimulation of food intake. The peptides were administered ICV in doses ranging from 2.5 to 160 micrograms (0.75-48 nmol) and their effects on the three motor variables as well as thermal and feeding responses were evaluated and compared. Globally, results indicate that, similarly to NPY, the N-terminal fragment NPY(1-30), decreased spontaneous activity and induced hypothermia. However, the fragment displayed approximately half of the potency of NPY for producing these effects. On the other hand, contrary to NPY, NPY(1-30) did not affect muscle tone or food consumption and did not induced catalepsy in animals. These results demonstrate for the first time central actions of a N-terminal fragment of NPY and lend further support to the hypothesis that the receptors mediating the central actions of NPY are pharmacologically different.

Animals↗
PubMed1994

Aging differentially modifies arterial sensitivity to endothelin-1 and 5-hydroxytryptamine: studies in dog coronary arteries and rat arterial mesenteric bed.

The influence of age on vascular reactivity to endothelin-1 (ET-1) and 5-hydroxytryptamine (5-HT) was studied in coronary artery rings from dogs of 9 years of age or younger, and dogs older than 9 years. ET-1 caused concentration-dependent contractions that developed about 100% of the 70 mM KCl-induced tension in the younger dogs; those from older dogs did not generate more than 20%. In contrast, 5-HT developed only about 20% of the KCl-induced tension in rings from young dogs, whereas in the older animals, it developed up to 120% of the KCl tension. No significant difference in the tension developed by 70 mM KCl was noted between both groups of dogs. Mechanical denudation of the endothelial cell layer caused a modest, yet significant, leftward shift of the ET-1 and 5-HT concentration-response curves only in the younger dogs. N omega-Nitro-L-arginine (15 microM) shifted the ET-1 concentration-response curves to the left in rings from both groups of dogs. Rings precontracted with 20 mM KCl relaxed in a concentration-dependent fashion with acetylcholine; its sensitivity was about threefold less in the older group of dogs. To validate the changes in vascular reactivity with age, a parallel study was performed perfusing the arterial mesenteric bed of rats of 3, 7, and 30 weeks of age. In this experimental model, the efficacy of ET-1 significantly decreased with age and that of 5-HT was significantly increased. The vasomotor reactivity of noradrenaline was modestly affected by aging, whereas the acetylcholine-induced vasorelaxation was significantly reduced with age.

Acetylcholine↗
PubMed1994

Adynamic bone disease in patients with uremia.

Adynamic (or aplastic) bone disease is a bone histologic pattern characterized by decreased bone formation rate, low cellularity, and normal or decreased osteoid thickness. It was first described in symptomatic patients undergoing dialysis who were overloaded with aluminum because of contaminated dialysate or chronic ingestion of aluminic phosphate binders; the evidence of the overload was extensive coloration (more than 25%) with aurin tricarboxylic acid, whereas the Perls stain coloration for iron was negative. We have, however, reported these histologic changes in asymptomatic patients with uremia who were never exposed to aluminum, in two patients before end-stage renal failure and in six patients undergoing dialysis. The main step in the prevention of adynamic bone disease is the absolute exclusion of aluminum exposition even by so-called "safe doses" of aluminum phosphate binders because in the long term they are never actually safe. Because idiopathic adynamic bone disease may nevertheless occur, parathyroid hormone suppressive treatment by oral calcium taken with meals as phosphate binders (+/- 1 alpha-hydroxyvitamin D3 derivatives) should be carefully monitored by measurements of plasma concentrations of not only calcium and phosphate but also of intact parathyroid hormone levels. In order to have normal bone formation rate levels, patient intact parathyroid hormone levels should be between one and three times the upper limit of the normal level. Although adynamic bone disease may not be a true bone disease when not due to aluminum, it is a risk factor for increased incidence of hypercalcemia and hyperphosphatemia and therefore for metastatic calcifications. Therefore, when hypercalcemia occurs with hyperphosphatemia and normal intact parathyroid hormone in patients treated with 1 alpha-hydroxyvitamin D3, it is proposed that the latter drug should be discontinued first, whereas oral calcium is increased to correct hyperphosphatemia, and calcium concentration is decreased in the dialysate to prevent hypercalcemia, even though plasma parathyroid hormone may increase up to three times the upper limit of the normal level. In patients previously exposed to aluminum, a deferoxamine test should be performed and a deferoxamine treatment started if the test is positive.

Aluminum↗