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Biomedical subjects

S Picard

Publications and source records attributed to S Picard.

At least 55 records · Page 3Linked to original sources
PubMed1998

Median eminence dopaminergic activation is critical for the early long-day inhibition of luteinizing hormone secretion in the ewe.

In ewes, photoperiod modulates LH release. The median eminence (ME) dopaminergic activity seems to be implicated in the inhibition of LH secretion by photoperiod. This study investigated the functional importance of ME dopaminergic activity for LH secretion inhibition in three inhibitory photoperiodic treatments: after 33 long days (LD) (LD1 treatment), after 72 LD (LD2 treatment), and after 34 short days. Using reverse microdialysis on three groups of seven ewes, a solution of alpha-methyl-paratyrosine [alphaMPT, an inhibitor of tyrosine hydroxylase (TH); 10 mM in Ringer's lactate] was infused into the ME for 5 h, preceded by a 5-h control period during which only vehicle was infused, in each of the three photoperiodic treatments. AlphaMPT dramatically decreased the 3,4-dihydroxyphenylacetic acid concentration, similarly in all three photoperiodic treatments, suggesting a similar inhibition of TH activity. In the LD1 treatment, alphaMPT significantly increased LH pulse frequency (+1.22 +/- 0.46 pulse/5 h from control period, mean +/- SEM, n = 9; P < 0.05) and mean concentration (+51 +/- 28%; P < 0.001). In the other two photoperiodic treatments, alphaMPT had no significant effect on LH release. Thus, blockade of dopamine synthesis in the ME seems to stimulate LH secretion in early, but not long-term, inhibition by LD nor after the transition to short days. Therefore, dopaminergic activity of the ME seems to be critical for LH secretion inhibition in some photoperiodic inhibitory treatments but not in others.

Animals↗
PubMed1998

Predominant androgenic component in the stimulatory effect of dehydroepiandrosterone on bone mineral density in the rat.

In order to assess the relative roles of the androgenic and/or estrogenic components in the stimulatory effect of dehydroepiandrosterone (DHEA) on bone mineral content (BMC) and density (BMD), ovariectomized (OVX) female rats received DHEA administered alone or in combination with the antiandrogen flutamide (FLU) or the antiestrogen EM-800 for 12 months. We also evaluated, for comparison, the effect of estradiol (E2) and dihydrotestosterone (DHT) constantly released by Silastic implants as well as medroxyprogesterone acetate (MPA) released from poly(lactide-co-glycolide) microspheres. Femoral BMD was decreased by 11% 1 year after OVX, but treatment of OVX animals with DHEA increased BMD to a value 8% above that of intact animals. The administration of FLU reversed by 76% the stimulatory effect of DHEA on femoral BMD and completely prevented the stimulatory effect of DHEA on total body and lumbar spine BMD. Similar results were obtained for BMC. On the other hand, treatment with the antiestrogen EM-800 did not reduce the action of DHEA on BMD or BMC. At the doses used, MPA, E2 and DHT increased femoral BMD, but to a lesser degree than observed with DHEA. Bone histomorphometry measurements were also performed. While DHEA treatment partially reversed the marked inhibitory effect of OVX on the tibial trabecular bone volume, the administration of FLU inhibited by 51% (P < 0.01) the stimulatory effect of DHEA on this parameter. The addition of EM-800 to DHEA, on the other hand, increased trabecular bone volume to a value similar to that of intact controls. DHEA administration markedly increased trabecular number while causing a marked decrease in the intertrabecular area. The above stimulatory effect of DHEA on trabecular number was reversed by 54% (P < 0.01) by the administration of FLU, which also reversed by 29% the decrease in intertrabecular area caused by DHEA administration. On the other hand, the addition of EM-800, while further decreasing the intertrabecular space achieved by DHEA treatment, also led to a further increase in trabecular number to a value not significantly different from that of intact control animals, suggesting an additional effect of EM-800 over that achieved by DHEA. Treatment with DHEA caused a 4-fold stimulation of serum alkaline phosphatase, a marker of bone formation, while the urinary excretion of hydroxyproline, a marker of bone resorption, was decreased by DHEA treatment. Treatment with DHEA and DHEA + EM-800 decreased serum cholesterol levels by 22 and 65% respectively, while the other treatments had no significant effect on this parameter. The present data indicate that the potent stimulatory effect of DHEA on bone in the rat is mainly due to the local formation of androgens in bone cells and their intracrine action in osteoblasts.

Androgen Antagonists↗
PubMed1998

Association between plasma HDL-cholesterol concentration and Taq1B CETP gene polymorphism in non-insulin-dependent diabetes mellitus.

The effects of CETP gene Taq1B polymorphism on plasma lipoproteins were investigated in 176 patients with non-insulin-dependent diabetes mellitus. The distribution of CETP genotypes was similar to that previously described in the general population. A significant association was found between CETP genotype and both CETP and HDL cholesterol (HDL-c) concentrations. B1B1 had the highest CETP and the lowest HDL-c whereas B2B2 had the lowest CETP and the highest HDL-c. However, HDL-c was not correlated with CETP concentration, even when genetic groups were separately considered. By multivariate analysis, the determinants of HDL were body mass index, triglycerides concentration, net mass CE transfer, and CETP genotype. No association was found between CETP genetic groups and HDL or LDL size distribution. In contrast, net mass CET was positively and HDL and LDL sizes were negatively correlated with plasma triglyceride concentration. Overall, our work demonstrates that, in a population of diabetic patients where lipoprotein-related parameters vary over a large range, the association of CETP gene polymorphism with HDL-c is independent of plasma CETP concentration.

Adult↗
PubMed1997

Suppression of leukotriene B4 biosynthesis by endogenous adenosine in ligand-activated human neutrophils.

Adenosine (Ado) has been shown to suppress several functional responses of human polymorphonuclear leukocytes (PMNs). The current study investigated whether endogenous Ado regulates the biosynthesis of leukotriene (LT)B4 in ligand-stimulated PMNs. Measurements of Ado in PMN resuspended in Hanks' buffered salt solution (HBSS) or plasma showed a cell concentration- and time-dependent accumulation of the nucleoside. The removal of endogenous Ado with either Ado deaminase or the blockade of its action by the Ado A2a receptor antagonist, 8-(3-chlorostyryl) caffeine, markedly increased LTB4 biosynthesis upon ligand stimulation in HBSS. Similarly, LTB4 synthesis by ligand-stimulated PMNs in plasma (containing recombinant LTA4 hydrolase to allow the conversion of protein-bound LTA4) was strongly enhanced by addition of Ado deaminase. Addition of red blood cells to suspensions of PMNs in plasma mimicked the effect of adding Ado deaminase and LTA4 hydrolase in enhancing LTB4 biosynthesis upon ligand stimulation. This effect of red blood cells on LTB4 biosynthesis was blocked by dipyridamole, an inhibitor of Ado transport, or captopril, an inhibitor of LTA4 hydrolase. These results demonstrate that endogenous Ado efficiently downregulates ligand-stimulated LTB4 biosynthesis in PMN suspensions, pointing out a potentially important regulatory function of Ado in inflammatory exudates. These results also unveil a dual role for red blood cells in upregulating LTB4 biosynthesis, namely, the removal of endogenous Ado and the conversion of LTA4 released by activated PMNs.

Adenosine↗
PubMed1997

Cyclic GMP inhibits a pharmacologically distinct Na+/H+ exchanger variant in cultured rat astrocytes via an extracellular site of action.

There is growing evidence that cyclic GMP (cGMP) plays important roles in the brain. In cultured rat astrocytes, we observed that the cGMP-inducing C-type natriuretic peptide (CNP) and cGMP analogues caused a decrease in intracellular pH (pHi). To examine whether this effect was due to inhibition of an Na+/H+ exchanger (NHE), we acidified cells by replacing extracellular Na+ by choline and examined the kinetics of the pHi recovery that occurred on reintroduction of Na+ in the extracellular medium. Both CNP and amiloride analogues inhibited the Na(+)-dependent pHi recovery, even in the nominal absence of CO2/HCO3-. This indicated that CNP inhibited the activity of an exchanger that was Na(+)-dependent, HCO3(-)-independent, and sensitive to known inhibitors of NHE. However, comparison of the potencies of four distinct amiloride analogues revealed a pharmacological profile that was different from that of any other NHE characterized to date. cGMP mimicked the effect of CNP on sodium-dependent pHi recovery, but the native nucleotide was as potent as membrane-permeant analogues. Intracellularly produced cGMP was very rapidly exported out of astrocytes. Probenecid and niflumic acid slowed down the rate of cGMP egression and inhibited the effect of CNP on Na(+)-dependent recovery, but not that of extracellular cGMP. Altogether, our data indicate that cGMP inhibits a novel type of NHE in astrocytes via an extracellular site of action. If these results with primary cultures transfer to brain, this phenomenon may constitute a mechanism by which natriuretic peptides exert some of their actions in the brain, as pHi transients have been shown to modulate several important astrocytic functions.

Amiloride↗
PubMed1997

Effects of dihydropyridines on aldosterone secretion in adrenal capsule preparations from pregnant rats.

The primary aim of this study was to determine when sensitivity in the aldosterone response to extracellular potassium (K+) decreases during pregnancy. Second, it tested the hypothesis that calcium channel alterations occur in the adrenal cortex during pregnancy. The decreased sensitivity to K+, observed at 22 days of gestation, was not evident at 15 days and between 18 and 36 h postpartum. Increases in extracellular calcium concentration heightened sensitivity to K+ in adrenal capsule preparations derived from nonpregnant rats but had no effect in pregnant animals. The influence of nifedipine and BAY K 8644 (blocker and activator, respectively, of voltage-operated calcium channels) on the aldosterone response to K+ and to adrenocorticotropic hormone (ACTH) was studied. Sensitivity to K+ in nonpregnant rats decreased in the presence of nifedipine and became similar to that in pregnant rats. Responses to ACTH were not affected by nifedipine. BAY K 8644 produced a larger increase in sensitivity in adrenal capsule preparations from pregnant than from nonpregnant rats, leading to superposition of the two dose-response curves to K+. These results indicate that voltage-operated calcium channels involved in aldosterone secretion are functionally impaired during pregnancy.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1997

Comparison of ANP binding and sensitivity in brains from hypertensive and normotensive rats.

We compared the abundance and sensitivity of atrial natriuretic peptides (ANP) receptors in the brains of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats and examined the effect of blood pressure on the abundance of brain ANP receptors in several other experimental rat models. Brain slices from SHR generated more guanosine 3',5'-cyclic monophosphate in response to ANP than brain slices from WKY rats. No differences were found in brain particulate guanylate cyclase activity in both strains of rats. In rat brain homogenates, we observed that ANP bound in a specific and saturable fashion to samples from WKY rats, but not in samples from SHR. In vitro receptor autoradiography revealed that ANP binding was reduced in the subfornical organ, the choroid plexus, and the paraventricular nucleus of SHR compared with WKY rat brains. Correction of hypertension in SHR or induction of hypertension in other strains did not affect ANP binding in any of these brain regions. Altogether, our data suggest that the increased sensitivity of SHR brains to the action of ANP may be a consequence of factors other than the abundance of receptors and that it is not secondary to the elevation of blood pressure.

1-Methyl-3-isobutylxanthine↗
PubMed1997

Effects of gestation on enzymes controlling aldosterone synthesis in the rat adrenal.

In the present study, the effects of gestation on various enzymes implicated in corticosteroid synthesis were evaluated in adrenal zona glomerulosa and zona fasciculata-reticularis of the Sprague-Dawley rat. The activity and expression of cholesterol side-chain cleavage cytochrome P450, 11beta-hydroxylase cytochrome P450, and aldosterone synthase cytochrome P450 (P450aldo) were analyzed. Plasma aldosterone levels were increased significantly at 22 days gestation (n = 10) and fell below the nonpregnant levels at 18-36 h postpartum (n = 11). The activity and expression of 11beta-hydroxylase cytochrome P450 and cholesterol side-chain cleavage cytochrome P450 were not modified by gestation. P450aldo activity increased at 14 days gestation (n = 4) and returned to the prepregnancy level at 2 weeks postpartum (n = 5). As shown by Northern blot analysis (n = 3), P450aldo messenger RNA increased significantly at 22 days gestation and decreased 18-36 h postpartum. We clearly demonstrated that elevated plasma aldosterone levels during pregnancy are associated with augmented activity and messenger RNA levels of P450aldo in the zona glomerulosa.

Adrenal Cortex↗
PubMed1996

Initiation of the oestradiol-induced inhibition of pulsatile LH secretion in ewes under long days: comparison of peripheral versus central treatment and neurochemical correlates.

In the ewe, the inhibition of pulsatile LH secretion by oestradiol during long days depends on dopaminergic activity and could involve amino acid transmitters. In the first experiment of the present study we observed the changes in LH secretion in ovariectomised ewes under long days immediately after subcutaneous implantation of oestradiol (peripheral treatment). In the second experiment, in order to identify the site of action of oestradiol, we observed the LH changes following intracerebral infusion of oestradiol through a microdialysis membrane (central treatment) within the preoptic area, the mediobasal hypothalamus (MBH) or the retrochiasmatic area (RCh) and measured amino acids and catecholaminergic transmitters and metabolites within the dialysates. With peripheral treatment, the amplitude, the nadir and the area under the LH pulse curve decreased within 4 to 8 h of the insertion of a subcutaneous oestradiol implant. After 18 h, the amplitude and the area under the pulses increased, as well as the intervals between pulses (from 49.9 + 1.4 min to 75.6 +/- 5.9 min). With central oestradiol treatment. LH changes were similar whatever the site of oestradiol infusion, suggesting either multiple sites of action or diffusion between structures. Twenty hours after the beginning of intracerebral oestradiol treatment, the amplitude and the area under the pulses increased, as did the interval between LH pulses (from 49.5 +/- 4.1 min to 73.2 +/- 14.2 min). Comparison of peripheral with central oestradiol treatment suggested that the long-lasting decrease in the nadir, as well as the transitory decrease in the amplitude and area, before 18 h in experiment 1 are reflections of hypophysial effects. In contrast, the increases in amplitude and area under the LH pulse curve seen 18-20 h after oestradiol in the two experiments could be due to the higher amplitude of LHRH pulses, as a result of an early stimulatory effect of oestradiol. After central oestradiol infusion, there was a decline in the concentration in the dialysate of two metabolites of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid in the RCh, suggesting an early inhibition of monoamine oxidase by the steroid. During the inhibition of LH pulsatility the concentration of gamma-aminobutyric acid in the dialysate from the RCh and the MBH increased, suggesting the participation of this transmitter in the changes induced by oestradiol under long days.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

Minimally oxidised LDL as estimated by a new method increase in plasma of type 2 diabetic patients with atherosclerosis or nephropathy.

A new sensitive and reproducible method was used to assess LDL oxidative status in Type 2 diabetic patients and control subjects, and the relationships between LDL oxidation and atherosclerosis or nephropathy were determined. LDL oxidation was measured in 35 patients with Type 2 diabetes and 15 control subjects 40 to 60 years of age. Atherosclerosis was assessed by clinical examination, vascular ultrasound, and measurement of intima-media thickness (IMT). Twenty-four hour urinary albumin excretion measurements were performed. Although no differences in lipid values were found between the 22 diabetic patients with atherosclerosis (ATS+) and the 13 without (ATS-), LDL oxidation was significantly higher in ATS+ than ATS- patients (p = 0.009) or control subjects (p = 0.007). LDL oxidation was also increased in the 15 patients with nephropathy (p = 0.003). Oxidation was correlated with IMT in patients with normal to moderately increased IMT ( < or = 1.05 mm). Determination of LDL oxidative status could thus be very helpful in assessing cardiovascular risk, especially in high-risk subjects such as patients with diabetes mellitus.

Adult↗
PubMed1996

[Role of oxidation of lipoproteins in the pathogenesis of atherosclerosis].

There is increasing evidence suggesting an important role of LDL oxidation in the pathogenesis of atherosclerosis. It has been shown that oxidized LDL is present in vivo and that it is atherogenic in many ways. LDL sensitivity to oxidation depends on many factors. Oxidation occurs mainly in the arterial wall and the methods usually available to measure oxidation are not sensitive enough to detect the minimally oxidized LDL which could be present in the circulation. A more sensitive method would be very useful in clinical trials to test the potential benefits of antioxidant therapy in the prevention and/or the treatment of atherosclerosis. One has to wait for the results of long, prospective, randomized, double blind studies before considering dietary and/or therapeutic recommandations for the use of antioxidants.

Antioxidants↗
PubMed1995

The membranes of cultured rat brain astrocytes contain endothelin-converting enzyme activity.

Both endothelins and their big-endothelin precursors were found capable of inducing the release of arachidonic acid from purified cultures of rat astrocytes. Their order of potency was as follows: big-endothelin-3 < big-endothelin-1 < endothelin-1 = endothelin-3. Mature endothelins induced the release of arachidonic acid in a rapid fashion. In contrast, much longer incubation times were required for big-endothelins to exert an effect, suggesting that their activity was dependent on their conversion. When big-endothelin-1 was added to the incubation medium of intact live astrocytes, it was converted into mature endothelin-1 in a time-dependent manner and the conversion was inhibited by phosphoramidon. This suggests that astrocytic endothelin-converting enzyme is (at least in part) an external membrane-bound metalloprotease. Some conversion of big-endothelin-3 into endothelin-3 also occurred. However, it was less efficient than the conversion of big-endothelin-1, which is compatible with the lower bioactivity of big-endothelin-3 vs. that of big-endothelin-1 in astrocytes.

Animals↗
PubMed1995

Tomato exo-(1-->4)-beta-D-galactanase. Isolation, changes during ripening in normal and mutant tomato fruit, and characterization of a related cDNA clone.

An exo-(1-->4)-beta-D-galactanase was isolated from ripe tomato fruit (Lycopersicon esculentum Mill. cv Ailsa Craig and cv Better Boy) using anion-exchange, gel filtration, and cation-exchange chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the most active fraction revealed a predominant protein band at 75 kD and several minor bands. A 30-amino acid N-terminal sequence from this 75-kD protein showed a high degree of homology with other recently identified beta-galactosidase/ galactanase proteins from persimmon and apple fruits (I.-K. Kang, S.-G. Suh, K.C. Gross, J.-K. Byun [1994] Plant Physiol 105: 975-979; G.S. Ross, T. Wegrzyn, E.A. MacRae, R.J. Redgwell [1994] Plant Physiol 106: 521-528) and with the predicted polypeptide sequence encoded by the ethylene-regulated SR12 gene in carnation (K.G. Raghothama, K.A. Lawton, P.B. Goldsbrough, W.R. Woodson [1991] Plant Mol Biol 17: 61-71). The enzyme focused to a single band of beta-galactosidase activity on an isoelectrofocusing gel at pH 9.8. The enzyme was specific for (1-->4)-beta-D-galactan substrates with a pH optimum of 4.5. The only reaction product detected was monomeric galactose, indicating that the enzyme was an exo (1-->4)-beta-D-galactanase. beta-Galactanase activity increased at the onset of ripening in normal fruit, but no similar increase was detected in the nonripening mutants nor and rin. A tomato homolog (pTombetagal1) was isolated using the SR12 cDNA clone from carnation as a probe. This clone showed 73% identify at the amino acid level with beta-galactosidase-related sequences from apple and asparagus and 66% identity with SR12. pTombetagal1 is a member of a gene family. Northern analysis demonstrated that pTombetagal1 expression was ripening related in normal fruits, with lower levels apparent in the nonsoftening mutants.

Amino Acid Sequence↗
PubMed1995

Aminoguanidine has both pro-oxidant and antioxidant activity toward LDL.

We previously demonstrated that aminoguanidine (AMGN) was able to prevent oxidative modification of LDL. Initially, we thought that this occurred solely because AMGN trapped reactive breakdown products of lipid peroxidation and prevented apoB modification, similar to AMGN's proposed ability to trap reactive glucose intermediates and prevent advanced glycosylation end-product formation. We now demonstrate that AMGN also displays dose-dependent pro-oxidant and antioxidant activity toward LDL. Moderate doses of AMGN (0.05 to 1.0 mmol/L) prevented lipid peroxidation in LDL exposed to copper. AMGN prevented the loss of polyunsaturated fatty acids and delayed or prevented conjugated-diene formation, both of which are sensitive indicators of lipid peroxidation. The same doses of AMGN also prevented apoB modification, a step distal to lipid peroxidation, as evidenced by the ability to (1) prevent fluorescence at 420 nm, (2) block enhanced electrophoretic mobility, and (3) prevent changes leading to enhanced macrophage uptake. Thus, AMGN inhibits LDL modification both by inhibiting lipid peroxidation as well as by trapping reactive breakdown products of lipid peroxidation. It was also demonstrated that for every LDL, there was also a very low dose of AMGN (about 0.01 mmol/L) that actually promoted lipid oxidation and subsequent protein modification. This activity of AMGN could be enhanced by increasing the content of lipid hydroperoxide in the LDL, eg, by aging or radioiodinating the LDL. Conversely, the pro-oxidant activity could be reduced by pretreatment of LDL with ebselen or vitamin E. We propose a mechanism by which AMGN effects pro-oxidant activity toward LDL at very low concentrations and antioxidant activity at higher concentrations and discuss the practical implications of these observations.

Antioxidants↗
PubMed1995

Lipoprotein glyco-oxidation.

Cardiovascular diseases are the leading cause of death during diabetes, and qualitative changes in lipoproteins play a role in the pathogenesis of atherosclerosis. Hyperglycaemia induces glycation of lipoproteins, particularly low-density lipoproteins (LDL), preventing the recognition of apoprotein B by the specific receptor and favouring the accumulation of LDL in macrophages and their oxidation. Other effects contribute to increased LDL oxidation in diabetes: higher production (and decreased degradation) of free radicals, the association of hypertriglyceridemia with the presence of small, dense, more easily oxidizable LDL, and high-density lipoprotein anomalies which reduce LDL antioxidant capacities. Glycation- oxidation interactions are complex. Although glycated LDL are more easily oxidizable, antioxidants could also reduce protein glycation independently of glycaemic balance. The role of glyco-oxidative changes in the pathogenesis of atherosclerosis during diabetes is difficult to determine, partly because of methodological problems related to the presence of circulating antioxidants which allow only minimal (and not easily demonstrable) LDL oxidation. The development of measurements sensitive to lipoprotein oxidation should facilitate the determination of LDL oxidative status. The main means of preventing and treating glyco-oxidative alterations are the normalisation of LDL-cholesterol concentrations and the improvement of glycaemic balance. Prospective studies are needed to determine the role of antioxidants in the prevention and/or treatment of atheromatous disease during diabetes.

Diabetes Mellitus↗