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Biomedical subjects

G Rousseau

Publications and source records attributed to G Rousseau.

At least 19 recordsLinked to original sources
PubMed2006

Reduction of apoptosis in the amygdala by an A2A adenosine receptor agonist following myocardial infarction.

It has been observed that a cytokine synthesis inhibitor, pentoxifylline, prevents the apoptotic processes taking place in the amygdala following myocardial infarction. However, it is unknown if the cardioprotective effect of A(2A) adenosine receptor agonist, CGS21680, which reduces cytokine synthesis, would lead to such amygdala apoptosis regression. Thus, this study was designed to investigate whether cardioprotective A(2A) adenosine receptor activation reduces apoptosis in the amygdala following myocardial infarction. Anesthetized rats were subjected to left anterior descending coronary artery occlusion for 40 min, followed by 72 h of reperfusion. The A(2A) agonist CGS21680 (0.2 mug/kg/min i.v.) was administered continuously for 120 min, starting (1) five minutes prior to instituting reperfusion (Early) or (2) five minutes after the beginning of reperfusion (Late). After reperfusion, myocardial infarct size was determined and the amygdala was dissected from the brain. Infarct size was reduced significantly in the Early compared to the Control group (34.6 +/- 1.8% and 52.3 +/- 2.8% respectively; p < 0.05), with no difference compared to the Late group (40.1 +/- 6.1%). Apoptosis regression was documented in the amygdala of the Early group by an enhanced phosphatidylinositol 3-kinase-Akt pathway activation and Bcl-2 expression concurrently to a caspase-3 activation limitation and reduction in TUNEL-positive cells staining. On the other hand, amygdala TUNEL-positive cell numbers were not reduced in the Late group. Moreover, TNFalpha was significantly reduced in the amygdala of the Early group compared to the Control and Late groups. These results indicate that A(2A) adenosine receptor stimulation is associated with apoptosis regression in the amygdala following myocardial infarction.

Adenosine↗
PubMed2001

Ca(2+)-dependent sensitization of adenylyl cyclase activity.

It has been shown that intracellular Ca(2+) concentrations have multiple modulatory influences on hormone-stimulated adenylyl cyclase activity. Here, we report that increasing intracellular Ca(2+) concentration by treating cells with the Ca(2+) ionophore A23187 leads to a sensitization of the beta-adrenoceptor-stimulated adenylyl cyclase activity in Ltk(-) cells expressing the human beta(2)-adrenoceptor. The ionophore treatment led to a 20+/-5% increase of the maximal isoproterenol-stimulated cyclase activity that could be prevented by chelation of the extracellular Ca(2+) using EGTA. A similar Ca(2+)-mediated sensitization (20+/-6%) was observed when the adenylyl cyclase was directly stimulated by the diterpene forskolin indicating that the catalytic activity of the enzyme itself is modulated by the change in Ca(2+) concentration. Sensitization of both the isoproterenol- and forskolin-stimulated adenylyl cyclase activities were completely blocked by treatment with KN-62[1-[N,O-bis-(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine], an inhibitor of the Ca(2+)-calmodulin-dependent protein kinase (CamKinase). Taken together, our data reveal the existence of a CamKinase-dependent sensitization process acting at the level of the adenylyl cyclase catalytic moiety.

Adenylyl Cyclases↗
PubMed2001

Evaluation of exo-endo ratios in the halolactonization of omega-unsaturated acids.

The reaction of 2-(omega-alkenyl)benzoic acids with bis(collidine)iodine and bis(collidine)bromine hexafluorophosphate was examined. Except with 2-but-3-enylbenzoic acid, for which only the exo lactone was obtained, for the other acids a mixture of exo-endo lactones was always obtained. The proportion of endo lactone was important for the acid chain length of 11 carbons (formation of a 12-membered ring endo lactone) and for the acid chain lengths higher than 14 carbons. The formation of the endo lactones was explained, on the base of molecular calculations, by competition between electronic and steric effects. These latter were developed by transannular interactions (for the acid chain lengths 8-11) and/or the conformations adopted by the chains (for the acid chain lengths > or = 14,) which disfavored the formation of the exo lactones. The larger proportion of endo lactones observed with the bromo reagent compared to the iodo reagent seemed due to electronic factors.

Journal Article↗
PubMed2001

Developmental variation of sugars, carboxylic acids, purine alkaloids, fatty acids, and endoproteinase activity during maturation of Theobroma cacao L. seeds.

The changes of mono- and oligosaccharides, carboxylic acids, purine alkaloids, and fatty acid composition, and of aspartic endoproteinase activity, were analyzed during seed development in two varieties of cacao (Theobroma cacao). The majority of the components examined either decreased or accumulated steadily in concentration during the second half of bean development. Sucrose is the major sugar in the mature embryo, whereas fructose and glucose are at higher concentrations in the endosperm tissue. Considerable amounts of malate are found in the endosperm, whereas citrate is the dominant carboxylic acid in the embryo. A major change in the fatty acid composition occurs in the young embryo when the proportion of stearic acid increases rapidly at the expense of linoleic acid, which is reduced from about 18 to 3%. Theobromine is the dominant purine alkaloid (ca. 80%), and caffeine appears only toward the end of seed maturity. Aspartic endoproteinase activity increases rapidly during embryo expansion, reaching a maximal activity before final maturity. The results are discussed in conjunction with physiological changes in developing seeds, and the potential contributions of the compounds analyzed for cocoa quality.

Aspartic Acid Endopeptidases↗
PubMed2001

The palmitoylation state of the beta(2)-adrenergic receptor regulates the synergistic action of cyclic AMP-dependent protein kinase and beta-adrenergic receptor kinase involved in its phosphorylation and desensitization.

Although palmitoylation of the beta(2)-adrenergic receptor (beta(2)AR), as well as its phosphorylation by the cyclic AMP-dependant protein kinase (PKA) and the beta-adrenergic receptor kinase (beta ARK), are known to play important roles in agonist-promoted desensitization, their relative contribution and mutual regulatory influences are still poorly understood. In this study, we investigated the role that the carboxyl tail PKA site (Ser(345,346)) of the beta(2)AR plays in its rapid agonist-promoted phosphorylation and desensitization. Mutation of this site (Ala(345,346)beta(2)AR) significantly reduced the rate and extent of the rapid desensitization promoted by sustained treatment with the agonist isoproterenol. The direct contribution of Ser(345,346) in desensitization was then studied by mutating all other putative PKA and beta ARK phosphorylation sites (Ala(261,262)beta ARK(-)beta(2)AR). We found this mutant receptor to be phosphorylated upon receptor activation but not following direct activation of PKA, suggesting a role in receptor-specific (homologous) but not heterologous phosphorylation. However, despite its phosphorylated state, Ala(261,262)beta ARK(-)beta(2)AR did not undergo rapid desensitization upon agonist treatment, indicating that phosphorylation of Ser(345,346) alone is not sufficient to promote desensitization. Taken with the observation that mutation of either Ser(345,346) or of the beta ARK phosphorylation sites prevented both the hyper-phosphorylation and constitutive desensitization of a palmitoylation-less mutant (Gly(341)beta(2)AR), our data suggest a concerted/synergistic action of the two kinases that depends on the palmitoylation state of the receptor. Consistent with this notion, in vitro phosphorylation of Gly(341)beta(2)AR by the catalytic subunit of PKA facilitated further phosphorylation of the receptor by purified beta ARK. Our study therefore allows us to propose a coordinated mechanism by which sequential depalmitoylation, and phosphorylation by PKA and beta ARK lead to the functional uncoupling and desensitization of the ss(2)AR.

Animals↗
PubMed2001

Functional desensitization to isoproterenol without reducing cAMP production in canine failing cardiocytes.

To corroborate alterations in the functional responses to beta-adrenergic receptor (beta-AR) stimulation with changes in beta-AR signaling in failing cardiomyocytes, contractile and L-type Ca(2+) current responses to isoproterenol along with stimulated cAMP generation were compared among cardiomyocytes isolated from canines with tachycardia-induced heart failure or healthy hearts. The magnitude of shortening of failing cardiomyocytes was significantly depressed (by 22 +/- 4.4%) under basal conditions, and the maximal response to isoproterenol was significantly reduced (by 45 +/- 18%). Similar results were obtained when the responses in the rate of contraction and rate of relaxation to isoproterenol were considered. The L-type Ca(2+) current amplitude measured in failing cardiomyocytes under basal conditions was unchanged, but the responses to isoproterenol were significantly reduced compared with healthy cells. Isoproterenol-stimulated cAMP generation was similar in sarcolemmal membranes derived from the homogenates of failing (45 +/- 6.8) and healthy cardiomyocytes (52 +/- 8.5 pmol cAMP. mg protein(-1). min(-1)). However, stimulated cAMP generation was found to be significantly reduced when the membranes were derived from the homogenates of whole tissue (failing: 67 +/- 8.1 vs. healthy: 140 +/- 27.8 pmol cAMP. mg protein(-1). min(-1)). Total beta-AR density was not reduced in membranes derived from either whole tissue or isolated cardiomyocyte homogenates, but the beta(1)/beta(2) ratio was significantly reduced in the former (failing: 45/55 vs. healthy: 72/28) without being altered in the latter (failing: 72/28, healthy: 77/23). We thus conclude that, in tachycardia-induced heart failure, reduction in the functional responses of isolated cardiomyocytes to beta-AR stimulation may be attributed to alterations in the excitation-contraction machinery rather than to limitation of cAMP generation.

1-Methyl-3-isobutylxanthine↗
PubMed2001

Pimozide (Orap) prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current in native cardiac myocytes.

BACKGROUND: Several cases of QT prolongation and ventricular tachyarrhythmia have been reported with pimozide, a potent neuroleptic useful in the management of motor and phonic tics associated with Tourette syndrome. To further elucidate the mechanism underlying these clinical observations, the effects of pimozide on monophasic action potential duration (MAPD(90)) and on potassium currents involved in the repolarization of native isolated ventricular myocytes were examined. METHODS AND RESULTS: Studies were undertaken in eight isolated guinea pig hearts that demonstrated reverse rate-dependent prolongation of cardiac repolarization by pimozide 100 nmol/L. Action potential duration increased 24% from baseline 115 +/- 2 to 142 +/- 4 msec with pimozide 100 nmol/L during pacing at 250 msec cycle length, while a 10% increase from 97 +/- 2 to 107 +/- 3 msec was seen with pacing at a cycle length of 150 msec. Experiments in native isolated ventricular myocytes (n = 20) demonstrated concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current: tail current was decreased by 50% at 15 nmol/L. CONCLUSIONS: Pimozide possesses cardiac electrophysiological effects similar to those of class III antiarrhythmic drugs. These effects are concentration-dependent and observed at recommended dosages of the drug. Since pimozide is strongly metabolized by CYP3A4, special care should be taken to avoid potential pharmacokinetic interactions leading to high plasma levels of pimozide and proarrhythmia.

Action Potentials↗
PubMed2000

Domperidone should not be considered a no-risk alternative to cisapride in the treatment of gastrointestinal motility disorders.

BACKGROUND: Several cases of QT prolongation and ventricular tachyarrhythmia have been reported with domperidone, a gastrokinetic and antiemetic agent available worldwide but still under investigation in the United States. Although electrolyte disturbances such as hypokalemia could account for some of these events, we hypothesized that domperidone may have unsuspected electrophysiological effects predisposing some patients to proarrhythmia. METHODS AND RESULTS: Studies were undertaken in 9 isolated guinea pig hearts, which demonstrated reverse use-dependent prolongation of cardiac repolarization by 100 nmol/L domperidone. Action potential duration increased 27% from baseline with domperidone (from 114+/-3 to 145+/-2 ms) during pacing at a cycle length of 250 ms, and a 9% increase (from 97+/-2 to 106+/-3 ms) was seen with pacing at a cycle length of 150 ms. Experiments in human ether-a-go-go-related gene (HERG)-transfected Chinese hamster ovary cells (n=32) demonstrated a concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current. The tail current decreased by 50% at 162 nmol/L domperidone. CONCLUSIONS: Domperidone possesses cardiac electrophysiological effects similar to those of cisapride and class III antiarrhythmic drugs. These effects are observed at clinically relevant concentrations of the drug. Therefore, domperidone should not be considered a no-risk alternative to cisapride, a drug that was recently withdrawn from the US market.

Action Potentials↗
PubMed2000

Sildenafil (Viagra) prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current.

BACKGROUND-Several cases of unexpected death have been reported with sildenafil in patients predisposed to ischemic cardiac events. Although acute episodes of ischemia could account for some of these deaths, we hypothesized that sildenafil may have unsuspected electrophysiological effects predisposing some patients to proarrhythmia. METHODS AND RESULTS-Studies were undertaken in 10 isolated guinea pig hearts that demonstrated prolongation of cardiac repolarization in a reverse use-dependent manner by sildenafil 30 mcmol/L. Action potential duration increased 15% from baseline 117+/-3 to 134+/-2 ms with sildenafil during pacing at 250 ms cycle length, whereas a 6% increase from 99+/-2 to 105+/-2 ms was seen with pacing at 150 ms cycle length. Experiments in human ether-a-go-go-related gene (HERG)-transfected HEK293 cells (n=30) demonstrated concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current: activating current was 50% decreased at 100 mcmol/L. This effect was confirmed using HERG-transfected Chinese hamster ovary (CHO) cells, which exhibit no endogenous I(K)-like current. CONCLUSIONS-Sildenafil possesses direct cardiac electrophysiological effects similar to class III antiarrhythmic drugs. These effects are observed at concentrations that may be found in conditions of impaired drug elimination such as renal or hepatic insufficiency, during coadministration of another CYP3A substrate/inhibitor, or after drug overdose and offer a new potential explanation for sudden death during sildenafil treatment.

Action Potentials↗
PubMed2000

Vitamin K modulates cardiac action potential by blocking sodium and potassium ion channels.

BACKGROUND: Cardiovascular collapses, syncopes, and sudden deaths have been observed following the rapid administration of intravenous vitamin K. Our objectives were to characterize the effects of vitamin K on cardiac action potentials and to evaluate effects of vitamin K on sodium and potassium currents, namely I(Na), I(Kr), and I(Ks). METHODS AND RESULTS: Guinea pig hearts (n = 21) were paced at a cycle length of 250 msec and exposed to vitamin K at 1.15-4.6 micromol/L (2.5-10 mg/L). Monophasic action potential duration measured at 90% repolarization (MAPD(90)) was not significantly reduced (-1.6 +/- 0.3 msec; P >.05; N.S.) at 1.15 micromol/L, but increased by 6.5 +/- 0.4 msec (P <.05) at 2.3 micromol/L. MAPD(90) was not measurable at 4.6 micromol/L, as a result of inexcitability. Patch-clamp experiments in ventricular myocytes demonstrated a approximately 50% reduction in I(Na) by 10 micromol/L vitamin K and a concentration-dependent reduction of the K(+) current elicited by short depolarizations (250 msec; I(K250)). Estimated IC(50) for I(K250), mostly representing I(Kr), was 2.3 micromol/L. Vitamin K was less potent to block the K(+) current elicited by long depolarizations (5,000 msec; I(K5000)), mostly representing I(Ks), with an estimated IC(50) over 100 micromol/L. CONCLUSIONS: Therapeutic concentrations ( approximately 1.5 micromol/L) of intravenous vitamin K modulate cardiac action potential by blocking ionic currents involved in cardiac depolarization and repolarization.

Action Potentials↗
PubMed2000

Depression's forgotten genealogy: notes towards a history of depression.

The history of depression remains unwritten, yet historians harbor plentiful assumptions about its pre-1800 past. These views are necessarily colored, even shaped, by modern views of depression formed after its nineteenth-century medicalization. A history of depression from ancient to modern times is an impossible task to complete successfully and would require, as a minimum, the historian's utmost vigilance to nuance, difference, and the inclusion of non-medical literature, especially poetry, drama and non-didactic prose. Nevertheless, five points about depression's pre-1800 European profile can confidently be made: (1) it developed along lines of female rather than male gender; (2) was transformed in the long eighteenth century when it blended with male madness under the sway of the cults of a pan-European sensibility movement; (3) always embedded a problematic pseudo-depressive state, or feigned version, which acted to permit female escape from dire socio-economic situation; (4) included sustained chronic duration as a requirement in its theory from the Renaissance forward; (5) is richly documented in its pre-1800 versions in imaginative literature, its often overlooked genealogy.

Depression↗
PubMed1999

Effects of calcitonin on animal and in vitro models of skeletal metabolism.

During the 40 years since its discovery, calcitonin (CT) has been regarded primarily as an inhibitor of bone resorption and its therapeutic applications have been based on this property. A significant body of literature also indicates additional anabolic effects in animal and in vitro models. In a variety of bone loss histomorphometric models in the rat, CT, especially the salmon species, prevents or retards bone loss. In other species, similar results have been obtained, except in the beagle given human CT, in which a recent study reported increased bone resorption and bone loss. Consonant with the histomorphometric effects in several different species, bone mass (density) measured by a variety of methods increases, reversing the bone loss induced by the model. In related studies of mechanical properties, bone strength is increased by CT except in the beagle study which utilized human CT. In other species, experimentally induced fractures show either accelerated healing or heal normally, and there is no effect of CT to impair healing. Finally, studies of bone formation/mineralization strongly suggest an anabolic effect on cartilage formation, bone matrix synthetic activity, and bone growth. These animal effects are reflected by recent fracture prevention studies in humans. If its anabolic effects are ultimately found to be separable and additive to CT's basic action to inhibit bone resorption, new approaches to osteoporosis prevention, and possibly other treatment situations such as cartilage regeneration, may evolve using novel CT-like molecules.

Animals↗
PubMed1998

Determination of ubiquinone-9 and 10 levels in rat tissues and blood by high-performance liquid chromatography with ultraviolet detection.

A high-performance liquid chromatographic (HPLC) method is presented for the simultaneous detection of ubiquinone-9 and 10 in rat tissues such as blood, myocardium, and muscle. After liquid-liquid extraction, the ubiquinones are subsequently analyzed by HPLC with ultraviolet (UV) detection at their maximum absorbance (275 nm). Reference calibration curves in ethanol are used to determine tissular levels of ubiquinones. Because a treatment with HMG-CoA reductase inhibitors is expected to decrease the ubiquinone levels, reference calibration curves are performed to ensure that the ratios (ubiquinone/internal standard) observed in such an experiment could be evaluated directly on a calibration curve. The assay is sensitive (0.0625 microgram/mL), reproducible (4% coefficient of variation for ubiquinone-9 and 6% for ubiquinone-10), and linear up to 20 micrograms/mL (or 100 mg of tissue) for ubiquinone-9 and up to 10 micrograms/mL (or 100 mg of tissue) for ubiquinone-10. The ubiquinone levels in control tissues or blood are within the ranges of those previously reported.

Animals↗
PubMed1998

[Pathology of the ureterovesical junction in neurogenic bladders in children and adolescents. A retrospective study of 119 patients].

Ureterovesical junction dysfunction in congenital or acquired neurogenic bladders represents a threat for the renal parenchyma. In order to evaluate the incidence, mechanisms of development and preventive and curative treatments proposed in diseases of the ureterovesical junction associated with neurogenic bladders, the files of 119 children were retrospectively evaluated. 68 patients suffered from congenital neurogenic bladder and 51 had an acquired neurogenic bladder. In the congenital neurogenic bladder group, vesico-ureteric reflux was observed in 22 cases (32%) and dilatation was observed in 18 cases (26.5%), while 21 patients had both dilatation and reflux. In the acquired neurogenic bladder group, reflux was observed in 8 cases (16%) and dilatation was observed in 3 cases (10%), one of whom had both reflux and dilatation. The predominant mechanism of decompensation of the ureterovesical junction in the two groups was a combination of low compliance and high peripheral resistance. In patients with abnormalities of the ureterovesical junction, the incidence of associated parenchymal lesions was similar (30%) whether neurogenic bladder was congenital or acquired. The disparities between these two comparable patient groups, the preventive and curative treatments proposed and their results are analysed in comparison with the data reported in the literature.

Adolescent↗
PubMed1997

Influence of receptor density on the patterns of beta2-adrenocepter desensitization.

Sustained stimulation of the beta2-adrenoceptor leads to a desensitization of the receptor-mediated adenylyl cyclase stimulation. While desensitization promoted by nanomolar concentrations of isoproterenol involves the phosphorylation of the beta2-adrenoceptor by protein kinase A alone, both protein kinase A- and beta-adrenoceptor kinase-mediated phosphorylation leading to the binding of beta-arrestin contribute to the desensitization evoked by micromolar concentrations of agonist. In the present study, we assessed the influence of receptor density on the patterns of desensitization induced by these two different levels of stimulation. Murine L cells were transfected with a cDNA encoding the human beta2-adrenoceptor and clonal cell lines expressing various levels of beta2-adrenoceptor were used for the study. In cell lines expressing the highest number of receptor, approx. 150000 sites/cell (approx. 3000 fmol/mg of membrane proteins), pretreatment with micromolar concentrations of isoproterenol causes a desensitization pattern characterized by a reduction in both the potency and the efficacy of isoproterenol to further stimulate the adenylyl cyclase activity. In contrast, desensitization induced by 10 nM isoproterenol resulted only in a decrease in the potency of isoproterenol. This distinct pattern of desensitization is not seen in cells expressing 12000 receptors/cell (approx. 200 fmol/mg of membrane proteins) and, in that case, pretreatment with 10 nM isoproterenol leads to a reduction in both the sensitivity and the maximal response. Similar effects on the beta-adrenoceptor-stimulated adenylyl cyclase were observed in these cells following treatment with dibutyryl cAMP. Receptor density therefore dramatically influences the pattern of desensitization evoked by low level of stimulation. The results also demonstrate that although different molecular events are involved in the desensitization evoked by different levels of stimulation, its phenotypic expression can be qualitatively identical in cells expressing a relatively small number of receptors. Hence, protein kinase A-mediated desensitization cannot be qualitatively distinguished from the beta-adrenoceptor kinase-mediated process in these cells.

Adenylyl Cyclases↗
PubMed1997

Chronic beta-blockade increases skeletal muscle beta-adrenergic-receptor density and enhances contractile force.

The effects of a chronic 14-day administration of a selective beta2-adrenergic-receptor antagonist (ICI-118551) on skeletal muscle were evaluated in female Sprague-Dawley rats. Chronic ICI-118551 treatment did not modify muscle mass, oxidative potential, or protein concentration of the medial gastrocnemius muscle, suggesting that maintenance of these skeletal muscle characteristics is not dependent on beta2-adrenergic-receptor stimulation. However, the drug treatment increased beta-adrenergic-receptor density of the lateral gastrocnemius (42%) and caused an increase in specific (g/g) isometric in situ contractile forces of the medial gastrocnemius [twitch, 56%; tetanic (200 Hz), 28%]. The elevated contractile forces observed after a chronic treatment with ICI-118551 were completely abolished when the beta2-adrenergic antagonist was also administered acutely before measurement of contractile forces, suggesting that this response is beta2-adrenergic-receptor dependent. Possible mechanisms for the increased forces were studied. Caffeine administration potentiated twitch forces but had little effect on tetanic force in control animals. Administration of dibutyryl adenosine 3',5'-cyclic monophosphate in control animals also resulted in small increases of twitch force but did not modify tetanic forces. We conclude that increases in beta-adrenergic-receptor density and the stimulation of the receptors by endogenous catecholamines appear to be responsible for increased contractile forces but that the mechanism remains to be demonstrated.

Adrenergic beta-Antagonists↗