bluuebunny/crossref_metadata_2025 huggingface dataset:
Impaired Regulation of Synaptic Strength in Hippocampal Neurons from GluR1‐Deficient Mice
Authors: Andrásfalvy Bertalan K. , Smith Mark A. , Borchardt Thilo , Sprengel Rolf , Magee Jeffrey C.
Published: October 2003

Neurons of the central nervous system (CNS) exhibit a variety of forms of synaptic plasticity, including associative long‐term potentiation and depression (LTP/D), homeostatic activity‐dependent scaling and distance‐dependent scaling. Regulation of synaptic neurotransmitter receptors is currently thought to be a common mechanism amongst many of these forms of plasticity. In fact, glutamate receptor 1 (GluR1 or GluRA) subunits containing L‐α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate (AMPA) receptors have been shown to be required for several forms of hippocampal LTP and a particular hippocampal‐dependent learning task. Because of this importance in associative plasticity, we sought to examine the role of these receptors in other forms of synaptic plasticity in the hippocampus. To do so, we recorded from the apical dendrites of hippocampal CA1 pyramidal neurons in mice lacking the GluR1 subunit (GluR1 −/−). Here we report data from outside‐out patches that indicate GluR1‐containing receptors are essential to the extrasynaptic population of AMPA receptors, as this pool was nearly empty in the GluR1 −/− mice. Additionally, these receptors appear to be a significant component of the synaptic glutamate receptor pool because the amplitude of spontaneous synaptic currents recorded at the site of input and synaptic AMPA receptor currents evoked by focal glutamate uncaging were both substantially reduced in these mice. Interestingly, the impact on synaptic weight was greatest at distant synapses such that the normal distance‐dependent synaptic scaling used by these cells to counter dendritic attenuation was lacking in GluR1 −/− mice. Together the data suggest that the highly regulated movement of GluR1‐containing AMPA receptors between extrasynaptic and synaptic receptor pools is critically involved in establishing two functionally diverse forms of synaptic plasticity: LTP and distance‐dependent scaling.
Inhibition of Nitric Oxide Synthase by L‐NAME Speeds Phase II Pulmonary V̇O2 Kinetics in the Transition to Moderate‐Intensity Exercise in Man
Authors: Jones Andrew M. , Wilkerson Daryl P. , Koppo Katrien , Wilmshurst Sally , Campbell Iain T.
Published: October 2003

There is evidence that the rate at which oxygen uptake (V̇O2) rises at the transition to higher metabolic rates within the moderate exercise intensity domain is modulated by oxidative enzyme inertia, and also that nitric oxide regulates mitochondrial function through competitive inhibition of cytochrome c oxidase in the electron transport chain. We therefore hypothesised that inhibition of nitric oxide synthase (NOS) by nitro‐L‐arginine methyl ester (L‐NAME) would alleviate the inhibition of mitochondrial V̇O2 by nitric oxide and result in a speeding of V̇O2 kinetics at the onset of moderate‐intensity exercise. Seven males performed square‐wave transitions from unloaded cycling to a work rate requiring 90 % of predetermined gas exchange threshold with and without prior intravenous infusion of L‐NAME (4 mg kg−1 in 50 ml saline over 60 min). Pulmonary gas exchange was measured breath‐by‐breath and V̇O2 kinetics were determined from the averaged response to four exercise bouts performed in each condition using a mono‐exponential function following elimination of the phase I response. There were no significant differences between the control and L‐NAME conditions for baseline V̇O2 (means ±s.e.m. 797 ± 32 vs. 794 ± 29), the duration of phase I (15.4 ± 0.8 vs. 17.2 ± 0.6), or the steady‐state increment in V̇O2 above baseline (1000 ± 83 vs. 990 ± 85 ml min−1), respectively. However, the phase II time constant of the V̇O2 response was significantly smaller following L‐NAME infusion (22.1 ± 2.4 vs. 17.9 ± 2.3; P < 0.05). These data indicate that inhibition of NOS by L‐NAME results in a significant (19 %) speeding of pulmonary V̇O2 kinetics in the transition to moderate‐intensity cycle exercise in man. At least part of the intrinsic inertia to oxidative metabolism at the onset of moderate‐intensity exercise may result from competitive inhibition of mitochondrial V̇O2 by nitric oxide at cytochrome c oxidase, although other mechanisms for the effect of L‐NAME on V̇O2 kinetics remain to be explored.
Dehydroepiandrosterone Potentiates Native Ionotropic ATP Receptors Containing the P2X2 Subunit in Rat Sensory Neurones
Authors: De Roo Mathias , Rodeau Jean‐Luc , Schlichter Rémy
Published: October 2003

We have studied the modulatory effect of dehydroepiandrosterone (DHEA), the most abundant neurosteroid produced by glial cells and neurones, on membrane currents induced by the activation of ionotropic ATP (P2X) receptors in neonatal rat dorsal root ganglion neurones. ATP (1 μm) induced three types of currents/responses termed F (fast and transient), S (slowly desensitizing) and M (mixed, sum of F‐ and S‐type responses). DHEA (10 nm to 100 μm) concentration‐dependently increased the amplitude of plateau‐like currents of S‐ and M‐type responses evoked by submaximal (1 μm) but not saturating (100 μm or 1 mM) concentrations of ATP. αβ‐Methylene ATP (αβme‐ATP, 5 μm) also evoked F‐, S‐ and M‐type responses, the plateau phases of which were potentiated by lowering external pH (6.3) and by ivermectin (IVM, 3 μm), indicating the presence heteromeric P2X2‐containing receptors and possibly of functional native P2X4/6 receptors. There was a strict correlation between the potentiating effects of low pH and DHEA on αβme‐ATP responses but not between that of IVM and DHEA, suggesting that DHEA selectively modulated P2X2‐containing receptors. DHEA also potentiated putative homomeric P2X2 receptor responses recorded in the continuous presence of 1 μm 2′‐(or 3′)‐O‐(2,4,6‐trinitrophenyl) adenosine 5′‐triphosphate (TNP‐ATP). Our results constitute the first demonstration of a fast potentiation of P2X receptors by a neurosteroid and suggest that DHEA could be an endogenous modulator of P2X2‐containing receptors thereby contributing to the facilitation of the detection and/or the transmission of nociceptive messages, particularly under conditions of inflammatory pain where the P2X receptor signalling pathway appears to be upregulated.
Non‐Contractile Cells with Thin Processes Resembling Interstitial Cells of Cajal Found in the Wall of Guinea‐Pig Mesenteric Arteries
Authors: Pucovský Vladimír , Moss Ray F. , Bolton Thomas B.
Published: October 2003

Arterial interstitial cells of Cajal (ICC)‐like cells (AIL cells) with a multipolar, irregular, elongated shape and with numerous thin (often less than 1 μm), sometimes branching, processes with lengths up to ≈60 μm were isolated enzymatically from 1st to 7th order branches of guinea‐pig mesenteric artery. Some of the processes of AIL cells were growing (average speed ≈0.15 μm min−1) and their growth was blocked by 10 μM latrunculin B, an inhibitor of actin polymerisation. Staining with BODIPY phalloidin, a fluorescent dye selective for F‐actin, showed the presence of F‐actin in the processes of AIL cells. Voltage clamp of single AIL cells revealed an inward current that was four times more dense than in myocytes and was abolished by 10 μM nicardipine, and an outward current carried exclusively by potassium ions that was reduced by 1 mM 4‐aminopyridine and/or 100 nM iberiotoxin but unaffected by 10 nM dendrotoxin‐K. Imaging of intracellular ionised calcium with fluo‐4 using a laser scanning confocal microscope showed local or global calcium transients lasting several seconds in ≈28 % of AIL cells. When membrane current was recorded simultaneously, the calcium transients were found to correspond to long‐lasting transient outward currents, which occurred at potentials positive to −40 mV. Unlike myocytes, AIL cells did not contract in response to 1 mM caffeine or 5 μM noradrenaline, although they responded with a [Ca2+]i increase. The segments of intact arteries did not stain for c‐kit, a marker of ICCs. Single AIL cells stained positive for vimentin, desmin and smooth muscle myosin. The presence of ICC‐like cells is demonstrated for the first time in the media of resistance arteries.
Sympathetic Nerves Inhibit Conducted Vasodilatation Along Feed Arteries during Passive Stretch of Hamster Skeletal Muscle
Authors: Haug Sara J. , Welsh Donald G. , Segal Steven S.
Published: October 2003

Ascending vasodilatation is integral to blood flow control in exercising skeletal muscle and is attributable to conduction from intramuscular arterioles into proximal feed arteries. Passive stretch of skeletal muscle can impair muscle blood flow but the mechanism is not well understood. We hypothesized that the conduction of vasodilatation along feed arteries can be modulated by changes in muscle length. In anaesthetized hamsters, acetylcholine (ACh) microiontophoresis triggered conducted vasodilatation along feed arteries (diameter, 50‐70 μm) of the retractor muscle secured at 100 % resting length or stretched by 30 %. At 100 % length, ACh evoked local dilatation (> 30 μm) and this response conducted rapidly along the feed artery (14 ± 1 μm dilatation at 1600 μm upstream). During muscle stretch, feed arteries constricted ≈10 μm (P < 0.05) and local vasodilatation to ACh was maintained while conducted vasodilatation was reduced by half (P < 0.01). Resting diameter and conduction recovered upon restoring 100 % length. Sympathetic nerve stimulation (4‐8 Hz) produced vasoconstriction and attenuated conduction in the manner observed during muscle stretch, as did noradrenaline or phenylephrine (10 nM). Inhibiting nitric oxide production (Nω‐nitro‐L‐arginine, 50 μM) produced similar vasoconstriction yet had no effect on conduction. Phentolamine, prazosin, or tetrodotoxin (1 μM) during muscle stretch abolished vasoconstriction and restored conduction. Inactivation of sensory nerves with capsaicin had no effect on vasomotor responses. Thus, muscle stretch can attenuate conducted vasodilatation by activating α‐adrenoreceptors on feed arteries through noradrenaline released from perivascular sympathetic nerves. This autonomic feedback mechanism can restrict muscle blood flow during passive stretch.
Protein Phosphatases Decrease Sarcoplasmic Reticulum Calcium Content by Stimulating Calcium Release in Cardiac Myocytes
Authors: Terentyev Dmitry , Viatchenko‐Karpinski Serge , Gyorke Inna , Terentyeva Radmila , Gyorke Sandor
Published: October 2003

Phosphorylation/dephosphorylation of Ca2+ transport proteins by cellular kinases and phosphatases plays an important role in regulation of cardiac excitation−contraction coupling; furthermore abnormal protein kinase and phosphatase activities have been implicated in heart failure. However, the precise mechanisms of action of these enzymes on intracellular Ca2+ handling in normal and diseased hearts remains poorly understood. We have investigated the effects of protein phosphatases PP1 and PP2A on spontaneous Ca2+ sparks and SR Ca2+ load in myocytes permeabilized with saponin. Exposure of myocytes to PP1 or PP2A caused a dramatic increase in frequency of Ca2+ sparks followed by a nearly complete disappearance of events. These effects were accompanied by depletion of the SR Ca2+ stores, as determined by application of caffeine. These changes in Ca2+ release and SR Ca2+ load could be prevented by the inhibitors of PP1 and PP2A phosphatase activities okadaic acid and calyculin A. At the single channel level, PP1 increased the open probability of RyRs incorporated into lipid bilayers. PP1‐medited RyR dephosphorylation in our permeabilized myocytes preparations was confirmed biochemically by quantitative immunoblotting using a phosphospecific anti‐RyR antibody. Our results suggest that increased intracellular phosphatase activity stimulates RyR‐mediated SR Ca2+ release leading to depleted SR Ca2+ stores in cardiac myocytes.
Role of Elastin in Spontaneously Hypertensive Rat Small Mesenteric Artery Remodelling
Authors: Briones Ana M. , González José M. , Somoza Beatriz , Giraldo Jesús , Daly Craig J. , Vila Elisabet , Carmen González M. , McGrath John C. , Arribas Silvia M.
Published: October 2003

Chronic hypertension is associated with resistance artery remodelling and mechanical alterations. However, the contribution of elastin has not been thoroughly studied. Our objective was to evaluate the role of elastin in vascular remodelling of mesenteric resistance arteries (MRA) from spontaneously hypertensive rats (SHR). MRA segments from Wistar Kyoto rats (WKY) and SHR were pressurised under passive conditions at a range of physiological pressures with pressure myography. Confocal microscopy was used to determine differences in the quantity and organisation of elastin in intact pressure‐fixed arteries. To assess the contribution of elastin to MRA structure and mechanics, myograph‐mounted vessels were studied before and after elastase incubation. When compared with WKY, MRA from SHR showed: (1) a smaller lumen, (2) decreased distensibility at low pressures, (3) a leftward shift of the stress‐strain relationship, (4) redistribution of elastin within the internal elastic lamina (IEL) leading to smaller fenestrae but no change in fenestrae number or elastin amount. Elastase incubation (1) fragmented the structure of IEL in a concentration‐dependent fashion, (2) abolished all the structural and mechanical differences between strains, and (3) decreased distensibility at low pressures. The study shows the overriding role of elastin in determining vascular dimensions and mechanical properties in a resistance artery. In addition, it informs hypertensive remodelling. MRA remodelling and increased stiffness are accompanied by elastin restructuring within the IEL and elastin degradation reverses structural and mechanical alterations of SHR MRA. Differences in elastin organisation are, therefore, a central element in small artery remodelling in hypertension.
Role of the Hyperpolarization‐Activated Cation Current (Ih) in Pacemaker Activity in Area Postrema Neurons of Rat Brain Slices
Authors: Funahashi Makoto , Mitoh Yoshihiro , Kohjitani Atsushi , Matsuo Ryuji
Published: October 2003

To clarify the functional properties of the hyperpolarization‐activated cation current (Ih) as a pacemaker current in area postrema neurons, whole‐cell recordings were made in visually identified cells in rat brain slices. The activation of Ih was identified in approximately 62 % of area postrema neurons tested. The cells displaying Ih showed a depolarizing ‘sag’ in responses to hyperpolarizing current injection in current‐clamp mode. The reversal potential for the Ih was −36 mV, and this was shown to depend on the external concentration of Na+ and K+ ions. Extracellular Cs+ ions (2 mM) and ZD7288 (100 μm), a potent selective Ih channel antagonist, blocked Ih and induced a membrane potential hyperpolarization, suggesting the sustained activation of Ih near the resting potential and a contribution from Ih to membrane potential maintenance at more depolarized levels. In contrast, extracellular Ba2+ ions caused a depolarization of the membrane potential, suggesting the blockade of inward rectifier K+ currents. ZD7288 decreased the spontaneous discharge rate by prolonging the slow depolarization between two spikes, with minimal effect on the amplitude of the afterhyperpolarization or action potential waveforms. Ih stabilized the latency of rebound action potentials. Ih was weakly activated by external 8‐bromoadenosine 3′,5′ cyclic monophosphate (1 mM) or forskolin (50‐100 μM), indicating that the Ih channel subtypes in area postrema cells could be modulated by intracellular cAMP. Our findings indicate that Ih contributes to the subthreshold membrane and firing properties of rat area postrema neurons and may regulate their resting membrane potential and firing patterns.
Mechanisms of H+ Modulation of Glycinergic Response in Rat Sacral Dorsal Commissural Neurons
Authors: Li Yan‐Fang , Wu Long‐Jun , Li Yong , Xu Lin , Xu Tian‐Le
Published: October 2003

Many ionotropic receptors are modulated by extracellular H+. So far, few studies have directly addressed the role of such modulation at synapses. In the present study, we investigated the effects of changes in extracellular pH on glycinergic miniature inhibitory postsynaptic currents (mIPSCs) as well as glycine‐evoked currents (IGly) in mechanically dissociated spinal neurons with native synaptic boutons preserved. H+ modulated both the mIPSCs and IGly biphasically, although it activated an amiloride‐sensitive inward current by itself. Decreasing extracellular pH reversibly inhibited the amplitude of the mIPSCs and IGly, while increasing external pH reversibly potentiated these parameters. Blockade of acid‐sensing ion channels (ASICs) with amiloride, the selective antagonist of ASICs, or decreasing intracellular pH did not alter the modulatory effect of H+ on either mIPSCs or IGly. H+ shifted the EC50 of the glycine concentration‐response curve from 49.3 ± 5.7 μm at external pH 7.4 to 131.5 ± 8.1 μM at pH 5.5, without altering the Cl− selectivity of the glycine receptor (GlyR), the Hill coefficient and the maximal IGly, suggesting a competitive inhibition of IGly by H+. Both Zn2+ and H+ inhibited IGly. However, H+ induced no further inhibition of IGly in the presence of a saturating concentration of Zn2+. In addition, H+ significantly affected the kinetics of glycinergic mIPSCs and IGly. It is proposed that H+ and/or Zn2+ compete with glycine binding and inhibit the amplitude of glycinergic mIPSCs and IGly. Moreover, binding of H+ induces a global conformational change in GlyR, which closes the GlyR Cl− channel and results in the acceleration of the seeming desensitization of IGly as well as speeding up the decay time constant of glycinergic mIPSCs. However, the deprotonation rate is faster than the unbinding rate of glycine from the GlyR, leading to reactivation of the undesensitized GlyR after washout of agonist and the appearance of a rebound IGly. H+ also modulated the glycine cotransmitter, GABA‐activated current (IGABA). Taken together, the results support a ‘conformational coupling’ model for H+ modulation of the GlyR and suggest that H+ may act as a novel modulator for inhibitory neurotransmission in the mammalian spinal cord.
Conductance of GABAA Channels Activated by Pentobarbitone in Hippocampal Neurons from Newborn Rats
Authors: Eghbali Mansoureh , Birnir Bryndis , Gage Peter W.
Published: October 2003

Neurons were obtained from the CA1 region of the hippocampus of newborn rats and maintained in culture. Channels were activated by pentobarbitone in cell‐attached, inside‐out or outside‐out patches, normally by applying pentobarbitone in flowing bath solution. Currents were outwardly rectifying and blocked by bicuculline, properties of GABAA channels in these cells. Maximum channel conductance increased as pentobarbitone concentration was increased to 500 μm but conductance then decreased as pentobarbitone concentration was raised further. The best fit of a Hill‐type equation to the relationship between maximum channel conductance and pentobarbitone concentration (up to 500 μm) gave an EC50 of 41 μm, a maximum conductance of 36 pS and a Hill coefficient of 1.6. Bicuculline decreased the maximum conductance of the channels activated by pentobarbitone, with an IC50 of 224 μm. Diazepam increased channel conductance, with a maximum effect being obtained with 1 μM diazepam. Diazepam (1 μM) decreased the EC50 of the pentobarbitone effect on channel conductance from 41 μM to 7.2 μM and increased maximum conductance to 72 pS. We conclude that GABAA channel conductance is related to the concentration of the allosteric agonist pentobarbitone.
5‐Hydroxytryptamine 1A Receptors Inhibit Cold‐Induced Sympathetically Mediated Cutaneous Vasoconstriction in Rabbits
Authors: Ootsuka Y. , Blessing W. W.
Published: October 2003

5‐HT1A receptor agonists lower body temperature. We have investigated whether activation of 5‐HT1A receptors inhibits cutaneous sympathetic discharge so that dilatation of the cutaneous vascular bed lowers body temperature by increasing heat transfer to the environment. We measured ear pinna blood flow in conscious rabbits (with chronically implanted Doppler ultrasound flow probes), and postganglionic sympathetic vasomotor nerve activity in anaesthetized rabbits. Recordings from conscious rabbits were made in a cage at 26 °C and the rabbit was then transferred to a cage at 10 °C. The ear pinna Doppler signal fell from 56 ± 4 cm s−1 in the 26 °C cage to 4 ± 1 cm s−1 (P < 0.0001, n= 24) after 30 min in the 10 °C cage, and body temperature increased from 38.8 ± 0.2 to 39.0 ± 0.2 °C (P < 0.01, n= 24). The 5‐HT1A agonist 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT; 0.1 mg kg−1 I.V.) reversed the cold‐induced fall in ear pinna blood flow (Doppler signal increased from 5 ± 1 to 55 ± 8 cm s−1, P < 0.001, n= 7) within 5 min when administered 30 min after transfer to the 10 °C cage, and prevented the fall in ear pinna blood flow when administered before the rabbit was transferred to the 10 °C cage. Body temperature decreased after administration of 8‐OH‐DPAT. These changes were abolished by the specific 5‐HT1A antagonist WAY‐100635 (0.1 mg kg−1 I.V.). In anaesthetized rabbits, 8‐OH‐DPAT (0.1 mg kg−1 I.V.) reduced resting postganglionic cutaneous sympathetic vasomotor discharge, and prevented the increase normally elicited by cooling the trunk. Our experiments constitute the first demonstration that activation of 5‐HT1A receptors powerfully inhibits cold‐induced increases in cutaneous sympathetic vasomotor discharge, thereby dilating the cutaneous vascular bed and increasing transfer of heat to the environment.
Cerebral Metabolism during Cord Occlusion and Hypoxia in the Fetal Sheep: A Novel Method of Continuous Measurement Based on Heat Production
Authors: Hunter Christian J. , Blood Arlin B. , Power Gordon G.
Published: October 2003

This study was undertaken to validate a new method of measuring cerebral metabolic rate in the fetal sheep based on heat production in a local region of the brain. Heat production was compared to oxygen use in 20 near‐term fetuses during basal conditions, moderate hypoxia and cord occlusion. Thermocouples were placed to measure core and brain temperature and a composite probe placed in the parietal cortex to measure changes in cortical blood flow (CBF) using laser Doppler flowmetry and tissue PO2 using fluorescent decay. Catheters were inserted in a brachiocephalic artery and sagittal sinus for blood sampling. With moderate hypoxia, induced by administering 10−12 % oxygen to the ewes, fetal arterial PO2 declined from 23 ± 1 to 11 ± 1 Torr and brain tissue PO2 fell from 7.6± 0.7 to a nadir of 0.8 ± 0.4 Torr, while CBF increased to 139 ± 5 % of baseline. Cortical heat production, calculated as the product of CBF, the temperature gain from artery to brain tissue, and the specific heat of blood, decreased by 45 ± 11 % in parallel to similar declines in oxygen uptake. With severe asphyxia induced by complete cord occlusion for 10 min, fetal arterial PO2 declined from 23 ± 1 to 9 ± 2 Torr and brain tissue PO2 fell from 7.0 ± 0.7 to essentially 0 Torr while CBF decreased 40 ± 5 %. Cortical heat production decreased by 78 ± 6 % while oxygen use declined by 90 ± 3 %. Glucose uptake increased significantly relative to oxygen use and lactate concentration increased in sagittal sinus blood. We conclude that local measurements of heat production in the brain provide a useful index of overall metabolic rate, closely reflecting oxygen use in moderate hypoxia and indicating a significant contribution from anaerobic metabolism during severe asphyxia.
Intermittent Hypoxia Increases Insulin Resistance in Genetically Obese Mice
Authors: Polotsky Vsevolod Y. , Li Jianguo , Punjabi Naresh M. , Rubin Arnon E. , Smith Philip L. , Schwartz Alan R. , O'Donnell Christopher P.
Published: October 2003

Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin‐deficient obese (C57BL/6J−Lepob) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 ± 11 mg dl−1 on day 0 to 138 ± 10 mg dl−1 on day 5, P < 0.01), improvement in glucose tolerance without a change in serum insulin levels and an increase in serum leptin levels in comparison with control (2.6 ± 0.3 vs. 1.7 ± 0.2 ng ml−1, P < 0.05). Microarray mRNA analysis of adipose tissue revealed that leptin was the only upregulated gene affecting glucose uptake. In obese mice, short‐term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 ± 136 % (P < 0.01) increase in serum insulin levels. This increase in insulin secretion after 5 days of intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time‐dependent increase in fasting serum insulin levels (from 3.6 ± 1.1 ng ml−1 at baseline to 9.8 ± 1.8 ng ml−1 at week 12, P < 0.001) and worsening glucose tolerance, consistent with an increase in insulin resistance. We conclude that the increase in insulin resistance in response to intermittent hypoxia is dependent on the disruption of leptin pathways.
Reduced Left Ventricular Compliance and Mechanical Efficiency after Prolonged Inhibition of NO Synthesis in Conscious Dogs
Authors: Post Heiner , D'Agostino Chiara , Lionetti Vincenzo , Castellari Michele , Kang Elaine Y. , Altarejos Martin , Xu Xiaobin , Hintze Thomas H. , Recchia Fabio A.
Published: October 2003

Acute inhibition of NO synthesis decreases left ventricular (LV) work and external efficiency, but it is unknown whether compensatory mechanisms can limit the alterations in LV mechanoenergetics after prolonged NO deficiency. Eight chronically instrumented male mongrel dogs received 35 mg kg−1 day−1 of Nω‐nitro‐L‐arginine methyl ester orally for 10 days to inhibit NO synthesis. At spontaneous beating frequency, heart rate, coronary blood flow, peak LV pressure, end‐diastolic LV pressure and the maximum derivative of LV pressure (dP/dtmax) were not significantly different vs. baseline, whereas LV end‐diastolic diameter (32.5 ± 1.0 vs. 37.6 ± 1.4 mm) and LV stroke work (515 ± 38 vs. 650 ± 44 mmHg mm), were reduced (all P < 0.05). The slope of the LV end‐systolic pressure‐diameter relationship was increased at 10 days vs. baseline (13.9 ± 1.0 vs. 9.6 ± 0.9 mmHg mm−1, P < 0.05), while the end‐diastolic LV diameter was smaller at matched LV end‐diastolic pressures. At fixed heart rate (130 beats min−1), cardiac oxygen consumption was increased (12.2 ± 1.5 vs. 9.9 ± 1.0 ml min−1), and the ratio between stroke work and oxygen consumption was decreased by 33 ±7 % (all P < 0.05) after NO inhibition. We conclude that sustained inhibition of NO synthesis in dogs causes a decrease in LV work despite an increased contractility, which is most probably due to reduced diastolic compliance and a decrease in external efficiency. Thus, prolonged NO deficiency is not compensated for on the level of LV mechanoenergetics in vivo.
Molecular Mechanism for ATP‐Dependent Closure of the K+ Channel Kir6.2
Authors: John Scott A. , Weiss James N. , Xie Lai‐Hua , Ribalet Bernard
Published: October 2003

In the ATP‐dependent K+ (KATP) channel pore‐forming protein Kir6.2, mutation of three positively charged residues, R50, K185 and R201, impairs the ability of ATP to close the channel. The mutations do not change the channel open probability (Po) in the absence of ATP, supporting the involvement of these residues in ATP binding. We recently proposed that at least two of these positively charged residues, K185 and R201, interact with ATP phosphate groups to cause channel closure: the β phosphate group of ATP interacts with K185 to initiate closure, while the α phosphate interacts with R201 to stabilize the channel's closed state. In the present study we replaced these three positive residues with residues of different charge, size and hydropathy. For K185 and R201, we found that charge, more than any other property, controls the interaction of ATP with Kir6.2. At these positions, replacement with another positive residue had minor effects on ATP sensitivity. In contrast, replacement of K185 with a negative residue (K185D/E) decreased ATP sensitivity much more than neutral substitutions, suggesting that an electrostatic interaction between the β phosphate group of ATP and K185 destabilizes the open state of the channel. At R201, replacement with a negative charge (R201E) had multiple effects, decreasing ATP sensitivity and preventing full channel closure at high concentrations. In contrast, the R50E mutation had a modest effect on ATP sensitivity, and only residues such as proline and glycine that affect protein structure caused major decreases in ATP sensitivity at the R50 position. Based on these results and the recently published structure of Kir3.1 cytoplasmic domain, we propose a scheme where binding of the β phosphate group of ATP to K185 induces a motion of the surrounding region, which destabilizes the open state, favouring closure of the M2 gate. Binding of the α phosphate group of ATP to R201 then stabilizes the closed state. R50 on the N‐terminus controls ATP binding by facilitating the interaction of the β phosphate group of ATP with K185 to destabilize the open state.
Cold Exposure Induces Tissue‐Specific Modulation of the Insulin‐Signalling Pathway in Rattus Norvegicus
Authors: Gasparetti Alessandra L. , de Souza Cláudio T. , Pereira‐da‐Silva Márcio , Oliveira Rachel L. G. S. , Saad Mário J. A. , Carneiro Everardo M. , Velloso Lício A.
Published: October 2003

Cold exposure provides a reproducible model of improved glucose turnover accompanied by reduced steady state and glucose‐induced insulin levels. In the present report we performed immunoprecipitation and immunoblot studies to evaluate the initial and intermediate steps of the insulin‐signalling pathway in white and brown adipose tissues, liver and skeletal muscle of rats exposed to cold. Basal and glucose‐induced insulin secretion were significantly impaired, while glucose clearance rates during a glucose tolerance test and the constant for glucose decay during a 15 min insulin tolerance test were increased, indicating a significantly improved glucose turnover and insulin sensitivity in rats exposed to cold. Evaluation of protein levels and insulin‐induced tyrosine (insulin receptor, insulin receptor substrates (IRS)‐1 and −2, ERK (extracellular signal‐related kinase)) or serine (Akt; protein kinase B) phosphorylation of proteins of the insulin signalling cascade revealed a tissue‐specific pattern of regulation of the molecular events triggered by insulin such that in white adipose tissue and skeletal muscle an impaired molecular response to insulin was detected, while in brown adipose tissue an enhanced response to insulin was evident. In muscle and white and brown adipose tissues, increased 2‐deoxy‐D‐glucose (2‐DG) uptake was detected. Thus, during cold exposure there is a tissue‐specific regulation of the insulin‐signalling pathway, which seems to favour heat‐producing brown adipose tissue. Nevertheless, muscle and white adipose tissue are able to take up large amounts of glucose, even in the face of an apparent molecular resistance to insulin.
Human Muscle Protein Synthesis is Modulated by Extracellular, Not Intramuscular Amino Acid Availability: A Dose‐Response Study
Authors: Bohé Julien , Low Aili , Wolfe Robert R. , Rennie Michael J.
Published: October 2003

To test the hypothesis that muscle protein synthesis (MPS) is regulated by the concentration of extracellular amino acids, we investigated the dose‐response relationship between the rate of human MPS and the concentrations of blood and intramuscular amino acids. We increased blood mixed amino acid concentrations by up to 240 % above basal levels by infusion of mixed amino acids (Aminosyn 15, 44‐261 mg kg−1h−1) in 21 healthy subjects, (11 men 10 women, aged 29 ± 2 years) and measured the rate of incorporation of D5‐phenylalanine or D3‐leucine into muscle protein and blood and intramuscular amino acid concentrations. The relationship between the fold increase in MPS and blood essential amino acid concentration ([EAA], mM) was hyperbolic and fitted the equation MPS = (2.68 ×[EAA])/(1.51 +[EAA]) (P< 0.01). The pattern of stimulation of myofibrillar, sarcoplasmic and mitochondrial protein was similar. There was no clear relationship between the rate of MPS and the concentration of intramuscular EAAs; indeed, when MPS was increasing most rapidly, the concentration of intramuscular EAAs was below basal levels. We conclude that the rates of synthesis of all classes of muscle proteins are acutely regulated by the blood [EAA] over their normal diurnal range, but become saturated at high concentrations. We propose that the stimulation of protein synthesis depends on the sensing of the concentration of extracellular, rather than intramuscular EAAs.
Dual Action of Hydrogen Peroxide on Synaptic Transmission at the Frog Neuromuscular Junction
Authors: Giniatullin A. R. , Giniatullin R. A.
Published: October 2003

There is evidence that reactive oxygen species (ROS) are produced and released during neuromuscular activity, but their role in synaptic transmission is not known. Using a two‐electrode voltage‐clamp technique, at frog neuromuscular junctions, the action H2O2 on end‐plate currents (EPC) was studied to determine the targets for this membrane‐permeable ROS. In curarized or cut muscles, micromolar concentrations of H2O2 increased the amplitude of EPCs. Higher (> 30 μm) doses inhibited EPCs and prolonged current decay. These effects were presynaptic since H2O2 did not change the amplitude or duration of miniature EPCs (although it reduced the rate of spontaneous release at high concentrations). Quantal analysis and deconvolution methods showed that facilitation of EPCs was due to increased quantal release, while depression was accompanied by temporal dispersion of evoked release. Extracellular recordings revealed prolonged presynaptic Ca2+ entry in the presence of high H2O2. Both low and high H2O2 increased presynaptic potentiation during high‐frequency stimulation. Pro‐oxidant Fe2+ did not affect facilitation by low doses of H2O2 but augmented the inhibition of EPCs by high H2O2, indicating involvement of hydroxyl radicals. High Mg2+ and the ROS scavenger N‐acetylcysteine eliminated both the facilitatory and depressant effects of H2O2. The facilitatory effect of H2O2 was prevented by protein kinase C (PKC) inhibitors and 4β‐phorbol 12‐myristate, 13‐acetate (PMA), an activator of PKC. PKC inhibitors but not PMA also abolished the depressant effect of H2O2. Our data suggest complex presynaptic actions of H2O2, which could serve as a fast feedback modulator of intense neuromuscular transmission.
Ceramide, Stress, and a "LAG" in Aging
Authors: Obeid Lina M. , Hannun Yusuf A.
Published: October 2003

Recent studies have implicated the longevity assurance gene
LAG1
in ceramide synthesis. In light of a role for ceramide in yeast and mammalian stress responses and mammalian cellular senescence, important connections are emerging between ceramide and organismal aging. In this Perspective, we examine the evidence for these connections in yeast,
Drosophila
, and mammals, and speculate on their implications.
Convection Displacement Current and Generalized Form of Maxwell–Lorentz Equations
Authors: Chubykalo Andrew E. , Smirnov-Rueda Roman
Published: October 2003

Some mathematical inconsistencies in the conventional form of Maxwell's equations extended by Lorentz for a single charge system are discussed. To surmount these in the framework of Maxwellian theory, a novel convection displacement current is considered as additional and complementary to the famous Maxwell displacement current. It is shown that this form of the Maxwell–Lorentz equations is similar to that proposed by Hertz for electrodynamics of bodies in motion. Original Maxwell's equations can be considered as a valid approximation for a continuous and closed (or going to infinity) conduction current. It is also proved that our novel form of the Maxwell–Lorentz equations is relativistically invariant. In particular, a relativistically invariant gauge for quasistatic fields has been found to replace the non-invariant Coulomb gauge. The new gauge condition contains the famous relationship between electric and magnetic potentials for one uniformly moving charge that is usually attributed to the Lorentz transformations. Thus, for the first time, using the convection displacement current, a physical interpretation is given to the relationship between the components of the four-vector of quasistatic potentials. A rigorous application of the new gauge transformation with the Lorentz gauge transforms the basic field equations into a pair of differential equations responsible for longitudinal and transverse fields, respectively. The longitudinal components can be interpreted exclusively from the standpoint of the instantaneous "action at a distance" concept and leads to necessary conceptual revision of the conventional Faraday–Maxwell field. The concept of electrodynamics dualism is proposed for self-consistent classical electrodynamics. It implies simultaneous coexistence of instantaneous long-range (longitudinal) and Faraday–Maxwell short-range (transverse) interactions that resembles in this aspect the basic idea of Helmholtz's electrodynamics.
Factorial Correlators and Split-Bin Correlation Functions in p-Nucleus Interactions at 800 GeV
Authors: Dheer Simi , Das Geetanjali , Shivpuri R. K. , Soni S. K.
Published: October 2003

We present the first results on correlations in multiparticle production in p-nucleus interactions at 800 GeV using scaled factorial correlators and split-bin correlation functions. The behaviors of factorial correlators as a function of bin-bin distance in pseudorapidity as well as bin width is consistent with the random cascading picture of hadronization. From the analysis of the split-bin correlation functions as a function of bin-width, it is found that the two-particle dynamical correlations are due to resonance-like production mechanism.
Bounds on the Mass of Excited Fermions
Authors: Diaz-Cruz J. L. , Sampayo O. A. , Aranda J. I. , Toscano J. J.
Published: October 2003

According to the present limits, it is possible that the mass of the excited fermions (M*), which arise in composite models of quarks and leptons, could lay in the range: mW<M*≪Λ, where Λ denotes the scale of compositeness. For this scenario, the effective Lagrangian approach should be applied to study systematically the effects of these new fermions. Using this approach, we discuss the validity of the limits on M* obtained at FNAL from the direct search. We also derive indirect bounds on M*, which are independent of Λ, from high precision measurements, using three models (sequential, mirror and homodoublet).
Stabilizing the Dilaton Through the Axion
Authors: Dick Rainer
Published: October 2003

We propose that instantons and axionic domain boundaries stabilize the dilaton. An estimate of the resulting dilaton potential yields a relation between the axion mass and the dilaton mass. A decay constant of the dilaton of the order of the Planck scale then implies mϕ m P ~ mafa, and the dilaton should be strongly aligned at the onset of oscillations, in order not to overclose the universe.
New Phase Equivalent Partners to Eckart and Bargmann Potentials
Authors: Bagchi B. , Roychoudhury R.
Published: October 2003

Using techniques of supersymmetric quantum mechanics we derive phase equivalent partner potentials to Eckart and Bargmann potentials. It is found that the partner potentials pick up new singularities which are absent in the parent potentials.
Multiple Model of Anti-Grand Unification, The Regularization with Wilson Loop Action and Critical Coupling Constants
Authors: Laperashvili L. V. , Nielsen H. B.
Published: October 2003

The present work considers the phase transition between the confinement and "Coulomb" phases in U(1) gauge theory described by Wilson loop action. It was shown (using as an example the approximation of circular loops) that the critical coupling constant is rather independent of the regularization method. Taking into account the renormalization by artefact monopole contributions and the existence of strings in confinement phase assuming the maximal value of the effective fine structure constant equal to α max =π/12≈0.26, we obtain α c ≈0.204, in agreement with Monte Carlo lattice simulation result: α c ≈0.20. Such an approximate regularization independence ("universality") of the critical couplings is needed for the fine structure constant predictions claimed from "the multiple-point criticality principle".
SU(3) Breaking and Annihilation Effects in the η and η′ Masses
Authors: Carvalho W. S. , Antunes A. C. B. , de Castro A. S.
Published: October 2003

The mass splitting of the pseudoscalar mesons η and η′ is approached by taking into account the SU(3)-flavor symmetry breaking and annihilation effects. An extended version of the Schwinger sum rule and a mixing angle equal to -19.51° are obtained.
Apparent and Actual Shifts in Mass and Width of ϕ Mesons Produced in Heavy-Ion Collisions
Authors: Bhalerao R. S. , Gupta S. K.
Published: October 2003

We present a method of analyzing invariant-mass spectra of kaon pairs resulting from decay of ϕ mesons produced in high-energy heavy-ion collisions. It can be used to extract the shifts in the mass and the width (ΔM and ΔΓ) of the ϕ mesons when they are inside the dense matter formed in these collisions. We illustrate our method with the help of available preliminary data. Extracted values of ΔM and ΔΓ are significantly larger than those obtained with an earlier method. Our results are consistent with the experimentally observed pT dependence of the mass shift. Finally, we present a phenomenological relation between ΔM and ΔΓ. It provides a useful constraint on theories which predict the values of these two quantities.
Renormalization of Twist-Four Operators in QCD Bjorken and Ellis–Jaffe Sum Rules
Authors: Kawamura Hiroyuki , Uematsu Tsuneo , Yasui Yoshiaki , Kodaira Jiro
Published: October 2003

The QCD effects of twist-four operators on the first moment of nucleon spin-dependent structure function g1(x,Q2) are studied in the framework of operator product expansion and renormalization group method. We investigate the operator mixing through renormalization of the twist-four operators including those proportional to the equation of motion by evaluating off-shell Green's functions in the usual covariant gauge as well as in the background gauge. Through this procedure we extract the one-loop anomalous dimension of the spin-1 and twist-four operator which determines the logarithmic correction to the 1/Q2 behavior of the contribution from the twist-four operators to the first moment of g1(x,Q2).
Creation of Nonconformal Particles from Vacuum by A Test-Model Isotropic Gravitational Field
Authors: Bezerra V. B. , Mostepanenko V. M. , Romero C.
Published: October 2003

The quantized scalar field with arbitrary coupling in a nonstationary isotropic gravitational field evolving between two singularities is investigated. The number of pairs created from vacuum is demonstrated to have a very drastic dependence on the value of the coupling coefficient ξ. In other words the vacuum quantum effects of nonconformal field may be important in the early cosmology.
Null Fluid Collapse in the Plane Symmetric Anti-de Sitter Spacetime
Authors: Cai Rong-Gen , Qiao Ling-Zhi , Zhang Yuan-Zhong
Published: October 2003

The stability of the plane anti-de Sitter spacetime and the gravitational collapse in the plane symmetric anti-de Sitter spacetime are investigated. A scalar curvature singularity will be formed at the r=0 plane when the anti-de Sitter spacetime is perturbed by null dust. By employing the method suggested recently by Husain we find a family of non-static exact solution of the null fluid collapse with equation of state P=kρ in the plane anti-de Sitter spacetime. The late time limit of the solutions results in a black plane solution possessing multiple horizon structure.
Holstein–Primakoff Realizations on Coadjoint Orbits
Authors: Oh Phillial , Rim Chaiho
Published: October 2003

We derive the Holstein–Primakoff oscillator realization on the coadjoint orbits of the SU (N+1) and SU (1,N) group by treating the coadjoint orbits as a constrained system and performing the symplectic reduction. By using the action-angle variables transformations, we transform the original variables into Darboux variables. The Holstein–Primakoff expressions emerge after quantization in a canonical manner with a suitable normal ordering. The corresponding Dyson realizations are also obtained and some related issues are discussed.
On Possible Study of Quark–Pomeron Coupling Structure at the Compass Spectrometer
Authors: Goloskokov S. V.
Published: October 2003

We analyze the diffractive [Formula: see text] production and final jet kinematics in polarized deep-inelastic lp scattering at [Formula: see text] GeV. We show that this reaction can be used in the new spectrometer of the COMPASS collaboration at CERN to study the quark–pomeron coupling structure.
D-Brane Configurations and Nicolai Map in Supersymmetric Yang–Mills Theory
Authors: Kogan I. I. , Szabo R. J. , Semenoff G. W.
Published: October 2003

We discuss some properties of a supersymmetric matrix model that is the dimensional reduction of supersymmetric Yang–Mills theory in 10 dimensions and which has been recently argued to represent the short-distance structure of M-theory in the infinite momentum frame. We describe a reduced version of the matrix quantum mechanics and derive the Nicolai map of the simplified supersymmetric matrix model. We use this to argue that there are no phase transitions in the large-N limit, and hence that S-duality is preserved in the full 11-dimensional theory.
One-Instanton Calculations in N = 2 SU(Nc) Supersymmetric QCD
Authors: Ito Katsushi , Sasakura Naoki
Published: October 2003

We study the low-energy effective theory in N=2 SU (Nc) supersymmetric QCD with Nf≤2Nc fundamental hypermultiplets in the Coulomb branch by microscopic and exact approaches. We calculate the one-instanton correction to the modulus [Formula: see text] from microscopic instanton calculation. We also study the one-instanton corrections from the exact solutions for Nc=3 with massless hypermultiplets. They agree with each other except for Nf=2Nc-2 and 2Nc cases. These differences come from possible ambiguities in the constructions of the exact solutions or the definitions of the operators in the microscopic theories.
Quantization of gl(1, R) Generalized Chern–Simons Theory in 1+1 Dimensions
Authors: Kawamoto Noboru , Ozawa Eisaku , Suehiro Kazuhiko
Published: October 2003

We present a quantization of previously proposed generalized Chern–Simons theory with gl(1, R) algebra in 1+1 dimensions. This simplest model shares the common features of generalized CS theories: on-shell reducibility and violations of regularity. On-shell reducibility of the theory requires us to use the Lagrangian Batalin–Vilkovisky and/or Hamiltonian Batalin–Fradkin–Vilkovisky formulation. Since the regularity condition is violated, their quantization is not straightforward. In the present case we can show that both formulations give an equivalent result. It leads to an interpretation that a physical degree of freedom which does not exist at the classical level appears at the quantum level.