bluuebunny/crossref_metadata_2025 huggingface dataset:
Gating properties of girk channels activated by gαo‐ and Gαi‐Coupled Muscarinic m2 Receptors in Xenopus Oocytes: The Role of Receptor Precoupling in RGS Modulation
Authors: Zhang Qingli , Pacheco Mary A. , Doupnik Craig A.
Published: November 2002

‘Regulators of G protein Signalling’ (RGSs) accelerate the activation and deactivation kinetics of G protein‐gated inwardly rectifying K+ (GIRK) channels. In an apparent paradox, RGSs do not reduce steady‐state GIRK current amplitudes as expected from the accelerated rate of deactivation when reconstituted in Xenopus oocytes. We present evidence here that this kinetic anomaly is dependent on the degree of G protein‐coupled receptor (GPCR) precoupling, which varies with different Gαi/o‐RGS complexes. The gating properties of GIRK channels (Kir3.1/Kir3.2a) activated by muscarinic m2 receptors at varying levels of G protein expression were examined with or without the co‐expression of either RGS4 or RGS7 in Xenopus oocytes. Different levels of specific m2 receptor‐Gα coupling were established by uncoupling endogenous pertussis toxin (PTX)‐sensitive Gαi/o subunits with PTX, while expressing varying amounts of a single PTX‐insensitive subunit (Gαi1(C351G), Gαi2(C352G), Gαi3(C351G), GαoA(C351G), or GαoB(C351G)). Co‐expression of each of the PTX‐insensitive Gαi/o subunits rescued acetylcholine (ACh)‐elicited GIRK currents (IK,ACh) in a concentration‐dependent manner, with Gαo isoforms being more effective than Gαi isoforms. Receptor‐independent ‘basal’ GIRK currents (IK,basal) were reduced with increasing expression of PTX‐insensitive Gα subunits and were accompanied by a parallel rise in IK,ACh. These effects together are indicative of increased Gβγ scavenging by the expressed Gα subunit and the subsequent formation of functionally coupled m2 receptor‐G protein heterotrimers (Gα(GDP)βγ). Co‐expression of RGS4 accelerated all the PTX‐insensitive Gαi/o‐coupled GIRK currents to a similar extent, yet reduced IK,ACh amplitudes 60‐90 % under conditions of low Gαi/o coupling. Kinetic analysis indicated the RGS4‐dependent reduction in steady‐state GIRK current was fully explained by the accelerated deactivation rate. Thus kinetic inconsistencies associated with RGS4‐accelerated GIRK currents occur at a critical threshold of G protein coupling. In contrast to RGS4, RGS7 selectively accelerated Gαo‐coupled GIRK currents. Co‐expression of Gβ5, in addition to enhancing the kinetic effects of RGS7, caused a significant reduction (70‐85 %) in steady‐state GIRK currents indicating RGS7‐Gβ5 complexes disrupt Gαo coupling. Altogether these results provide further evidence for a GPCR‐Gαβγ‐GIRK signalling complex that is revealed by the modulatory affects of RGS proteins on GIRK channel gating. Our functional experiments demonstrate that the formation of this signalling complex is markedly dependent on the concentration and composition of G protein‐RGS complexes.
Regulation by Rab3A of an endogenous modulator of neurotransmitter release at mouse motor nerve endings
Authors: Hirsh Jody K. , Searl Timothy J. , Silinsky Eugene M.
Published: November 2002

Rab3A, a small GTP‐binding protein attached to synaptic vesicles, has been implicated in several stages in the process of neurosecretion, including a late stage occurring just prior to the actual release of neurotransmitter. The inhibitory neuromodulator adenosine also targets a late step in the neurosecretory pathway. We thus compared neuromuscular junctions from adult Rab3A−/‐ mutant mice with those from wild‐type mice with respect to: (a) the basic electrophysiological correlates of neurotransmitter release at different stimulation frequencies, and (b) the actions of exogenous and endogenous adenosine on neurotransmitter release in normal calcium solutions. Neither the spontaneous quantal release of acetylcholine (ACh) nor basal evoked ACh release (0.05 Hz) differed between the mutant and wild‐type mice. At 50‐100 Hz stimulation (10‐19 stimuli), facilitation of release was observed in the mutant mice but not in wild‐type, followed by a depression of ACh release in both strains. ACh release at the end of the stimulus train in the mutant mouse was approximately double that of the wild‐type mouse. The threshold concentration for inhibition of ACh release by exogenous adenosine was over 20‐fold lower in the mutant mouse than in the wild‐type mouse. The adenosine A1 receptor antagonist 8‐cyclopentyltheophylline (CPT) increased ACh release (0.05‐1 Hz stimulation) in the mutant mouse under conditions in which it had no effect in the wild‐type mouse. CPT had no effect on the pattern of responses recorded during repetitive stimulation in either strain. The results suggest that Rab3A reduces the potency of adenosine as an endogenous mediator of neuromuscular depression.
A role for the redox site in the modulation of the NMDA receptor by light
Authors: Leszkiewicz Daniel , Aizenman Elias
Published: November 2002

Light has been shown to modulate NMDA receptor function. In this study, we have performed experiments aimed at elucidating the putative site of action of light within the receptor structure. Whole‐cell recordings were performed in Chinese hamster ovary cells expressing various combinations of NMDA receptor subunits. Although there was no apparent difference in the actions of light between wild‐type NR1‐NR2A and NR1‐NR2B subunit configurations, the light enhancement of NMDA‐induced currents was either completely abolished or substantially diminished in the redox site mutants NR1a (C744A, C798A)‐NR2B and NR1a (C744A, C798A)‐NR2A. Further studies demonstrated that chemical reduction of NR1a‐NR2B NMDA receptors decreased its sensitivity to light. In addition, sodium (2‐sulfonatoethyl) methanethiosulfonate (MTSES), used to irreversibly bind free sulfhydryl groups and inactivate the redox site, abolished the effects of light on wild‐type receptors. In contrast, no free sulfhydryls were available for MTSES following light stimulation, suggesting that light itself could not reduce the redox modulatory site. Our results suggest that a functionally intact, oxidized redox site is necessary for light‐induced potentiation. Hence, light and redox modulation of the NMDA receptor may share a common intramolecular pathway for altering the function of this ion channel.
Flufenamic acid blocks depolarizing afterpotentials and phasic firing in rat supraoptic neurones
Authors: Ghamari‐Langroudi Masoud , Bourque Charles W.
Published: November 2002

Depolarizing afterpotentials (DAPs) that follow action potentials in magnocellular neurosecretory cells (MNCs) are thought to underlie the generation of phasic firing, a pattern that optimizes vasopressin release from the neurohypophysis. Previous work has suggested that the DAP may result from the Ca2+‐dependent reduction of a resting K+ conductance. Here we examined the effects of flufenamic acid (FFA), a blocker of Ca2+‐dependent non‐selective cation (CAN) channels, on DAPs and phasic firing using intracellular recordings from supraoptic MNCs in superfused explants of rat hypothalamus. Application of FFA, but not solvent (0.1 % DMSO), reversibly inhibited (IC50+ 13.8 μm; R+ 0.97) DAPs and phasic firing with a similar time course, but had no significant effects (P > 0.05) on membrane potential, spike threshold and input resistance, nor on the frequency and amplitude of spontaneous synaptic potentials. Moreover, FFA did not affect (P > 0.05) the amplitude, duration, undershoot, or frequency‐dependent broadening of action potentials elicited during the spike trains used to evoke DAPs. These findings suggest that FFA inhibits the DAP by directly blocking the channels responsible for its production, rather than by interfering with Ca2+ influx. They also support a role for DAPs in the generation of phasic firing in MNCs. Finally, the absence of a depolarization and increased membrane resistance upon application of FFA suggests that the DAP in MNCs may not be due to the inhibition of resting K+ current, but to the activation of CAN channels.
MATCHING WEAK COUPLING AND QUASICLASSICAL EXPANSIONS FOR DUAL QES PROBLEMS
Authors: KAVIC MICHAEL
Published: November 2002

Certain quasi-exactly solvable systems exhibit an energy reflection property that relates the energy levels of a potential or of a pair of potentials. We investigate two sister potentials and show the existence of this energy reflection relationship between the two potentials. We establish a relationship between the lowest energy edge in the first potential using the weak coupling expansion and the highest energy level in the sister potential using a WKB approximation carried out to higher order.
CPn, OR, ENTANGLEMENT ILLUSTRATED
Authors: BENGTSSON INGEMAR , BRÄNNLUND JOHAN , ŻYCZKOWSKI KAROL
Published: November 2002

We show that many topological and geometrical properties of complex projective space can be understood just by looking at a suitably constructed picture. The idea is to view CPn as a set of flat tori parametrized by the positive octant of a round sphere. We pay particular attention to submanifolds of constant entanglement in CP3 and give a few new results concerning them.
ON THE EXPECTED PHOTON SPECTRUM IN B → Xs+ γ AND ITS USES
Authors: BIGI IKAROS , URALTSEV NIKOLAI
Published: November 2002

Measuring the photon energy spectrum in radiative B decays provides essential help for gaining theoretical control over semileptonic B transitions. The hadronic recoil mass distribution in B → Xuℓ ν promises the best environment for determining |Vub|. The theoretical uncertainties are largest in the domain of low values of the lepton pair mass q2. Universality relations allow us to describe this domain reliably in terms of the photon spectrum in B → Xs+ γ. A method is proposed to incorporate 1/mbcorrections into this relation. The low-Eγtail in radiative decays is important in the context of extracting |Vub|. We argue that CLEO's recent fit to the spectrum underestimates the fraction of the photon spectrum below 27thinsp;GeV. Potentially significant uncertainties enter in the theoretical evaluation of the integrated end point lepton spectrum or the B → Xuℓ ν width with a too high value of the lower cut on q2in alternative approaches to |Vub|.
NONCOMMUTATIVE BRANES IN D-BRANE BACKGROUNDS
Authors: ASANO MASAKO
Published: November 2002

We study Myers' world volume effective action of coincident D-branes. We investigate a system of N0D0-branes in the geometry of Dp-branes with p = 2 or p = 4. The choice of coordinates can make the action simplified and tractable. For p = 4, we show that a certain pointlike D0-brane configuration solving equations of motion of the action can expand to form a fuzzy two-sphere via magnetic moment effect without changing quantum numbers. We compare noncommutative D0-brane configurations with dual spherical D(6 - p)-brane systems. We also discuss the relation between these configurations and giant gravitons in 11 dimensions.
CURVED MEMBRANE SOLUTIONS IN D = 11 SUPERGRAVITY
Authors: BHATTACHARYYA SANDIP , KUMAR ALOK , MUKHOPADHYAY SUBIR
Published: November 2002

We present a class of static membrane solutions, with nonflat world volume geometry, in the eleven-dimensional supergravity with source terms. This class of solutions contains supersymmetric as well as a large class of nonsupersymmetric configurations. We comment about the near horizon limit and stability of these solutions and point out an interesting relation with a certain two-dimensional dilaton gravity system.
LOW ENERGY THEOREM FOR SUSY BREAKING WITH GAUGE SUPERMULTIPLETS
Authors: SAKAI NORISUKE , SUGISAKA RYO
Published: November 2002

Low energy theorems of Nambu–Goldstone fermion associated with spontaneously broken supersymmetry are studied for gauge supermultiplets. Two possible terms in the effective Lagrangian are needed to deal with massless gaugino and/or massless gauge boson. As an illustrative example, a concrete model is worked out which can interpolate massless as well as massive gaugino and/or gauge boson to examine the low energy effective interaction of NG-fermion.
GAUGE FIXING IN THE CHAIN-BY-CHAIN METHOD
Authors: SHIRZAD A. , LORAN F.
Published: November 2002

In a recent work7 we showed that for a Hamiltonian system with constraints, the set of constraints can be investigated in the first- and second-class constraint chains. We show here that using this "chain-by-chain" method for an arbitrary system. One can fix the gauges in the most economical and consistent way. We show that it is enough to assume some gauge fixing conditions conjugate to the last elements of first-class chains. The remaining necessary conditions would emerge from consistency conditions.
THE JORDANIAN Uh(2) YANG–MILLS THEORY
Authors: MESREF L.
Published: November 2002

In this paper, we investigate the Jordanian analog of Yang–Mills theory. For h = 0, this is just the usual one as it should be. We compute the h-trace which leads to the h-metric. This Jordanian quantum metric is an important ingredient for the construction of a Uh(2) Yang–Mills Lagrangian. Finally, we find the Weinberg angle in terms of this h-metric.
SOLITON SOLUTIONS IN A MODIFIED ϕ4 MODEL
Authors: ZAIT R. A.
Published: November 2002

We consider a ϕ4 model in 1+1 dimensions modified by the addition of an extra kinetic term similar to the Skyrme term in higher dimensions and a potential term. We generalize the procedures of the leading order method to include elliptic functions and obtain cnoidal wave type solutions of the familiar ϕ4 model. As a limit case, we re-obtain the well-known solitary and travelling wave solutions of this model from the constructed cnoidal wave solutions. A further kink solution of the pure ϕ4 model is also obtained. We obtain soliton solutions of the modified ϕ4 model and show that it possesses two ϕ4 kink solutions, with the same velocity and total energy, as well as a double-kink solution. We study some properties of the modified model. In particular, we see that the two ϕ4 kinks have a definite velocity and this velocity is a critical velocity for the double-kink structures. Finally, we conclude the paper with some features and comments.
BOUND STATES OF KLEIN–GORDON PARTICLES IN SCALAR SCREENED COULOMB POTENTIAL
Authors: RAO NAGALAKSHMI A. , KAGALI B. A. , SIVRAMKRISHNA VIJAY
Published: November 2002

One-dimensional Klein–Gordon equation with screened Coulomb potential generates genuine bound states in the scalar coupling scheme. In this article we have obtained the exact solutions of the problem. The results are compared with those of the vector coupling scheme.
CAN BLACK HOLES AND NAKED SINGULARITIES BE DETECTED IN ACCELERATORS?
Authors: CASADIO ROBERTO , HARMS BENJAMIN
Published: November 2002

We study the conditions for the existence of black holes that can be produced in colliders at the TeV-scale if the space–time is higher dimensional. On employing the microcanonical picture, we find that their life-times strongly depend on the details of the model. If the extra dimensions are compact (ADD model), microcanonical deviations from thermality are in general significant near the fundamental TeV mass, and tiny black holes decay more slowly than predicted by the canonical expression but still fast enough to disappear almost instantaneously. However, with one warped extra dimension (RS model), microcanonical corrections are much larger and tiny black holes appear to be (meta)stable. Further, if the total charge is not zero, we argue that naked singularities do not occur provided the electromagnetic field is strictly confined on an infinitely thin brane. However, they might be produced in colliders if the effective thickness of the brane is of the order of the fundamental length scale (~TeV-1).
ON THE STABILITY OF RAPIDITY GAP ANALYSIS
Authors: LIAO HONGBO , WU YUANFANG
Published: November 2002

It is argued that the newly introduced moments of rapidity gaps for the event-by-event fluctuations depends on the number of events and multiplicity. The interesting ones are unstable under ISR energies of h–h collisions. The instability is well improved when multiplicity increases.
GENERALIZED POISSON MECHANICS IN D-BRANES
Authors: GUHA PARTHA
Published: November 2002

Following the work of David Fairlie and his collaborators, we discuss the geometry of the equations of motion for the companion Lagrangian. This arises while we attempt to construct the field theoretic Lagrangians for strings and branes. These equations are related to generalized Bateman equations. Interestingly, an inhomogeneous form of these equations are related to what Dubrovin and Novikov called equations of the hydrodynamic type. We translate this set of equations into (Nambu)–Poisson equations and formulate the Lax representation of these systems. We deform all this set of equations by the Moyal product. We also present the Lax pair of the Moyal deformed systems for some special cases.
Regulation of the Brain’s Vascular Responses to Oxygen
Authors: Demchenko Ivan T. , Oury Tim D. , Crapo James D. , Piantadosi Claude A.
Published: November 2002

The mechanism of oxygen-induced cerebral vasoconstriction has been sought for more than a century. Using genetically altered mice to enhance or disrupt extracellular superoxide dismutase (EC-SOD, SOD3), we tested the hypothesis that this enzyme plays a critical role in the physiological response to oxygen in the brain by regulating nitric oxide (NO
·
) availability. Cerebral blood flow responses in these genetically altered mice to changes in P
o
2
demonstrate that SOD3 regulates equilibrium between superoxide (·O
2
−
) and NO
·
, thereby controlling vascular tone and reactivity in the brain. That SOD3 opposes inactivation of NO
·
is shown by absence of vasoconstriction in response to P
o
2
in the hyperbaric range in SOD3
+/+
mice, whereas NO-dependent relaxation is attenuated in SOD3
−/−
mutants. Thus, EC-SOD promotes NO
·
vasodilation by scavenging ·O
2
−
while hyperoxia opposes NO
·
and promotes constriction by enhancing endogenous ·O
2
−
generation and decreasing basal vasodilator effects of NO
·
.
Superoxide Mediates the Actions of Angiotensin II in the Central Nervous System
Authors: Zimmerman Matthew C. , Lazartigues Eric , Lang Julie A. , Sinnayah Puspha , Ahmad Iman M. , Spitz Douglas R. , Davisson Robin L.
Published: November 2002

Angiotensin II (Ang II) has profound effects in the central nervous system (CNS), including promotion of thirst, regulation of vasopressin secretion, and modulation of sympathetic outflow. Despite its importance in cardiovascular and volume homeostasis, angiotensinergic mechanisms are incompletely understood in the CNS. Recently, a novel signaling mechanism for Ang II involving reactive oxygen species (ROS) has been identified in a variety of peripheral tissues, but the involvement of ROS as second messengers in Ang II–mediated signaling in the CNS has not been reported. The hypothesis that superoxide is a key mediator of the actions of Ang II in the CNS was tested in mice using adenoviral vector–mediated expression of superoxide dismutase (AdSOD). Changes in blood pressure, heart rate, and drinking elicited by injection of Ang II in the CNS were abolished by prior treatment with AdSOD in the brain, whereas the cardiovascular responses to carbachol, another central vasopressor agent, were unaffected. In addition, Ang II stimulated superoxide generation in primary CNS cell cultures, and this was prevented by the Ang II receptor (Ang II type 1 subtype) antagonist losartan or AdSOD. These results identify a novel signaling mechanism mediating the actions of Ang II in the CNS. Dysregulation of this signaling cascade may be important in hypertension and heart failure triggered by Ang II acting in the CNS.
Local Expression of C-Type Natriuretic Peptide Suppresses Inflammation, Eliminates Shear Stress–Induced Thrombosis, and Prevents Neointima Formation Through Enhanced Nitric Oxide Production in Rabbit Injured Carotid Arteries
Authors: Qian Jian-Yong , Haruno Akihiro , Asada Yujiro , Nishida Takahiro , Saito Yasushi , Matsuda Takehisa , Ueno Hikaru
Published: November 2002

We previously observed that adenovirus-mediated expression of C-type natriuretic peptide (CNP) markedly inhibits neointima formation after balloon injury in rat carotid arteries, suggesting that CNP has multiple effects over its modest inhibitory effect on cellular proliferation. We hypothesized that local expression of CNP might have antithrombotic and antiinflammatory effects. Balloon-injured rabbit carotid arteries were infected with an adenovirus expressing human CNP (AdCNP), human tissue factor pathway inhibitor (AdTFPI), or bacterial β-galactosidase (AdLacZ) or infused with saline. Seven days later, shear stress–induced thrombosis was evaluated by cyclic flow variation (CFV), reflecting recurrent cycles of thrombus formation and dislodgment. CFV was observed in all AdLacZ-infected and saline-infused arteries but not in arteries infected with AdCNP or AdTFPI even in the presence of epinephrine. Injury increased the expressions of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and infiltration of macrophages. However, these effects were markedly reduced in AdCNP-treated arteries but not in AdTFPI-infected ones. In AdCNP-infected arteries, injury-induced expression of inducible NO synthase (iNOS) was enhanced, leading to increased NO generation. Interestingly, when the enhanced NO production was inhibited, neither inhibitory effect was observed, and suppression of neointima formation by CNP was canceled. Our study demonstrates that overexpression of CNP shows antithrombotic and antiinflammatory effects and reduces neointima formation mainly through enhanced NO production.
Abnormal Ca
2+
Release, but Normal Ryanodine Receptors, in Canine and Human Heart Failure
Authors: Jiang Ming Tao , Lokuta Andrew J. , Farrell Emily F. , Wolff Matthew R. , Haworth Robert A. , Valdivia Héctor H.
Published: November 2002

Sarcoplasmic reticulum (SR) Ca
2+
transport proteins, especially ryanodine receptors (RyR) and their accessory protein FKBP12.6, have been implicated as major players in the pathogenesis of heart failure (HF), but their role remain controversial. We used the tachycardia-induced canine model of HF and human failing hearts to investigate the density and major functional properties of RyRs, SERCA2a, and phospholamban (PLB), the main proteins regulating SR Ca
2+
transport. Intracellular Ca
2+
is likely to play a role in the contractile dysfunction of HF because the amplitude and kinetics of the [Ca
2+
]
i
transient were reduced in HF. Ca
2+
uptake assays showed 44±8% reduction of V
max
in canine HF, and Western blots demonstrated that this reduction was due to decreased SERCA2a and PLB levels. Human HF showed a 30±5% reduction in SERCA2a, but PLB was unchanged. RyRs from canine and human HF displayed no major structural or functional differences compared with control. The P
o
of RyRs was the same for control and HF over the range of pCa 7 to 4. Subconductance states, which predominate in FKBP12.6-stripped RyRs, were equally frequent in control and HF channels. An antibody that recognizes phosphorylated RyRs yields equal intensity for control and HF channels. Further, phosphorylation of RyRs by PKA did not appear to change the RyR/FKBP12.6 association, suggesting minor β-adrenergic stimulation of Ca
2+
release through this mechanism. These results support a role for SR in the pathogenesis of HF, with abnormal Ca
2+
uptake, more than Ca
2+
release, contributing to the depressed and slow Ca
2+
transient characteristic of HF.
Inflammatory Mediators and the Failing Heart
Authors: Mann Douglas L.
Published: November 2002

Recent studies have identified the importance of proinflammatory mediators in the development and progression of heart failure. The growing appreciation of the pathophysiological consequences of sustained expression of proinflammatory mediators in preclinical and clinical heart failure models culminated in a series of multicenter clinical trials that used “targeted” approaches to neutralize tumor necrosis factor in patients with moderate to advanced heart failure. However, these targeted approaches have resulted in worsening heart failure, thereby raising a number of important questions about what role, if any, proinflammatory cytokines play in the pathogenesis of heart failure. This review will summarize the tremendous growth of knowledge that has taken place in this field, with a focus on what we have learned from the negative clinical trials, as well as the potential direction of future research in this area.
H11 Kinase Is a Novel Mediator of Myocardial Hypertrophy In Vivo
Authors: Depre Christophe , Hase Makoto , Gaussin Vinciane , Zajac Anna , Wang Li , Hittinger Luc , Ghaleh Bijan , Yu Xianzhong , Kudej Raymond K. , Wagner Thomas , Sadoshima Junichi , Vatner Stephen F.
Published: November 2002

By subtractive hybridization, we found a significant increase in H11 kinase transcript in large mammalian models of both ischemia/reperfusion (stunning) and chronic pressure overload with hypertrophy. Because this gene has not been characterized in the heart, the goal of the present study was to determine the function of H11 kinase in cardiac tissue, both in vitro and in vivo. In isolated neonatal rat cardiac myocytes, adenoviral-mediated overexpression of H11 kinase resulted in a 37% increase in protein/DNA ratio, reflecting hypertrophy. A cardiac-specific transgene driven by the αMHC-promoter was generated, which resulted in an average 7-fold increase in H11 kinase protein expression. Transgenic hearts were characterized by a 30% increase of the heart weight/body weight ratio, by the reexpression of a fetal gene program, and by concentric hypertrophy with preserved contractile function at echocardiography. This phenotype was accompanied by a dose-dependent activation of Akt/PKB and p70
S6
kinase, whereas the MAP kinase pathway was unaffected. Thus, H11 kinase represents a novel mediator of cardiac cell growth and hypertrophy.
Erythrocyte and the Regulation of Human Skeletal Muscle Blood Flow and Oxygen Delivery
Authors: González-Alonso José , Olsen David B. , Saltin Bengt
Published: November 2002

Blood flow to contracting skeletal muscle is tightly coupled to the oxygenation state of hemoglobin. To investigate if ATP could be a signal by which the erythrocyte contributes to the regulation of skeletal muscle blood flow and oxygen (O
2
) delivery, we measured circulating ATP in 8 young subjects during incremental one-legged knee-extensor exercise under conditions of normoxia, hypoxia, hyperoxia, and CO+normoxia, which produced reciprocal alterations in arterial O
2
content and thigh blood flow (TBF), but equal thigh O
2
delivery and thigh O
2
uptake. With increasing exercise intensity, TBF, thigh vascular conductance (TVC), and femoral venous plasma [ATP] augmented significantly (
P
<0.05) in all conditions. However, with hypoxia, TBF, TVC, and femoral venous plasma [ATP] were (
P
<0.05) or tended (
P
=0.14) to be elevated compared with normoxia, whereas with hyperoxia they tended to be reduced. In CO+normoxia, where femoral venous O
2
Hb and (O
2
+CO)Hb were augmented compared with hypoxia despite equal arterial deoxygenation, TBF and TVC were elevated, whereas venous [ATP] was markedly reduced. At peak exercise, venous [ATP] in exercising and nonexercising limbs was tightly correlated to alterations in venous (O
2
+CO)Hb (
r
2
=0.93 to 0.96;
P
<0.01). Intrafemoral artery infusion of ATP at rest in normoxia (n=5) evoked similar increases in TBF and TVC than those observed during exercise. Our results in humans support the hypothesis that the erythrocyte functions as an O
2
sensor, contributing to the regulation of skeletal muscle blood flow and O
2
delivery, by releasing ATP depending on the number of unoccupied O
2
binding sites in the hemoglobin molecule.
Ventricular Hypertrophy Plus Neurohumoral Activation Is Necessary to Alter the Cardiac β-Adrenoceptor System in Experimental Heart Failure
Authors: Leineweber Kirsten , Brandt Katja , Wludyka Beate , Beilfuß Anja , Pönicke Klaus , Heinroth-Hoffmann Ingrid , Brodde Otto-Erich
Published: November 2002

Treatment of rats with monocrotaline (MCT) leads to pulmonary hypertension, right ventricular (RV) hypertrophy, and finally to RV heart failure. This is associated with characteristic changes in right ventricular β-adrenoceptors (β-AR), neuronal noradrenaline transporter (NAT) density and activity (uptake
1
), and G protein–coupled receptor kinase (GRK) activity. This study aimed to find out factors that determine β-AR, uptake
1
, and GRK changes. Thus, 6-week-old rats were treated with 50 mg/kg MCT subcutaneous or 0.9% saline. Within 13 to 19 days after MCT application (group A), RV weight (222±6 versus 147±5 mg) and RV/left ventricular (LV) weight ratio (0.42±0.01 versus 0.29±0.01) were significantly increased, whereas plasma noradrenaline, RV β-AR density, RV NAT density and activity, and RV GRK activity were not significantly altered. Twenty-one to twenty-eight days after MCT (group B), however, not only RV weight (316±4 versus 148±2 mg) and RV/LV weight ratio (0.61±0.01 versus 0.3±0.01) were markedly increased but also plasma noradrenaline (645±63 versus 278±18 pg/mL); now, RV β-AR density (13.4±1.3 versus 26.5±1.1 fmol/mg protein), RV NAT density (50.9±11.3 versus 79.6±2.9 fmol/mg protein), and RV NAT activity (65.4±7.4 versus 111.8±15.9 pmol [
3
H]-NA/mg tissue slices/15 min) were significantly decreased and RV-membrane GRK activity (100±15 versus 67±6 [
32
P]-rhodopsin in cpm) significantly increased. LV parameters of MCT-treated rats were only marginally different from control LV. We conclude that in MCT-treated rats ventricular hypertrophy per se is not sufficient to cause characteristic alterations in the myocardial β-AR system often seen in heart failure; only if ventricular hypertrophy is associated with neurohumoral activation β-ARs are downregulated and GRK activity is increased.
Spatial and Temporal Inhomogeneities During Ca
2+
Release From the Sarcoplasmic Reticulum in Pig Ventricular Myocytes
Authors: Heinzel Frank R. , Bito Virginie , Volders Paul G.A. , Antoons Gudrun , Mubagwa Kanigula , Sipido Karin R.
Published: November 2002

The [Ca
2+
]
i
transient of ventricular myocytes during normal excitation-contraction coupling is the summation of primary Ca
2+
release events, which originate at the junction of the sarcoplasmic reticulum (SR) and the T-tubular system. Studies in small mammals have shown a high density of release sites, but little is known of larger mammals. We have studied the spatial distribution of SR Ca
2+
release in pig ventricular myocytes using a confocal microscopy. In 69 of 107 cells, large inhomogeneities of Ca
2+
release were observed along the longitudinal scan line. Areas where the increase of [Ca
2+
]
i
was delayed (time to 50% of peak F/F
0
[where F indicates fluorescence intensity, and F
0
indicates F at rest] was 26±1 ms in delayed areas versus 11±2 ms in early areas) and smaller (peak F/F
0
was 2.27±0.10 for delayed areas versus 2.69±0.13 for early areas; n=13 cells,
P
<0.05) could be up to 26 μm wide. The sum of all delayed areas could make up to 55% of the line scan. The spatial pattern was constant during steady-state stimulation and was not altered by enhancing Ca
2+
channel opening or SR Ca
2+
content (Bay K8644, isoproterenol). Imaging of sarcolemmal membranes revealed several areas devoid of T tubules, but SR Ca
2+
release channels were homogeneously distributed. In contrast, compared with pig myocytes, mouse myocytes had a very dense T-tubular network, no large inhomogeneities of release, and a faster rate of rise of [Ca
2+
]
i
. In conclusion, in pig ventricular myocytes, areas of delayed release are related to regional absence of T tubules but not ryanodine receptors. This lower number of functional couplons contributes to a slower overall rate of rise of [Ca
2+
]
i
.
Peroxynitrite Inhibits Ca
2+
-Activated K
+
Channel Activity in Smooth Muscle of Human Coronary Arterioles
Authors: Liu Yanping , Terata Ken , Chai Qiang , Li Hongwei , Kleinman Leonard H. , Gutterman David D.
Published: November 2002

We examined the hypothesis that ONOO
−
, a product of the interaction between superoxide (O
2
·−
) and nitric oxide (NO), inhibits calcium-activated K
+
(K
Ca
) channel activity in vascular smooth muscle cells (VSMCs) of human coronary arterioles (HCAs), thereby reducing hyperpolarization-mediated vasodilation. HCAs were dissected from right atrial appendages. The interaction of ONOO
−
with microvessels was determined by immunohistochemistry using a nitrotyrosine antibody. Strong staining was observed in arteries exposed to authentic ONOO
−
or to sodium nitroprusside (SNP)+xanthine (XA)+xanthine oxidase (XO). Dilation to 10
−8
mol/L bradykinin (BK) was abolished in vessels exposed to ONOO
−
(−2.5±8%;
P
<0.05) but not DC-ONOO
−
(65±8%). Reduced dilation to BK was also observed after application of XO and SNP. Dilation to NS1619 (K
Ca
channel opener) was reduced in endothelial denuded arterioles treated with ONOO
−
. In isolated VSMCs, whole-cell peak K
+
current density was reduced by ONOO
−
(control 65±15 pA/pF; ONOO
−
42±9 pA/pF;
P
<0.05). Iberiotoxin had no further effect on whole-cell K
+
current. In inside-out patches, ONOO
−
but not DC-ONOO
−
decreased open state probability (NP
o
) of K
Ca
channel by 50±12%. O
2
·−
generated by XA+XO had no effect on BK-induced dilation and NP
o
of K
Ca
channels. These results suggest that ONOO
−
, but not O
2
·−
, inhibits K
Ca
channel activity in VSMCs possibly by a direct effect. This mechanism may contribute to impaired EDHF-mediated dilation in conditions such as ischemia/reperfusion where increased activity of NO synthase occurs in the presence of excess of O
2
·−
.
PPARα Inhibits TGF-β–Induced β
5
Integrin Transcription in Vascular Smooth Muscle Cells by Interacting With Smad4
Authors: Kintscher Ulrich , Lyon Christopher , Wakino Shu , Bruemmer Dennis , Feng Xu , Goetze Stephan , Graf Kristof , Moustakas Aristidis , Staels Bart , Fleck Eckart , Hsueh Willa A. , Law Ronald E.
Published: November 2002

Integrins play an important role in vascular smooth muscle cell (VSMC) migration, a crucial event in the development of restenosis and atherosclerosis. Transforming growth factor-β (TGF-β) is highly expressed in restenotic and atherosclerotic lesions, and known to induce integrin expression. Peroxisome proliferator-activated receptor α (PPARα), a member of the nuclear receptor superfamily, regulates gene expression in a variety of vascular cells. We investigated the effects of PPARα ligands on TGF-β–induced β
3
and β
5
integrin expression and potential interaction between PPARα and TGF-β signaling. PPARα ligands WY-14643 (100 μmol/L) and 5,8,11,14-eicosatetranoic acid (ETYA, 50 μmol/L) inhibited TGF-β–induced β
5
integrin protein expression by 72±6.8% and 73±7.1%, respectively (both
P
<0.05). TGF-β–stimulated β
3
integrin expression was not affected by PPARα ligands. Both PPARα ligands also suppressed TGF-β–induced β
5
integrin mRNA levels. PPARα ligands inhibited TGF-β–inducible transcription of β
5
integrin by an interaction with a TGF-β response element between nucleotides −63 and −44, which contains a Sp1/Sp3 transcription factor binding site. Nuclear complexes binding to the TGF-β response region contained Sp1/Sp3 and TGF-β–regulated Smad 2, 3, and 4 transcription factors. TGF-β–stimulated Sp1/Smad4 nuclear complex formation was inhibited by WY-14643 and ETYA with a parallel induction of PPARα/Smad4 interactions. However, in vitro pull-down experiments failed to demonstrate direct binding between PPARα/Smad4. Both PPARα ligands blocked PDGF-directed migration of TGF-β–pretreated VSMCs, a process mediated, in part, by β
5
integrins. The present study demonstrates that PPARα activators inhibit TGF-β–induced β
5
integrin transcription in VSMCs through a novel indirect interaction between ligand-activated PPARα and the TGF-β–regulated Smad4 transcription factors. The full text of this article is available at http://www.circresaha.org.
Genetic variants of coagulation factor XIII, postmenopausal estrogen therapy, and risk of nonfatal myocardial infarction
Authors: Reiner Alexander P. , Heckbert Susan R. , Vos Hans L. , Ariëns Robert A. S. , Lemaitre Rozenn N. , Smith Nicholas L. , Lumley Thomas , Rea Thomas D. , Hindorff Lucia A. , Schellenbaum Gina D. , Rosendaal Frits R. , Siscovick David S. , Psaty Bruce M.
Published: November 2002

We hypothesized that possession of either of 2 functional coagulation factor XIII polymorphisms, one within subunit A (Val34Leu) and one within subunit B (His95Arg), might modulate the prothrombotic effects of estrogen and help to explain the variation in incidence of arterial thrombotic events among postmenopausal women using hormone replacement therapy. In a population-based case-control study of 955 postmenopausal women, we assessed the associations of factor XIII genotypes and their interactions with estrogen therapy on risk of nonfatal myocardial infarction (MI). The presence of the factor XIIIA Leu34 allele was associated with a reduced risk of MI (odds ratio [OR] = 0.70, 95% confidence interval [95% CI] = 0.51-0.95). The presence of the factor XIIIB Arg95 allele had little association with MI risk. Neither factor XIII polymorphism alone significantly modified the association between the risk of MI and current estrogen use. In exploratory analyses, however, there was a significant factor XIII subunit gene-gene interaction. Compared to women homozygous for both common factor XIII alleles, the Arg95 variant was associated with a reduced risk of MI in the presence of the Leu34 variant (OR = 0.36, 95% CI = 0.17-0.75) but not in the absence of the Leu34 variant (OR = 1.11, 95% CI = 0.69-1.79). Moreover, among women who had at least 2 copies of the variant factor XIII alleles and were current estrogen users, the risk of MI was reduced by 70% relative to estrogen nonusers with fewer than 2 factor XIII variant alleles (P value for interaction = .03). If confirmed, these findings may permit a better assessment of the cardiovascular risks and benefits associated with postmenopausal estrogen therapy. (Blood. 2003;102:25-30)
From passive subjects to equal partners
Authors: Trivedi Premila , Wykes Til
Published: November 2002

Background

The Department of Health and UK funding bodies have suggested that clinical academics work closely with mental health service users in research projects. Although there are helpful guidelines on the issues that have to be dealt with, there have been few examples of how this partnership research might be undertaken.

Aims

To illustrate the challenges in joint research projects.

Method

We subjected the process of user involvement to ten questions which arose in the development of a joint research project. The answers are an amalgamation of the user and clinical researcher considerations and are affected by hindsight.

Results

The involvement of the user-researcher changed the focus of the study and its design and content. More attention was paid to the intervention itself and the way in which it was delivered. This process increased the amount of time taken to carry out and write up the project as well as incurring financial costs for user consultation payments and dissemination.

Conclusions

This experience has clarified the contribution that users can make, for example by raising new research questions, by ensuring interventions are kept ‘user friendly’, and the selection of outcome measures.
Stigma by association
Authors: Östman Margareta , Kjellin Lars
Published: November 2002

Background

Stigma affects not only people with mental illnesses, but their families as well. Understanding how stigma affects family members in terms of both their psychological response to the ill person and their contacts with psychiatric services will improve interactions with the family.

Aims

To investigate factors of psychological significance related to stigma of the relatives.

Method

In a Swedish multi-centre study, 162 relatives of patients in acute psychiatric wards following both voluntary and compulsory admissions were interviewed concerning psychological factors related to stigma.

Results

A majority of relatives experienced psychological factors of stigma by association. Eighteen per cent of the relatives had at times thought that the patient would be better off dead, and 10% had experienced suicidal thoughts. Stigma by association was greater in relatives experiencing mental health problems of their own, and was unaffected by patient background characteristics.

Conclusions

Interventions are needed to reduce the negative effects of psychological factors related to stigma by association in relatives of people with mental illness.
Advance directives for patients compulsorily admitted to hospital with serious mental illness
Authors: Papageorgiou Alexia , King Michael , Janmohamed Anis , Davidson Oliver , Dawson John
Published: November 2002

Background

An advance directive is a statement of a person's preferences for treatment, should he or she lose capacity to make treatment decisions in the future.

Aims

To evaluate whether use of advance directives by patients with mental illness leads to lower rates of compulsory readmission to hospital.

Method

In a randomised controlled trial in two psychiatric services in inner London, 156 in-patients about to be discharged from compulsory treatment under the Mental Health Act were recruited. The trial compared usual psychiatric care with usual care plus the completion of an advance directive. The primary outcome was the rate of compulsory readmission.

Results

Fifteen patients (19%) in the intervention group and 16 (21%) in the control group were readmitted compulsorily within 1 year of discharge. There was no difference in the numbers of compulsory readmissions, numbers of patients readmitted voluntarily, days spent in hospital or satisfaction with psychiatric services.

Conclusions

Users' advance instruction directives had little observable impact on the outcome of care at 12 months.
Maternal recall bias, obstetric history and schizophrenia
Authors: McIntosh A. M. , Holmes S. , Gleeson S. , Burns J. K. , Hodges A. K. , Byrne M. M. , Dobbie R. , Miller P. , Lawrie S. M. , Johnstone E. C.
Published: November 2002

Background

This study sought to clarify the role of obstetric complications (OCs) and maternal recall bias for patients with first episodes of schizophrenia and those at increased risk of the disorder.

Method

Subjects at high risk of schizophrenia were compared with people with first-episode schizophrenia and with healthy volunteers. Consenting mothers of subjects were interviewed using a standardised questionnaire for the recall of OCs, and OCs were also measured from records collected at the time of pregnancy and delivery.

Results

High-risk subjects and first-episode patients had higher rates of OCs recalled by their mother than controls, but hospital records showed no differences in OCs between groups. The number of OCs recalled by mothers of the high-risk group was not related to whether the mother had schizophrenia or not, but was related to the maternally rated abnormal childhood behaviour as measured by the Child Behaviour Checklist.

Conclusions

These results suggest that studies that rely on maternal recall alone are susceptible to bias. The excess of OCs recalled by the mother could be related to abnormal behaviour in their child rather than maternal illness, family history or psychotic symptoms.
Brunswick House: a weekend crisis house in North
Staffordshire
Authors: Hodgson Richard , Carr Darren , Wealleans Lynne
Published: November 2002

Aims and Method

To describe Brunswick House, the first crisis house in North
Staffordshire, and to assess the use of acute psychiatric wards and the
local accident and emergency department by Brunswick House residents. A
mirror design study compared the use of these facilities in the year
before with the year after a resident's first admission to Brunswick
House.

Results

Data collected on a cohort of Brunswick House residents between March
1999 and December 1999 showed a reduction in both the use of acute
psychiatric wards and use of the accident and emergency department after
the index admission to Brunswick House.

Clinical Implications

Brunswick House provides an alternative to NHS facilities for people in
crisis.
Induction agents in electroconvulsive therapy: a comparison of
methohexitone and propofol
Authors: Scott Allan , Boddy Harold
Published: November 2002

Aims and Method

To compare methohexitone and propofol in electroconvulsive therapy (ECT).
A retrospective within-subject comparison was made of the use of these
drugs in separate courses of bilateral ECT in one clinic over 10 years.
Patients taking mood stabilising or anti-epileptic drugs were excluded.
The initial seizure threshold and seizure duration were of particular
interest.

Results

The median initial seizure thresholds were identical (75 mC). The median
initial seizure duration with threshold stimulation was 25% shorter with
propofol (21v.28 s). The median total numbers of
treatments in the courses were identical (eight treatments).

Clinical Implications

The shorter seizure duration observed with propofol was not associated
with a commensurate rise in the initial seizure threshold. The shorter
seizure duration may therefore have no effect on the therapeutic efficacy
of treatment.
Acute wards: problems and solutions
Authors: Allen Cris , Jones Julia
Published: November 2002

A woman, who was an in-patient, provided an interesting summary of mental health wards when she stated that she felt extremely sorry for the nursing staff. She disliked intensely the experience of being an in-patient but, she said, at least she would soon be discharged. The nurses, she declared, had no such hope and were destined to remain incarcerated in the ward, unless they could get another nursing job.
Benzodiazepines and disinhibition: a review
Authors: Paton Carol
Published: November 2002

AIMS AND METHODS

To describe and attempt to quantify the incidence of disinhibitory
reactions to benzodiazepines and to identify those at risk. Medline
search, 1966–January 2002.

Results

The overall incidence of disinhibitory reactions is small, but those with
impulse control problems, neurological disorders, learning disabilities,
the under 18s and the over 65s are at significant risk.

Clinical Implications

It is important to be aware of the ability of benzodiazepines to cause
behavioural disinhibition and to maintain a high degree of vigilance when
these drugs are administered to patients known to be at risk. In patients
who have experienced behavioural disinhibition with benzodiazepines,
antipsychotic drugs should be used to modify behaviour in any future
emergencies.
Patient management problems: ‘the vignettes’
Authors: McCreadie R. G.
Published: November 2002

In spring 2003, the format of the Patient Management Problems (PMP) part of
the MRCPsych Part 2 will change. At present, examiners bring their
‘vignettes' to the examination. The Examinations committee believes that the
examination should be more structured, and that there should be a ‘bank’ of
vignettes. The working group, which I chair, was set up to make
recommendations about the best way forward.