bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma membrane‐associated nucleoside diphosphate kinase (nm23) in the heart is regulated by β‐adrenergic signaling
Authors: Lutz Susanne , Mura Roman A , Hippe Hans Joerg , Tiefenbacher Christiane , Niroomand Feraydoon 
Published: November 2003

A receptor‐independent activation of heterotrimeric G proteins by plasma membrane‐associated nucleoside diphosphate kinase (NDPK) has been demonstrated in vivo, and elevated levels of NDPK were found in purified sarcolemmal membranes of patients with end‐stage heart failure.
Among 22 consecutive patients with chronic heart failure who underwent cardiac transplantation, those treated with a β‐blocker (n=8) had a 65% lower NDPK content and activity in the cardiac sarcolemma, compared to patients with similar base line characteristics who had no β‐blocker therapy (n=14).
The lower NDPK was associated with a reduced NDPK‐dependent, Gi‐mediated inhibition of adenylyl cyclase activity, as assessed by in vitro measurement of adenylyl cyclase activity in the presence of GDP or its kinase‐resistant analog guanosine 5′‐O‐(2‐thio)diphosphate (GDPβS).
We further tested whether treatment with a β‐adrenergic agonist would induce an increase in sarcolemmal NDPK. Rats treated with isoproterenol developed myocardial hypertrophy, and NDPK in the sarcolemma rose by 60% during 14 days of treatment. The β‐blocker propranolol prevented both effects. When hypertrophy was induced with thyroid hormone, NDPK did not increase.
In conclusion, chronic activation of β‐adrenergic receptors increases the binding of NDPK to cardiac sarcolemma, where it may activate heterotrimeric G proteins.

British Journal of Pharmacology (2003) 140, 1019–1026. doi:10.1038/sj.bjp.0705527
Histamine induces cytoskeletal changes in human eosinophils via the H4 receptor
Authors: Buckland Karen F , Williams Timothy J , Conroy Dolores M 
Published: November 2003

Histamine (0.004–2 μM) induced a concentration‐dependent shape change of human eosinophils, but not of neutrophils or basophils, detected as an increase in forward scatter (FSC) in the gated autofluorescence/forward scatter (GAFS) assay.
The histamine‐induced eosinophil shape change was completely abolished by thioperamide (10 μM), an H3/H4 receptor antagonist, but was not inhibited by pyrilamine or cimetidine (10 μM), H1 and H2 receptor antagonists, respectively. The H4 receptor agonists, clobenpropit and clozapine (0.004–2 μM), which are also H3 receptor antagonists, both induced eosinophil shape change, which was inhibited by thioperamide (10 μM). The H3/H4 receptor agonists, imetit, R‐α‐methyl histamine and N‐α‐methyl histamine (0.004–2 μM) also induced eosinophil shape change.
Histamine induced actin polymerisation (0.015–10 μM), intracellular calcium mobilisation (10–100 μM) and a significant upregulation of expression of the cell adhesion molecule CD11b (0.004–10 μM) in eosinophils, all of which were inhibited by thioperamide (10–100 μM). In addition, the H4 receptor agonist/H3 receptor antagonist clozapine (20 μM) stimulated a rise in intracellular calcium in eosinophils.
Activation of H4 receptors by histamine (1 μM) primed eosinophils for increased chemotactic responses to eotaxin, but histamine (0.1–10 μM) did not directly induce chemotaxis of eosinophils.
Pertussis toxin (1 μg ml−1) inhibited shape change and actin polymerisation responses induced by histamine showing that these effects are mediated by coupling to a Gαi/o G‐protein.
This study demonstrates that human eosinophils express functional H4 receptors and may provide a novel target for allergic disease therapy.

British Journal of Pharmacology (2003) 140, 1117–1127. doi:10.1038/sj.bjp.0705530
ATP analogues with modified phosphate chains and their selectivity for rat P2X2 and P2X2/3 receptors
Authors: Spelta Valeria , Mekhalfia Abdelaziz , Rejman Dominik , Thompson Mark , Blackburn G Michael , North R Alan 
Published: November 2003

Heteromeric P2X2/3 receptors are much more sensitive than homomeric P2X2 receptors to αβ‐methylene‐ATP, and this ATP analogue is widely used to discriminate the two receptors on sensory neurons and other cells.
We sought to determine the structural basis for this selectivity by synthesising ADP and ATP analogues in which the αβ and/or βγ oxygen atoms were replaced by other moieties (including –CH2–, –CHF–, –CHCl–, –CHBr–, –CF2–, –CCl2–, –CBr2–, –CHSO3–, –CHPO3–, –CFPO3–, –CClPO3–, –CH2–CH2–, –C≡C–, –NH–, –CHCOOH–).
We tested their actions as agonists or antagonists by whole‐cell recording from human embryonic kidney cells expressing P2X2 subunits alone (homomeric P2X2 receptors), or cells expressing both P2X2 and P2X3 subunits, in which the current through heteromeric P2X2/3 receptors was isolated.
ADP analogues had no agonist or antagonist effect at either P2X2 or P2X2/3 receptors. All the ATP analogues tested were without agonist or antagonist activity at homomeric P2X2 receptors, except βγ‐difluoromethylene‐ATP, which was a weak agonist.
At P2X2/3 receptors, βγ‐imido‐ATP, βγ‐methylene‐ATP, and βγ‐acetylene‐ATP were weak agonists, whereas αβ,βγ‐ and βγ,γδ‐bismethylene‐AP4 were potent full agonists. βγ‐Carboxymethylene‐ATP and βγ‐chlorophosphonomethylene‐ATP were weak antagonists at P2X2/3 receptors (IC50 about 10 μM).
The results indicate (a) that the homomeric P2X2 receptor presents very stringent structural requirements with respect to its activation by ATP; (b) that the heteromeric P2X2/3 receptor is much more tolerant of αβ and βγ substitution; and (c) that a P2X2/3‐selective antagonist can be obtained by introduction of additional negativity at the βγ‐methylene.

British Journal of Pharmacology (2003) 140, 1027–1034. doi:10.1038/sj.bjp.0705531
Signal transduction for inhibition of inducible nitric oxide synthase and cyclooxygenase‐2 induction by capsaicin and related analogs in macrophages
Authors: Chen Ching‐Wen , Lee Sho Tone , Wu Wen Tung , Fu Wen‐Mei , Ho Feng‐Ming , Lin Wan Wan 
Published: November 2003

Although capsaicin analogs might be a potential strategy to manipulate inflammation, the mechanism is still unclear. In this study, the effects and action mechanisms of vanilloid analogs on iNOS and COX‐2 expression were investigated in RAW264.7 macrophages.
Capsaicin and resiniferatoxin (RTX) can inhibit LPS‐ and IFN‐γ‐mediated NO production, and iNOS protein and mRNA expression with similar IC50 values of around 10 μM.
Capsaicin also transcriptionally inhibited LPS‐ and PMA‐induced COX‐2 expression and PGE2 production. However, this effect exhibited a higher potency (IC50: 0.2 μM), and RTX failed to elicit such responses at 10 μM.
Interestingly, we found that capsazepine, a competitive TRPV1 antagonist, did not prevent the inhibition elicited by capsaicin or RTX. Nevertheless, it mimicked vanilloids in inhibiting iNOS/NO and COX‐2/PGE2 induction with an IC50 value of 3 μM. RT–PCR and immunoblotting analysis excluded the expression of TRPV1 in RAW264.7 macrophages.
The DNA binding assay demonstrated the abilities of vanilloids to inhibit LPS‐elicited NF‐κB and AP‐1 activation and IFN‐γ‐elicited STAT1 activation. The reporter assay of AP‐1 activity also supported this action.
The kinase assay indicated that ERK, JNK, and IKK activation by LPS were inhibited by vanilloids.
In conclusion, vanilloids can modulate the expression of inflammatory iNOS and COX‐2 genes in macrophages through interference with upstream signalling events of LPS and IFN‐γ. These findings provide new insights into the potential benefits of the active ingredient in hot chilli peppers in inflammatory conditions.

British Journal of Pharmacology (2003) 140, 1077–1087. doi:10.1038/sj.bjp.0705533
Role of sarcoplasmic reticulum in control of membrane potential and nitrergic response in opossum lower esophageal sphincter
Authors: Zhang Yong , Paterson William G 
Published: November 2003

We previously demonstrated that a balance of Ca2+‐activated Cl− current (ICl(Ca)) and K+ current activity sets the resting membrane potential of opossum lower esophageal sphincter (LES) circular smooth muscle at ∼−41 mV, which leads to continuous spike‐like action potentials and the generation of basal tone. Ionic mechanisms underlying this basal ICl(Ca) activity and its nitrergic regulation remain unclear. Recent studies suggest that spontaneous Ca2+ release from sarcoplasmic reticulum (SR) and myosin light chain kinase (MLCK) play important roles. The current study investigated this possibility. Conventional intracellular recordings were performed on circular smooth muscle of opossum LES. Nerve responses were evoked by electrical square wave pulses of 0.5 ms duration at 20 Hz.
In the presence of nifedipine (1 μM), substance P (1 μM), atropine (3 μM) and guanethidine (3 μM), intracellular recordings demonstrated a resting membrane potential (MP) of −38.1±0.7 mV (n=25) with spontaneous membrane potential fluctuations (MPfs) of 1–3 mV. Four pulses of nerve stimulation induced slow inhibitory junction potentials (sIJPs) with an amplitude of 6.1±0.3 mV and a half‐amplitude duration of 1926±147 ms (n=25).
1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ), a specific guanylyl cyclase inhibitor, abolished sIJPs, but had no effects on MPfs. Caffeine, a ryanodine receptor agonist, hyperpolarized MP and abolished sIJPs and MPfs. Ryanodine (20 μM) inhibited the sIJP and induced biphasic effects on MP, an initial small hyperpolarization followed by a large depolarization. sIJPs and MPfs were also inhibited by cyclopiazonic acid, an SR Ca2+ ATPase inhibitor. Specific ICl(Ca) and MLCK inhibitors hyperpolarized the MP and inhibited MPfs and sIJPs.
These data suggest that (1) spontaneous release of Ca2+ from the SR activates ICl(Ca), which in turn contributes to resting membrane potential; (2) MLCK is involved in activation of ICl(Ca); (3) inhibition of ICl(Ca) is likely to underlie sIJPs induced by nitrergic innervation.

British Journal of Pharmacology (2003) 140, 1097–1107. doi:10.1038/sj.bjp.0705537
Effects of acute treatment with paroxetine, citalopram and venlafaxine in vivo on noradrenaline and serotonin outflow: a microdialysis study in Swiss mice
Authors: David D J P , Bourin M , Jego G , Przybylski C , Jolliet P , Gardier A M 
Published: November 2003

This study investigated whether a single administration of a range of doses (1, 4 and 8 mg kg−1, i.p.) of paroxetine, citalopram or venlafaxine may simultaneously increase extracellular levels of 5‐HT ([5‐HT]ext) and noradrenaline ([NA]ext) by using in vivo microdialysis in the frontal cortex (FCx) of awake, freely moving Swiss mice.
In vivo, paroxetine induced similar increases in cortical [5‐HT]ext at the three doses tested, and induced a statistically significant increase in cortical [NA]ext at 4 and 8 mg kg−1. Citalopram increased neither [5‐HT]ext nor [NA]ext at the lowest dose, but increased both neurotransmitter levels at 4 and 8 mg kg−1. At these doses, citalopram induced greater increases in cortical [5‐HT]ext than in [NA]ext. Venlafaxine increased [5‐HT]ext and [NA]ext to about 400 and 140% of the respective basal values at 8 mg kg−1.
Citalopram and paroxetine have the highest potency to increase cortical [5‐HT]ext and [NA]ext, respectively. In addition, the rank of order of efficacy of these antidepressant drugs to increase [5‐HT]ext in vivo in the FCx of mice was as follows: venlafaxine>citalopram>paroxetine, while the efficacy to increase cortical [NA]ext in mice of paroxetine and citalopram is similar, and greater than that of venlafaxine.
In conclusion, extracellular levels of cortical [NA]ext increase with the highest doses of the very selective SSRI citalopram, as well as with the very potent SSRI paroxetine. Surprisingly, the SNRI venlafaxine increased cortical [5‐HT]ext to a greater extent rather than [NA]ext in the range of doses studied in mice.

British Journal of Pharmacology (2003) 140, 1128–1136. doi:10.1038/sj.bjp.0705538
Effects of insulin on vascular responses to spinal cord stimulation and vasoactive agents in pithed rats
Authors: Takatori Shingo , Mizote Masako , Zamami Yoshito , Kurosaki Yuji , Kawasaki Hiromu 
Published: November 2003

Effects of insulin (2–600 pmol kg−1 min−1, i.v.) on vascular responses to spinal cord (lower thoracic vertebra, Th 9–12) stimulation (SCS) and to i.v. injection of noradrenaline (NA, 125–500 ng kg−1), angiotensin II (Ang II, 40–200 pmol kg−1), acetylcholine (ACh, 1 nmol kg−1), calcitonin gene‐related peptide (CGRP, 0.1 nmol kg−1) and sodium nitroprusside (SNP, 5 μg kg−1) were examined in pithed rats.
In euglycemic pithed rats, low and medium doses of insulin dose‐dependently potentiated vasopressor responses to SCS (2–8 Hz), NA, while higher doses of insulin had little effect on SCS‐ and NA‐induced pressor responses. All doses of insulin significantly augmented pressor responses to Ang II.
In pithed rats with artificially increased blood pressure, SCS (2 and 4 Hz) induced a frequency‐dependent depressor response, which was blocked by infusion of CGRP(8–37) (CGRP receptor antagonist, 60 nmol kg−1 min−1).
In euglycemic pithed rats, low‐doses of insulin significantly attenuated depressor responses to SCS and CGRP, but medium and high doses of insulin remained unaffected.
All doses of insulin significantly inhibited depressor response to ACh, while SNP‐induced depressor response was not significantly affected by any doses of insulin.
These results suggest that insulin at low and medium concentrations increases adrenergic vasoconstriction, which is partly associated with inhibition of CGRPergic nerve function and endothelium function. It is also suggested that lack of insulin effect at higher concentrations may result from acute desensitization of insulin action, possibly via insulin receptors.

British Journal of Pharmacology (2003) 140, 1137–1145. doi:10.1038/sj.bjp.0705539
D‐Cycloserine facilitates synaptic plasticity but impairs glutamatergic neurotransmission in rat hippocampal slices
Authors: Rouaud E , Billard J‐M 
Published: November 2003

The glycine‐binding site of the glutamatergic N‐methyl‐D‐aspartate receptor subtype (NMDAr) has been proposed as a putative target for treating cognitive impairments in neurodegenerative disorders and schizophrenia. Although behavioural evidence has been accumulated showing that the partial agonist D‐cycloserine (DCS) facilitated learning and memory, physiological mechanisms of the drug still remained to be characterized. In the present study, we have investigated the effects of DCS on glutamatergic neurotransmission and synaptic plasticity in CA1 region of rat hippocampal slices, using extracellular field excitatory postsynaptic potentials.
We showed that DCS facilitated NMDAr‐mediated synaptic potentials. In addition, we found that the magnitude of NMDAr‐dependent long‐term depression was significantly enhanced by the agonist, while the threshold for the induction of lasting potentiations was lowered.
We found that DCS decreased neurotransmission mediated by α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)/kainate subtypes of glutamate receptors. This inhibition was not prevented by the γ‐aminobutyric acid GABAA antagonist bicuculline, but was antagonized by the glycine antagonist strychnine.
These results, therefore, show opposite effects of DCS on NMDA and non‐NMDA synaptic responses within the hippocampus. They also demonstrate that DCS facilitates long‐term synaptic plasticity that may support the DCS‐induced enhanced cognitive performances.

British Journal of Pharmacology (2003) 140, 1051–1056. doi:10.1038/sj.bjp.0705541
Hypoxia‐inducible factor‐1 and activator protein‐1 modulate the upregulation of CYP3A6 induced by hypoxia
Authors: Fradette Caroline , Souich Patrick du 
Published: November 2003

Moderate hypoxia in vivo and serum from rabbits subjected to moderate hypoxia (SHYPO) in vitro reduce CYP1A1 and 1A2 P450 isoforms and upregulate CYP3A6. The aim of this project was to investigate the signal transduction pathways implicated in the upregulation of CYP3A6 expression by hypoxia.
Hypoxia in vivo and SHYPO in vitro increased the expression of hypoxia‐inducible factor‐1α (HIF‐1α) and c‐jun, as well as CYP3A6. By electrophoresis mobility shift assay, it was shown that HIF‐1 and activator protein‐1 (AP‐1) bind to CYP3A6 oligonucleotide probe after exposure to hypoxia in vivo and SHYPO in vitro. The effects of hypoxia in vivo or SHYPO in vitro were reproduced by CoCl2 and lead acetate, activators of HIF‐1 and AP‐1, respectively.
PD98059, a p42/44 MAPK inhibitor, prevented the increase of CYP3A6 and c‐jun, but did not impede the increase of HIF‐1α and binding to CYP3A6 oligonucleotide probe. Genistein, an inhibitor of protein tyrosine kinases (PTKs), prevented the increase in HIF‐1α, c‐jun and CYP3A6, as well as HIF‐1 and AP‐1 binding to CYP3A6 oligonucleotide probe. Moreover, hypoxia in vivo induced constitutive androstane receptor (CAR) as well as CAR binding to the CYP3A6 oligonucleotide probe, but not the pregnane X receptor.
In conclusion, hypoxia in vivo and SHYPO induce the expression of CYP3A6. The in vitro induction of CYP3A6 by SHYPO is PTK‐ and p42/44 MAPK‐dependent. The present data support the hypothesis that HIF‐1 and AP‐1 are part of the signalling pathway leading to CYP3A6 induction by hypoxia.

British Journal of Pharmacology (2003) 140, 1146–1154. doi:10.1038/sj.bjp.0705543
Nursing practice and the definition of human death
Authors: Edwards Steven D. , Forbes Kevin 
Published: November 2003

EDWARDS SD and FORBES K. Nursing Inquiry 2003; 10: 229–235 Nursing practice and the definition of human death This paper aims to highlight the gap in nursing literature of discussion of the definition of human death — to show that nurses should engage in such discussion. For the nursing role in the care of brain dead patients and their relatives may unwittingly promote and foster a definition of human death which is fundamentally flawed.A person can be warm, pink, have an independently beating heart and be breathing, yet still be diagnosed as brainstem dead. Nursing literature which discusses issues surrounding brain death (as opposed to brain death itself), proposes that nurses should suppress any reservations which they may have in accepting that a patient with the characteristics described is dead; and that they should try to allay any reservations which relatives of such dead patients might have. But what if the concept of brainstem death is flawed? Surely, as accountable professionals, nurses should not accept the role just referred to without satisfying themselves that the concept of brainstem death is coherent and robust. This paper tries to show that, on examination, this is not the case.The definition of human death which guides practice in the UK and elsewhere is fundamentally flawed. Instead of suppressing their own intuitions, and the intuitions of patients’ relatives in the management of patients diagnosed as brainstem dead, nurses should critically examine the definition of death which currently informs clinical practice. Our conclusion is that this definition is false.
Lacticacidosis after short‐term infusion of propofol for anaesthesia in a child with osteogenesis imperfecta
Authors: Kill Clemens , Leonhardt Andreas , Wulf Hinnerk 
Published: November 2003

SummaryWe describe the case of a 7‐year‐old boy with osteogenesis imperfecta, who underwent anaesthesia with propofol–fentanyl–nitrous oxide–suxamethonium for orthopaedic surgery of a distal femur fracture. He developed lacticacidosis after short‐term propofol infusion (150 min, mean infusion rate 13.5 mg·kg−1·h−1) associated with a prolonged recovery time without serious haemodynamic changes. The highest lactate concentration was 9.2 mmol·l−1 at 160 min after discontinuation of propofol. There was no significant increase in body temperature. The boy fully recovered.
RENAL RESEARCH INSTITUTE SYMPOSIUM: The Longitudinal Chronic Kidney Disease Study: A Prospective Cohort Study of Predialysis Renal Failure
Authors: Perlman Rachel L. , Kiser Margaret , Finkelstein Fredric , Eisele George , Roys Erik , Liu Lei , Burrows‐Hudson Sally , Port Friedrich , Messana Joseph M. , Bailie George , Rajagopalan Sanjay , Saran Rajiv 
Published: November 2003

AbstractChronic kidney disease (CKD) is a significant public health problem: every year the number of Americans living with CKD and requiring renal replacement therapy increases. In addition, individuals with CKD have substantially increased morbidity and mortality compared to the general population. The Longitudinal Chronic Kidney Dialysis (LCKD) Study is a multicenter, prospective, observational study of patients with moderate to severe CKD that was designed to better describe the course of the disease and the determinants of patient outcomes. Patients with moderate to severe CKD (glomerular filtration rate [GFR] < 60 ml/min/m2) from four academic nephrology clinics were enrolled between 2000 and 2002. Special cardiac and vascular testing has recently commenced as phase II of this study. Areas that have been or are currently being studied include anemia management, health‐related quality of life (HRQOL), medication use, and markers of cardiovascular disease. This article describes the LCKD Study in the context of current knowledge of CKD.
RENAL RESEARCH INSTITUTE SYMPOSIUM: Efforts to Determine the Role of Oxidant Stress in Dialysis Outcomes
Authors: Handelman Garry J. 
Published: November 2003

AbstractThe role of elevated markers of oxidant stress needs to be established in longitudinal studies. Oxidant stress markers such as malonaldehyde (MDA), isoprostanes, and breath hydrocarbons warrant rigorous application to outcomes, if they are to be used as clinical parameters. For example, investigations of C‐reactive protein (CRP), parathyroid hormone (PTH), and several other clinical indicators have shown that these markers can be used to predict outcomes such as morbidity and mortality. Long‐term followup is needed for intervention studies with antioxidants, since effects with short‐term studies may be focused on critically‐ill individuals where intervention would not be expected to be effective. Oxidant stress studies in this population especially need a long‐term approach to test the hypothesis that antioxidant intervention is beneficial.
STABILITY OF SHEAR BANDS IN AN ELASTOPLASTIC MODEL FOR GRANULAR FLOW: THE ROLE OF DISCRETENESS
Authors: SHEARER MICHAEL , SCHAEFFER DAVID G. , WITELSKI THOMAS P. 
Published: November 2003

Continuum models for granular flow generally give rise to systems of nonlinear partial differential equations that are linearly ill-posed. In this paper we introduce discreteness into an elastoplasticity model for granular flow by approximating spatial derivatives with finite differences. The resulting ordinary differential equations have bounded solutions for all time, a consequence of both discreteness and nonlinearity. We study how the large-time behavior of solutions in this model depends on an elastic shear modulus ℰ. For large and moderate values of ℰ, the model has stable steady-state solutions with uniform shearing except for one shear band; almost all solutions tend to one of these as t→∞. However, when ℰ becomes sufficiently small, the single-shear-band solutions lose stability through a Hopf bifurcation. The value of ℰ at the bifurcation point is proportional to the ratio of the mesh size to the macroscopic length scale. These conclusions are established analytically through a careful estimation of the eigenvalues. In numerical simulations we find that: (i) after stability is lost, time-periodic solutions appear, containing both elastic and plastic waves, and (ii) the bifurcation diagram representing these solutions exhibits bi-stability.