bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of neuronal Ca2+ influx by gabapentin and subsequent reduction of neurotransmitter release from rat neocortical slices
Authors: Fink Klaus , Meder Wolfgang , Dooley David J , Göthert Manfred 
Published: January 2005

Cytosolic calcium ion concentrations ([Ca2+]i) were measured in rat neocortical synaptosomes using fura‐2, and depolarization of synaptosomal membranes was induced by K+ (30 mM). The release of the endogenous excitatory amino acids glutamate and aspartate was evoked by K+ (50 mM) and determined by HPLC. The release of [3H]‐noradrenaline from rat neocortical synaptosomes or slices was evoked by K+ (15 and 25 mM) and measured by liquid scintillation counting.
Gabapentin produced a concentration‐dependent inhibition of the K+‐induced [Ca2+]i increase in synaptosomes (IC50=14 μM; maximal inhibition by 36%). The inhibitory effect of gabapentin was abolished in the presence of the P/Q‐type Ca2+ channel blocker ω‐agatoxin IVA, but not by the N‐type Ca2+ channel antagonist ω‐conotoxin GVIA.
Gabapentin (100 μM) decreased the K+‐evoked release of endogenous aspartate and glutamate in neocortical slices by 16 and 18%, respectively.
Gabapentin reduced the K+‐evoked [3H]‐noradrenaline release in neocortical slices (IC50=48 μM; maximal inhibition of 46%) but not from synaptosomes.
In the presence of the AMPA receptor antagonists 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX) and 2,3‐dioxo‐6‐nitro‐1,2,3,4‐tetrahydro[f]quinoxaline‐7‐sulphonamide (NBQX), gabapentin did not reduce [3H]‐noradrenaline release. Gabapentin did, however, cause inhibition in the presence of the NMDA receptor antagonist DL‐(E)‐2‐amino‐4‐methyl‐5‐phosphono‐3‐pentanoic acid (CGP 37849).
Gabapentin is concluded to reduce the depolarization‐induced [Ca2+]i increase in excitatory amino acid nerve terminals by inhibiting P/Q‐type Ca2+ channels; this decreased Ca2+ influx subsequently attenuates K+‐evoked excitatory amino acid release. The latter effect leads to a reduced activation of AMPA receptors which contribute to K+‐evoked noradrenaline release from noradrenergic varicosities, resulting in an indirect inhibition of noradrenaline release.

British Journal of Pharmacology (2000) 130, 900–906; doi:10.1038/sj.bjp.0703380
Regional haemodynamic effects of recombinant murine or human leptin in conscious rats
Authors: Gardiner S M , Kemp P A , March J E , Bennett T 
Published: January 2005

Regional haemodynamic responses to recombinant murine or human leptin were assessed in conscious, chronically‐instrumented, male, Long‐Evans rats (350–450 g).
Human, but not murine, leptin caused a slight hindquarters vasoconstriction, but neither peptide had any effect on mean arterial blood pressure or heart rate.
In the presence of the β2‐adrenoceptor antagonist, ICI 118551, a hindquarters vasoconstrictor response to human leptin was not seen, and there was a tachycardia, as there was to murine leptin.
The nitric oxide synthase inhibitor, NG‐nitro‐L‐arginine methyl ester, (L‐NAME), did not influence the cardiovascular effects of murine or human leptin.
The results indicate that the previously reported sympathoexcitatory effects of murine leptin in anaesthetized rats are not manifest as regional haemodynamic changes in conscious rats, and this is not due to β2‐adrenoceptor‐mediated vasodilator mechanisms opposing any vasoconstrictor responses. Moreover, the ability of L‐NAME to unmask a pressor effect of murine leptin in anaesthetized rats may not be apparent in the conscious state.

British Journal of Pharmacology (2000) 130, 805–810; doi:10.1038/sj.bjp.0703381
Characterization of a novel VPAC1 selective agonist and identification of the receptor domains implicated in the carboxyl‐terminal peptide recognition
Authors: Van Rampelbergh Jean , Juarranz Maria‐Guillerma , Perret Jason , Bondue Antoine , Solano Rosa Maria , Delporte Christine , De Neef Philippe , Robberecht Patrick , Waelbroeck Magali 
Published: January 2005

Vasoactive Intestinal Polypeptide (VIP) interacts with a high affinity to two subclasses of G protein coupled receptors named VPAC1 and VPAC2, and has a 3–10 fold preference for VPAC1 over VPAC2 receptors. Selective ligands for each receptor subclass were recently described. [R16]‐PACAP (1–23) and [L22]‐VIP are two selective VPAC1 agonists.
Chimaeric human VPAC2‐VPAC1 recombinant receptors expressed in CHO cells were used to identify the receptor domains implicated in these two selective ligands recognition.
The VPAC2 preference for [R16]‐PACAP (1–27) over [R16]‐PACAP (1–23) did not require the receptor's NH2‐terminus domain but involved the whole transmembrane domain.
In contrast, the selectivity of [L22]‐VIP depended only on the presence of the NH2 terminus and EC2 domains of the VPAC1 receptor.
The present data support the idea that in the GPCR‐B family of receptors the different selective ligands require different domains for their selectivity, and that the peptides carboxyl terminal sequence (amino acids 24–27) folds back on the transmembrane receptor domain, close to the peptides, aminoterminus.

British Journal of Pharmacology (2000) 130, 819–826; doi:10.1038/sj.bjp.0703384
Effects of 5‐aminoisoquinolinone, a water‐soluble, potent inhibitor of the activity of poly (ADP‐ribose) polymerase on the organ injury and dysfunction caused by haemorrhagic shock
Authors: McDonald Michelle C , Mota‐Filipe Helder , Wright James A , Abdelrahman Maha , Threadgill Michael D , Thompson Andrew S , Thiemermann Christoph 
Published: January 2005

Poly (ADP‐ribose) synthetase (PARP) is a nuclear enzyme activated by strand breaks in DNA, which are caused inter alia by reactive oxygen species (ROS). Here we report on (i) a new synthesis of a water‐soluble and potent PARP inhibitor, 5‐aminoisoquinolinone (5‐AIQ) and (ii) investigate the effects of 5‐AIQ on the circulatory failure and the organ injury/dysfunction caused by haemorrhage and resuscitation in the anaesthetized rat.
Exposure of human cardiac myoblasts (Girardi cells) to hydrogen peroxide (H2O2, 3 mM for 1 h, n=9) caused a substantial increase in PARP activity. Pre‐treatment of these cells with 5‐AIQ (1 μM–1 mM, 10 min prior to H2O2) caused a concentration‐dependent inhibition of PARP activity (IC50: ∼0.01 mM, n=6).
Haemorrhage and resuscitation resulted (within 4 h after resuscitation) in a delayed fall in blood pressure (circulatory failure) as well as in rises in the serum levels of (i) urea and creatinine (renal dysfunction), (ii) aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma‐glutamyl‐transferase (γ‐GT) (liver injury and dysfunction), (iii) lipase (pancreatic injury) and (iv) creatine kinase (CK) (neuromuscular injury) (n=10).
Administration (5 min prior to resuscitation of 5‐AIQ) (0.03 mg kg−1 i.v., n=8, or 0.3 mg kg−1 i.v., n=10) reduced (in a dose‐related fashion) the multiple organ injury and dysfunction, but did not affect the circulatory failure, associated with haemorrhagic shock.
Thus, 5‐AIQ abolishes the multiple organ injury caused by severe haemorrhage and resuscitation.

British Journal of Pharmacology (2000) 130, 843–850; doi:10.1038/sj.bjp.0703391
Interaction between copper and zinc at GABAA receptors in acutely isolated cerebellar Purkinje cells of the rat
Authors: Sharonova Irina N , Vorobjev Vladimir S , Haas Helmut L 
Published: January 2005

Nanomolar concentrations of Cu2+ induce a slowly reversible block of GABAA receptor‐mediated currents which can be removed by chelating substances.
The possible interaction of Cu2+ with the Zn2+ binding site on the GABAA receptor complex was studied in acutely isolated Purkinje cells using whole‐cell recording and a fast drug application system.
When Zn2+ was applied together with 2 μM GABA, the Zn2+‐induced block of GABA‐mediated currents was not additive to the Cu2+‐induced block. In the presence of 0.1 μM Cu2+ in the bath solution the degree of inhibition of GABA‐mediated responses by Zn2+ was strongly attenuated.
Preapplication of 100 μM Zn2+ during 10 s, terminated 1 s before exposure to 2 μM GABA did not affect the GABA current in Cu2+‐free solution, but relieved its block by 0.1 μM Cu2+. This effect of Zn2+ was concentration‐dependent with an EC50 of 72 μM.
When the Cu2+‐induced block was removed by histidine, preapplication of Zn2+ did not increase the GABA current, indicating that the relief of Cu2+ block by Zn2+ is the result of its ability to actively remove Cu2+ from the GABA receptor complex.
It is proposed that the inhibitory effects of Zn2+ and Cu2+ on GABA‐induced currents result from an action of these metal ions at distinct, but conformationally linked sites on the GABAA receptor protein. Under physiological conditions Zn2+ would liberate Cu2+ from the GABAA receptor, thus facilitating Cu2+ turnover and its binding by other endogenous chelating molecules.

British Journal of Pharmacology (2000) 130, 851–856; doi:10.1038/sj.bjp.0703392
5‐HT1A receptor agonist‐antagonist binding affinity difference as a measure of intrinsic activity in recombinant and native tissue systems
Authors: Watson J , Collin L , Ho M , Riley G , Scott C , Selkirk J V , Price G W 
Published: January 2005

It has been reported that radiolabelled agonist : antagonist binding affinity ratios can predict functional efficacy at several different receptors. This study investigates whether this prediction is true for recombinant and native tissue 5‐HT1A receptors.
Saturation studies using [3H]‐8‐OH‐DPAT and [3H]‐MPPF revealed a single, high affinity site (KD∼1 nM) in HEK293 cells expressing human 5‐HT1A receptors and rat cortex. In recombinant cells, [3H]‐MPPF labelled 3–4 fold more sites than [3H]‐8‐OH‐DPAT suggesting the presence of more than one affinity state of the receptor. [3H]‐Spiperone labelled a single, lower affinity site in HEK293 cells expressing h5‐HT1A receptors but did not bind to native tissue 5‐HT1A receptors. These data suggest that, in transfected HEK293 cells, human 5‐HT1A receptors exist in different affinity states but in native rat cortical tissue the majority of receptors appear to exist in the high agonist affinity state.
Receptor agonists inhibited [3H]‐MPPF binding from recombinant 5‐HT1A receptors in a biphasic manner, whereas antagonists and partial agonists gave monophasic inhibition curves. All compounds displaced [3H]‐8‐OH‐DPAT and [3H]‐spiperone binding in a monophasic manner. In rat cortex, all compounds displaced [3H]‐MPPF and [3H]‐8‐OH‐DPAT in a monophasic manner.
Functional evaluation of compounds, using [35S]‐GTPγS binding, produced a range of intrinsic activities from full agonism, displayed by 5‐HT and 5‐CT to inverse agonism displayed by spiperone.
[3H]‐8‐OH‐DPAT : [3H]‐MPPF pKi difference correlated well with functional intrinsic activity (r=0.86) as did [3H]‐8‐OH‐DPAT : [3H]‐spiperone pKi difference with functional intrinsic activity (r=0.96).
Thus agonist : antagonist binding affinity differences may be used to predict functional efficacy at human 5‐HT1A receptors expressed in HEK293 cells where both high and low agonist affinity states are present but not at native rat cortical 5‐HT1A receptors in which only the high agonist affinity state was detectable.

British Journal of Pharmacology (2000) 130, 1108–1114; doi:10.1038/sj.bjp.0703394
Inhibition of mitochondrial proton F0F1‐ATPase/ATP synthase by polyphenolic phytochemicals
Authors: Zheng Jianbiao , Ramirez Victor D 
Published: January 2005

Mitochondrial proton F0F1‐ATPase/ATP synthase synthesizes ATP during oxidative phosphorylation. In this study, we examined the effects of several groups of polyphenolic phytochemicals on the activity of the enzyme.
Resveratrol, a stilbene phytoalexin that is present in grapes and red wine, concentration‐dependently inhibited the enzymatic activity of both rat brain and liver F0F1‐ATPase/ATP synthase (IC50 of 12–28 μM).
Screening of other polyphenolic phytochemicals using rat brain F0F1‐ATPase activity resulted in the following ranking potency (IC50 in parenthesis): piceatannol (8 μM)>resveratrol (19 μM)=(−)epigallocatechin gallate (17 μM)>(−)epicatechin gallate, curcumin (45 μM)>genistein=biochanin A=quercetin=kaempferol=morin (55–65 μM)>phloretin=apigenin=daidzein (approx. 100 μM). Genistin, quercitrin, phloridzin, (+)catechin, (+)epicatechin, (−)epicatechin and (−)epigallocatechin had little effect at similar concentrations. Tannic acid, theaflavins (tea extract) and grape seed proanthocyanidin extract (GSPE) had IC50 values of 5, 20 and 30 μg ml−1, respectively. Several monophenolic antioxidants and non‐phenolic compounds were ineffective at concentrations of 210 μM or higher.
The inhibition of F0F1‐ATPase by resveratrol and genistein was non‐competitive in nature.
The effects of polyphenolic phytochemicals were additive.
Both resveratrol and genistein had little effect on the Na+/K+‐ATPase activity of porcine cerebral cortex, whereas quercetin had similar inhibitory potency as for F0F1‐ATPase.
In conclusion, the ATP synthase is a target for dietary phytochemicals. This pharmacological property of these phytochemicals should be included in the examination of their health benefits as well as potential cytotoxicity.

British Journal of Pharmacology (2000) 130, 1115–1123; doi:10.1038/sj.bjp.0703397
On the regulation of ischaemia‐induced glutamate efflux from rat cortex by GABA; in vitro studies with GABA, clomethiazole and pentobarbitone
Authors: Nelson R M , Green A R , Lambert D G , Hainsworth A H 
Published: January 2005

Prisms of adult rat cortex were maintained in vitro in either aerobic conditions (control) or conditions simulating an acute ischaemic challenge (hypoxia with no added glucose).
Endogenous glutamate efflux increased with time in ischaemic conditions, being 2.7 fold higher than control efflux at 45 min. Returning prisms to control solution after 20 min of simulated ischaemia resulted in glutamate efflux returning to near‐control values. Endogenous GABA efflux in ischaemic conditions also increased, being 4.5 fold higher than control efflux at 45 min.
Ischaemia‐induced glutamate efflux was not accompanied by increased lactate dehydrogenase efflux and was unaltered by omitting calcium from the extra‐cellular solution and adding EGTA (0.1 mM).
Both GABA and the GABA‐mimetic clomethiazole inhibited ischaemia‐induced glutamate efflux, with IC50 values of 26 and 24 μM respectively. The maximum inhibition by either drug was 60–70%. Bicuculline (10 μM) abolished the inhibitory effect of GABA (100 μM) but not clomethiazole (100 μM). Picrotoxin (100 μM) abolished the action of both GABA and clomethiazole.
Pentobarbitone inhibited glutamate efflux at 100–300 μM (maximal inhibition: 39%). Bicuculline (10 μM) abolished this effect.
These data suggest that ischaemia‐induced glutamate efflux from rat cerebral cortex is calcium‐independent and not due to cell damage up to 45 min. The inhibitory effect of GABA, clomethiazole and pentobarbitone on ischaemia‐induced glutamate efflux appears to be mediated by GABAA receptors. The results suggest that clomethiazole, unlike pentobarbitone, is able to activate the GABAA receptor‐linked chloride channel directly and not merely potentiate the effect of endogenous GABA.

British Journal of Pharmacology (2000) 130, 1124–1130; doi:10.1038/sj.bjp.0703398
Different intrinsic activities of bucindolol, carvedilol and metoprolol in human failing myocardium
Authors: Maack C , Cremers B , Flesch M , Höper A , Südkamp M , Böhm M 
Published: January 2005

Clinical studies have shown different effects of β‐blockers on the β‐adrenergic system, tolerability and outcome in patients with heart failure.
The study examines β‐adrenoceptor‐G‐protein coupling and intrinsic activity of bucindolol, carvedilol and metoprolol in human ventricular myocardium.
Radioligand binding studies ([125I]‐Iodocyanopindolol) were performed in membrane preparations of human failing and nonfailing myocardium. Functional experiments were carried out in isolated muscle preparations of human left ventricular myocardium from failing hearts.
Bucindolol and carvedilol bound non‐selectively to β1‐ and β2‐adrenoceptors and exerted guanine nucleotide modulatable binding. Metoprolol was 35‐fold β1‐selective and lacked guanine nucleotide modulatable binding.
All β‐blockers antagonized isoprenaline‐induced enhancement of contractility.
In preparations in which the coupling of the stimulatory G‐protein to adenylate cyclase was facilitated by forskolin, bucindolol increased force of contraction in three and decreased it in five experiments. Carvedilol increased force in one and decreased it in six experiments. Metoprolol decreased force in all experiments by 89.4±2.2% (P<0.01 metoprolol vs carvedilol and bucindolol). The negative inotropic effect of metoprolol was antagonized by bucindolol.
It is concluded that differences in intrinsic activity can be detected in human myocardium and have an impact on cardiac contractility. In human ventricular myocardium, bucindolol displays substantially higher intrinsic activity than metoprolol and carvedilol. Bucindolol can behave as partial agonist or partial inverse agonist depending on the examined tissue.
Differences in intrinsic activity may contribute to differences in β‐adrenoceptor regulation and possibly to differences in tolerability and outcomes of patients with heart failure.

British Journal of Pharmacology (2000) 130, 1131–1139; doi:10.1038/sj.bjp.0703400
Apocynin inhibits peroxynitrite formation by murine macrophages
Authors: Muijsers R B R , Van Den Worm E , Folkerts G , Beukelman C J , Koster A S , Postma D S , Nijkamp F P 
Published: January 2005

Peroxynitrite (ONOO−) the highly reactive coupling product of nitric oxide and superoxide, has been implicated in the pathogenesis of an increasing number of (inflammatory) diseases. At present, however, selective peroxynitrite antagonizing agents with therapeutic potential are not available. Therefore, the NADPH‐oxidase inhibitor apocynin (4‐hydroxy‐3‐methoxy‐acetophenone) was tested for its ability to inhibit peroxynitrite formation in vitro
The murine macrophage cell‐line J774A.1, stimulated with IFNγ/LPS, was used as a model. Conversion of 123‐dihydrorhodamine (123‐DHR) to its oxidation product 123‐rhodamine was used to measure peroxynitrite production.
Stimulated peroxynitrite formation could be completely inhibited by apocynin, by the superoxide scavenger TEMPO as well as by the nitric oxide synthase inhibitor aminoguanidine. Apocynin and aminoguanidine specifically inhibited superoxide and nitric oxide formation respectively as confirmed by measuring lucigenin enhanced chemiluminescence and nitrite accumulation.
It is concluded that J774A.1 macrophages produce significant amounts of peroxynitrite, which is associated with nitric oxide production and NADPH‐oxidase dependent superoxide formation. The NADPH‐oxidase inhibitor apocynin proved to be a potent inhibitor of both superoxide and peroxynitrite formation by macrophages, which may be of future therapeutic significance in a wide range of inflammatory disorders.

British Journal of Pharmacology (2000) 130, 932–936; doi:10.1038/sj.bjp.0703401
Murine myeloid progenitor responses to GM‐CSF and eosinophil precursor responses to IL‐5 represent distinct targets for downmodulation by prostaglandin E2
Authors: Gaspar Elsas Maria Ignez C , Joseph Danielle , Lintomen Letícia , Maximiano Elisabeth S , Bodstein Michael , Elsas P Xavier , Vargaftig B Boris 
Published: January 2005

Because Prostaglandin E2 (PGE2) and dibutiryl cyclic AMP (dbcAMP) modulate the production and effects of haemopoietic cytokines in allergy, we examined their ability to modulate responses of myeloid progenitors to GM‐CSF, and of eosinophil precursors to IL‐5.
The ability of PGE2, dbcAMP, rolipram, forskolin, dbcGMP and PGD2, to modulate the responses to GM‐CSF and IL‐5 in colony formation (progenitor) and eosinophil differentiation (precursor) assays using bone‐marrow from nonsensitized or from intranasally‐challenged, ovalbumin‐sensitized mice of five strains was studied.
PGE2 (10−7 M) inhibited GM‐CSF‐stimulated colony formation in bone‐marrow from BP‐2 mice. This effect was duplicated by dbcAMP (0.3–1×10−6 M), Rolipram (10−5 M) and forskolin (3×10−5 M), but not Prostaglandin D2 (10−6 M). Inhibition affected similarly all myeloid colony types. Progenitors from sensitized and challenged BP‐2 mice were also inhibited by PGE2 and cyclic AMP. PGE2 inhibited progenitors from C57BL/10, CBA/J and A/J, but not BALB/c mice. However, BALB/c progenitors were sensitive to dbcAMP and Forskolin (10−4 M). In contrast, in precursor assays, PGE2 (10−7–10−9 M) blocked responses to IL‐5 in bone‐marrow from BP‐2 and BALB/c mice, either naïve or sensitized and challenged, to a similar extent. PGD2 (10−6 M) was ineffective, as was PGE2 (10−7 M), if added after 48 h of culture.
In conclusion, PGE2 inhibits the responses of bone‐marrow myeloid progenitors to GM‐CSF and of eosinophil precursors to IL‐5, in naïve or ovalbumin sensitized and challenged mice. These effects are duplicated by cyclic AMP‐elevating agents. In the BALB/c strain, the resistance of progenitors, but not precursors, to PGE2 inhibition, indicates these developmental stages are separate targets for PGE2 modulation.

British Journal of Pharmacology (2000) 130, 1362–1368; doi:10.1038/sj.bjp.0703403
Blockade of phencyclidine‐induced effects by a nitric oxide donor
Authors: Bujas‐Bobanovic M , Bird D C , Robertson H A , Dursun S M 
Published: January 2005

Phencyclidine (PCP) is widely used as an animal model of schizophrenia. The aim of this study was to better understand the role of nitric oxide (NO) in the mechanism of action of PCP and to determine whether positive NO modulators may provide a new approach to the treatment of schizophrenia.
The effects of the NO donor, sodium nitroprusside (SNP), were studied in PCP‐treated rats. Following drug administration, behavioural changes and the expression of c‐fos, a metabolic marker of functional pathways in the brain, were simultaneously monitored.
Acute PCP (5 mg kg−1, i.p.) treatment induced a complex behavioural syndrome, consisting of hyperlocomotion, stereotyped behaviours and ataxia. Treatment with SNP (2–6 mg kg−1, i.p.) by itself produced no effect on any behaviour studied but completely abolished PCP‐induced behaviour in a dose‐ and time‐dependent manner.
PCP had differential regional effects on c‐fos expression in rat brain, suggesting regionally different patterns of neuronal activity. The most prominent immunostaining was observed in the cortical regions. Pre‐treatment with SNP blocked PCP‐induced c‐fos expression at doses similar to those that suppress PCP‐induced behavioural effects.
These results implicate the NO system in the mechanism of action of PCP. The fact that SNP abolished effects of PCP suggests that drugs targeting the glutamate‐NO system may represent a novel approach to the treatment of PCP‐induced psychosis and schizophrenia.

British Journal of Pharmacology (2000) 130, 1005–1012; doi:10.1038/sj.bjp.0703406