bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impaired vasodilator response to organic nitrates in isolated basilar arteries
Authors: Martens Dorothee , Kojda Georg 
Published: January 2005

The differential responsiveness of various sections and regions in the vascular system to the vasodilator activity of organic nitrates is important for the beneficial antiischaemic effects of these drugs. In this study we examined the vasodilator activity of organic nitrates in cerebral arteries, where vasodilation causes substantial nitrate induced headache.
Isolated porcine basilar and coronary arteries were subjected to increasing concentrations of glyceryl trinitrate (GTN), isosorbide‐5‐nitrate (ISMN) and pentaerythritol tetranitrate (PETN). S‐nitroso‐N‐acetyl‐D,L‐penicillamine (SNAP) and endothelium‐dependent vasodilation was investigated for comparison purpose.
The vasodilator potency (halfmaximal effective concentration in −logM) of GTN (4.33±0.1, n=8), ISMN (1.61±0.07, n=7) and PETN (>10 μM, n=7) in basilar arteries was more than 100 fold lower than that of GTN (6.52±0.06, n=12), ISMN (3.66±0.08, n=10) and PETN (6.3±0.13, n=8) observed in coronary arteries.
In striking contrast, the vasodilator potency of SNAP (halfmaximal effective concentration in −logM) was almost similar in basilar (7.76±0.05, n=7) and coronary arteries (7.59±0.05, n=9). Likewise, no difference in endothelium dependent relaxation was observed.
Denudation of the endothelium resulted in a small increase of the vasodilator potency (halfmaximal effective concentration in −logM) of GTN (4.84±0.09, n=7, P<0.03) in basilar arteries and similar results were obtained in the presence of the NO‐synthase inhibitor Nω‐nitro‐L‐arginine (4.59±0.05, n=9, P<0.03).
These results suggest that cerebral conductance blood vessels such as porcine basilar arteries seems to have a reduced expression and/or activity of certain cellular enzymatic electron transport systems such as cytochrome P450 enzymes, which are necessary to bioconvert organic nitrates to NO.

British Journal of Pharmacology (2001) 132, 30–36; doi:10.1038/sj.bjp.0703768
Pre‐ and postjunctional protective effect of neocuproine on the nitrergic neurotransmitter in the mouse gastric fundus
Authors: De Man Joris G , Moreels Tom G , De Winter Benedicte Y , Herman Arnold G , Pelckmans Paul A 
Published: January 2005

Electrical field stimulation (EFS) of non‐adrenergic non‐cholinergic nerves of the mouse gastric fundus induced frequency‐dependent transient relaxations which were mimicked by nitric oxide (NO), added as acidified NaNO2. The NO donors S‐nitrosocysteine, S‐nitrosoglutathione, SIN‐1 and hydroxylamine induced sustained concentration‐dependent relaxations. The NO synthase blocker L‐nitro arginine (L‐NOARG; 300 μM) abolished the relaxations to EFS without affecting the relaxations to NO.
The copper(I) chelator neocuproine (10 μM) enhanced the relaxations to EFS and NO but inhibited those to S‐nitrosocysteine and S‐nitrosoglutathione. Neocuproine potentiated the relaxations to SIN‐1, which releases NO extracellularly, without affecting the relaxations to hydroxylamine, which releases NO intracellularly.
The potentiating effect of neocuproine on the relaxations to EFS was more pronounced after inhibition of catalase with 3‐amino‐1,2,4‐triazole (1 mM) but not after inhibition of Cu/Zn superoxide dismutase (SOD) with diethyl dithiocarbamic acid (DETCA, 1 mM). The potentiating effect of neocuproine on relaxations to NO was not altered by 3‐amino‐1,2,4‐triazole or DETCA treatment.
The relaxations to EFS were significantly inhibited by the oxidants hydrogen peroxide (70 μM) and duroquinone (10 μM) but only after inhibition of catalase with 3‐amino‐1,2,4‐triazole or after inhibition of Cu/ZnSOD with DETCA respectively.
Our results suggest that neocuproine can act as an antioxidant in the mouse gastric fundus and that both catalase and Cu/ZnSOD protect the nitrergic neurotransmitter from oxidative breakdown. Since inhibition of catalase but not inhibition of Cu/ZnSOD potentiated the effect of neocuproine on relaxations to EFS without affecting the relaxations to NO, catalase may protect the nitrergic neurotransmitter mainly at a prejunctional site whereas Cu/ZnSOD protects at a postjunctional site.

British Journal of Pharmacology (2001) 132, 277–285; doi:10.1038/sj.bjp.0703772
Potentiation of cytokine induction of group IIA phospholipase A2 in rat mesangial cells by ATP and adenosine via the A2A adenosine receptor
Authors: Scholz‐Pedretti Kirsten , Pfeilschifter Josef , Kaszkin Marietta 
Published: January 2005

In rat mesangial cells extracellular nucleotides were found to increase arachidonic acid release by a cytosolic phospholipase A2 through the P2Y2 purinergic receptor.
In this study we investigated the effects of ATP and UTP on interleukin‐1β (IL‐1β)‐induced mRNA expression and activity of group IIA phospholipase A2 (sPLA2‐IIA) in rat mesangial cells.
Treatment of cells for 24 h with extracellular ATP potentiated IL‐1β‐stimulated sPLA2‐IIA induction, whereas UTP had no effect.
We obtained the following evidence that the P2Y2 receptor is not involved in the potentiation of sPLA2‐IIA induction: (i) ATP‐γ‐S had no enhancing effect; (ii) suramin, a P2 receptor antagonist, did not inhibit ATP‐mediated potentiation; (iii) inhibition of degradation of extracellular nucleotides by the 5′‐ectonucleotidase inhibitor AOPCP did not enhance sPLA2‐IIA induction and (iv) adenosine deaminase treatment completely abolished the ATP‐mediated potentiation of sPLA2‐IIA induction.
In contrast, treatment of mesangial cells with adenosine or the A2A receptor agonist CGS 21680 mimicked the effects of ATP in enhancing IL‐1β‐stimulated sPLA2‐IIA induction, whereas the specific A2A receptor antagonist ZM 241385 completely abolished the potentiating effect of ATP or adenosine.
The protein kinase A inhibitor Rp‐8‐Br‐cyclic AMPS dose‐dependently inhibited the enhancing effect of ATP or adenosine indicating the participation of an adenosine receptor‐mediated cyclic AMP‐dependent signalling pathway.
These data indicate that ATP mediates proinflammatory long‐term effects in rat mesangial cells via its degradation product adenosine through the A2A receptor resulting in potentiation of sPLA2‐IIA induction.

British Journal of Pharmacology (2001) 132, 37–46; doi:10.1038/sj.bjp.0703774
Role of PGE2 in protease‐activated receptor‐1, −2 and −4 mediated relaxation in the mouse isolated trachea
Authors: Lan Rommel S , Knight Darryl A , Stewart Geoff A , Henry Peter J 
Published: January 2005

The potential mediator role of the prostanoid PGE2 in airway smooth muscle relaxations induced by peptidic and proteolytic activators of PAR‐1, PAR‐2, PAR‐3 and PAR‐4 was investigated in carbachol‐precontracted mouse isolated tracheal segments.
The tethered ligand domain sequences of murine PAR‐1 (SFFLRN‐NH2), PAR‐2 (SLIGRL‐NH2) and PAR‐4 (GYPGKF‐NH2), but not PAR‐3 (SFNGGP‐NH2), induced smooth muscle relaxation that was abolished by the non‐selective cyclo‐oxygenase (COX) inhibitor, indomethacin. The relative order for mean peak relaxation was SLIGRL‐NH2>GYPGKF‐NH2 ∼amp; SFFLRN‐NH2>SFNGGP‐NH2.
SFFLRN‐NH2, SLIGRL‐NH2 and GYPGKF‐NH2, but not SFNGGP‐NH2, induced significant PGE2 release that was abolished by indomethacin. Like that for relaxation, the relative order for mean PGE2 release was SLIGRL‐NH2>GYPGKF‐NH2>SFFLRN‐NH2>SFNGGP‐NH2.
In dose‐response studies, SLIGRL‐NH2 induced concentration‐dependent increases in PGE2 release (EC50=20.4 μM) and smooth muscle relaxation (EC50=15.8 μM).
The selective COX‐2 inhibitor, nimesulide, but not the COX‐1 inhibitor valeryl salicylate, significantly attenuated SLIGRL‐NH2‐induced smooth muscle relaxation and PGE2 release.
Exogenously applied PGE2 induced potent smooth muscle relaxation (EC50=60.3 nM) that was inhibited by the mixed DP/EP1/EP2 prostanoid receptor antagonist, AH6809. SLIGRL‐NH2‐induced relaxation was also significantly inhibited by AH6809.
In summary, the results of this study strongly suggest that PAR‐mediated relaxation in murine tracheal smooth muscle is dependent on the generation of the spasmolytic prostanoid, PGE2. PAR‐stimulated PGE2 release appears to be generated preferentially by COX‐2 rather than COX‐1, and induces relaxation via activation of the EP2 receptor.

British Journal of Pharmacology (2001) 132, 93–100; doi:10.1038/sj.bjp.0703776
Pharmacological block of the slow component of the outward delayed rectifier current (IKs) fails to lengthen rabbit ventricular muscle QTc and action potential duration
Authors: Lengyel Csaba , Iost Norbert , Virág László , Varró András , Lathrop David A , Papp Julius Gy 
Published: January 2005

The effects of IKs block by chromanol 293B and L‐735,821 on rabbit QT‐interval, action potential duration (APD), and membrane current were compared to those of E‐4031, a recognized IKr blocker. Measurements were made in rabbit Langendorff‐perfused whole hearts, isolated papillary muscle, and single isolated ventricular myocytes.
Neither chromanol 293B (10 μM) nor L‐735,821 (100 nM) had a significant effect on QTc interval in Langendorff‐perfused hearts. E‐4031 (100 nM), on the other hand, significantly increased QTc interval (35.6±3.9%, n=8, P<0.05).
Similarly both chromanol 293B (10 μM) and L‐735,821 (100 nM) produced little increase in papillary muscle APD (less than 7%) while pacing at cycle lengths between 300 and 5000 ms. In contrast, E‐4031 (100 nM) markedly increased (30 – 60%) APD in a reverse frequency‐dependent manner.
In ventricular myocytes, the same concentrations of chromanol 293B (10 μM), L‐735,821 (100 nM) and E‐4031 (1 μM) markedly or totally blocked IKs and IKr, respectively.
IKs tail currents activated slowly (at +30 mV, τ=888.1±48.2 ms, n=21) and deactivated rapidly (at −40 mV, τ=157.1±4.7 ms, n=22), while IKr tail currents activated rapidly (at +30 mV, τ=35.5±3.1 ms, n=26) and deactivated slowly (at −40 mV, τ1=641.5±29.0 ms, τ2=6531±343, n=35). IKr was estimated to contribute substantially more to total current density during normal ventricular muscle action potentials (i.e., after a 150 ms square pulse to +30 mV) than does IKs.
These findings indicate that block of IKs is not likely to provide antiarrhythmic benefit by lengthening normal ventricular muscle QTc, APD, and refractoriness over a wide range of frequencies.

British Journal of Pharmacology (2001) 132, 101–110; doi:10.1038/sj.bjp.0703777
Vasoconstrictor actions of isoprostanes via tyrosine kinase and Rho kinase in human and canine pulmonary vascular smooth muscles
Authors: Janssen L J , Premji M , Netherton S , Coruzzi J , Lu‐Chao H , Cox P G 
Published: January 2005

We examined the effects of several E‐ring and F‐ring isoprostanes on mechanical activity in pulmonary artery and vein.
8‐iso PGE2 and 8‐iso PGF2α were powerful spasmogens in human vasculature and in canine pulmonary vein. 8‐iso PGE1 and 8‐iso PGF2β also exhibited moderate spasmogenic activity in canine pulmonary vein; 8‐iso PGF1α, 8‐iso PGF1β, and 8‐iso PGF3α were generally ineffective. Canine pulmonary arteries did not exhibit excitatory responses to any of the isoprostanes.
The spasmogenic effects of 8‐iso PGE2 were markedly attenuated by the TP‐receptor blocker ICI 192605 and by the EP‐receptor blocker AH 6809 (−log KB=8.4 and 5.7, respectively). PGE2 was a very weak agonist (∼100 fold less so than 8‐iso PGE2).
In the presence of ICI 192605 (10−6 M), 8‐iso PGE1 evoked modest dose‐dependent relaxations in human and canine pulmonary vein, and in canine pulmonary artery, but not in the human pulmonary artery. The other isoprostanes were generally ineffective as vasodilators in the pulmonary vasculature of both species.
The spasmogenic effects of 8‐iso PGE2 and 8‐iso PGF2α did not involve elevation of [Ca2+]i.
8‐iso PGE2‐evoked contractions were blocked by inhibitors of tyrosine kinase (genistein) and Rho kinase (Y 27632 and HA 1077), but not by inhibitors of protein kinase C (calphostin C or chelerythrine), mitogen‐activated protein kinase kinase (PD 98059) or p38‐kinase (SB 203580).
The actions of 8‐isoprostanes in the lungs are compound‐, species‐ and tissue‐dependent. Several isoprostanes evoke vasoconstriction: in the case of 8‐iso PGE2, this involves activation of TP‐receptors, tyrosine kinases and Rho kinases. 8‐iso PGE1 is also able to cause vasodilation.

British Journal of Pharmacology (2001) 132, 127–134; doi:10.1038/sj.bjp.0703784
Modulation of cell adhesion and viability of cultured murine bone marrow cells by arsenobetaine, a major organic arsenic compound in marine animals
Authors: Sakurai Teruaki , Fujiwara Kitao 
Published: January 2005

In this study, we investigated the biological effects of trimethyl (carboxymethyl) arsonium zwitterion, namely arsenobetaine (AsBe), which is a major organic arsenic compound in marine animals using murine bone marrow (BM) cells and compared them with those of an inorganic arsenical, sodium arsenite, in vitro.
Sodium arsenite showed strong cytotoxicity in BM cells, and its IC50 was 6 μM. In contrast, AsBe significantly enhanced the viability of BM cells in a dose‐dependent manner during a 72‐h incubation; about a twofold increase in the viability of cells compared with that of control cells cultured with the medium alone was observed with a μM level of AsBe.
In morphological investigations, AsBe enhanced the numbers of large mature adherent cells, especially granulocytes, during a 72‐h BM culture. When BM cells were cultured together with AsBe and a low dose (1 u ml−1) of recombinant murine granulocyte/macrophage colony‐stimulating factor (rMu GM‐CSF), significant additive‐like increasing effects were observed on the numbers of both granulocytes and macrophages originated from BM cells. However, AsBe did not cause proliferation of BM cells at all as determined by colony‐forming assay using a gelatious medium.
These findings demonstrate the unique and potent biological effects in mammalian cells of AsBe, a major organic arsenic compound in various marine animals which are ingested daily as seafood in many countries.

British Journal of Pharmacology (2001) 132, 143–150; doi:10.1038/sj.bjp.0703790
Pharmacokinetic‐pharmacodynamic modelling in the early development phase of anti‐psychotics: a comparison of the effects of clozapine, S 16924 and S 18327 in the EEG model in rats
Authors: Parker T J , Della Pasqua O E , Loizillon E , Chezaubernard C , Jochemsen R , Danhof M 
Published: January 2005

The use of pharmacokinetic/pharmacodynamic (PK/PD) analysis in early compound development was investigated in the rat for two developmental anti‐psychotic compounds with clozapine as a positive control.
Three plasma samples were collected from each of eight animals according to a pre‐defined sampling matrix allowing a total of 12 time points for PK analysis. Quantitative electroencephalography (QEEG), particularly the theta and beta frequencies, was used as a measurement of pharmacological effect.
PK/KD modelling of the sparse PK data available relative to a rich set of PD data was achieved using a population approach in NONMEM (IV). Individual PK parameter estimates were incorporated into a PK/PD model.
Qualitative EEG changes in rat and human were similar for clozapine, but different for the two developmental compounds, suggesting that changes in these PD parameters may not be specifically related to the anti‐psychotic activity.
Although no definitive data are available concerning the signal specificity of EEG frequency bands with respect to dopaminergic or serotonergic receptor activity, qualitative and quantitative differences seen in EEG parameters are likely to result from the multiple receptor occupancy for these compounds.
The results confirm the value of population PK/PD modelling in conjunction with sparse sampling to enable determination of concentration effect relationships in the pre‐clinical development programme of CNS‐active drugs.

British Journal of Pharmacology (2001) 132, 151–158; doi:10.1038/sj.bjp.0703791
Simvastatin inhibits noradrenaline‐induced hypertrophy of cultured neonatal rat cardiomyocytes
Authors: Luo Jian‐Dong , Xie Fang , Zhang Wei‐Wen , Ma Xiao‐Dong , Guan Jin‐Xia , Chen Xiu 
Published: January 2005

Oxidative mechanisms have been implicated in neonatal cardiomyocyte hypertrophy. We and others have shown that a HMG‐CoA reductase inhibitor preserves endogenous antioxidant enzyme activity and inhibits cardiac hypertrophy in vivo. We therefore have examined whether noradrenaline (NA) induces the generation of reactive oxygen species (ROS) during its induction of neonatal cardiomyocyte hypertrophy and whether simvastatin, a HMG‐CoA reductase inhibitor, attenuates ROS production and thus NA‐induced hypertrophy of cardiomyocytes.
NA increased the intracellular ROS levels in a concentration‐dependent manner. This increase of ROS was significantly inhibited by simvastatin and catalase. Prazosin partially suppressed NA‐induced increase of ROS and beating, while preincubation with both prazosin and propranolol completely abolished NA‐evoked increase of ROS and beating. Simvastatin did not affect NA‐induced increase of beating.
The NA‐induced increase of protein content was partially suppressed by prazosin and completely abolished by preincubation with both prazosin and propranolol. Simvastatin inhibited the increase of NA‐induced increase of RNA content and [3H]‐leucine incorporation in a concentration‐dependent manner. Mevalonic acid (MVA) reversed the inhibition of NA‐induced RNA and protein increase by simvastatin. Catalase also inhibited the NA‐induced increase of RNA and protein.
We conclude that the inhibitory effects of simvastatin on myocyte hypertrophy were associated with its antioxidant effects and inhibition of MVA‐metabolism pathway in neonatal rat cardiomyocytes. NA‐induced increases of intracellular ROS and cardiomyocyte hypertrophy requires both α and β adrenoceptors activation in neonatal rat cardiomyocytes. The increases of ROS induced by NA is required for hypertrophy.

British Journal of Pharmacology (2001) 132, 159–164; doi:10.1038/sj.bjp.0703792
Knockdown of spinal metabotropic glutamate receptor 1 (mGluR1) alleviates pain and restores opioid efficacy after nerve injury in rats
Authors: Fundytus Marian E , Yashpal Kiran , Chabot Jean‐Guy , Osborne Michael G , Lefebvre Celeste D , Dray Andy , Henry James L , Coderre Terence J 
Published: January 2005

Nerve injury often produces long‐lasting spontaneous pain, hyperalgesia and allodynia that are refractory to treatment, being only partially relieved by clinical analgesics, and often insensitive to morphine. With the aim of assessing its therapeutic potential, we examined the effect of antisense oligonucleotide knockdown of spinal metabotropic glutamate receptor 1 (mGluR1) in neuropathic rats.
We chronically infused rats intrathecally with either vehicle, or 50 μg day−1 antisense or missense oligonucleotides beginning either 3 days prior to or 5 days after nerve injury. Cold, heat and mechanical sensitivity was assessed prior to any treatment and again every few days after nerve injury.
Here we show that knockdown of mGluR1 significantly reduces cold hyperalgesia, heat hyperalgesia and mechanical allodynia in the ipsilateral (injured) hindpaw of neuropathic rats.
Moreover, we show that morphine analgesia is reduced in neuropathic rats, but not in sham‐operated rats, and that knockdown of mGluR1 restores the analgesic efficacy of morphine.
We also show that neuropathic rats are more sensitive to the excitatory effects of intrathecally injected N‐methyl‐D‐aspartate (NMDA), and have elevated protein kinase C (PKC) activity in the spinal cord dorsal horn, two effects that are reversed by knockdown of mGluR1.
These results suggest that activity at mGluR1 contributes to neuropathic pain through interactions with spinal NMDA receptors and PKC, and that knockdown of mGluR1 may be a useful therapy for neuropathic pain in humans, both to alleviate pain directly, and as an adjunct to opioid analgesic treatment.

British Journal of Pharmacology (2001) 132, 354–367; doi:10.1038/sj.bjp.0703810
Effect of 4‐trifluoromethyl derivatives of salicylate on nuclear factor κB‐dependent transcription in human astrocytoma cells
Authors: Hernández Marita , Arriba Alberto Fernández de , Merlos Manel , Fuentes Lucía , Crespo Mariano Sánchez , Nieto María Luisa 
Published: January 2005

The effect of two derivatives of salicylate, 2‐hydroxy‐4‐trifluoromethylbenzoic acid (HTB) and 2‐acetoxy‐4‐trifluoromethylbenzoic acid (triflusal), on the expression of several proteins displaying pro‐inflammatory activities the regulation of which is associated to the transcription factor NF‐κB, was assayed in the human astrocytoma cell line 1321N1.
Tumour necrosis factor‐α (TNF‐α) activated NF‐κB as judged from both the appearance of κB‐binding activity in the nuclear extracts, the degradation of IκB proteins in the cell lysates, and the activation of IκB kinases using an immunocomplex kinase assay with glutathione S‐transferase (GST)‐IκB proteins as substrates.
HTB up to 3 mM did not inhibit the nuclear translocation of NK‐κB/Rel proteins as judged from electrophoretic mobility‐shift assays; however, HTB inhibited the degradation of IκBβ without significantly affecting the degradation of both IκBα and IκBε.
In keeping with their inhibitory effect on IκBβ degradation in the cell lysates, both HTB and triflusal inhibited the phosphorylation of GST‐IκBβ elicited by TNF‐α, without affecting the phosphorylation of GST‐IκBα.
The effect of both HTB and triflusal on κB‐dependent trans‐activation was studied by assaying the expression of both cyclo‐oxygenase‐2 (COX‐2) and vascular cell adhesion molecule‐1 (VCAM‐1). HTB and triflusal inhibited in a dose‐dependent manner the expression of COX‐2 and VCAM‐1 mRNA and the induction of COX‐2 protein at therapeutically relevant concentrations.
These findings show the complexity of the biochemical mechanisms underlying the activation of NF‐κB in the different cell types and extend the anti‐inflammatory effects of HTB and triflusal to neural cells.

British Journal of Pharmacology (2001) 132, 547–555; doi:10.1038/sj.bjp.0703820
Effects of extracellular nucleotides and nucleosides on prostate carcinoma cells
Authors: Janssens Rodolphe , Boeynaems Jean‐Marie 
Published: January 2005

The purpose of this work was to characterize the receptors involved in the action of nucleotides on the human prostate carcinoma cell lines LNCaP, PC‐3 and DU145.
Northern blotting revealed the presence of P2Y2, P2Y6 and P2Y11 messengers in the three cell lines. P2Y1 mRNA was only observed in the DU145 cells. In both PC‐3 and DU145 cells, ATP and UTP stimulated inositol phosphate accumulation in an equipotent, equiactive and non‐additive way, suggesting the involvement of P2Y2 receptors. ATP also increased cyclic AMP, but this effect is likely to result from degradation into adenosine and activation of A2 receptor. A2 receptor activation led to a synergistic enhancement of prostate‐specific antigen secretion induced by vasoactive intestinal peptide.
RT – PCR experiments detected the expression of the P2X4 and P2X5 receptors in the DU145 cells and the P2X4, P2X5 and P2X7 receptors in the PC‐3 cells. The calcium influx induced by BzATP confirmed the functional expression of P2X receptors.
ATP inhibited the growth of PC‐3 and DU145 cells. This effect was mimicked neither by UTP nor by adenosine, indicating that it does not result from phospholipase C or adenylyl cyclase activation. On the contrary, in PC‐3 cells, BzATP reproduced the effect of ATP, which was associated to a moderate decrease of proliferation and an increase of apoptosis. In DU145 cells, ATP was more potent than BzATP and growth inhibition was mainly associated with necrosis. We suggest that P2X receptors might be involved in the inhibition by nucleotides of prostate carcinoma cell growth.

British Journal of Pharmacology (2001) 132, 536–546; doi:10.1038/sj.bjp.0703833