bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancement by galactosamine of lipopolysaccharide(LPS)‐induced tumour necrosis factor production and lethality: its suppression by LPS pretreatment
Authors: Endo Yasuo , Shibazaki Masahiko , Yamaguchi Kouji , Kai Kenzou , Sugawara Shunji , Takada Haruhiko , Kikuchi Hideaki , Kumagai Katsuo 
Published: January 2005

D‐Galactosamine (GalN) depletes UTP primarily in the liver, resulting in decreased RNA synthesis in hepatocytes. Co‐injection of GalN and lipopolysaccharide (LPS) into mice produces fulminant hepatitis with severe hepatic congestion, resulting in rapid death. Although the underlying mechanism is uncertain, GalN enhances the sensitivity to tumour necrosis factor (TNF). Administration of uridine (a precursor of UTP) prior injection of either LPS itself or interleukin‐1 (IL‐1) reduces the lethality of GalN+LPS. The present study focused on the effects of these agents on TNF production.
Intraperitoneal injection of GalN+LPS into mice greatly elevated serum TNF. Although large doses of LPS alone also greatly elevated serum TNF, LPS itself induced neither hepatic congestion nor rapid death. Administration of a macrophage depletor, liposomes encapsulated with dichloromethylene bisphosphonate, reduced both the TNF production and mortality induced by GalN+LPS.
Uridine, when injected 0.5 h after the injection of GalN+LPS, reduced the production of TNF. Prior injection of LPS, but not of IL‐1, also reduced this TNF production.
Serum from LPS‐injected mice reduced the TNF production induced by GalN+LPS, but it was less effective at reducing the lethality. Its ability to reduce TNF production was abolished by heat‐treatment.
We hypothesize that a factor inhibiting TNF production by macrophages is produced by hepatocytes in response to LPS. Possibly, production of this hepatocyte‐derived TNF‐down‐regulator (TNF‐DRh) may be: (i) inhibited by GalN, causing over‐production of TNF by macrophages and (ii) stimulated by LPS‐pretreatment (and restored by uridine), causing reduced TNF production.

British Journal of Pharmacology (1999) 128, 5–12; doi:10.1038/sj.bjp.0702747
Functional characterization of agonists at recombinant human 5‐HT2A, 5‐HT2B and 5‐HT2C receptors in CHO‐K1 cells
Authors: Porter R H P , Benwell K R , Lamb H , Malcolm C S , Allen N H , Revell D F , Adams D R , Sheardown M J 
Published: January 2005

The goal of this study was to characterize the agonist pharmacology of human 5‐HT2A, 5‐HT2B and 5‐HT2C (VSV) receptors expressed in CHO‐K1 (Chinese hamster ovary) cells.
We used a fluorometric imaging plate reader (FLIPR) which allows rapid detection of rises in intracellular calcium levels upon the addition of agonists.
Stimulation of all three receptors by 5‐HT caused a robust concentration dependent increase in intracellular calcium levels. No such effect was observed from non‐transfected control CHO‐K1 cells.
The rank order of potency of agonists at the different receptor subtypes varied. Tryptamines, BW‐723C86, d‐norfenfluramine, Ro 60‐0175 and LSD exhibited the following rank order of potency; 5‐HT2B>5‐HT2C>5‐HT2A. Piperazines such as m‐Chlorophenylpiperazine (mCPP), ORG‐12962, MK‐212 and also ORG‐37684 exhibited a rank order of potency of 5‐HT2C>5‐HT2B>5‐HT2A. The phenylisopropylamines DOI and DOB had a rank order of 5‐HT2A>5‐HT2B>5‐HT2C.
Many agonists tested had partial agonist actions when compared to 5‐HT, and a wide range of relative efficacies were exhibited, which was cell line dependent. For example, mCPP had a relative efficacy of 65% at 5‐HT2C receptors but <25% at either 5‐HT2A or 5‐HT2B receptors.
Interpretation of literature values of functional assays using different cell lines, different receptor expression levels and different receptor isoforms, is complex. Species differences and the previous use of antagonist radioligands to characterize agonist potency in binding assays emphasizes the importance of studying agonists in the same experiment using the same assay conditions and parental cell lines.

British Journal of Pharmacology (1999) 128, 13–20; doi:10.1038/sj.bjp.0702751
A new experimental approach in endothelium‐dependent pharmacological investigations on isolated porcine coronary arteries mounted for impedance planimetry
Authors: Tankó László B , Mikkelsen Erich O , Simonsen Ulf 
Published: January 2005

The aim of this study was to investigate whether the balloon‐based impedance planimetry technique could be a useful tool in endothelium‐dependent investigations.
Porcine large coronary arteries contracted with prostaglandin F2α (PGF2α, 10 μM) did not relax to bradykinin (0.1 nM–0.1 μM), but did relax to sodium nitroprusside (SNP, 10 μM). However, after eversion of the segments, bradykinin induced relaxations with pD2 values and maximal responses of 8.78±0.09 and 75±2% (n=6), respectively.
Incubation with captopril (1 μM) did not reveal a relaxation to bradykinin in the normal vessel configuration and had no influence on the concentration‐relaxation relationship in everted segments.
Lowering the luminal pressure in contracted segments from 131±5 mmHg (isometric, n=5) to 60 mmHg (isobaric, n=5) did not facilitate the action of bradykinin.
Eversion of segments did not influence the concentration‐response relationship for K+ (4.7–125 mM), PGF2α (0.3–30 μM), and SNP (30 nM–30 μM), although the time‐courses of responses were faster when the agents were added from the intimal compared to the adventitial side of the preparation.
In the same everted segment contracted with PGF2α, the concentration‐response relationship for bradykinin was not different under isometric and isobaric conditions.
These results indicate that, (1) reduced endothelium‐dependent relaxations to adventitially administered substances can be ascribed to a diffusion barrier in the vessel wall, while enzymatic degradation, luminal pressure and precontractile responses seem not to play a role, (2) impedance planimetry applied to everted cylindrical segments could be a useful experimental approach in pharmacological studies of endothelium‐dependent responses under isobaric and isometric conditions.

British Journal of Pharmacology (1999) 128, 165–173; doi:10.1038/sj.bjp.0702752
Hepatocyte growth factor regulates human trophoblast motility and invasion: a role for nitric oxide
Authors: Cartwright Judith E , Holden Desmond P , Whitley Guy St J 
Published: January 2005

The expression of hepatocyte growth factor (HGF) is essential for normal placental development although its function is unknown. In this study we examined the effect of HGF on trophoblast cell motility and invasion of fibrin gels and investigated the possible role of nitric oxide (NO) in this process.
The human extravillous trophoblast cell line SGHPL‐4 express both the constitutive and inducible isoforms of nitric oxide synthase (NOS).
HGF significantly stimulates cell motility in monolayer culture, the invasion of fibrin gels and the production of guanosine 3′:5′‐cyclic monophosphate (cyclic GMP).
Invasion, motility and cyclic GMP production were inhibited by Ng‐monomethyl‐L‐arginine (L‐NMMA).
Cell motility was also significantly inhibited by the inducible NOS specific inhibitor 1400 W.
Neither 8 Br‐cyclic GMP nor the NO donor spermine‐NO had any significant effect on basal trophoblast cell motility.
The data presented in this study demonstrate a direct effect of trophoblast‐derived NO synthesis on trophoblast cell function and support the idea that HGF is involved in the regulation of trophoblast invasion through mechanisms that involve the production of NO. However neither exogenous NO nor activation of cyclic GMP‐dependent pathways alone are sufficient to stimulate trophoblast cell motility.

British Journal of Pharmacology (1999) 128, 181–189; doi:10.1038/sj.bjp.0702757
P2Y2 receptor‐mediated inhibition of ion transport in distal lung epithelial cells
Authors: Ramminger S J , Collett A , Baines D L , Murphie H , McAlroy H L , Olver R E , Inglis S K , Wilson S M 
Published: January 2005

Rat foetal distal lung epithelial cells were plated onto permeable supports where they became integrated into epithelial sheets that spontaneously generated short circuit current (ISC).
Apical ATP (100 μM) evoked a transient fall in ISC that was followed by a rise to a clear peak which, in turn, was succeeded by a slowly developing decline to a value below control. Apical UTP evoked an essentially identical response.
UDP and ADP were ineffective whilst ATP had no effect when added to the basolateral solution. These effects thus appear to be mediated by apical P2Y2 receptors.
The rising phase of the responses to ATP/UTP was selectively inhibited by anion transport inhibitors but persisted in the presence of amiloride, which abolished the inhibitory effects of both nucleotides. Thus, apical nucleotides appear to evoke a transient stimulation of anion secretion and sustained inhibition of Na+ absorption.
Basolateral isoprenaline (10 μM) elicited a rise in ISC but subsequent addition of apical ATP reversed this effect. Conversely, isoprenaline restored ISC to its basal level following stimulation with ATP. Apical P2Y2 receptors and basolateral β‐adrenoceptors thus allow their respective agonists to exert mutually opposing effects on ISC.

British Journal of Pharmacology (1999) 128, 293–300; doi:10.1038/sj.bjp.0702767
Pharmacological and molecular evidence for kinin B1 receptor expression in urinary bladder of cyclophosphamide‐treated rats
Authors: Belichard P , Luccarini J M , Defrêne E , Faye P , Franck R M , Duclos H , Paquet J L , Pruneau D 
Published: January 2005

In the present study, we developed an experimental model of cystitis induced by cyclophosphamide (CYP). In order to characterize des‐Arg9‐BK‐induced contraction on the urinary bladder (UB) during the development of inflammation and to quantify kinin B1 receptor gene expression using a quantitative RT–PCR technique.
In the presence of peptidase inhibitors captopril (10 μM), DL‐thiorphan (1 μM) and DL‐2‐mercaptomethyl‐3‐guanidino‐ethylthiopropanoic acid (MERGEPTA 5 μM), bradykinin (BK) (0.3–3,000 nM) evoked a concentration‐dependent contraction of rat UB which was not different between the CYP‐ and vehicle‐treated groups. Unlike BK, des‐Arg9‐BK (0.3–100,000 nM) did not contract UB from vehicle‐treated rats but contracted vigorously bladder strips from CYP‐treated rats 14, 24 and 168 h after treatment. In UB of 24 h treated rat, the pD2 value of des‐Arg9‐BK was 7.3±0.1.
The cyclo‐oxygenase inhibitor indomethacin (3 μM) reduced by 30% the maximal response of des‐Arg9‐BK. Both the kinin B1 receptor antagonists des‐Arg9‐[Leu8]BK (10 μM) and des‐Arg10‐Hoe 140 (10 μM) produced a rightward shift of the concentration‐response curve to des‐Arg9‐BK yielding pKB values of 6.8±0.2 and 7.2±0.1, respectively, whilst the kinin B2 receptor antagonist Hoe 140 (1 μM) had no effect.
After CYP treatment, mRNA coding for the kinin B1 receptor appeared predominantly in UB. In this organ, the induction was progressive, reaching a maximum 48 h after CYP treatment.
In conclusion, the present study provides strong evidence for an induction of kinin B1 receptors in UB of CYP‐treated rats. This was associated at a molecular level with an increase in mRNA expression of the gene coding for the kinin B1 receptor. This kinin receptor displayed the whole features of a classical rat kinin B1 receptor.

British Journal of Pharmacology (1999) 128, 213–219; doi:10.1038/sj.bjp.0702769
Sulphonic acid derivatives as probes of pore properties of volume‐regulated anion channels in endothelial cells
Authors: Droogmans Guy , Maertens Chantal , Prenen Jean , Nilius Bernd 
Published: January 2005

We have used the whole‐cell patch‐clamp technique to study the effects of 4‐sulphonic‐calixarenes and some other poly‐sulphonic acid agents, such as suramin and basilen blue, on volume‐regulated anion channel (VRAC) currents in cultured endothelial cells (CPAE cells).
The 4‐sulphonic‐calixarenes induced a fast inhibition at positive potentials but were ineffective at negative potentials. At small positive potentials, 4‐sulphonic‐calix[4]arene was a more effective inhibitor than 4‐sulphonic‐calix[6]arene and ‐calix[8]arene, which became more effective at more positive potentials.
Also suramin and basilen blue induced a voltage dependent current inhibition, reaching a maximum around +40 mV and declining at more positive potentials.
The voltage dependence of inhibition was modelled by assuming that these negatively charged molecules bind to a site inside VRAC that senses a fraction δ of the applied electrical field, ranging beween 0.16 to 0.32. 4‐Sulphonic‐calix[4]arene, suramin and basilen blue bind and occlude VRAC at moderate potentials, but permeate the channel at more positive potentials. 4‐Sulphonic‐calix[6]arene and ‐calix[8]arene however do not permeate the channel. From the structural information of the calixarenes, we estimate a lower and upper limit of 11*12 and 17*12 Å2 respectively for the cross‐sectional area of the pore.

British Journal of Pharmacology (1999) 128, 35–40; doi:10.1038/sj.bjp.0702770
Involvement of phospholipid signal transduction pathways in morphine tolerance in mice
Authors: Smith Forrest L , Lohmann Alka B , Dewey William L 
Published: January 2005

Opioid tolerance involves an alteration in the activity of intracellular kinases such as cyclic AMP‐dependent protein kinase (PKA). Drugs that inhibit PKA reverse morphine antinociceptive tolerance. The hypothesis was tested that phospholipid pathways are also altered in morphine tolerance. Inhibitors of the phosphatidylinositol and phosphatidylcholine pathways were injected i.c.v. in an attempt to acutely reverse morphine antinociceptive tolerance.
Seventy‐two hours after implantation of placebo or 75 mg morphine pellets, mice injected i.c.v. with inhibitor drug were challenged with morphine s.c. for generation of dose‐response curves in the tail‐flick test. Placebo pellet‐implanted mice received doses of inhibitor drug having no effect on morphine's potency, in order to test for tolerance reversal in morphine pellet‐implanted mice. Injection of the phosphatidylinositol‐specific phospholipase C inhibitor ET‐18‐OCH3 significantly reversed tolerance, indicating a potential role for inositol 1,4,5‐trisphosphate (IP3) and protein kinase C (PKC) in tolerance. Alternatively, phosphatidylcholine‐specific phospholipase C increases the production of diacylglycerol and activation of PKC, without concomitant production of IP3. D609, an inhibitor of phosphatidylserine‐specific phospholipase C, also reversed tolerance. Heparin is an IP3 receptor antagonist. Injection of low molecular weight heparin also reversed tolerance. PKC was also examined with three structurally dissimilar inhibitors. Bisindolylmaleimide I, Go‐7874, and sangivamycin significantly reversed tolerance.
Chronic opioid exposure leads to changes in phospholipid metabolism that have a direct role in maintaining a state of tolerance. Evidence is accumulating that opioid tolerance disrupts the homeostatic balance of several important signal transduction pathways.

British Journal of Pharmacology (1999) 128, 220–226; doi:10.1038/sj.bjp.0702771
Inhibition of the human ether‐a‐go‐go‐related gene (HERG) potassium channel by cisapride: affinity for open and inactivated states
Authors: Walker B D , Singleton C B , Bursill J A , Wyse K R , Valenzuela S M , Qiu M R , Breit S N , Campbell T J 
Published: January 2005

Cisapride is a prokinetic agent which has been associated with QT prolongation, torsades de pointes and cardiac arrest. The cellular mechanism for these observations is high affinity blockade of IKr (encoded by HERG).
In a chronic transfection model using CHO‐K1 cells, cisapride inhibited HERG tail currents after a step to +25 mV with similar potency at room and physiological temperatures (IC50 16.4 nM at 20–22°C and 23.6 nM at 37°C).
Channel inhibition exhibited time‐, voltage‐ and frequency‐dependence. In an envelope of tails test, channel blockade increased from 27±8% after a 120 ms depolarizing step to 50±4% after a 1.0 s step. These findings suggested affinity for open and/or inactivated channel states.
Inactivation was significantly accelerated by cisapride in a concentration‐dependent manner and there was a small (−7 mV) shift in the voltage dependence of steady state inactivation.
Channel blockade by cisapride was modulated by [K+]o, with a 26% reduction in the potency of channel blockade when [K+]o was increased from 1 to 10 mM.
In conclusion, HERG channel inhibition by cisapride exhibits features consistent with open and inactivated state binding and is sensitive to external potassium concentration. These features may have significant clinical implications with regard to the mechanism and treatment of cisapride‐induced proarrhythmia.

British Journal of Pharmacology (1999) 128, 444–450; doi:10.1038/sj.bjp.0702774
Prevention of the expression of inducible nitric oxide synthase by a novel positive inotropic agent, YS 49, in rat vascular smooth muscle and RAW 264.7 macrophages
Authors: Kang Young Jin , Koo Eui Bon , Lee Young Soo , Yun‐Choi Hye Sook , Chang Ki Churl 
Published: January 2005

The effects of a novel positive inotropic isoquinoline compound, YS 49, on NO production and iNOS protein expression were investigated in cultured rat aortic vascular smooth muscle cells (RAVSMC) and RAW 264.7 cells exposed to lipopolysaccharide (LPS) plus interferon‐γ (IFN‐γ). In addition, the effects of YS 49 on vascular hyporeactivity in vitro and ex vivo, and on survival rate (mice) and serum NOx (rat) levels, were also investigated in LPS‐treated animals.
Pre‐ or co‐treatment of YS 49 with LPS plus IFN‐γ, concentration‐dependently reduced NO production in RAVSMC and RAW 264.7 cells (IC50 values, 22 and 30 μM, respectively). Although the inhibitory effect on NO production was reduced when YS 49 was applied 2 and 4 h after cytokine in RAW 264.7 cells, it was still statistically significant (P<0.05).
YS 49 reduced iNOS mRNA expression in LPS‐treated rat aorta in vitro, an effect which was associated with restoration of contractility to the vasoconstrictor, phenylephrine (PE), and reduction in L‐arginine‐induced relaxation.
Serum NOx levels were significantly (P<0.01) reduced by YS 49 (5 mg kg−1, i.p.) in LPS‐treated rats (10 mg kg−1, i.p.). Administration of YS 49 (10 and 20 mg kg−1) 30 min prior to LPS (10 mg kg−1) also significantly (P<0.01) increased the subsequent survival rates in mice.
Finally, expression of iNOS protein induced by LPS plus IFN‐γ in RAVSMC and RAW 264.7 cells was suppressed by YS 49, in a concentration‐dependent manner.
These data strongly suggest that YS 49 suppresses iNOS gene expression induced by LPS and/or cytokines in RAVSMC and RAW 264.7 cells at the transcriptional level. YS 49 could therefore be beneficial in septic shock and other diseases associated with iNOS over‐expression.

British Journal of Pharmacology (1999) 128, 357–364; doi:10.1038/sj.bjp.0702787
Regulation of cyclic AMP by extracellular ATP in cultured brain capillary endothelial cells
Authors: Anwar Zubeya , Albert Jennifer L , Gubby Sharon E , Boyle John P , Roberts Jonathon A , Webb Tania E , Boarder Michael R 
Published: January 2005

In primary unpassaged rat brain capillary endothelial cell cultures (RBECs), using reverse‐transcriptase PCR with primers specific for P2Y receptor subtypes, we detected mRNA for P2Y2, P2Y4 and P2Y6, but not P2Y1 receptors.
None of the various nucleotides tested reduced forskolin elevated cyclic AMP levels in RBECs. ATP and ATPγS, as well as adenosine, enhanced cyclic AMP accumulation in the presence of forskolin.
Comparison of the concentration response curves to ATPγS with those for ATP and adenosine, at different incubation times, indicated that the response to purine nucleotides was not wholly dependent on conversion to adenosine. Adenosine deaminase abolished the response to adenosine but only reduced the response to ATP by about 50%. These results suggest the participation of a receptor responsive to nucleotides.
Isobutylmethylxanthine and 8‐sulphophenyltheophylline prevented the cyclic AMP response, while neither 8‐cyclopentyl‐1,3‐dipropylxanthine nor SCH58261 were effective antagonists. 2‐chloradenosine gave a robust response, but neither 2‐chloro‐N6‐cyclopentyladenosine nor CGS 21680 were agonists.
These results show that adenosine and ATP can elevate the cyclic AMP levels of brain endothelial cells by acting on receptors which have a pharmacology apparently distinct from known P2Y and adenosine receptors.

British Journal of Pharmacology (1999) 128, 465–471; doi:10.1038/sj.bjp.0702792
Effect of hypoxia alone or combined with inflammation and 3‐methylcholanthrene on hepatic cytochrome P450 in conscious rabbits
Authors: Kurdi J , Maurice H , El‐Kadi A O S , Ong H , Dalkara S , Bélanger P M , Du Souich P 
Published: January 2005

To investigate the effect of moderate hypoxia alone or combined with an inflammatory reaction or after 3‐methylcholanthrene (3MC) pre‐treatment on cytochrome P450 (P450), conscious rabbits were exposed for 24 h to a fractional concentration of inspired O2 of 10% (mean PaO2 of 34 mmHg). Hypoxia decreased theophylline metabolic clearance (ClM) from 1.73±0.43 to 1.48±0.13 ml min−1 kg−1 (P<0.05), and reduced (P<0.05) the formation clearance of theophylline metabolites, 3‐methylxanthine (3MX), 1‐methyluric acid (1MU) and 1,3‐dimethyluric acid (1,3DMU). Hypoxia reduced the amount of CYP1A1 and 1A2 but increased CYP3A6 proteins.
Turpentine‐induced inflammatory reaction reduced (P<0.05) the formation clearance of 3MX, 1MU, and 1,3DMU, and diminished the amount of CYP1A1, 1A2 and 3A6 proteins. However, when combined with hypoxia, inflammation partially prevented the decrease in ClM, especially by impeding the reduction of 1,3DMU. The amount of CYP1A1 and 1A2 remained reduced but the amount of CYP3A6 protein returned to normal values.
Pre‐treatment with 3MC augmented the ClM by 114% (P<0.05) due to the increase in the formation clearance of 3MX, 1MU and 1,3DMU. 3MC treatment increased the amount of CYP1A1 and 1A2 proteins. Pre‐treatment with 3MC prevented the hypoxia‐induced decrease in amount and activity of the P450.
It is concluded that acute moderate hypoxia and an inflammatory reaction individually reduce the amount and activity of selected apoproteins of the P450. However, the combination of hypoxia and the inflammatory reaction restores P450 activity to near normal values. On the other hand, pre‐treatment with 3MC prevents the hypoxia‐induced depression of the P450.

British Journal of Pharmacology (1999) 128, 365–373; doi:10.1038/sj.bjp.0702795