bluuebunny/crossref_metadata_2025_split huggingface dataset:
α1B adrenergic receptors in gonadotrophin‐releasing hormone neurones: relation to Transport‐P
Authors: Al‐Damluji S , Shen W B , White S , Barnard E A 
Published: January 2005

Peptidergic neurones accumulate amines via an unusual uptake process, designated Transport‐P. [3H]‐prazosin binds to α1 adrenoceptors on these cells and is displaceable by unlabelled prazosin in concentrations up to 10−7 M. However, at greater concentrations of prazosin, there is a paradoxical accumulation of [3H]‐prazosin which we have attributed to Transport‐P. Uptake of prazosin via Transport‐P is detectable at 10−10 M prazosin concentration, is linear up to 10−7 M and at greater concentrations becomes non‐linear. In contrast, in noradrenergic neurones, noradrenaline uptake is linear and saturates above 10−7 M. In noradrenergic neurones and in non‐neuronal cells, there is no uptake of prazosin in concentrations up to 10−6 M, suggesting that Transport‐P is a specialised function of peptidergic neurones.
Using a mouse peptidergic (gonadotrophin‐releasing hormone, GnRH) neuronal cell line which possesses Transport‐P, we have studied the interaction of α1 adrenoceptors with Transport‐P. Polymerase chain reactions and DNA sequencing of the products demonstrated that only the α1B sub‐type of adrenoceptors is present in GnRH cells.
In COS cells transfected with α1b adrenoceptor cDNA and in DDT1 MF‐2 cells which express native α1B adrenoceptors, [3H]‐prazosin was displaced by unlabelled prazosin in a normal equilibrium process, with no prazosin paradox in concentrations up to 10−6 M. In DDT1 MF‐2 cells, [3H]‐prazosin was displaced likewise by a series of α1 adrenergic agonists, none of which increased the binding of [3H]‐prazosin. Hence, the prazosin paradox is not due to some function of α1 adrenoceptors, such as internalization of ligand‐receptor complexes.
In neurones which possess Transport‐P, transfection with α1b adrenoceptor cDNA resulted in over‐expression of α1B adrenoceptors, but the prazosin paradox was unaltered. Thus, α1 adrenoceptors and Transport‐P mediate distinct functions in peptidergic neurones.

British Journal of Pharmacology (2001) 132, 336–344; doi:10.1038/sj.bjp.0703781
Effects of tyrosine kinase inhibitors on cell death induced by sodium fluoride and pertussis toxin in the pancreatic β‐cell line, RINm5F
Authors: Elliott Jim , Scarpello John H B , Morgan Noel G 
Published: January 2005

Sodium fluoride causes apoptosis of pancreatic β‐cells and this response is enhanced by pre‐treatment with pertussis toxin. In the present study, tyrosine kinase inhibitors were used to investigate the mechanisms of action of NaF and pertussis toxin in the β‐cell line, RINm5F.
Exposure of RINm5F cells to low concentrations of genistein or tyrphostin A25 resulted in significant inhibition of cell death induced by 5 mM NaF. Higher concentrations (>25 μM) were cytotoxic in the absence of NaF but, paradoxically, the combination of genistein and NaF induced less cell death than when each agent was used alone.
The increase in cell death induced by 100 μM genistein was markedly inhibited by ciprofloxacin, a drug which binds to topoisomerase II. Etoposide (which inhibits topoisomerase II but has no effect on tyrosine kinase activity) also caused an increase in RINm5F cell death. Neither etoposide nor ciprofloxacin altered the response to 5 mM NaF.
Pertussis toxin markedly enhanced the extent of RINm5F cell death induced by NaF and this effect was completely prevented by 25 μM genistein. The inhibition caused by genistein was not affected by ciprofloxacin but was reproduced by a structurally dissimilar tyrosine kinase inhibitor, herbimycin A.
The results demonstrate that RINm5F β‐cells express a pertussis toxin sensitive pathway that is anti‐apoptotic. The activity of this pathway is most evident in cells exposed to pro‐apoptotic stimuli where the effects of pertussis toxin can be blocked by inhibitors of tyrosine kinase enzymes. A genistein‐sensitive tyrosine kinase does not appear to be involved in RINm5F cell survival under basal conditions.

British Journal of Pharmacology (2001) 132, 119–126; doi:10.1038/sj.bjp.0703783
Gastric mucosal resistance to acute injury in experimental portal hypertension
Authors: Calatayud Sara , Ramírez M Carmen , Sanz M Jesús , Moreno Lucrecia , Hernández Carlos , Bosch Jaume , Piqué Jose M , Esplugues Juan V 
Published: January 2005

The gastric mucosa of portal hypertensive rats exhibits important microvascular changes and a nitric oxide (NO)‐dependent hyperemia. This study analyses whether portal hypertensive mucosa exhibits changes in its ability to withstand aggression.
Portal hypertension was induced by partial portal vein ligation (PPVL) or common bile duct ligation (CBDL) and gastric damage was induced by oral administration of ethanol or aspirin. Experiments were performed in conscious or anaesthetized rats and some animals were pre‐treated with the NO‐synthesis inhibitor L‐NAME.
Conscious PPVL or CBDL rats showed an increased resistance to the damaging effects of ethanol. Oral administration of aspirin produced less gastric damage in PPVL conscious rats than in the control group.
The protective effects of portal hypertension were maintained in animals anaesthetized with ketamine and absent when pentobarbital was employed.
Pre‐treatment with L‐NAME restored the damaging effects of ethanol and aspirin in PPVL rats without modifying the level of damage in control animals.
Gastric bleeding induced by oral aspirin, as measured by the luminal release of 51Cr‐labelled erythrocytes, was significantly greater in PPVL rats than in control animals.
Semi‐quantitiative analysis by RT – PCR of the mRNA for endothelial NO‐synthase (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS) levels showed that the expression of iNOS was slightly increased in both the gastric mucosa and smooth muscle of PPVL rats. No changes were observed in eNOS and nNOS expression.
Conscious portal hypertensive rats exhibit an enhanced resistance to acute gastric damage which is absent under the influence of some types of anaesthesia and seems related to an increased synthesis of nitric oxide. However, mucosal lesions in these animals show an augmented bleeding per area of injury.

British Journal of Pharmacology (2001) 132, 309–317; doi:10.1038/sj.bjp.0703785
N‐acetylcysteine attenuates TNF‐α‐induced p38 MAP kinase activation and p38 MAP kinase‐mediated IL‐8 production by human pulmonary vascular endothelial cells
Authors: Hashimoto Shu , Gon Yasuhiro , Matsumoto Ken , Takeshita Ikuko , Horie Takashi 
Published: January 2005

We have previously shown that tumour necrosis factor‐α (TNF‐α) activates p38 mitogen‐activated protein (MAP) kinase to produce interleukin‐8 (IL‐8) by human pulmonary vascular endothelial cells. Reactive oxygen species (ROS) including H2O2 generated by TNF‐α can act as signalling intermediates for cytokine induction; therefore, scavenging ROS by anti‐oxidants is important for the regulation of cytokine production. However, the effect of N‐acetylcysteine (NAC), which acts as a precursor of glutathione (GSH) synthesis, on TNF‐α‐induced activation of p38 MAP kinase pathway and p38 MAP kinase‐mediated IL‐8 production by human pulmonary vascular endothelial cells has not been determined. To clarify these issues, we examined the effect of NAC on TNF‐α‐induced activation of p38 MAP kinase, MAP kinase kinase (MKK) 3 and MKK6 which are upstream regulators of p38 MAP kinase, and p38 MAP kinase‐mediated IL‐8 production.
Human pulmonary vascular endothelial cells that had been preincubated with NAC were stimulated with TNF‐α and then the activation of p38 MAP kinase and MKK3/MKK6 in the cells and IL‐8 concentrations in the culture supernatants were determined.
Intracellular GSH levels increased in NAC‐treated cells.
NAC attenuated TNF‐α‐induced activation of p38 MAP kinase and MKK3/MKK6.
NAC attenuated p38 MAP kinase‐mediated IL‐8 production by TNF‐α‐stimulated cells.
These results indicate that the cellular reduction and oxidation (redox) regulated by intracellular GSH is critical for TNF‐α‐induced activation of p38 MAP kinase pathway and p38 MAP kinase‐mediated IL‐8 production by human pulmonary vascular endothelial cells, and we emphasize that anti‐oxidant therapy is an important strategy for the treatment of acute lung injury.

British Journal of Pharmacology (2001) 132, 270–276; doi:10.1038/sj.bjp.0703787
Modulation of BzATP and formalin induced nociception: attenuation by the P2X receptor antagonist, TNP‐ATP and enhancement by the P2X3 allosteric modulator, cibacron blue
Authors: Jarvis Michael F , Wismer Carol T , Schweitzer Edmund , Yu Haixia , Van Biesen Tim , Lynch Kevin J , Burgard Edward C , Kowaluk Elizabeth A 
Published: January 2005

Exogenous ATP produces acute and localized pain in humans, and P2X receptor agonists elicit acute nociceptive behaviours in rodents following intradermal administration to the hindpaw. The predominant localization of P2X3 mRNA in sensory neurones has led to the hypothesis that activation of P2X3 and/or P2X2/3 receptors contributes to nociception.
The local administration of the P2X receptor agonist, BzATP (100 – 1000 nmol paw−1, s.c.) into the rat hindpaw produced an acute (<15 min) paw flinching response that was similar to that observed in the acute phase of the formalin (5%) test.
The co‐administration of the potent P2X receptor antagonist, TNP‐ATP (30 – 300 nmol paw−1), but not an inactive analogue, TNP‐AMP, with BzATP into the rat hindpaw attenuated BzATP‐induced nociception. Similarly, co‐administration of TNP‐ATP, but not TNP‐AMP, with 5% formalin reduced both acute and persistent nociception in this test.
Co‐administration of cibacron blue (30 and 100 nmol paw−1), a selective allosteric enhancer of P2X3 and P2X2/3 receptor activation, with BzATP (30 and 100 nmol paw−1) into the rat hindpaw produced significantly greater nociception as compared to the algogenic effects of BzATP alone. Intradermal co‐administration of cibacron blue (30 and 100 nmol paw−1) with formalin (1 and 2.5%) into the rat hindpaw also produced significantly greater nociceptive behaviour as compared to formalin alone.
The ability of TNP‐ATP and cibacron blue to respectively attenuate and enhance nociceptive responses elicited by exogenous BzATP and formalin provide further support for the hypothesis that activation of peripheral P2X3 containing channels contributes specifically to both acute and persistent nociception in the rat.

British Journal of Pharmacology (2001) 132, 259–269; doi:10.1038/sj.bjp.0703793
Rho‐kinase inhibitors prevent agonist‐induced vasospasm in human internal mammary artery
Authors: Batchelor Timothy J P , Sadaba J Rafael , Ishola Adekunle , Pacaud Pierre , Munsch Christopher M , Beech David J 
Published: January 2005

Vasospasm of arterial conduits used for coronary artery surgery is an important cause of graft failure and is likely to result partly from raised levels of vasoconstrictor substances such as thromboxane A2 and endothelin‐1. Our aim was to find pharmacological agents that could prevent agonist‐induced vasospasm.
Isometric tension was recorded from discarded segments of human left internal mammary artery (LIMA). Submaximal contraction evoked by the thromboxane A2 mimetic U46619 (10 nM) was not inhibited by a blocker of store‐ and receptor‐operated Ca2+ channels (30 μM SKF96365) in the presence of diltiazem. Furthermore, contractions to 1 nM U46619 were preserved when extracellular Ca2+ was reduced from 2.5 mM to 60 nM. Thus, sustained U46619‐evoked contraction occurred without Ca2+ influx.
We hypothesized that contraction might occur via Rho‐kinase‐mediated Ca2+‐sensitization of myofilaments. Inhibitors of Rho‐kinase (Y27632 and HA1077) were profound relaxants. If contraction was pre‐evoked by 10 nM U46619, Y27632 and HA1077 caused full relaxation with EC50s of 1.67±0.22 μM and 3.58±0.35 μM respectively. Y27632 was also effective if applied before U46619, but was less potent.
Y27632 abolished contraction evoked by endothelin‐1 and significantly reduced resting tone in the absence of a vasoconstrictor.
Rho‐kinase‐mediated Ca2+‐sensitization appears to be a major mechanism of vasoconstriction in human LIMA. Rho‐kinase inhibitors may have an important role in preventing vasospasm in arterial grafts used for coronary artery surgery.

British Journal of Pharmacology (2001) 132, 302–308; doi:10.1038/sj.bjp.0703809
Cardiostimulant effects of urotensin‐II in human heart in vitro
Authors: Russell Fraser D , Molenaar Peter , O'Brien Donalee M 
Published: January 2005

The effects of the recently identified human peptide urotensin‐II (hU‐II) were investigated on human cardiac muscle contractility and coronary artery tone. In right atrial trabeculae from non‐failing hearts, hU‐II caused a concentration‐dependent increase in contractile force (pEC50=9.5±0.1; Emax=31.3±4.8% compared to 9.25 mM Ca2+; n=9) with no change in contraction duration. In right ventricular trabeculae from explanted hearts, 20 nM hU‐II caused a small increase in contractile force (7.8±1.4% compared to 9.25 mM Ca2+; n=3/6 tissues from 2 out of 4 patients). The peptide caused arrhythmic contractions in 3/26 right atrial trabeculae from 3/9 patients in an experimental model of arrhythmia and therefore has less potential to cause arrhythmias than ET‐1. hU‐II (20 nM) increased tone (17.9% of the response to 90 mM KCI) in 7/7 tissues from 1 patient, with no response detected in 8/8 tissues from 2 patients. hU‐II is a potent cardiac stimulant with low efficacy.British Journal of Pharmacology (2001) 132, 5–9; doi:10.1038/sj.bjp.0703811
Formation of nitric oxide from nitroxyl anion: role of quinones and ferricytochrome c
Authors: Buyukafsar Kansu , Nelli Silvia , Martin William 
Published: January 2005

Our previous finding that copper ions oxidize nitroxyl anion released from Angeli's salt to nitric oxide prompted us to examine if copper‐containing enzymes shared this property.
The copper‐containing enzyme, tyrosinase, which catalyses the hydroxylation of monophenols to diphenols and the subsequent oxidation of these to the respective unstable quinone, failed to generate nitric oxide from Angeli's salt by itself, but did so in the presence of tyrosine.
L‐DOPA, the initial product of the reaction of tyrosinase with tyrosine, was not the active species, since it failed to generate nitric oxide from Angeli's salt. Nevertheless, L‐DOPA and two other substrates, namely, catechol and tyramine did produce nitric oxide from Angeli's salt in the presence of tyrosinase, suggesting involvement of the respective unstable quinones. In support, we found that 1,4‐benzoquinone produced a powerful nitric oxide signal from Angeli's salt.
Coenzyme Qo, an analogue of ubiquinone, failed to generate nitric oxide from Angeli's salt by itself, but produced a powerful signal in the presence of its mitochondrial complex III cofactor, ferricytochrome c.
Experiments conducted on rat aortic rings with the mitochondrial complex III inhibitor, myxothiazol, to determine if this pathway was responsible for the vascular conversion of nitroxyl to nitric oxide were equivocal: relaxation to Angeli's salt was inhibited but so too was that to unrelated relaxants.
Thus, certain quinones oxidize nitroxyl to nitric oxide. Further work is required to determine if endogenous quinones contribute to the relaxant actions of nitroxyl donors such as Angeli's salt.

British Journal of Pharmacology (2001) 132, 165–172; doi:10.1038/sj.bjp.0703812
Constitutive neuropeptide Y Y4 receptor expression in human colonic adenocarcinoma cell lines
Authors: Cox Helen M , Tough Iain R , Zandvliet Dorothea W J , Holliday Nicholas D 
Published: January 2005

Three human adenocarcinoma cell lines, Colony‐24 (Col‐24), Col‐6 and Col‐1 have been studied as confluent epithelial layers able to transport ions vectorially in response to basolateral vasoactive intestinal polypeptide (VIP) and pancreatic polypeptides (PP).
Different species PP stimulated responses in Col‐24 with Y4‐like pharmacology. Bovine (b)PP, human (h)PP and porcine (p)PP were equipotent (EC50 values 3.0 – 5.0 nM) while rat (r)PP, avian (a)PP and [Leu31, Pro34]PYY (Pro34PYY) were significantly less potent. PYY was inactive. The PP pharmacology in Col‐1 was comparable with Col‐24. However, Col‐6 cells were different; pPP had an EC50 intermediate (22.0 nM) between that of bPP (3.0 nM) and hPP (173.2 nM), with aPP and rPP being at least a further fold less potent.
Deamidation of Tyr36 in bPP (by O‐methylation or hydroxylation) or removal of the residue resulted in significant loss of activity in Col‐24.
GR231118 (1 μM) had no PP‐like effects. In Col‐24 and Col‐1, GR231118 significantly attenuated bPP (30 nM) or hPP (100 nM) responses, but it did not alter bPP responses in Col‐6. BIBP3226 and GR231118 both inhibited Y1‐mediated responses which were only present in Col‐6.
RT – PCR analysis confirmed the presence of hY4 receptor mRNA in Col‐24 and Col‐1 epithelia but a barely visible hY4 product was observed in Col‐6 and we suggest that an atypical Y4 receptor is expressed in this cell line.

British Journal of Pharmacology (2001) 132, 345–353; doi:10.1038/sj.bjp.0703815
The critical role of adenosine and guanosine in the affinity of dinucleoside polyphosphates to P2X‐receptors in the isolated perfused rat kidney
Authors: Van Der Giet Markus , Westhoff Tim , Cinkilic Okan , Jankowski Joachim , Schlüter Hartmut , Zidek Walter , Tepel Martin 
Published: January 2005

The activation of P2x‐receptors in the rat renal vasculature by dinucleoside polyphosphates with variable phosphate group chain length (XpnX; X=Adenin (A) /Guanin (G), n=4 – 6) was studied by measuring their effects on perfusion pressure of the isolated perfused rat kidney at constant flow in an open circuit.
Like Ap4A, Ap5A and Ap6A the dinucleoside polyphosphates Ap4G, Ap5G and Ap6G exerted a vasoconstriction which could be blocked by suramin and pyridoxal‐phosphate‐6‐azophenyl‐2; 4‐disulphonic acid (PPADS).
Gp4G, Gp5G and Gp6G showed only very weak vasoconstriction at high doses.
Ap6A and α, β‐meATP could not be blocked by the selective P2x1‐receptor antagonisten NF023 (30 μM), whereas Ap4A, Ap4G, Ap5A, Ap5G and Ap6G were partially blocked by NF023.
Inhibition of endothelial NO‐synthase by Nω‐nitro‐L‐arginine methyl ester (L‐NAME) did not affect vasoconstrictions induced by dinucleosidepolyphosphates.
P2x‐receptor can only be activated if at least one adenosine moiety is present in the molecule.
ApnG show a weaker vasoconstrictive action than corresponding ApnA, concluding that two adenosine moieties enhance the P2x‐receptor binding and activation.
XpnX containing five phosphate groups show the most pronounced vasoconstrictive effect whereas four phosphate groups show the less effect, therefore the number of phosphate groups critically changes receptor affinity.
Additional experiments using permanent perfusion with α, β‐methylene ATP (α,β‐meATP) and the selective P2x1‐receptor antagonist NF023 showed that the newly discovered human dinucleoside polyphosphates activated the vascular P2x1‐receptor and an recently identified new P2x‐receptor subtype.
The differential effects of dinucleoside polyphosphates allow a fine tuning of local perfusion via composition of XpnXs.

British Journal of Pharmacology (2001) 132, 467–474; doi:10.1038/sj.bjp.0703817
Chronic treatment with reboxetine by osmotic pumps facilitates its effect on extracellular noradrenaline and may desensitize α2‐adrenoceptors in the prefrontal cortex
Authors: Invernizzi R W , Parini S , Sacchetti G , Fracasso C , Caccia S , Annoni K , Samanin R 
Published: January 2005

This study investigated the effect of acute (2 days) and chronic (14 days) treatment with a selective inhibitor of noradrenaline uptake, reboxetine (10 mg kg−1 day−1) by osmotic pumps, on extracellular noradrenaline and the sensitivity of α2‐adrenoceptors in the prefrontal cortex of rats.
The effect of continuous infusion of reboxetine for 14 days on cortical extracellular noradrenaline was significantly higher (599% of vehicle levels) than after 2 days (263% of vehicle levels).
Brain concentrations of reboxetine after 2 and 14 days of infusion were 37.9±17.8 and 37.1±7.7 ng g−1, respectively.
Reboxetine infused for 2 and 14 days significantly increased extracellular dopamine in the prefrontal cortex, to a similar extent (257 and 342% of vehicle levels, respectively), whereas extracellular 5‐HT was not modified by either treatment.
Clonidine (10 and 30 μg kg−1 i.p.) reduced cortical extracellular noradrenaline similarly in animals treated with reboxetine or vehicle for 2 days whereas the effects in rats infused with reboxetine for 14 days were markedly less than in vehicle‐treated animals.
Clonidine (0.05 and 0.2 μM), infused through the dialysis probe into the prefrontal cortex, reduced cortical extracellular noradrenaline much less in rats treated with reboxetine for 14 days than in vehicle‐treated animals.
Reboxetine's effect on extracellular noradrenaline in the prefrontal cortex was greater after chronic treatment and could be associated with desensitization of terminal α2‐adrenoceptors that normally serve to inhibit noradrenaline release.

British Journal of Pharmacology (2001) 132, 183–188; doi:10.1038/sj.bjp.0703821
Effect of the long‐acting tachykinin NK1 receptor antagonist MEN 11467 on tracheal mucus secretion in allergic ferrets
Authors: Khan Safina , Liu Yu‐Chih , Khawaja Aamir M , Manzini Stefano , Rogers Duncan F 
Published: January 2005

We investigated the effect of MEN 11467 ((1R,2S)‐2‐N[1(H)indol‐3‐yl‐carbonyl]‐1‐N‐{Nα(p‐tolylacetyl)‐Nα(methyl)‐D‐3‐(2‐naphthyl)alanyl}diaminocyclohexane) on tachykinin‐induced mucus secretion in ferret trachea in vitro and determined its effect on secretion by tracheae from allergic ferrets in response to allergen challenge.
Repeated administration of [Sar9,Met(O2)11]‐substance P ([Sar9]SP, 1 μM) maintained mucus output above control values for at least 1.75 h. MEN 11467 inhibited secretion in a concentration‐dependent manner with maximal inhibition at 10 μM and an approximate IC50 of 0.3 μM. Inhibition by MEN 11467 (0.1 – 10 μM) was maintained, to varying degree, for at least 1.75 h after washout in the continued presence of [Sar9]SP.
In electrically stimulated tracheae, tachykininergic neural secretion was virtually abolished by 1 μM MEN 11467.
In tracheae from ovalbumin‐sensitised animals, repeated administration of ovalbumin maintained mucus output above controls for 1.5 h. MEN 11467 inhibited ovalbumin‐induced secretion in a concentration‐dependent manner, with complete inhibition at 1 μM. Inhibition by MEN 11467 (1 and 10 μM) was maintained, to varying degree, after drug washout for the 1.5 h of ovalbumin stimulation.
MEN 11467 1 μM did not affect secretion induced by either acetylcholine or histamine, whereas 10 μM MEN 11467 did inhibit agonist‐induced secretion.
We conclude that, in ferret trachea in vitro, MEN 11467 at concentrations of 0.1 – 1 μM is a long acting and selective inhibitor of tachykininergic‐induced mucus secretion, and may have therapeutic potential for bronchial hypersecretion associated with allergic conditions, for example in asthma.

British Journal of Pharmacology (2001) 132, 189–196; doi:10.1038/sj.bjp.0703822