bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelin‐1 enhances neutrophil adhesion to human coronary artery endothelial cells: role of ETA receptors and platelet‐activating factor
Authors: Zouki Christine , Baron Chantal , Fournier Alain , Filep János G 
Published: January 2005

The potent coronary vasoconstrictor, endothelin‐1 (ET‐1) may also regulate neutrophil traffic into tissues. The aim of the present study was to characterize the endothelin receptors responsible and to investigate the underlying mechanisms.
ET‐1 (1 nM–1 μM) markedly enhanced attachment of human neutrophils to lipopolysaccharide‐, and to a lesser extent, to ET‐1‐activated human coronary artery endothelial cells (HCAEC). This can partially be blocked by monoclonal antibodies against E‐selectin, L‐selectin or CD18, whereas combination of the three antibodies inhibited adhesion by ∼83%. Increases in neutrophil adhesion evoked by ET‐1 were also blocked by the platelet‐activating factor (PAF) antagonists, BN 52021 (50 μM) and WEB 286 (10 μM).
ET‐1 downregulated the expression of L‐selectin and upregulated expression of CD11b/CD18 and CD45 on the neutrophil surface and induced gelatinase release with EC50 values of ∼2 nM. These actions of ET‐1 were almost completely prevented by the ETA receptor antagonist FR 139317 (1 μM) and the ETA/ETB receptor antagonist bosentan (10 μM), whereas the ETB receptor antagonist BQ 788 (1 μM) had no effect. ET‐1 slightly increased the expression of E‐selectin and ICAM‐1 on HCAEC, that was prevented by BQ 788, but not by FR 139317.
Receptor binding studies indicated the presence of ETB receptors (KD: 40 pM) on phosphoramidon‐treated HCAEC and the predominant expression of ETA receptors (KD: 38 pM) on neutrophils.
These results indicate that promotion by ET‐1 of neutrophil adhesion to HCAEC is predominantly mediated through activation of ETA receptors on neutrophils and subsequent generation of PAF.

British Journal of Pharmacology (1999) 127, 969–979; doi:10.1038/sj.bjp.0702593
NPY receptor subtype in the rabbit isolated ileum
Authors: Félétou Michel , Nicolas Jean‐Paul , Rodriguez Marianne , Beauverger Philippe , Galizzi Jean‐Pierre , Boutin Jean A , Duhault Jacques 
Published: January 2005

The purpose of this work was to verify the hypothesis that the rabbit ileum is a selective preparation for the NPY Y5 receptor by using new selective antagonists recently synthesized. Spontaneous contractions of the rabbit isolated ileum were recorded and binding experiments were performed in cells expressing the human NPY Y1, Y2, Y4 or Y5 receptor subtype.
NPY analogues produced a concentration‐dependent transient inhibition of the spontaneous contractions of the rabbit ileum with the following order of potency hPP>rPP>PYY[Leu31,Pro34]‐NPY>NPY>>NPY13–36. Pre‐exposure to rPP, PYY, [Leu31,Pro34]‐NPY or NPY (but not NPY13–36) inhibited the effect of subsequent administration of hPP suggesting cross‐desensitization of the preparation. The apparent affinity of the various agonists studied was correlated to the affinity reported for the human Y4 receptor subtype (and to a lesser extent for the rat Y4 subtype) but not to the affinity for the Y5 receptor subtype.
BIBO 3304, a selective NPY Y1 receptor antagonist, and CGP 71683A, a selective NPY Y5 receptor antagonist, did not affect the response to hPP. JCF 109, another NPY Y5 receptor antagonist, produced an inhibition of the response to hPP but only at the highest dose tested (10 μM) which also, by itself, produced intrinsic inhibitory effects.
1229U91, a non‐selective ligand for Y1, Y2, Y4 and Y5 receptors with high affinity toward the Y1 and Y4 receptor subtypes, produced a concentration‐dependent transient inhibition of the spontaneous contractions of the rabbit ileum and a dose‐dependent inhibition of the response to hPP (apparent pKB: 7.2).
These results suggest that in the rabbit ileum, the NPY receptor involved in the inhibition of the spontaneous contractile activity is a NPY Y4 receptor subtype.

British Journal of Pharmacology (1999) 127, 795–801; doi:10.1038/sj.bjp.0702594
Nociceptin/orphanin FQ and nocistatin on learning and memory impairment induced by scopolamine in mice
Authors: Hiramatsu Masayuki , Inoue Kaori 
Published: January 2005

Nociceptin, also known as orphanin FQ, is an endogenous ligand for the orphan opioid receptor‐like receptor 1 (ORL1) and involves in various functions in the central nervous system (CNS). On the other hand, nocistatin is recently isolated from the same precursor as nociceptin and blocks nociceptin‐induced allodynia and hyperalgesia.
Although ORL1 receptors which display a high degree of sequence homology with classical opioid receptors are abundant in the hippocampus, little is known regarding their role in learning and memory.
The present study was designed to investigate whether nociceptin/orphanin FQ and nocistatin could modulate impairment of learning and memory induced by scopolamine, a muscarinic cholinergic receptor antagonist, using spontaneous alternation of Y‐maze and step‐down type passive avoidance tasks in mice.
While nocistatin (0.5–5.0 nmol mouse−1, i.c.v.) administered 30 min before spontaneous alternation performance or the training session of the passive avoidance task, had no effect on spontaneous alternation or passive avoidance behaviours, a lower per cent alternation and shorter median step‐down latency in the retention test were obtained in nociceptin (1.5 and/or 5.0 nmol mouse−1, i.c.v.)‐treated normal mice.
Administration of nocistatin (1.5 and/or 5.0 nmol mouse−1, i.c.v.) 30 min before spontaneous alternation performance or the training session of the passive avoidance task, attenuated the scopolamine‐induced impairment of spontaneous alternation and passive avoidance behaviours.
These results indicated that nocistatin, a new biologically active peptide, ameliorates impairments of spontaneous alternation and passive avoidance induced by scopolamine, and suggested that these peptides play opposite roles in learning and memory.

British Journal of Pharmacology (1999) 127, 655–660; doi:10.1038/sj.bjp.0702595
Analysis of α1L‐adrenoceptor pharmacology in rat small mesenteric artery
Authors: Stam Wiro B , Van der Graaf Pieter H , Saxena Pramod R 
Published: January 2005

To illuminate the controversy on α1A‐ or α1L‐adrenoceptor involvement in noradrenaline‐mediated contractions of rat small mesenteric artery (SMA), we have studied the effects of subtype‐selective α1‐adrenoceptor agonists and antagonists under different experimental conditions.
The agonist potency order in rat SMA was: A61603 >> SKF89748‐A > cirazoline > noradrenaline > ST‐587 > methoxamine. Prazosin antagonized all agonists with a low potency (pA2: 8.29–8.80) indicating the involvement of α1L‐ rather than α1A‐adrenoceptors.
The putative α1L‐adrenoceptor antagonist JTH‐601, but not the α1B‐adrenoceptor antagonist chloroethylclonidine (10 μM) antagonized noradrenaline‐induced contractions of SMA. The potency of the selective α1D‐adrenoceptor antagonist BMY 7378 against noradrenaline (pA2=6.16±0.13) and of the selective α1A‐adrenoceptor antagonist RS‐17053 against noradrenaline (pKB=8.35±0.10) and against the selective α1A‐adrenoceptor agonist A‐61603 (pKB=8.40±0.09) were too low to account for α1D‐ and α1A‐adrenoceptor involvement.
The potency of RS‐17053 (pKB/pA2's=7.72–8.46) was not affected by lowering temperature, changing experimental protocol or inducing myogenic tone via KCl or U46619.
Selective protection of a putative α1A‐adrenoceptor population against the irreversible action of phenoxybenzamine also failed to increase the potency of RS‐17053 (pA2=8.25±0.06 against A61603).
Combined concentration‐ratio analysis demonstrated that tamsulosin, which does not discriminate between α1A‐ and α1L‐adrenoceptors, and RS‐17053 competed for binding at the same site in the SMA.
In summary, data obtained in our experiments in rat SMA indicate that the α1‐adrenoceptor mediating noradrenaline‐induced contraction displays a distinct α1L‐adrenoceptor pharmacology. This study does not provide evidence for the hypothesis that α1L‐adrenoceptors represent an affinity state of the α1A‐adrenoceptor in functional assays. Furthermore, there is no co‐existing α1A‐adrenoceptor in the SMA.

British Journal of Pharmacology (1999) 127, 661–670; doi:10.1038/sj.bjp.0702598
Stimulant action of pituitary adenylate cyclase‐activating peptide on normal and drug‐compromised peristalsis in the guinea‐pig intestine
Authors: Heinemann Ákos , Holzer Peter 
Published: January 2005

Pituitary adenylate cyclase‐activating peptide (PACAP) is known to influence the activity of intestinal smooth muscle. This study set out to examine the action of PACAP on normal and drug‐inhibited peristalsis and to shed light on its site and mode of action.
Peristalsis in isolated segments of the guinea‐pig small intestine was elicited by distension through a rise of the intraluminal pressure. Drug‐induced motility changes were quantified by alterations of the peristaltic pressure threshold at which aborally moving peristaltic contractions were triggered.
PACAP (1–30 nM) stimulated normal peristalsis as deduced from a concentration‐related decrease in the peristaltic pressure threshold (maximum decrease by 55%). The peptide's stimulant effect remained intact in segments pre‐exposed to apamin (0.5 μM), N‐nitro‐L‐arginine methyl ester (300 μM), naloxone (0.5 μM), atropine (1 μM) plus naloxone (0.5 μM) or hexamethonium (100 μM) plus naloxone (0.5 μM).
PACAP (10 nM) restored peristalsis blocked by morphine (10 μM), noradrenaline (1 μM) or N6‐cyclopentyladenosine (0.3 μM) and partially reinstated peristalsis blocked by Rp‐adenosine‐3′,5′‐cyclic monophosphothioate triethylamine (100 μM) but failed to revive peristalsis blocked by hexamethonium (100 μM) or atropine (1 μM). The peptide's spectrum of properistaltic activity differed from that of naloxone (0.5 μM) and forskolin (0.3 μM).
The distension‐induced ascending reflex contraction of the circular muscle was facilitated by PACAP (1–30 nM) which itself evoked transient nerve‐mediated contractions of intestinal segment preparations.
These data show that PACAP stimulates normal peristalsis and counteracts drug‐induced peristaltic arrest by a stimulant action on excitatory enteric motor pathways, presumably at the intrinsic sensory neurone level. The action of PACAP seems to involve multiple signalling mechanisms including stimulation of adenylate cyclase.

British Journal of Pharmacology (1999) 127, 763–771; doi:10.1038/sj.bjp.0702602
Characterization of β‐adrenoceptor mediated smooth muscle relaxation and the detection of mRNA for β1‐, β2‐ and β3‐adrenoceptors in rat ileum
Authors: Roberts S J , Papaioannou M , Evans B A , Summers R J 
Published: January 2005

Functional and molecular approaches were used to characterize the β‐AR subtypes mediating relaxation of rat ileal smooth muscle.
In functional studies, (−)‐isoprenaline relaxation was unchanged by CGP20712A (β1‐AR antagonist) or ICI118551 (β2‐AR antagonist) but shifted by propranolol (pKB=6.69). (±)‐Cyanopindolol, CGP12177 and ICID7114 did not cause relaxation but antagonized (−)‐isoprenaline relaxation.
BRL37344 (β3‐AR agonist) caused biphasic relaxation. The high affinity component was shifted with low affinity by propranolol, (±)‐cyanopindolol, tertatolol and alprenolol. CL316243 (β3‐AR agonist) relaxation was unaffected by CGP20712A or ICI118551 but blocked by SR58894A (β3‐AR antagonist; pA2=7.80). Enhanced relaxation after exposure to forskolin and pertussis toxin showed that β3‐AR relaxation can be altered by manipulation of components of the adenylate cyclase signalling pathway.
The β1‐AR agonist RO363 relaxed the ileum (pEC50=6.18) and was blocked by CGP20712A. Relaxation by the β2‐AR agonist zinterol (pEC50=5.71) was blocked by SR58894A but not by ICI118551.
In rat ileum, β1‐, β2‐ and β3‐AR mRNA was detected. Comparison of tissues showed that β3‐AR mRNA expression was greatest in WAT>colon=ileum>cerebral cortex>soleus; β1‐AR mRNA was most abundant in cerebral cortex>WAT>ileum=colon>soleus; β2‐AR mRNA was expressed in soleus>WAT>ileum=colon>cerebral cortex.
These results show that β3‐ARs are the predominant β‐AR subtype mediating rat ileal relaxation while β1‐ARs may produce a small relaxation. The β2‐AR agonist zinterol produces relaxation through β3‐ARs and there was no evidence for the involvement of β2‐ARs in relaxation despite the detection of β2‐AR mRNA.

British Journal of Pharmacology (1999) 127, 949–961; doi:10.1038/sj.bjp.0702605
Failure of 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ) to inhibit soluble guanylyl cyclase in rat ventricular cardiomyocytes
Authors: Wegener Jörg W , Closs Ellen I , Förstermann Ulrich , Nawrath Hermann 
Published: January 2005

The effects of 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ), an inhibitor of soluble guanylyl cyclase (sGC), were investigated in aortic rings and ventricular cardiomyocytes from rats. The production of cyclic GMP was stimulated by NO•‐donors or carbachol. Additionally, the effects of ODQ were studied in cytosolic extracts from both tissues in which the cyclic GMP production was stimulated by S‐nitroso‐N‐acetylpenicillamine (SNAP).
In endothelium‐intact aortic rings, SNAP (100 μM), 2,2′‐(hydroxynitrosohydrazino)bis‐ethanamine (DETA NONOate; 100 μM), or carbachol (10 μM) increased cyclic GMP levels about 4 fold. These effects were abolished by ODQ (50 μM).
In cardiomyocytes, SNAP (100 μM), DETA NONOate (100 μM), or carbachol (10 μM) increased cyclic GMP levels about 2 fold. These effects were not affected by ODQ (50 μM).
In cytosolic extracts from aortic rings and cardiomyocytes, SNAP (100 μM) induced about 50 fold increases in cyclic GMP levels. ODQ (50 μM) reduced these effects by about 50%.
In extracts from cardiomyocytes, increases by SNAP (100 μM) of cyclic GMP levels were attenuated by myoglobin dependent on concentration: at 300 μM myoglobin, SNAP (100 μM) increased cyclic GMP levels only 3 fold. Inhibitory effects of ODQ (50 μM) were abolished by 300 μM myoglobin.
It is suggested that both NO• and ODQ can bind to myoglobin which, at high concentrations, can diminish their effects on sGC. Such a scavenger function of myoglobin could explain why NO• and ODQ exert only minor effects in cardiomyocytes (with high myoglobin content), but strong effects in aortic tissue (virtually devoid of myoglobin).

British Journal of Pharmacology (1999) 127, 693–700; doi:10.1038/sj.bjp.0702608
Molecular and pharmacological evidence for MT1 melatonin receptor subtype in the tail artery of juvenile Wistar rats
Authors: Ting K N , Blaylock N A , Sugden D , Delagrange P , Scalbert E , Wilson V G 
Published: January 2005

In this study reverse transcriptase‐polymerase chain reaction (RT–PCR) has been used to identify mt1 and MT2 receptor mRNA expression in the rat tail artery. The contributions of both receptors to the functional response to melatonin were examined with the putative selective MT2 receptor antagonists, 4‐phenyl‐2‐propionamidotetraline (4‐P‐PDOT) and 2‐benzyl‐N‐pentanoyltryptamine. In addition, the action of melatonin on the second messenger cyclic AMP was investigated.
Using RT–PCR, mt1 receptor mRNA was detected in the tail artery from seven rats. In contrast MT2 receptor mRNA was not detected even after nested PCR.
At low concentrations of the MT2 selective ligands, neither 10 nM 4‐P‐PDOT (pEC50=8.70±0.31 (control) vs 8.73±0.16, n=6) nor 60 nM 2‐benzyl‐N‐pentanoyltryptamine (pEC50=8.53±0.20 (control) vs 8.83±0.38, n=6) significantly altered the potency of melatonin in the rat tail artery.
At concentrations non‐selective for mt1 and MT2 receptors, 4‐P‐PDOT (3 μM) and 2‐benzyl‐N‐pentanoyltryptamine (5 μM) caused a significant rightward displacement of the vasoconstrictor effect of melatonin. In the case of 4‐P‐PDOT, the estimated pKB (6.17±0.16, n=8) is similar to the binding affinity for mt1 receptor.
Pre‐incubation with 1 μM melatonin did not affect the conversion of [3H]‐adenine to [3H]‐cyclic AMP under basal condition (0.95±0.19% conversion (control) vs 0.92±0.19%, n=4) or following exposure to 30 μM forskolin (5.20±1.30% conversion (control) vs 5.35±0.90%, n=4).
Based on the above findings, we conclude that melatonin receptor on the tail artery belongs to the MT1 receptor subtype, and that this receptor is probably independent of the adenylyl cyclase pathway.

British Journal of Pharmacology (1999) 127, 987–995; doi:10.1038/sj.bjp.0702612
Ligand‐induced differentiation of glucocorticoid receptor (GR) trans‐repression and transactivation: preferential targetting of NF‐κB and lack of I‐κB involvement
Authors: Adcock Ian M , Nasuhara Yasuyuki , Stevens David A , Barnes Peter J 
Published: January 2005

Glucocorticoids are highly effective in controlling chronic inflammatory diseases, such as asthma and rheumatoid arthritis, but the exact molecular mechanism of their anti‐inflammatory action remains uncertain. They act by binding to a cytosolic receptor (GR) resulting in activation or repression of gene expression. This may occur via direct binding of the GR to DNA (transactivation) or by inhibition of the activity of transcription factors such as AP‐1 and NF‐κB (transrepression).
The topically active steroids fluticasone propionate (EC50=1.8×10−11 M) and budesonide (EC50=5.0×10−11 M) were more potent in inhibiting GM‐CSF release from A549 cells than tipredane (EC50=8.3×10−10 M), butixicort (EC50=3.7×10−8 M) and dexamethasone (EC50=2.2×10−9 M). The anti‐glucocorticoid RU486 also inhibited GM‐CSF release in these cells (IC50=1.8×10−10 M).
The concentration‐dependent ability of fluticasone propionate (EC50=9.8×10−10 M), budesonide (EC50=1.1×10−9 M) and dexamethasone (EC50=3.6×10−8 M) to induce transcription of the β2‐receptor was found to correlate with GR DNA binding and occurred at 10–100 fold higher concentrations than the inhibition of GM‐CSF release. No induction of the endogenous inhibitors of NF‐κB, IκBα or I‐κBβ, was seen at 24 h and the ability of IL‐1β to degrade and subsequently induce IκBα was not altered by glucocorticoids.
The ability of fluticasone propionate (IC50=0.5×10−11 M), budesonide (IC50=2.7×10−11 M), dexamethasone (IC50=0.5×10−9 M) and RU486 (IC50=2.7×10−11 M) to inhibit a 3×κB was associated with inhibition of GM‐CSF release.
These data suggest that the anti‐inflammatory properties of a range of glucocorticoids relate to their ability to transrepress rather than transactivate genes.

British Journal of Pharmacology (1999) 127, 1003–1011; doi:10.1038/sj.bjp.0702613
The effect of site‐directed mutagenesis of two transmembrane serine residues on agonist‐specific coupling of a cloned human α2A‐adrenoceptor to adenylyl cyclase
Authors: Rudling Jane E , Kennedy Karen , Evans Peter D 
Published: January 2005

The effects of substitution of the Ser200 and Ser204 residues with alanine on the signalling properties of the cloned human α2A‐adrenoceptor, stably expressed in Chinese hamster ovary (CHO) cell lines, have been investigated using noradrenaline and the structural isomers of octopamine.
The Ser→Ala200 or the Ser→Ala204 mutant forms of the α2A‐adrenoceptor, when expressed in cells in the absence of pertussis toxin pretreatment, are two orders of magnitude more sensitive to inhibition of cyclic AMP production by (±)‐para‐octopamine and (±)‐meta‐octopamine, respectively, than cells expressing the wild‐type receptor. Binding studies indicate that the effects are not due to an increased agonist affinity for the mutant receptors and that they are likely to be due to agonist‐mediated conformational changes in receptor structure.
After incubation with pertussis toxin, (±)‐meta‐octopamine (100 μM and above) produced a stimulation of cyclic AMP levels in cells expressing the Ser→Ala204 mutant form of the α2A‐adrenoceptor but showed no stimulation in cells expressing the Ser→Ala200 mutant receptor. Under these conditions (±)‐para‐octopamine did not produce any increases in cyclic AMP production in cells expressing either of the mutant receptor forms or the wild‐type receptor.
The results emphasise the importance of the Ser200 and Ser204 residues of the α2A‐adrenoceptor in exerting an inhibitory influence on the ability of (±)‐para‐octopamine and (±)‐meta‐octopamine respectively, to induce a receptor‐agonist conformation capable of inhibiting forskolin‐stimulation of cyclic AMP levels.
It is clear that Ser204 also prevents meta‐octopamine from generating a receptor‐agonist conformation that can increase cyclic AMP levels, emphasising the importance of this residue in the agonist‐specific coupling of this receptor to different second messenger systems.

British Journal of Pharmacology (1999) 127, 877–886; doi:10.1038/sj.bjp.0702614
Effect of protein kinase C and phospholipase A2 inhibitors on the impaired ability of human diabetic platelets to cause vasodilation
Authors: Oskarsson Helgi J , Hofmeyer Timothy G , Coppey Lawrence , Yorek Mark A 
Published: January 2005

The aim of this study was to examine the mechanism of impaired platelet‐mediated endothelium‐dependent vasodilation in diabetes. Exposure of human platelets to high glucose in vivo or in vitro impairs their ability to cause endothelium‐dependent vasodilation. While previous data suggest that the mechanism for this involves increased activity of the cyclo‐oxygenase pathway, the signal transduction pathway mediating this effect is unknown.
Platelets from diabetic patients as well as normal platelets and normal platelets exposed to high glucose concentrations were used to determine the role of the polyol pathway, diacylglycerol (DAG) production, protein kinase C (PKC) activity and phospholipase A2 (PLA2) activity on vasodilation in rabbit carotid arteries.
We found that two aldose‐reductase inhibitors, tolrestat and sorbinil, caused only a modest improvement in the impairment of vasodilation by glucose exposed platelets. However, sorbitol and fructose could not be detected in the platelets, at either normal or hyperglycaemic conditions. We found that incubation in 17 mM glucose caused a significant increase in DAG levels in platelets. Furthermore, the DAG analog 1‐oleoyl‐2‐acetyl‐sn‐glycerol (OAG) caused significant impairment of platelet‐mediated vasodilation. The PKC inhibitors calphostin C and H7 as well as inhibitors of PLA2 activity normalized the ability of platelets from diabetic patients to cause vasodilation and prevented glucose‐induced impairment of platelet‐mediated vasodilation in vitro.
These results suggest that the impairment of platelet‐mediated vasodilation caused by high glucose concentrations is mediated by increased DAG levels and stimulation of PKC and PLA2 activity.

British Journal of Pharmacology (1999) 127, 903–908; doi:10.1038/sj.bjp.0702617