bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibitory effect of peptides derived from the N‐terminus of lipocortin 1 on arachidonic acid release and proliferation in the A549 cell line: identification of E‐Q‐E‐Y‐V as a crucial component
Authors: Croxtall J D. , Choudhury Q , Flower R J. 
Published: January 2005

The ability of the glucocorticoid‐induced protein lipocortin 1 (LC1) to inhibit arachidonic acid release and cell proliferation in A549 cells may be mimicked by a sequence taken from the N‐terminal, LC113–25 (FIENEEQEYVQTV). We have now synthesized and tested for biological activity a library of 25 smaller peptides derived from this sequence.
Peptides were tested in two assays: A549 cells were prelabelled with tritiated arachidonic acid and thapsigargin (50 nM) and EGF (10 nM) used to stimulate the release of this fatty acid. Cell proliferation was determined by counting cell numbers following 3 day incubation with these peptides, or controls.
Many of the peptides were highly insoluble but could be more readily dissolved in aqueous solution in the presence of commercial liposomes or phosphatidyl serine (5 μM). Since neither of these agents alone had any effect on arachidonic acid release or cell proliferation, all peptides were tested in the presence of 5 μM phosphatidyl serine. Under these conditions LC113–25 was active in both assay systems with an IC40 of 40.7 and 57.0 μM respectively.
Deletion of amino acids from the C‐terminus of the peptide progressively diminished (2–3 fold) the molar potency of LC113–25 in both assays: after the removal of Val22 biological activity was virtually undetectable or very weak (<30% of LC113–25).
Removal of amino acids from the N‐terminus also lead to a progressive reduction (3–5 fold) in the molar potency of the peptides and biological activity became undetectable, or very weak, after the removal of Glu18.
All active peptides contained the core sequence EQEYV(Glu‐Gln‐Glu‐Tyr‐Val) which seems to represent a crucial component of the pharmacophore, although this sequence on its own was inactive and the shortest peptide with significant activity was LC118–25 (EQEYVQTV).
Methoxylation of Tyr21 abolished the ability of LC1 18–25 to inhibit cell proliferation and arachidonic acid release. A cyclized version of LC118–25 was also tested and found to be inactive.
LC118–25 (178 μM) inhibits cPLA2 activation in A549 cells as judged by a band‐shift assay, whereas equimolar concentrations of an inactive peptide LC119–25 were without effect in this assay system.
Several possible mechanisms whereby these peptides act are discussed in the light of LC1 biology and of the effect of glucocorticoids on cell function.

British Journal of Pharmacology (1998) 123, 975–983; doi:10.1038/sj.bjp.0701679
The effect of prolonged treatment with imipramine on the biosynthesis and functional characteristics of D2 dopamine receptors in the rat caudate putamen
Authors: Dziedzicka‐Wasylewska Marta , Rogoż Renata 
Published: January 2005

The present study shows the effects of imipramine in a single dose (10 mg kg−1, p.o.) or following repeated (14 days, twice a day) treatment on the level of mRNA coding for D2 dopamine receptors in the rat caudate putamen (CP). Repeated administration of imipramine resulted in the increase of the level of mRNA coding for D2 dopamine receptors.
Radioligand binding studies with the D2 receptor agonist, [3H]‐N‐0437, indicated, that following imipramine administration, the affinity of the agonist for the D2 dopamine receptor significantly increased, though without any alterations in the Bmax.
Pharmacological manipulations (by use of forskolin, GppNHp and quinpirole) of the cyclic AMP generating system, ex vivo following administration of imipramine indicated that an up‐regulation of factors inhibiting cyclic GMP formation takes place.
Most probably it is the D2 dopamine receptor which undergoes functional up‐regulation, resulting from the enhancement of its biosynthesis.

British Journal of Pharmacology (1998) 123, 833–838; doi:10.1038/sj.bjp.0701681
Role of K+ channel opening and stimulation of cyclic GMP in the vasorelaxant effects of nicorandil in isolated piglet pulmonary and mesenteric arteries: relative efficacy and interactions between both pathways
Authors: Pérez‐Vizcaíno Francisco , Cogolludo Angel L. , Villamor Eduardo , Tamargo Juan 
Published: January 2005

The effects of the K+ channel opener levcromakalim, the guanylate cyclase stimulant nitroprusside and the dual drug nicorandil (K+ channel opener and guanylate cyclase stimulant) were analysed in piglet isolated endothelium‐denuded pulmonary (PA) and mesenteric (MA) arteries stimulated by noradrenaline (NA) or by the thromboxane A2 mimetic U46619.
Nicorandil, levcromakalim and verapamil were less potent in PA than in MA, the efficacy of levcromakalim was also reduced in PA. The effects of nicorandil and levcromakalim were similar in arteries pre‐contracted by NA and U46619, whereas verapamil was more potent in arteries pre‐contracted by NA. Nitroprusside was equipotent in MA pre‐contracted by either NA or U46619 and in PA pre‐contracted by NA whereas in PA pre‐contracted by U46619, nitroprusside showed lower potency and efficacy.
The relaxant effects of levcromakalim and nitroprusside were inhibited by 10−5 M glibenclamide and 10−6 M ODQ, respectively. Nicorandil‐induced relaxation was inhibited by ODQ in all experimental conditions, whereas glibenclamide had inhibitory effects in PA and MA pre‐contracted by U46619, had no effect in PA pre‐contracted by NA and in MA pre‐contracted by NA it was only inhibitory in the presence of ODQ.
No apparent interactions were found between nitroprusside and levcromakalim as indicated by the lack of effects of pretreatment with one of them (producing 20–35% relaxation) on the potency of the relaxant response to the other. However, in PA pre‐contracted by U46619, where nitroprusside or levcromakalim induced only partial relaxation, the combination of both mechanisms (either by combining nitroprusside plus levcromakalim or by nicorandil) was able to induce full vasodilatation.
In conclusion, K+ channel opening and guanylate cyclase stimulation are independent pathways that induce additive vasorelaxation in piglet PA and MA. The mechanism of action of nicorandil is dependent on the artery and on the nature of the agonist employed to precontract the artery. The relative efficacy of K+ channel opening vs guanylate cyclase stimulation may partially explain the preferential contribution of each mechanism to the relaxant effects of nicorandil.

British Journal of Pharmacology (1998) 123, 847–854; doi:10.1038/sj.bjp.0701693
Effect of γ‐mangostin through the inhibition of 5‐hydroxytryptamine2A receptors in 5‐fluoro‐α‐methyltryptamine‐induced head‐twitch responses of mice
Authors: Chairungsrilerd Nattaya , Furukawa Ken‐Ichi , Tadano Takeshi , Kisara Kensuke , Ohizumi Yasushi 
Published: January 2005

Intracerebronventricular (i.c.v.) injection of γ‐mangostin (10–40 nmol/mouse), a major compound of the fruit hull of Garcinia mangostana Lin., like ketanserin (10, 20 nmol/mouse, i.c.v.) inhibited 5‐fluoro‐α‐methyltryptamine (5‐FMT) (45 mg kg−1, i.p.)‐induced head‐twitch response in mice in the presence or absence of citalopram (a 5‐hydroxytryptamine (5‐HT)‐uptake inhibitor).
Neither the 5‐FMT‐ nor the 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (5‐HT1A‐agonist)‐induced 5‐HT syndrome (head weaving and hindlimb abduction) was affected by γ‐mangostin or ketanserin.
The locomotor activity stimulated by 5‐FMT through the activation of α1‐adrenoceptors did not alter in the presence of γ‐mangostin.
5‐HT‐induced inositol phosphates accumulation in mouse brain slices was abolished by ketanserin. γ‐Mangostin caused a concentration‐dependent inhibition of the inositol phosphates accumulation.
γ‐Mangostin caused a concentration‐dependent inhibition of the binding of [3H]‐spiperone, a specific 5‐HT2A receptor antagonist, to mouse brain membranes.
Kinetic analysis of the [3H]‐spiperone binding revealed that γ‐mangostin increased the Kd value without affecting the Bmax value, indicating the mode of the competitive nature of the inhibition by γ‐mangostin.
These results suggest that γ‐mangostin inhibits 5‐FMT‐induced head‐twitch response in mice by blocking 5‐HT2A receptors not by blocking the release of 5‐HT from the central neurone. γ‐Mangostin is a promising 5‐HT2A receptor antagonist in the central nervous system.

British Journal of Pharmacology (1998) 123, 855–862; doi:10.1038/sj.bjp.0701695
CGRP and nitric oxide of neuronal origin and their involvement in neurogenic vasodilatation in rat skin microvasculature
Authors: Merhi Merhi , Dusting Greg J. , Khalil Zeinab 
Published: January 2005

Sensory nerves are important for the initiation of neurogenic inflammation and tissue repair. Both calcitonin gene‐related peptide (CGRP) and nitric oxide (NO) have been implicated in neurogenic vasodilatation and inflammatory responses.
A blister model in the rat hind footpad was used as a site to induce neurogenic vasodilatation in response to antidromic electrical stimulation of the sciatic nerve. Blood flux was monitored with a laser Doppler flow monitor.
The quantitative contributions of CGRP and NO to vasodilatation were examined by use of the CGRP receptor antagonist CGRP8–37 and NO synthase inhibitors 7‐nitroindazole (7‐NI), 3‐bromo 7‐NI and NG‐nitro L‐arginine methyl ester (L‐NAME). The potential modulatory role of endothelin was examined by use of the ETA receptor antagonist BQ‐123.
CGRP8–37 (10 μM) was perfused over the blister base before nerve stimulation and continuously throughout the post‐stimulation period, resulting in a significant reduction (41%) in the blood flux vascular response.
Pretreatment with the specific neuronal NO synthase inhibitors, 7‐NI and 3‐bromo 7‐NI (10 mg kg−1, i.v.), and of the non‐specific L‐NAME (100 μM), resulted in significant inhibition of the blood flux response (36%, 72% and 57% decrease, respectively). In contrast, 7‐NI treatment in young rats pretreated with capsaicin had no further effect on the vascular response, suggesting that the source of NO is the sensory nerves.
BQ‐123 (10 μM) significantly enhanced the stimulation‐induced blood flux response (61% increase). When 7‐NI was co‐administered with either CGRP8–37 or BQ‐123, the drug actions were additive, suggesting that there was no interaction between NO and CGRP or endothelin.
These data suggest that both NO and CGRP participate in neurogenic vasodilatation in rat skin microvasculature and that this response is modulated by endogenous endothelin.

British Journal of Pharmacology (1998) 123, 863–868; doi:10.1038/sj.bjp.0701696
Elevated plasma endothelin‐1 level in streptozotocin‐induced diabetic rats and responsiveness of the mesenteric arterial bed to endothelin‐1
Authors: Makino Ayako , Kamata Katsuo 
Published: January 2005

Both the plasma endothelin‐1 (ET‐1) levels and the plasma glucose levels were markedly elevated in streptozotocin (STZ)‐induced diabetic rats.
The maximum contractile response of the mesenteric arterial bed to ET‐1 was significantly reduced, and the vasodilatation induced by the ETB‐receptor agonist IRL‐1620 in the mesenteric arterial bed was significantly reduced in STZ‐induced diabetic rats.
ET‐1 (10−8 M) caused a transient vasodilatation followed by a marked vasoconstriction in methoxamine‐preconstricted mesenteric arterial beds. The ET‐1‐induced vasodilatation was significantly larger in beds from diabetic rats than in those from age‐matched controls. By contrast, the ET‐1‐induced vasoconstriction was significantly smaller in STZ‐induced diabetic rats than in the controls.
Both removal of the endothelium with Triton X‐100 and preincubation with BQ‐788 (10−6 M) (ETB‐receptor antagonist) abolished the ET‐1‐induced vasodilatation. Preincubation with BQ‐485 (10−6 M) or BQ‐123 (3×10−6) (ETA‐receptor antagonist) significantly augmented the ET‐1‐induced vasodilatation in control mesenteric arterial beds, but not that in beds from diabetic rats.
These results demonstrate that marked increases not only in plasma glucose, but also in plasma ET‐1 occur in STZ‐induced diabetic rats. We suggest that the decreased contractile response and the increased vasodilator response of the mesenteric arterial bed to ET‐1 may both be due to desensitization of ETA receptors, though ETB receptors may also be desensitized. This desensitization may result from the elevation of the plasma ET‐1 levels seen in STZ‐induced diabetic rats.

British Journal of Pharmacology (1998) 123, 1065–1072; doi:10.1038/sj.bjp.0701704
Characterization of the recombinant human prostanoid DP receptor and identification of L‐644,698, a novel selective DP agonist
Authors: Hamish Wright D. , Metters Kathleen M. , Abramovitz Mark , Ford‐Hutchinson Anthony W. 
Published: January 2005

A human embryonic kidney cell line [HEK 293(EBNA)] stably expressing the human recombinant prostaglandin D2 (PGD2) receptor (hDP) has been characterized with respect to radioligand binding and signal transduction properties by use of prostanoids and prostanoid analogues. Radioligand binding studies included saturation analyses, the effects of nucleotide analogues, the initial rate of ligand‐receptor association and equilibrium competition assays. In addition, adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) generation in response to ligand challenge was also measured, as this is the predominant hDP signalling pathway.
L‐644,698 ((4‐(3‐(3‐(3‐hydroxyoctyl)‐4‐oxo‐2‐thiazolidinyl) propyl) benzoic acid) (racemate)) was identified as a novel ligand having high affinity for hDP with an inhibitor constant (Ki) of 0.9 nm. This Ki value was comparable to the Ki values obtained in this study for ligands that have previously shown high affinity for DP: PGD2 (0.6 nm), ZK 110841 (0.3 nm), BW245C (0.4 nm), and BW A868C (2.3 nm).
L‐644,698 was found to be a full agonist with an EC50 value of 0.5 nm in generating cyclic AMP following activation of hDP. L‐644,698 is, therefore, comparable to those agonists with known efficacy at the DP receptor (EC50): PGD2 (0.5 nm), ZK 110841 (0.2 nm) and BW245C (0.3 nm).
L‐644,698 displayed a high degree of selectivity for hDP when compared to the family of cloned human prostanoid receptors: EP1 (>25,400 fold), EP2 (∼300 fold), EP3‐III (∼4100 fold), EP4 (∼10000 fold), FP (>25,400 fold), IP (>25,400 fold) and TP (>25,400 fold). L‐644,698 is, therefore, one of the most selective DP agonists as yet described.
PGJ2 and Δ12‐PGJ2, two endogenous metabolites of PGD2, were also tested in this system and shown to be effective agonists with Ki and EC50 values in the nanomolar range for both compounds. In particular, PGJ2 was equipotent to known DP specific agonists with a Ki value of 0.9 nm and an EC50 value of 1.2 nm.

British Journal of Pharmacology (1998) 123, 1317–1324; doi:10.1038/sj.bjp.0701708
The effect of a secreted form of β‐amyloid‐precursor protein on intracellular Ca2+ increase in rat cultured hippocampal neurones
Authors: Koizumi Schuichi , Ishiguro Mariko , Ohsawa Ikuroh , Morimoto Takako , Takamura Chizuko , Inoue Kazuhide , Kohsaka Shinichi 
Published: January 2005

The effects of secreted forms of β‐amyloid‐precursor proteins (APPSs) on the intracellular Ca2+ concentration ([Ca2+]i) were investigated in rat cultured hippocampal neurones. APP695S, a secretory form of APP695, attenuated the increase in [Ca2+]i evoked by glutamate. In addition, APP695S itself evoked an increase in [Ca2+]i in 1 or 2 day‐cultured hippocampal cells, but not in 7 to 13 day‐cultured cells.
Eighty‐one percent of neurones which were immunocytochemically positive for microtubule‐associated protein 2 responded to APP695S with an increase in [Ca2+]i.
APP695S induced a transient rise in [Ca2+]i even in the absence of extracellular Ca2+ and produced an elevation in inositol‐1,4,5‐trisphosphate (IP3) in a concentration‐dependent manner from 100 to 500 ng ml−1. In the presence of extracellular Ca2+, APP695S caused a transient rise in [Ca2+]i followed by a sustained phase at high [Ca2+]i, suggesting Ca2+ entry from the extracellular space.
The [Ca2+]i elevation was mimicked by amino terminal peptides of APPS, but not by carboxy terminal peptides.
These results taken together suggest that APP695S induces an increase in [Ca2+]i in hippocampal neurones through an IP3‐dependent mechanism that changes according to the stage of development.

British Journal of Pharmacology (1998) 123, 1483–1489; doi:10.1038/sj.bjp.0701712
Zn2+ modulation of ATP‐responses at recombinant P2X2 receptors and its dependence on extracellular pH
Authors: Wildman S S. , King B F. , Burnstock G 
Published: January 2005

Using recombinant P2X2 receptors expressed in Xenopus oocytes, the modulatory effects of zinc (Zn2+) on ATP‐responses were studied under voltage‐clamp conditions and at different levels of extracellular pH.
Zn2+ (0.3–300 μM) added to the bathing medium potentiated ATP‐activated membrane currents, increasing ATP‐responses by up to 20 fold. This potentiating effect was reversed on washout. Zn2+‐potentiation was reduced in an exponential manner (decaying 1/e in 42 s) as the interval was lengthened between adding Zn2+ then ATP to the superfusate.
The potentiating effect of Zn2+ was progressively diminished by acidic shifts in extracellular pH (pHe) which, of itself, also potentiated ATP‐responses at P2X2 receptors. The maximal potentiating effects of Zn2+ and H+ were not additive.
Neither Zn2+ nor H+ potentiation of ATP‐responses was abolished by diethylpyrocarbonate (DEPC, 0.3–3 mM), which irreversibly denatures histidyl residues. Nine histidyl residues are present in the extracellular loop of P2X2 receptors.
Zn2+ also enhanced the blocking activity of the P2 receptor antagonist suramin at P2X2 receptors. Therefore, Zn2+ also mimics H+ in increasing suramin‐activity at P2X2 receptors.
In summary, Zn2+ and H+ potentiate agonist and antagonist activity at P2X2 receptors but their effects are not wholly alike for receptor agonism. There, the potentiating effects of Zn2+ are time‐dependent and gradually convert to inhibition while those of H+ are time‐independent, persistent and more potent, suggesting that either these modulators interact in a different way with a single allosteric site or with different allosteric sites.

British Journal of Pharmacology (1998) 123, 1214–1220; doi:10.1038/sj.bjp.0701717
Cholecystokinin‐8 regulation of NGF concentrations in adult mouse brain through a mechanism involving CCKA and CCKB receptors
Authors: Tirassa Paola , Stenfors Carina , Lundeberg Thomas , Aloe Luigi 
Published: January 2005

Nerve growth factor (NGF), a powerful agent for the growth, differentiation and regeneration of lesioned cells of the central and peripheral nervous systems, has in recent years been indicated as a potential therapeutic agent capable of reversing the processes of cell damage in neurodegenerative events in man. Since NGF does not cross the blood‐brain barrier and central NGF administration requires invasive surgical procedures, the discovery of substances modulating in vivo NGF synthesis in the brain will be extremely useful for a possible clinical use of NGF.
The aim of the present study to analyse if the content of NGF in the brain of adult mice can be affected by peripheral administration of cholecystokinin‐8 (CCK‐8), a well known neuropeptide which has stimulant actions on neurons in the brain and promotes a variety of neurobehavioural effects both in man and rodents.
The dose‐response and time course effects of an i.p. injection of CCK‐8 on the NGF concentrations in the hippocampus, cortex, hypothalamus and pituitary of adult male mice were analysed by use of a sensitive immunoenzymatic assay for NGF. The effects of pretreatment with selective CCKA and CCKB receptor antagonists and atropine on the NGF response to CCK injection were also studied.
The effects of CCK‐8 were dose‐ and time‐dependent and the injection of 8 nmol kg−1 resulted in a 3 fold increase of NGF levels in the hypothalamus and pituitary, and about a 60% increase in the hippocampus. No effects were observed in the cortex. Pretreatment with a selective CCKA receptor antagonist blocked the CCK‐induced NGF increase in the hypothalamus and pituitary. In the hippocampus the same effect was obtained with a CCKB receptor antagonist. Pretreatment with atropine suppressed the CCK‐induced effects on NGF levels in all the brain regions examined.
Our results showing that i.p. injection with CCK‐8 can modulate NGF levels in the brain through a mechanism which seems, in part, to be mediated via the vagal afferents, indicate that this neuropeptide may represent a useful pharmacological approach to enhance endogenous NGF levels in neuropathologies associated with a neurotrophin deficit.

British Journal of Pharmacology (1998) 123, 1230–1236; doi:10.1038/sj.bjp.0701718
SB‐205384: a GABAA receptor modulator with novel mechanism of action that shows subunit selectivity
Authors: Meadows H J. , Kumar C S. , Pritchett D B. , Blackburn T P. , Benham C D. 
Published: January 2005

SB‐205384, and its (+) enantiomer (+)‐SB‐205384 were tested for their modulatory effects on human GABAA receptor subunit combinations expressed in Xenopus oocytes by electrophysiological methods.
The slowing of the decay rate induced by SB‐205384 on native GABA‐activated currents in rat neurones was also seen on GABAA currents in oocytes expressing human GABAA subunits. This temporal effect was observed for the α3β2γ2 subunit combination with little effect in subunit combinations containing either α1 or α2.
Potentiation of the peak amplitude of the GABA‐activated currents by SB‐205384 or (+)‐SB‐205384 was less specific for a particular subunit combination, although the greatest effect at 10 μM drug was seen on the α3β2γ2 subunit combination.
In contrast, zolpidem, a benzodiazepine site modulator, did not significantly slow decay rates of GABAA currents in oocytes expressing the α3β2γ2 subunit combination. Zolpidem, as expected, did selectively potentiate GABA‐activated currents on oocytes expressing the γ2 subunit compared to those containing the γ1.
The results show that the novel kinetic modulatory profile of SB‐205384 is selective for the α3β2γ2 subunit combination. This suggests that the compound is binding to a novel regulatory site on the subunit complex.

British Journal of Pharmacology (1998) 123, 1253–1259; doi:10.1038/sj.bjp.0701721