bluuebunny/crossref_metadata_2025_split huggingface dataset:
B1 receptor involvement in the effect of bradykinin on venular endothelial cell proliferation and potentiation of FGF‐2 effects
Authors: Morbidelli Lucia , Parenti Astrid , Giovannelli Lisa , Granger Harris J. , Ledda Fabrizio , Ziche Marina 
Published: January 2005

Bradykinin (BK) contributes to the inflammatory response inducing vasodilation of postcapillary venules and has been demonstrated to induce neovascular growth in subcutaneous rat sponges.
In this study the ability of BK to stimulate cell growth and migration in cultured endothelium from coronary postcapillary venules (CVEC) has been investigated.
[3H]‐thymidine incorporation in subconfluent and synchronised CVEC was used to monitor DNA synthesis over 24 h. BK promoted a concentration‐dependent increase of DNA synthesis with maximal activity at 100 nm. At this concentration BK also induced 18 fold accumulation of c‐Fos protein immunoreactivity in the nucleus within 1 h from peptide exposure.
The total number of cells recovered after 48 h exposure to BK was increased in a concentration‐dependent manner. Maximal effect was produced by 100 nm concentration of the peptide which produced 50% increase in cell number. The selective B1 receptor agonist Des‐Arg9‐BK mimicked the proliferative effect of BK, while the B2 receptor agonist kallidin was devoid of any activity. The proliferation induced by BK was abolished in a concentration‐dependent manner by the addition of the B1 selective antagonist Des‐Arg9‐Leu8‐BK, while the selective B2 receptor antagonist HOE140 did not modify BK‐induced growth.
DNA synthesis and growth promoted by a threshold concentration of fibroblast growth factor‐2 (FGF‐2) (0.25 nm) were potentiated by increasing concentrations of BK and Des‐Arg9‐BK.
Endothelial cell migration assessed by the Boyden Chamber procedure was not promoted by BK or the selective B1 and B2 receptor agonists.
These data are the first demonstration that BK promotes growth of endothelial cells from postcapillary venules. The mitogenic activity of BK involves c‐Fos expression and potentiates the growth promoting effect of FGF‐2. Only the B1 receptor appears to be responsible for the proliferation induced by BK and suggests that this type of receptor might be implicated in favouring angiogenesis of coronary venules.

British Journal of Pharmacology (1998) 124, 1286–1292; doi:10.1038/sj.bjp.0701943
Inhibition of tumour necrosis factor and reversal of endotoxin‐induced shock by U‐83836E, a ‘second generation’ lazaroid in rats
Authors: Altavilla Domenica , Squadrito Francesco , Serrano Micaela , Campo Giuseppe M. , Squadrito Giovanni , Arlotta Mariarita , Urna Giuseppe , Sardella Aurora , Saitta Antonino , Caputi Achille P. 
Published: January 2005

Antioxidants can exert protective effects in endotoxic shock by either a reduction of the oxidant damage or attenuation of Tumour Necrosis Factor (TNF‐α) production.
Lazaroids are a family of compounds that inhibit lipid peroxidation. Besides, they can also reduce TNF‐α. U‐83836E is a new lazaroid lacking the glucocorticoid ring.
Aim of our study was to investigate the effect of U‐83836E on TNF‐α production either in vivo or in vitro. Endotoxic shock was produced in male rats by a single intravenous (i.v.) injection of 20 mg kg−1 of S. enteritidis lipopolysaccharide (LPS). LPS administration reduced survival rate (0% survival, 72 h after endotoxin administration), decreased mean arterial blood pressure, increased serum and macrophage TNF‐α and enhanced plasma malonylaldehyde (MAL) levels. Furthermore aortic rings from shocked rats showed a marked hyporeactivity to phenylephrine (PE 1 nm–10 μm).
Treatment with U‐83836E (7.5, 15 and 30 mg kg−1, i.v.) 5 min after endotoxin challenge significantly protected against LPS induced lethality (90% survival rate and 80% survival rate 24 h and 72 h after LPS injection respectively, following the highest dose of the drug), reduced hypotension, blunted plasma MAL, decreased serum and macrophage TNF‐α and restored the hyporeactivity of aortic rings to control values. In vitro LPS stimulation (50 μg ml−1 for 4 h) significantly increased cytokine production in macrophages (MΦ) harvested from untreated normal rats. Pretreatment with pertussis toxin (PT; 0.1, 1 and 10 ng ml−1 4 h before LPS) significantly increased TNF‐α production. PT effects on these LPS responses were correlated with a PT mediated ADP ribosylation of a 41 kDa protein. U‐83836E (50 μm) reduced, in a dose dependent manner, LPS induced TNF‐α production and inhibited the PT effects on cytokine production and on ADP ribosylation of the protein.
Our data suggest that lazaroids may affect the early events associated with LPS receptor mediated activation of a G protein in LPS induced TNF‐α production. These molecular events may explain, at least in part, the in vivo inhibition of cytokine production and reversal of endotoxic shock.

British Journal of Pharmacology (1998) 124, 1293–1299; doi:10.1038/sj.bjp.0701944
Evidence from microdialysis and synaptosomal studies of rat cortex for noradrenaline uptake sites with different sensitivities to SSRIs
Authors: Hughes Zoë A. , Stanford S. Clare 
Published: January 2005

Microdialysis of the frontal cortex of freely‐moving rats and uptake of [3H]noradrenaline into cortical synaptosomes were used to evaluate changes in efflux of noradrenaline in vivo and uptake of [3H]noradrenaline in vitro, respectively, induced by the selective serotonin reuptake inhibitors (SSRIs), fluoxetine and citalopram, and the tricyclic antidepressant, desipramine.
Noradrenaline efflux was increased during local infusion into the cortex of each of these drugs. All three agents also inhibited synaptosomal uptake of [3H]noradrenaline; this inhibition was unaffected by a substantial (50%) lesion of central 5‐hydroxytrytaminergic neurones induced by intracerebroventricular infusion of 5,7‐DHT (150 μg).
A noradrenergic lesion (70%), induced by pretreatment with the selective neurotoxin, N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP‐4, 40 mg kg−1 i.p.), 5 days earlier, abolished the increase in noradrenaline efflux caused by local infusion of fluoxetine. In contrast, the desipramine‐induced increase in efflux was greater than in non‐lesioned rats whereas the effect of citalopram on noradrenaline efflux was unaffected by DSP‐4 pretreatment.
The combined results of all these experiments suggest that there could be more than one, functionally distinct, noradrenaline uptake site in rat frontal cortex which can be distinguished by their different sensitivities to desipramine and the SSRIs, fluoxetine and citalopram.

British Journal of Pharmacology (1998) 124, 1141–1148; doi:10.1038/sj.bjp.0701947
Inhibition of excitatory amino acid‐activated currents by trichloroethanol and trifluoroethanol in mouse hippocampal neurones
Authors: Peoples Robert W. , Weight Forrest F. 
Published: January 2005

The effects of the active metabolite of chloral derivative sedative‐hypnotic agents, 2,2,2‐trichloroethanol (trichloroethanol), and its analog 2,2,2‐trifluoroethanol (trifluoroethanol), were studied on ion current activated by the excitatory amino acids N‐methyl‐d‐aspartate (NMDA) and kainate in mouse hippocampal neurones in culture using whole‐cell patch‐clamp recording.
Both trichloroethanol and trifluoroethanol inhibited excitatory amino acid‐activated currents in a concentration‐dependent manner. Trichloroethanol inhibited NMDA‐ and kainate‐activated currents with IC50 values of 6.4 and 12 mm, respectively, while trifluoroethanol inhibited NMDA‐ and kainate‐activated currents with IC50 values of 28 and 35 mm, respectively.
Both trichloroethanol and trifluoroethanol appeared to be able to inhibit excitatory amino acid‐activated currents by 100 per cent.
Concentration‐response analysis of NMDA‐ and kainate‐activated current revealed that trichloro‐ethanol decreased the maximal response to both agonists without significantly affecting their EC50 values.
Both trichloroethanol and trifluoroethanol inhibited excitatory amino acid‐activated currents more potently than did ethanol. The inhibitory potency of trichloroethanol and trifluoroethanol appears to be associated with their increased hydrophobicity.
The observation that trichloroethanol inhibits excitatory amino acid‐activated currents at anaesthetic concentrations suggests that inhibition of excitatory amino acid receptors may contribute to the CNS depressant effects of chloral derivative sedative‐hypnotic agents.

British Journal of Pharmacology (1998) 124, 1159–1164; doi:10.1038/sj.bjp.0701949
Role of endogenous nitric oxide in allergen‐induced airway responses in guinea‐pigs
Authors: Iijima Hiroaki , Uchida Yoshiyuki , Endo Takeo , Xiang Anbo , Shirato Manabu , Nomura Akihiro , Hasegawa Shizuo 
Published: January 2005

Endogenous nitric oxide (NO) can be detected in exhaled air and accumulates in inflamed airways. However its physiological role has not been fully elucidated. In this study, we investigated a role for endogenous NO in allergen‐induced airway responses. Sensitised guinea‐pigs were treated with NG‐nitro‐l‐arginine methyl ester l‐NAME (2.0 mm) or aminoguanidine (AG) (2.0 mm) 30 min before the allergen challenge, and 3 and 4 h after the challenge. Alternatively, l‐arginine (2.4 mm) treatment was performed 30 min before, and 2 and 3 h after the challenge. In all groups, ovalbumin (OVA) challenge (2 mg ml−1 for 2 min) was performed, and airway responses, NO production, infiltration of inflammatory cells, plasma exudation and histological details were examined.
Allergen‐challenged animals showed an immediate airway response (IAR) and a late airway response (LAR), which synchronised with an increase in exhaled NO. Treatment with l‐NAME and AG did not affect IAR while they significantly blocked LAR (72% and 80% inhibition compared to vehicle) and production of NO (35% and 40% inhibition). On the other hand, treatment with l‐arginine did not affect IAR but potentiated LAR (74% augmentation).
In bronchoalveolar lavage (BAL) fluid, allergen‐induced increases in eosinophils were reduced by 48% for l‐NAME treatment compared to vehicle, and increased by 56% for l‐arginine treatment.
Treatment with l‐NAME significantly decreased airway microvascular permeability to both Monastral blue (MB) and Evans blue (EB) dye (50.6% and 44% inhibition).
We conclude that allergen‐induced LAR is closely associated with NO production, and that NO plays a critical role in inflammatory cell infiltration and plasma exudation in the allergic condition.

British Journal of Pharmacology (1998) 124, 1019–1028; doi:10.1038/sj.bjp.0701951
Prostaglandins inhibit secretion of histamine and pancreastatin from isolated rat stomach ECL cells
Authors: Lindström Erik , Håkanson Rolf 
Published: January 2005

The present study examines the effect of naturally occurring prostanoids and prostaglandin (PG) congeners on gastrin‐ and pituitary adenylate cyclase‐activating peptide (PACAP)‐evoked histamine and pancreastatin secretion from isolated rat stomach ECL cells.
ECL cells (75–85% purity) were isolated from rat stomach using pronase digestion followed by repeated counter‐flow elutriation and cultured for 48 h before secretion experiments. The release of histamine and pancreastatin was determined by radioimmunoassay.
None of the PGs tested stimulated the release of either histamine or pancreastatin.
PGE1 and PGE2 inhibited both gastrin‐ and PACAP‐evoked histamine and pancreastatin secretion (IC50 = 1–2×10−10 m). Most other naturally occuring prostanoids and PG congeners had no or little inhibitory effect. The PGE analogues misoprostol and sulprostone were more potent (IC50 = 0.9×10−11 m and 2×10−11 m respectively) than PGE1 and PGE2. The rank order of potency was misoprostol>sulprostone>PGE1 = PGE2, suggesting the involvement of the so‐called EP3 receptor.
The effects of PGs on the stomach ECL cells may be direct or indirect, for instance through the stimulated release of somatostatin from contaminating D cells (2–3%). However, the amount of somatostatin in the cell culture after 48 h was below the limit of detection, and somatostatin immunoneutralization did not prevent misoprostol from inhibiting secretion from the ECL cells.
The misoprostol‐induced inhibition was reversed by pertussis toxin suggesting the involvement of G‐protein subunits Gα0 and/or Gαi.
In view of the potency by which PGE1, PGE2, misoprostol and sulprostone inhibited the stimulated release of histamine and pancreastatin, we suggest that the ECL cells represent a primary target for prostaglandins acting via an EP3 receptor in the oxyntic mucosa.
The results suggest that the clinically useful effect of misoprostol as an anti‐ulcer drug reflects its ability to inhibit stomach ECL‐cell histamine secretion.

British Journal of Pharmacology (1998) 124, 1307–1313; doi:10.1038/sj.bjp.0701953
Selective inhibition of M‐type potassium channels in rat sympathetic neurons by uridine nucleotide preferring receptors
Authors: Boehm Stefan 
Published: January 2005

UTP and UDP depolarize rat superior cervical ganglion neurons and trigger noradrenaline release from these cells. The present study investigated the mechanisms underlying this excitatory action of uridine nucleotides by measuring whole‐cell voltage‐dependent K+ and Ca2+ currents.
Steady‐state outward (holding) currents measured in the amphotericin B perforated‐patch configuration at a potential of −30 mV were reduced by 10 μm UTP in a reversible manner, but steady‐state inward (holding) currents at −70 mV were not affected. This action of UTP was shared by the muscarinic agonist oxotremorine‐M. In current‐voltage curves between −20 and −100 mV, UTP diminished primarily the outwardly rectifying current components arising at potentials positive to −60 mV.
Slow relaxations of muscarinic K+ currents (IM) evoked by hyperpolarizations from −30 to −55 mV were also reduced by 10 μm UTP (37% inhibition) and oxotremorine‐M (81% inhibition). In contrast, transient K+‐currents, delayed rectifier currents, fast and slow Ca2+‐dependent K+ currents, as well as voltage‐dependent Ca2+ currents were not altered by UTP.
In conventional (open‐tip) whole‐cell recordings, replacement of GTP in the pipette by GDPβS abolished the UTP‐induced inhibition of IM, whereas replacement by GTPγS rendered it irreversible.
The UTP‐induced reduction of IM was half maximal at 1.5 μm with a maximum of 37% inhibition; UDP was equipotent and equieffective, while ADP was less potent (half maximal inhibition at 29 μm). ATP had no effect at 30 μm.
The inhibition of IM induced by 10 μm UTP was antagonized by pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS) at 30 μm and by reactive blue 2 at 10 μm, but not by suramin at concentrations up to 30 μm.
These results show that rat superior cervical ganglion neurons possess uridine nucleotide preferring P2Y receptors which inhibit KM channels. This effect presumably forms the basis of the excitatory action of uridine nucleotides in rat sympathetic neurons.

British Journal of Pharmacology (1998) 124, 1261–1269; doi:10.1038/sj.bjp.0701956
4‐Oxystilbene compounds are selective ligands for neuronal nicotinic αBungarotoxin receptors
Authors: Gotti C. , Balestra B. , Moretti M. , Rovati G. E. , Maggi L. , Rossoni G. , Berti F. , Villa L. , Pallavicini M. , Clementi F. 
Published: January 2005

Starting from the structure of an old 4‐oxystilbene derivate with ganglioplegic activity (MG624), we synthesized two further derivates (F2 and F3) and two stereoisomers of F3 (F3A and F3B), and studied their selective effect on neuronal nicotinic acetylcholine receptor (AChR) subtypes.
MG 624, F3, F3A and F3B inhibited of 125I‐αBungarotoxin (αBgtx) binding to neuronal chick optic lobe (COL) membranes, with nM affinity, but inhibited 125I‐αBgtx binding to TE671 cell‐expressed muscle‐type AChR only at much higher concentrations.
We immobilized the α7, β2 and β4 containing chick neuronal nicotinic AChR subtypes using anti‐subunit specific antibodies. MG 624, F3, F3A and F3B inhibited 125I‐αBgtx binding to the α7‐containing receptors with nm affinity, but inhibited 3H‐Epi binding to β2‐containing receptors only at very high concentrations (more than 35 μm); their affinity for the β4‐containing receptors was ten times more than for the β2‐containing subtype.
Both MG624 and F3 compounds inhibited the ACh evoked currents in homomeric oocyte‐expressed chick α7 receptors with an IC50 of respectively 94 and 119 nm.
High doses of both MG 624 and F3 depressed the contractile response to vagus nerve stimulation in guinea pig nerve‐stomach preparations although at different IC50s (49.4 vs 166.2 μm) The effect of MG624 on rat nerve‐hemidiaphragm preparations was 33 times less potent than that of F3 (IC50 486 vs 14.5 μm).
In conclusion, MG624 and F3 have a high degree of antagonist selectivity for neuronal nicotinic αBgtx receptors containing the α7 subunit.

British Journal of Pharmacology (1998) 124, 1197–1206; doi:10.1038/sj.bjp.0701957
Effects of antagonists at the human recombinant P2X7 receptor
Authors: Chessell I. P. , Michel A. D. , Humphrey P. P. A. 
Published: January 2005

We have used whole‐cell patch clamping methods to examine the properties of the recombinant human P2X7 (P2Z) receptor stably expressed in HEK‐293 cells.
In an extracellular solution with lowered concentrations of divalent cations (zero Mg2+ and 0.5 mm Ca2+), both ATP and the nucleotide analogue, 2′‐ and 3′‐O‐(4‐benzoylbenzoyl)‐adenosine 5′‐triphosphate (Bz‐ATP) evoked concentration‐dependent whole‐cell inward currents with maxima of 4658±671 and 5385±990 pA, respectively, at a holding potential of −90 mV. Current‐voltage relationships determined using 100 μm Bz‐ATP reversed at −2.7±3.1 mV, and did not display significant rectification.
Repeated applications of 300 μm Bz‐ATP produced inward currents with similar rise‐times (approx. 450 ms, 5–95% current development) but with progressively slower 95–5% decay times, with the eighth application of this agonist yielding a decay time of 197% of the first application.
Concentration‐effect curves to ATP and Bz‐ATP produced estimated EC50 values of 780 and 52.4 μm, respectively. Consecutive concentration‐effect curves to Bz‐ATP produced curves with similar maxima and EC50 values.
The non‐selective P2 antagonists, pyridoxal‐phosphate‐6‐azophenyl‐, 2′,4′‐disulphonic acid (PPADS) and suramin, both produced concentration‐dependent increases in maximal inward currents to Bz‐ATP, with IC50 concentrations of approximately 1 μm and 70 μm, respectively. The profile of antagonism produced by PPADS was not that of a competitive antagonist.
The isoquinolene derivatives 1‐(N,O‐bis[5‐isoquinolinesulphonyl]‐N‐methyl‐l‐tyrosyl)‐4‐phenylpiperazine (KN‐62) and calmidazolium both produced antagonism which was not competitive, with IC50 concentrations of approximately 15 and 100 nm, respectively. HMA (5‐(N,N‐hexamethylene)‐ amiloride) was also an effective antagonist at a concentration of 10 μm. The group IIb metal, copper, also displayed antagonist properties at the human P2X7 receptor, reducing the maximum response to Bz‐ATP by about 50% at a concentration of 1 μm.
These data demonstrate that the human recombinant P2X7 receptor displays functional behaviour which is similar to the recombinant rat P2X7 receptor, but has a distinct pharmacological profile with respect to agonist and antagonist sensitivity.

British Journal of Pharmacology (1998) 124, 1314–1320; doi:10.1038/sj.bjp.0701958
Different receptors for angiotensin II at pre‐ and postjunctional level of the canine mesenteric and pulmonary arteries
Authors: Guimarães S. , Paiva M. Q. , Moura D. 
Published: January 2005

This investigation was undertaken to compare pre‐ and postjunctional receptors involved in the responses of the canine mesenteric and pulmonary arteries to angiotensin II.
In the mesenteric artery, angiotensin II caused an enhancement of tritium overflow evoked by electrical stimulation (EC30% = 5 nm), the maximal effect representing an increase by about 45%. Postjunctionally, angiotensin II caused concentration‐dependent contractions (pD2 = 8.57). Saralasin antagonized both pre‐ and postjunctional effects of angiotensin II, but it was more potent at post‐ than at prejunctional level (pA2 of 9.51 and 8.15, respectively), while losartan antagonized exclusively the postjunctional effects of angiotensin II (pA2 = 8.15). PD123319 had no antagonist effect either pre‐ or postjunctionally.
In the pulmonary artery, angiotensin II also caused an enhancement of the electrically‐evoked tritium overflow (EC30% = 1.54 nm), its maximal effect increasing tritium overflow by about 80%. Postjunctionally, angiotensin II caused contractile responses (pD2 = 8.52). As in the mesenteric artery, saralasin antagonized angiotensin II effects at both pre‐ and postjunctional level and it was more potent postjunctionally (pA2 of 9.58 and 8.10, respectively). Losartan antagonized only the postjunctional effects of angiotensin II (pA2 = 7.96) and PD123319 was ineffective.
It is concluded that in both vessels: (1) pre‐ and postjunctional receptors belong to a different subtype, since they are differently antagonized by the same antagonists; (2) postjunctional receptors belong to AT1 subtype, since they are blocked by losartan but not by AT2 antagonists; (3) prejunctional receptors apparently belong to neither AT1 or AT2 subtype since they are blocked by neither AT1 nor AT2 antagonists.

British Journal of Pharmacology (1998) 124, 1207–1212; doi:10.1038/sj.bjp.0701959
In vitro characterization of tachykinin NK2‐receptors modulating motor responses of human colonic muscle strips
Authors: Croci Tiziano , Aureggi Giulio , Manara Luciano , Emonds‐Alt Xavier , Le Fur Gerard , Maffrand Jean‐Pierre , Mukenge Sylvain , Ferla Gianfranco 
Published: January 2005

Human in vitro preparations of transverse or distal colonic circular smooth muscle were potently and dose‐dependently contracted by neurokinin A (EC50, 4.9 nm), the tachykinin NK2‐receptor selective agonist [β‐Ala8]neurokinin A (4–10) ([β‐Ala8]NKA (4–10)) (EC50, 5.0 nm), neurokinin B (EC50, 5.3 nm) and substance P (EC50, 160 nm), but not by the tachykinin NK1‐receptor selective agonist [Sar9Met(O2)11] substance P, or the NK3‐receptor selective agonists, senktide and [MePhe7] neurokinin B. No regional differences between transverse and distal colon were observed in response to [β‐Ala8]NKA (4–10).
Atropine (1 μm) and tetrodotoxin (1 μm) did not significantly inhibit responses to [β‐Ala8]NKA (4–10), neurokinin A, substance P or neurokinin B.
The newly developed non‐peptide antagonists for tachykinin NK2‐receptors SR 48968, SR 144190 and its N‐demethyl (SR 144743) and N,N‐demethyl (SR 144782) metabolites, were used to challenge agonist responses, as appropriate. SR 144190 and the metabolites all potently and competitively antagonized the response to [β‐Ala8]NKA (4–10), with similar potency (Schild plot pA2 values 9.4, 9.4 and 9.3, slope = 1). SR 48968 antagonism was not competitive: the Schild plot slope was biphasic with a high (X intercept∼9.3) and a low (X intercept 8.4, slope 1.6) affinity site. Co‐incubation of SR 48968 (10, 100 nm) and SR 144782 (10 nm) produced additive effects; in this experimental condition, SR 48968 apparent affinity (pKB) was 8.2. In addition, SR 144782 (0.1 μm) antagonized responses to neurokinin A, substance P and neurokinin B, with pKB consistent with its affinity for tachykinin NK2‐receptors. The potent and selective NK1 and NK3‐receptor antagonists, SR 140333 and SR 142801 (both 0.1 μm), failed to inhibit contractions induced by SP or NKB.
In conclusion, the in vitro mechanical responses of circular smooth muscle preparations from human colon are strongly consistent with the presence of non‐neuronal tachykinin NK2‐receptors, but not tachykinin NK1‐ or NK3‐receptors. Our findings with SR 48968 suggest the existence of two tachykinin NK2‐receptor subtypes, that it seems to distinguish, unlike SR 144190 and its metabolites. However, the precise nature of SR 48968 allotopic antagonism remains to be elucidated, since allosteric effects at the tachykinin NK2‐receptor might well account for the complexity of the observed interaction.

British Journal of Pharmacology (1998) 124, 1321–1327; doi:10.1038/sj.bjp.0701960