bluuebunny/crossref_metadata_2025_split huggingface dataset:
NCX4016 (NO‐Aspirin) has multiple inhibitory effects in LPS‐stimulated human monocytes
Authors: Minuz Pietro , Degan Maurizio , Gaino Stefania , Meneguzzi Alessandra , Zuliani Valeria , Santonastaso Clara Lechi , Soldato Piero Del , Lechi Alessandro 
Published: January 2005

NCX4016 (2 acetoxy‐benzoate 2‐(2‐nitroxymethyl)‐phenyl ester, NicOx S.A., France) is an anti‐thrombotic agent, chemically related to acetylsalicylic acid (ASA) and able to release NO.
We tested the effects of NCX4016 and ASA on the release of the thromboxane (TX) A2 metabolite TXB2, tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), expression and activity of tissue factor (TF) in stimulated, adherent human monocytes.
Both ASA and NCX4016 1 – 1000 μmol l−1 dose‐dependently reduced TXB2 concentration, measured by RIA in the supernatant of 10 μg ml−1 LPS‐stimulated cells. NCX4016 activity was comparable to that of equimolar ASA when incubation lasted 6 h (NCX4016 30 μmol l−1: −86.0±10.1%, NCX4016 300 μmol l−1: −92.2±9.0%, ASA 30 μmol l−1: −92.3±7.5%, ASA 300 μmol l−1: −97.3±1.0%, n=6, M±s.d.). Most of the activity of NCX4016 up to 100 μmol l−1 was prevented by 10 μmol l−1 ODQ, inhibitor of cyclic GMP.
NCX4016 100 – 300 μmol l−1 reduced TNF‐α (NCX4016 300 μmol l−1=−77.2±19.9%, n=6) and IL‐6 (NCX4016 300 μmol l−1: −61.9±15.2%, n=6) in LPS stimulated monocytes while ASA had no significant effects.
TF activity (NCX4016 300 μmol l−1: 53.7±39.9%, n=4) and immunoreactive TF (NCX4016 300 μmol l−1: −93.9±7.9%, n=7), measured in the supernatant of stimulated cells, were also dose‐dependently inhibited by NCX4016 but not by ASA.
The present results indicate that NCX4016 inhibits TXA2 generation as well as cytokine release and TF in human monocytes partly via NO‐dependent mechanisms. NCX4016 may have a favourable profile of activities in the clinical setting of athero‐thrombosis.

British Journal of Pharmacology (2001) 134, 905–911; doi:10.1038/sj.bjp.0704326
Phenanthrolines – a new class of CFTR chloride channel openers
Authors: Duszyk Marek , MacVinish Lesley , Cuthbert Alan W 
Published: January 2005

A number of phenanthrolines and benzoquinolines were examined for their ability to activate epithelial chloride secretion by measuring short circuit current (SCC) using the mouse colon epithelium. 1,10 phenanthroline stimulated electrogenic chloride secretion with an EC50 of 612±10 μM and a Hill slope of 4.9±0.3. A similar pharmacology was demonstrated by both 1,7 and 4,7 phenanthrolines, 7,8 benzoquinoline and phenanthridine.
Evidence that the increase in SCC caused by 1,10 phenanthroline was due to chloride secretion is based upon (a) inhibition of the current by furosemide, (b) failure of cystic fibrosis (CF) colons to respond and (c) an associated net flux of 36Cl−.
1,10 Phenanthroline affected neither the generation of cyclic AMP or the concentration of intracellular Ca2+ in colonic epithelial cells.
1,10 phenanthroline affected the chloride conductance of the apical membrane, as shown by an increase in chloride current in ‘apical membrane only’ preparations in the presence of an apical to basolateral chloride gradient. The increase in chloride current was inhibited by 5‐nitro‐2‐(3‐phenylpropylamino) benzoic acid (NPPB) and was not present in CF colons.
Additionally, 1,10 phenanthroline activated basolateral K+ channels, both Ca2+‐ and cyclic AMP‐sensitive channels, as shown by inhibitor studies with charybdotoxin (ChTX) and XE991, and after the apical membrane was permeabilized with nystatin.
The phenanthrolines and benzoquinolines described here, with dual actions affecting CFTR and basolateral K+ channels, may constitute useful lead compounds for adjunct therapy in CF.

British Journal of Pharmacology (2001) 134, 853–864; doi:10.1038/sj.bjp.0704328
Renoprotective effects of carvedilol in hypertensive‐stroke prone rats may involve inhibition of TGFβ expression
Authors: Wong Victoria Y , Laping Nicholas J , Nelson Allen H , Contino Lisa C , Olson Barbara A , Gygielko Eugene , Campbell Wallace G , Barone Frank , Brooks David P 
Published: January 2005

The effect of carvedilol on renal function, structure and expression of TGFβ and the matrix proteins fibronectin, collagen I and collagen III, was evaluated in spontaneously hypertensive stroke‐prone (SHR‐SP) rats fed a high fat, high salt diet.
Carvedilol treatment for 11 to 18 weeks did not alter systolic blood pressure in SHR‐SP rats, however, it resulted in a significant reduction in heart rate.
Carvedilol treatment reduced renal fibrosis and total, active and chronic renal damage to levels approaching those of WKY rats on a normal diet.
Urinary protein excretion was higher in SHR‐SP rats (51±10 mg day−1) than WKY rats (18±2 mg day−1) and this was further increased when SHR‐SP rats were fed a high fat, high salt diet (251±120 mg day−1). Treatment with carvedilol resulted in significantly lower urinary protein excretion (37±15 mg day−1).
The expression of TGFβ mRNA was significantly higher in SHR‐SP rats compared to WKY rats and a further increase was observed when rats were fed a high fat, high salt diet. Renal TGFβ expression was significantly reduced by treatment with carvedilol. The expression of fibronectin and collagen I and collagen III mRNA showed a pattern similar to that observed with TGFβ mRNA expression. Collagen I mRNA expression followed a pattern similar to renal fibrosis.
These data indicate that carvedilol can provide significant renal protection in the absence of any antihypertensive activity and that the mechanisms involved in this action may include reduced expression of profibrotic factors such as TGFβ.

British Journal of Pharmacology (2001) 134, 977–984; doi:10.1038/sj.bjp.0704329
A rapid and transient synthesis of nitric oxide (NO) by a constitutively expressed type II NO synthase in the guinea‐pig suprachiasmatic nucleus
Authors: Starkey Sarah J , Grant Andrea L , Hagan Russell M 
Published: January 2005

We have measured extracellular NO/NO2− concentrations in guinea‐pig suprachiasmatic nucleus (SCN) brain slices using fast cyclic voltammetry. A rapid and transient signal equivalent to 2.2±0.2 μM NO/NO2− (mean±s.e.mean, n=13) was detected at 1.26 V, the peak oxidation potential for NO, following local electrical stimulation (five pulses of 0.1 ms duration at 100 Hz, delivered every 5 min).
The NO/NO2− signal was inhibited by the non‐selective nitric oxide synthase (NOS) inhibitors L‐NAME, L‐NMMA and the highly selective type II NOS (iNOS) inhibitor 1400 W (Garvey et al., 1997) in a concentration‐dependent manner. IC50 values were 229 μM (65 – 801, n=3, geomean and 95% confidence intervals (C.I.)), 452 nM (88 – 2310, n=5), and 14.2 μM (3.6 – 54.4, n=5), with maximum inhibitions of 82.8±6.7, 46.0±8.1, and 90.6±3.6%, respectively.
Exposure of the slices to the protein synthesis inhibitor cyclohexamide or the inhibitor of type II NOS induction dexamethasone immediately following slice cutting, and for a subsequent 4 – 5 h, did not inhibit the NO/NO2− signal.
The evoked NO/NO2− signal was not reduced following 6 h perfusion in Ca2+‐free media, consistent with a Ca2+‐independent type II NOS activity.
PCR for type II NOS revealed the presence of this isotype in the SCN, even immediately following removal of the brain.
These studies provide the first evidence to suggest a functional, constitutively‐active type II NOS within the brain of normal, healthy adult animals, and add type II NOS to the multiple isotypes of NO synthase playing a role within the mammalian SCN.

British Journal of Pharmacology (2001) 134, 1084–1092; doi:10.1038/sj.bjp.0704330
Dominant role of an endothelium‐derived hyperpolarizing factor (EDHF)‐like vasodilator in the ciliary vascular bed of the bovine isolated perfused eye
Authors: McNeish Alister J , Wilson William S , Martin William 
Published: January 2005

The roles of the endothelium‐derived nitric oxide, prostacyclin and endothelium‐derived hyperpolarizing factor (EDHF) in mediating vasodilator responses to acetylcholine and bradykinin were assessed in the ciliary vascular bed of the bovine isolated perfused eye preparation.
Vasodilatation to acetylcholine or bradykinin was unaffected by the nitric oxide synthase inhibitor, L‐NAME (100 μM), or the cyclo‐oxygenase inhibitor, flurbiprofen (30 μM), but was virtually abolished following treatment with a high concentration of KCl (30 mM), or by damaging the endothelium with the detergent, CHAPS (0.3%, 2 min).
Acetylcholine‐induced vasodilatation was unaffected by glibenclamide (10 μM), an inhibitor of ATP‐sensitive K+ channels (K+ATP), but was significantly attenuated by TEA (10 mM), a non‐selective inhibitor of K+ channels.
The small conductance calcium‐sensitive K+ channel (SK+Ca) inhibitor, apamin (100 nM), and the large conductance calcium‐sensitive K+ channel (BK+Ca) inhibitor, iberiotoxin (50 nM), had no significant effect on acetylcholine‐induced vasodilatation. In contrast, the intermediate (IK+Ca)/large conductance calcium‐sensitive K+ channel inhibitor, charybdotoxin (50 nM), powerfully blocked these vasodilator responses, and uncovered a vasoconstrictor response.
The combination of apamin (100 nM) with a sub‐threshold concentration of charybdotoxin (10 nM) significantly attenuated acetylcholine‐induced vasodilatation, but the combination of apamin (100 nM) with iberiotoxin (50 nM) had no effect.
In conclusion, blockade by a high concentration of KCl, by charybdotoxin, or by the combination of apamin with a sub‐threshold concentration of charybdotoxin, strongly suggests that vasodilatation in the bovine isolated perfused eye is mediated by an EDHF.

British Journal of Pharmacology (2001) 134, 912–920; doi:10.1038/sj.bjp.0704332
Differential effects of serotonin reuptake inhibitors on erectile responses, NO‐production, and neuronal NO synthase expression in rat corpus cavernosum tissue
Authors: Angulo Javier , Peiró Concepción , Sanchez‐Ferrer Carlos F , Gabancho Sonia , Cuevas Pedro , Gupta Sandeep , Tejada Iñigo Sáenz de 
Published: January 2005

Increased incidence of impotence is associated with some selective serotonin‐reuptake‐inhibitors (SSRIs), but the pathophysiological mechanism is unknown. Paroxetine and citalopram are extensively used SSRIs, but only paroxetine has been shown to inhibit nitric oxide synthase (NOS) activity. NO is a key mediator of penile erection. Thus, the aim of this study was to determine the effects of paroxetine and citalopram on erectile function and NO production, in a rat model. Application of cavernosal nerve electrical stimulation produced frequency‐related intracavernosal pressure (ICP) increases, which were inhibited by the NOS inhibitor, NG‐nitro‐L‐arginine (0.3 mg kg−1). Acute or chronic (2 weeks) paroxetine‐treatment (10 mg kg−1) reduced ICP‐responses, while citalopram did not. Paroxetine, but not citalopram, significantly reduced nitrite+nitrate plasma levels by 61.4% and inhibited penile neuronal NOS (nNOS) protein expression by 31.2% after chronic treatment. The results show that paroxetine inhibits erectile responses in rats. We propose that this effect is due to reduced NO production and nNOS expression.British Journal of Pharmacology (2001) 134, 1190–1194; doi:10.1038/sj.bjp.0704351
P2 receptor‐types involved in astrogliosis in vivo
Authors: Franke Heike , Krügel Ute , Schmidt Renate , Grosche Jens , Reichenbach Andreas , Illes Peter 
Published: January 2005

In the nucleus accumbens (NAc) of rats, the involvement of P2X and P2Y receptors in the generation of astrogliosis in vivo, was investigated by local application of their respective ligands. The agonists used had selectivities for P2X1,3 (α,β‐methylene adenosine 5′‐triphosphate; α,β‐meATP), P2Y1,12 (adenosine 5′‐O‐(2‐thiodiphosphate; ADP‐β‐S) and P2Y2,4,6 receptors (uridine 5′‐O‐(3‐thiotriphosphate; UTP‐γ‐S). Pyridoxalphosphate‐6‐azophenyl‐2,4‐disulphonic acid (PPADS) was used as a non‐selective antagonist. The astroglial reaction was studied by means of immunocytochemical double‐labelling with antibodies to glial fibrillary acidic protein (GFAP) and 5‐bromo‐2′‐deoxyuridine (BrdU).
The agonist‐induced changes in comparison to the artificial cerebrospinal fluid (aCSF)‐treated control side reveal a strong mitogenic potency of ADP‐β‐S and α,β‐meATP, whereas UTP‐γ‐S was ineffective. The P2 receptor antagonist PPADS decreased the injury‐induced proliferation when given alone and in addition inhibited all agonist effects.
The observed morphogenic changes included hypertrophy of astrocytes, elongation of astrocytic processes and up‐regulation of GFAP. A significant increase of both GFAP‐immunoreactivity (IR) and GFA‐protein content (by using Western blotting) was found after microinfusion of α,β‐meATP or ADP‐β‐S. In contrast, UTP‐γ‐S failed to increase the GFAP‐IR. The morphogenic effects were also inhibited by pre‐treatment with PPADS.
A double immunofluorescence approach with confocal laser scanning microscopy showed the localisation of P2X3 and P2Y1 receptors on the GFAP‐labelled astrocytes.
In conclusion, the data suggest that P2Y (P2Y1 or P2Y12) receptor subtypes are involved in the generation of astrogliosis in the NAc of rats, with a possible minor contribution of P2X receptor subtypes.

British Journal of Pharmacology (2001) 134, 1180–1189; doi:10.1038/sj.bjp.0704353
Characterization of the prostanoid receptor types involved in mediating calcitonin gene‐related peptide release from cultured rat trigeminal neurones
Authors: Jenkins David W , Feniuk Wasyl , Humphrey Patrick P A 
Published: January 2005

Prostaglandins and the vasodilator neuropeptide, calcitonin‐gene related peptide (CGRP), have both been implicated in the pathogenesis of migraine headache. We have used primary cultures of adult rat trigeminal neurones to examine the effects of prostanoids on CGRP release in vitro.
CGRP release was stimulated by prostaglandin E2 (PGE2) and the IP receptor agonist, carbaprostacyclin (cPGI2). These responses were extracellular calcium‐dependent, and the PGE2‐induced CGRP release was unaltered by inhibition of nitric oxide synthase (NOS), ATP receptor blockade, or the addition of adenosine deaminase.
Increases in CGRP levels were also observed in response to prostaglandin D2 (PGD2), and the EP2 receptor selective agonist, butaprost. No increases in CGRP release were observed in response to prostaglandin F2α (PGF2α) or the TP receptor selective agonist, U46619, or the EP3 receptor selective agonist, GR63799X.
The selective DP receptor antagonist, BWA868C, antagonized the PGD2‐, but not PGE2‐ or cPGI2‐induced release. Furthermore, the EP1 selective antagonist, ZM325802, failed to antagonize the PGE2‐induced CGRP release from these cells.
These data indicate that activation of DP, EP and IP receptors can each cause CGRP release from trigeminal neurones, and suggest that the predominant EP receptor subtype involved may be the EP2 receptor. Together with evidence that the cyclo‐oxygenase inhibitor, aspirin, particularly when administered intravenously is effective in treating acute migraine, these findings further suggest a role for prostaglandins in migraine pathophysiology.

British Journal of Pharmacology (2001) 134, 1296–1302; doi:10.1038/sj.bjp.0704357
Relationship between endogenous colony stimulating factors and apoptosis in human colon cancer cells: role of cyclo‐oxygenase inhibitors
Authors: Calatayud Sara , Warner Timothy D , Breese Emma J , Mitchell Jane A 
Published: January 2005

Nonsteroidal anti‐inflammatory drug (NSAID) usage is associated with gastrointestinal inflammatory damage and aggravation of gut inflammatory conditions. NSAIDs also exert a preventive effect against colon cancer that seems to be due to increased colon cell apoptosis. NSAIDs have been shown to modulate the release of colony stimulating factors (CSFs) in some cells. In the present study we analysed the effect of these drugs on secretion of CSFs and apoptosis in human colon epithelial cells (HT‐29).
HT‐29 cells secreted bioactive levels of GM‐CSF, G‐CSF and M‐CSF when stimulated with IL‐1ß and TNF‐α, and diclofenac (10−7 – 10−4 M), indomethacin (10−7 – 10−4 M) and sodium salicylate (10−5 – 10−2 M) induced concentration‐dependent increases in GM‐CSF secretion.
Reduced secretion of G‐CSF and M‐CSF and increased cell apoptosis were observed with the highest concentrations of these non‐selective NSAIDs.
No changes in any CSF release or HT‐29 cell apoptosis were detected in the presence of the COX‐2 selective inhibitor DFP (10−7 – 10−4 M).
Neither the exogenous addition of CSFs nor the blockade of secreted CSFs modified apoptosis in HT‐29 cells stimulated with cytokines and/or NSAIDs.
These results suggest that colon epithelial cells can contribute to local inflammatory responses by releasing CSFs and thus extend the life span of local leukocytes. Modulation of CSF levels by non‐selective NSAIDs may be involved in the pro‐inflammatory effects of these agents in the gut.

British Journal of Pharmacology (2001) 134, 1237–1244; doi:10.1038/sj.bjp.0704358
Effects of cannabinoids on adrenaline release from adrenal medullary cells
Authors: Niederhoffer Nathalie , Hansen Henrik H , Fernandez‐Ruiz Javier J , Szabo Bela 
Published: January 2005

The objective of the present study was to analyse the peripheral effects of cannabinoids on adrenaline release from adrenal chromaffin cells.
In pithed rabbits with electrically stimulated sympathetic outflow, intravenous injection of the cannabinoid receptor agonists WIN55212‐2 and CP55940 (5, 50 and 500 μg kg−1) markedly lowered the plasma adrenaline concentration. The effect of WIN55212‐2 was attenuated by the selective CB1 cannabinoid receptor antagonist SR141716A (500 μg kg−1). WIN55212‐3 (same doses as WIN55212‐2), the enantiomer of WIN55212‐2 lacking affinity for cannabinoid receptors, had no effect on the plasma adrenaline concentration.
In rabbit isolated adrenal glands, the release of adrenaline elicited by electrical stimulation was measured by fast cyclic voltammetry. Electrically‐evoked adrenaline release was inhibited by WIN55212‐2 (0.3, 1, 3 and 10 μM) and this effect was antagonized by SR141716A (1 μM). The non‐cholinergic component of adrenaline release observed after blockade of nicotinic (by hexamethonium 100 μM) and muscarinic (by atropine 0.5 μM) acetylcholine receptors was not depressed by WIN55212‐2. WIN55212‐3 (10 μM) had no effect on adrenaline release.
No detectable specific CB1 receptor binding and mRNA expression were found in rabbit adrenal glands with autoradiography and in situ hybridization.
The results show that cannabinoids inhibit adrenaline secretion in rabbit isolated adrenal glands; the likely mechanism is a presynaptic CB1 receptor‐mediated inhibition of acetylcholine release from preganglionic sympathetic neurons. The inhibition of adrenaline secretion in adrenal glands most probably accounts for the decrease in the plasma adrenaline concentration observed after cannabinoid administration in pithed rabbits.

British Journal of Pharmacology (2001) 134, 1319–1327; doi:10.1038/sj.bjp.0704359
Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters
Authors: Pariante Carmine M , Makoff Andrew , Lovestone Simon , Feroli Susan , Heyden Alexandra , Miller Andrew H , Kerwin Robert W 
Published: January 2005

Previous data demonstrate that the tricyclic antidepressant, desipramine, induces glucocorticoid receptor (GR) translocation from the cytoplasm to the nucleus in L929 cells and increases dexamethasone‐induced GR‐mediated gene transcription in L929 cells stably transfected with the mouse mammary tumour virus‐chloramphenicol acetyltransferase (MMTV‐CAT) reporter gene (LMCAT cells) (Pariante et al., 1997).
To extend these findings, the present study has investigated the effects of 24 h coincubation of LMCAT cells with dexamethasone and amitriptyline, clomipramine, paroxetine, citalopram or fluoxetine.
All antidepressants, except fluoxetine, enhanced GR‐mediated gene transcription, with clomipramine having the greatest effect (10 fold increase). Twenty‐four hours coincubation of cells with desipramine, clomipramine or paroxetine, also enhanced GR function in the presence of cortisol, but not of corticosterone.
It is proposed that these effects are due to the antidepressants inhibiting the L929 membrane steroid transporter, which actively extrudes dexamethasone and cortisol from the cell, but not corticosterone. This is further confirmed by the fact that clomipramine failed to enhance GR‐mediated gene transcription in the presence of dexamethasone when the membrane steroid transporter was blocked by verapamil.
The membrane steroid transporters that regulate access of glucocorticoids to the brain in vivo, like the multiple drug resistance p‐glycoprotein, could be a fundamental target for antidepressant action.

British Journal of Pharmacology (2001) 134, 1335–1343; doi:10.1038/sj.bjp.0704368
Enhancement by histamine of vascular endothelial growth factor production in granulation tissue via H2 receptors
Authors: Ghosh Ajoy Kumar , Hirasawa Noriyasu , Ohuchi Kazuo 
Published: January 2005

Roles of histamine in the production of vascular endothelial growth factor (VEGF) in the carrageenin‐induced granulation tissue in rats were analysed in vitro and in vivo.
Incubation of the minced granulation tissue in the presence of histamine (1 and 10 μM) increased the content of VEGF protein in the conditioned medium in a time‐ and concentration‐dependent manner. The levels of VEGF mRNA in the minced granulation tissue were also increased by histamine in a concentration‐dependent manner.
The increase in the content of VEGF protein in the conditioned medium by histamine (10 μM) was suppressed by the H2 receptor antagonist cimetidine (IC50 0.37 μM), but not by the H1 receptor antagonist pyrilamine maleate, the H3 receptor antagonist thioperamide or the cyclo‐oxygenase inhibitor indomethacin.
The histamine‐induced increase in the content of VEGF protein in the conditioned medium was inhibited by the cyclic AMP antagonist Rp‐cAMP (IC50 6.8 μM), and the protein kinase A inhibitor H‐89 (IC50 12.5 μM), but not by the protein kinase C inhibitors Ro 31‐8425 and calphostin C or the tyrosine kinase inhibitor genistein.
Simultaneous injection of cimetidine (400 μg) and indomethacin (100 μg) into the air pouch of rats additively reduced the carrageenin‐induced increase in VEGF protein levels and angiogenesis in the granulation tissue as assessed by using carmine dye.
These findings indicate that histamine has an activity to induce VEGF production in the granulation tissue via the H2 receptor‐cyclic AMP‐protein kinase A pathway and augments angiogenesis in the granulation tissue.

British Journal of Pharmacology (2001) 134, 1419–1428; doi:10.1038/sj.bjp.0704372