bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cyclo‐oxygenase‐1 and −2 contribution to endothelial dysfunction in ageing
Authors: Heymes Christophe , Habib Aida , Yang Di , Mathieu Eric , Marotte Françoise , Samuel JaneLyse , Boulanger Chantal M 
Published: January 2005

Experiments were designed to investigate the role of cyclo‐oxygenase isoforms in endothelial dysfunction in ageing. Aortic rings with endothelium of aged and young (24 vs 4 month‐old) Wistar rats, were mounted in organ chambers for the recording of changes in isometric tension.
In young rats, acetylcholine (ACh) caused a complete relaxation which was not affected by indomethacin (0.3 μM), NS‐398 (a preferential COX‐2 inhibitor; 1 μM), SQ‐29548 (a thromboxane‐receptor antagonist; 1 μM), nor valeryl‐salicylate (VAS, a preferential inhibitor of COX‐1; 3 mM).
In aged rats, ACh caused a biphasic response characterized by a first phase of relaxation (0.01–1 μM ACh), followed by a contraction (3–100 μM ACh). Indomethacin, NS‐398 and SQ‐29548, but not VAS, augmented the first phase. Indomethacin, VAS, NS‐398 and SQ‐29548 decreased the contractions to high ACh concentrations. Then, the sensitivity to thromboxane receptor activation was investigated with U‐46619. The results show comparable EC50 values in young and aged rats.
In aged rats, the ACh‐stimulated release of prostacyclin, prostaglandin F2α and thromboxane A2 was decreased by either indomethacin, NS‐398, VAS or endothelium removal. However, in young animals, the ACh‐stimulated release of prostacyclin and prostaglandin F2α were smaller than in older animals and remained unaffected by NS‐398.
Aortic endothelial cells from aged – but not young – rats express COX‐2 isoform, while COX‐1 labelling was observed in endothelial cells from both young and aged rats.
These data demonstrate the active contribution of COX‐1 and −2 in endothelial dysfunction associated with ageing.

British Journal of Pharmacology (2000) 131, 804–810; doi:10.1038/sj.bjp.0703632
An orally active anti‐apoptotic molecule (CGP 3466B) preserves mitochondria and enhances survival in an animal model of motoneuron disease
Authors: Sagot Y , Toni N , Perrelet D , Lurot S , King B , Rixner H , Mattenberger L , Waldmeier P C , Kato A C 
Published: January 2005

Apoptosis and mitochondrial dysfunction are thought to be involved in the aetiology of neurodegenerative diseases. We have tested an orally active anti‐apoptotic molecule (CGP 3466B) that binds to glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) in an animal model with motoneuron degeneration, i.e. a mouse mutant with progressive motor neuronopathy (pmn).
In pmn/pmn mice, CGP 3466B was administered orally (10–100 nmol kg−1) at the onset of the clinical symptoms (2 weeks after birth). CGP 3466B slowed disease progression as determined by a 57% increase in life‐span, preservation of body weight and motor performance.
This improvement was accompanied by a decreased loss of motoneurons and motoneuron fibres as well as an increase in retrograde transport. Electron microscopic analysis showed that CGP 3466B protects mitochondria which appear to be selectively disrupted in the motoneurons of pmn/pmn mice.
The data support evaluation of CGP 3466B as a potential treatment for motor neuron disease.

British Journal of Pharmacology (2000) 131, 721–728; doi:10.1038/sj.bjp.0703633
In vivo transfer of antisense oligonucleotide against urinary kininase blunts deoxycorticosterone acetate‐salt hypertension in rats
Authors: Hayashi Izumi , Majima Masataka , Fujita Tomoe , Okumura Toshiaki , Kumagai Yuji , Tomita Naruya , Morishita Ryuichi , Higaki Jitsuo , Ogiwara Toshio 
Published: January 2005

We have previously reported that the renal kallikrein‐kinin system suppressed the development of deoxycorticosterone acetate (DOCA)‐salt hypertension. Kinins were degraded in the kidney mainly by carboxypeptidase Y (CPY)‐like kininase. Blockade of renal kinin degradation may reduce hypertension in the developmental stage.
We constructed an antisense oligonucleotide against rat CPY homologue (5′‐CAT‐CTC‐TGC‐TTC‐CTT‐GTG‐TC‐3′, AS) and its randomized control oligonucleotide (5′‐TCC‐TTC‐CTG‐CTT‐GAG‐TTC‐CT‐3′, RC), and prepared an HVJ‐liposome complex that prolongs and increases the effectiveness of the antisense oligonucleotide. Antisense oligonucleotide was transfected (25 nmole rat−1, in terms of nucleotide) into the kidney from the renal artery.
Blood pressure was measured through a catheter inserted into the abdominal aorta. Mean blood pressure (MBP) in DOCA‐salt treated (for 2 weeks) Sprague Dawley strain rats was 130±3 mmHg (n=11), and was reduced significantly (P<0.05) more by AS transfection (122±4 mmHg, n=6) than by RC treatment (137±6 mmHg, n=5) 4 days after the transfection.
This reduction in MBP was accompanied by increased urinary sodium excretion (AS, 8.4±1.5 mmole day−1; RC, 4.6±0.5 mmole day−1, P<0.05) and a reduction in urinary CPY‐like kininase activity.
Ebelactone B (5 mg kg−1, twice a day, p.o.), an inhibitor for urinary CPY‐like kininase, also reduced MBP and induced natriuresis to the same degree as AS.
Lisinopril, an inhibitor for angiotensin converting enzyme (ACE) failed to reduce the elevated MBP.
These results suggest that CPY‐like kininase may have more contribution than ACE to degrade kinin in the kidney, and that knockdown of CPY‐like kininase in the kidney may partly prevent rat DOCA‐salt hypertension.

British Journal of Pharmacology (2000) 131, 820–826; doi:10.1038/sj.bjp.0703634
The interaction between components of the fibrinolytic system and GPIb/V/IX of platelets thrombus formation in mice
Authors: Matsuno Hiroyuki , Kozawa Osamu , Ueshima Shigeru , Matsuo Osamu , Collen Désiré , Uematsu Toshihiko 
Published: January 2005

The interaction of fibrinolytic components with GPIb/V/IX of platelets on thrombus formation, was investigated in mice deficient in tissue type (tPA−/−), urokinase type plasminogen activator (uPA−/−) or plasminogen activator inhibitor‐1 (PAI‐1−/−) and in their wild type control (tPA+/+, uPA+/+, PAI‐1+/+).
A thrombus was induced in the murine carotid artery using a photochemical reaction. The times to occlusion after the initiation of endothelial injury in all wild type mice was within 12 min, and no significant changes in occlusion delay were observed in uPA−/− and tPA−/− mice compared to wild type mice, whereas that of PAI‐1 mice were significantly prolonged (16.9±2.9 min, P<0.05).
When high molecular weight aurintricarboxylic acid (ATA), an inhibitor of platelet glycoprotein Ib/V/IX, was administered, the time to occlusion was prolonged in a dose‐dependent manner in all types of mice. However, when this compound was injected in tPA−/− mice, the most significant changes were observed: i.e. the estimated ED50 was 20.2 times higher than that in tPA+/+ mice, but the estimated ED50 in uPA−/− mice was not changed as compared with that of wild type mice. On the other hand, when ATA was injected in PAI‐1−/− mice, the estimated ED50 was significantly decreased (P<0.05).
Platelet aggregation induced by botrocetin was not significantly different among all types of mice. The bleeding time was prolonged in a dose dependent‐manner when ATA was injected in all types of mice.
In conclusion, the antithrombotic effect of inhibition of platelet GPIb/V/IX is severely affected by the absence or presence of tPA‐production on thrombus formation and the inhibition of PAI‐1 could enhance this antithrombotic effect.

British Journal of Pharmacology (2000) 131, 858–864; doi:10.1038/sj.bjp.0703639
Effects of volatile solvents on recombinant N‐methyl‐D‐aspartate receptors expressed in Xenopus oocytes
Authors: Cruz Silvia L , Balster Robert L , Woodward John J 
Published: January 2005

We have previously shown that toluene dose‐dependently inhibits recombinant N‐methyl‐D‐aspartate (NMDA) receptors at micromolar concentrations. This inhibition was rapid, almost complete and reversible. The NR1/2B combination was the most sensitive receptor subtype tested with an IC50 value for toluene of 0.17 mM.
We now report on the effects of other commonly abused solvents (benzene, m‐xylene, ethylbenzene, propylbenzene, 1,1,1‐trichlorethane (TCE) and those of a convulsive solvent, 2,2,2‐trifluoroethyl ether (flurothyl), on NMDA‐induced currents measured in Xenopus oocytes expressing NR1/2A or NR1/2B receptor subtypes.
All of the alkylbenzenes and TCE produced a reversible inhibition of NMDA‐induced currents that was dose‐ and subunit‐dependent. The NR1/2B receptor subtype was several times more sensitive to these compounds than the NR1/2A subtype.
The convulsant solvent flurothyl had no effect on NMDA responses in oocytes but potently inhibited ion flux through recombinant GABA receptors expressed in oocytes.
Overall, these results suggest that abused solvents display pharmacological selectivity and that NR1/2B NMDA receptors may be an important target for the actions of these compounds on the brain.

British Journal of Pharmacology (2000) 131, 1303–1308; doi:10.1038/sj.bjp.0703666
Involvement of 5‐HT3 receptors in the nucleus accumbens in the potentiation of cocaine‐induced behaviours in the rat
Authors: Herges Sonja , Taylor David A 
Published: January 2005

The present study investigated the central effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the role of 5‐hydroxytryptamine3 (5‐HT3) receptors in the core of the nucleus accumbens (NAc) on cocaine‐induced behavioural changes in rats.
The 5‐HT3 receptor antagonist ondansetron (1 or 10 ng) was microinjected bilaterally into the core of the NAc 60 min prior to peripheral cocaine (15 mg kg−1, i.p.) administration followed by the assessment of locomotor activity, rearing activity and head bobs. Both doses of ondansetron attenuated cocaine's stimulatory effect on behaviours.
Fluoxetine (0.05 or 5 μg) microinjected bilaterally into the core of the NAc 30 min before peripheral administration of cocaine produced dose‐dependent biphasic effects on cocaine‐induced behaviours. Intra‐NAc administration of 0.05 μg fluoxetine resulted in a potentiation of cocaine‐induced behaviours, while the higher dose of the SSRI (5 μg) attenuated the stimulant effect of cocaine on behaviours.
To investigate a possible involvement of 5‐HT3 receptors in fluoxetine's facilitatory action, ondansetron (10 ng) was microinjected 30 min prior to fluoxetine (0.05 μg), which resulted in a significant attenuation of the facilitatory effect of fluoxetine on cocaine‐induced behaviours.
Thus, 5‐HT3 receptors in the core of the NAc appear to mediate stimulatory effects on cocaine‐induced locomotor activity, rears and head bobs, whereas the attenuation of cocaine‐induced behaviours by fluoxetine at the higher dose, suggests the involvement of a different 5‐HT receptor subtype.

British Journal of Pharmacology (2000) 131, 1294–1302; doi:10.1038/sj.bjp.0703687
The human prostanoid DP receptor stimulates mucin secretion in LS174T cells
Authors: Wright D Hamish , Ford‐Hutchinson Anthony W , Chadee Kris , Metters Kathleen M 
Published: January 2005

This study demonstrates the localization of the prostaglandin (PG)D2 receptor (DP) within the mucous‐secreting globlet cells of the human colon by in situ hybridization, which suggests a role for DP in mucous secretion. Selective high affinity ligands were used, therefore, to evaluate DP regulation of mucous secretion in LS174T human colonic adenocarcinoma cells.
The expression of hDP in LS174T cells was confirmed at the mRNA level by reverse transcriptase‐polymerase chain reaction, and at the protein level by radioligand binding assays and signal transduction (cyclic AMP accumulation) assays. PGD2 and the highly selective DP‐specific agonist L‐644,698 ((4‐(3‐(3‐(3‐hydroxyoctyl)‐4‐oxo‐2‐thiazolidinyl) propyl) benzoic acid) (racemate)), but not PGE2 competed for [3H]‐PGD2‐specific binding to LS174T cell membranes (Ki values of 0.4 nM and 7 nM, respectively). The DP‐specific agonists PGD2, PGJ2, BW245C (5‐(6‐carboxyhexyl)‐1‐(3‐cyclohexyl‐3‐hydroxypropylhydantoin)), and L‐644,698 showed similar potencies in stimulating cyclic AMP accumulation (EC50 values: 45–90 nM) and demonstrated the expected rank order of potency. PGE2 also elicited cyclic AMP production in this cell line (EC50 value: 162 nM).
The activation of cyclic AMP production by PGD2 and L‐644,698, but not PGE2, was inhibited by the selective DP antagonist BW A868C. Thus, PGD2 and L‐644,698 act through hDP in LS174T cells. PGD2, L‐644,698 and PGE2 (an established mucin secretagogue) potently stimulated mucin secretion in LS174T cells in a concentration‐dependent manner (EC50<50 nM). However, BW A868C effectively antagonized only the mucin secretion mediated by PGD2 and L‐644,698 and not PGE2. These data support a role for the DP receptor in the regulation of mucous secretion.

British Journal of Pharmacology (2000) 131, 1537–1545; doi:10.1038/sj.bjp.0703688
Evidence from immunoneutralization and antisense studies that the inhibitory actions of glucocorticoids on growth hormone release in vitro require annexin 1 (lipocortin 1)
Authors: Taylor A D , Christian H C , Morris J F , Flower R J , Buckingham J C 
Published: January 2005

Our previous studies have identified a role for annexin 1 as a mediator of glucocorticoid action in the neuroendocrine system. The present study centred on growth hormone (GH) and exploited antisense and immunoneutralization strategies to examine in vitro the potential role of annexin 1 in effecting the regulatory actions of glucocorticoids on the secretion of this pituitary hormone.
Rat anterior pituitary tissue responded in vitro to growth hormone releasing hormone, forskolin, 8‐Bromo‐cyclic adenosine 3′5′‐monophosphate (8‐Br‐cyclic AMP) and an L‐Ca2+ channel opener (BAY K8644) with concentration‐dependent increases GH release which were readily inhibited by corticosterone and dexamethasone.
The inhibitory actions of the steroids on GH release elicited by the above secretagogues were effectively reversed by an annexin 1 antisense oligodeoxynucleotide (ODN), but not by control (sense or scrambled) ODNs, as also were the glucocorticoid‐induced increases in annexin 1. Similarly, a specific anti‐annexin 1 monoclonal antibody quenched the corticosterone‐induced suppression of secretagogue‐evoked GH release while an isotype matched control antibody was without effect.
Transmission electron micrographs showed that the integrity and ultrastructural morphology of the pituitary cells were well preserved at the end of the incubation and unaffected by exposure to the ODNs, antibodies, steroids or secretagogues.
The results provide novel evidence for a role for annexin 1 as a mediator of the inhibitory actions of glucocorticoids on the secretion of GH by the anterior pituitary gland and suggest that its actions are effected at a point distal to the formation of cyclic AMP and Ca2+ entry.

British Journal of Pharmacology (2000) 131, 1309–1316; doi:10.1038/sj.bjp.0703694
RETRACTED: Cloricromene, a coumarine derivative, protects against collagen‐induced arthritis in Lewis rats
Authors: Cuzzocrea Salvatore , Mazzon Emanuela , Bevilaqua Carla , Costantino Giuseppina , Britti Domenico , Mazzullo Giuseppe , De Sarro Angela , Caputi Achille P 
Published: January 2005

The aim of the present study was to investigate the effects of cloricromene, a coumarine derivative, in rats subjected to collagen‐induced arthritis.
Collagen‐induced arthritis (CIA) was induced in Lewis rats by an intradermal injection of 100 μl of the emulsion (containing 100 μg of bovine type II collagen) (CII) and complete Freund's adjuvant (CFA) at the base of the tail. On day 21, a second injection of CII in CFA was administered.
Lewis rats developed an erosive hind paw arthritis when immunized with CII in CFA. Macroscopic clinical evidence of CIA first appeared as peri‐articular erythema and oedema in the hind paws. The incidence of CIA was 100% by day 27 in the CII challenged rats and the severity of CIA progressed over a 35‐day period with radiographic evaluation revealing focal resorption of bone together with osteophyte formation in the tibiotarsal joint and soft tissue swelling.
The histopathology of CIA included erosion of the cartilage at the joint margins. Treatment of rats with cloricromene (10 mg kg−1 i.p. daily) starting at the onset of arthritis (day 23), delayed the development of the clinical signs at days 24–35 and improved histological status in the knee and paw.
Immunohistochemical analysis for iNOS, COX‐2, nitrotyrosine and for poly (ADP‐ribose) synthetase (PARS) revealed a positive staining in inflamed joints from collagen‐treated rats. The degree of staining for iNOS, COX‐2, nitrotyrosine and PARS were markedly reduced in tissue sections obtained from collagen‐treated rats, which had received cloricromene.
Radiographic signs of protection against bone resorption and osteophyte formation were present in the joints of cloricromene‐treated rat.
This study provides the first evidence that cloricromene, a coumarine derivative, attenuates the degree of chronic inflammation and tissue damage associated with collagen‐induced arthritis in the rat.

British Journal of Pharmacology (2000) 131, 1399–1407; doi:10.1038/sj.bjp.0703695
Morphine‐6β‐glucuronide has a higher efficacy than morphine as a mu‐opioid receptor agonist in the rat locus coeruleus
Authors: Osborne Peregrine B , Chieng Billy , Christie MacDonald J 
Published: January 2005

The pharmacological properties of the active morphine metabolite, morphine‐6β‐D‐glucuronide (M6G), and the parent compound were compared in rat locus coeruleus neurons by electrophysiological recording in brain slices.
M6G and morphine activated potassium currents in voltage clamped neurons, which were blocked by the opioid receptor antagonist naloxone.
Both M6G and morphine behaved as partial agonists that produced maximal responses smaller than the system maximum, which was measured using [Met5]‐enkephalin. M6G produced a larger maximal response (78%) than morphine (62%), which we estimated was due to a 2–4 fold difference in the relative efficacy of the agonists.
3‐O‐methoxynaltrexone, which has been reported to behave as a selective antagonist of a M6G preferring receptor, was equally effective at blocking currents produced by M6G and the selective mu‐opioid receptor agonist DAMGO.
M6G currents were occluded by a prior application of morphine, and were reduced when mu‐opioid receptors were desensitized by using [Met5]‐enkephalin.
Morphine‐3β‐D‐glucuronide did not affect action potential firing or membrane currents in locus coeruleus neurons and had no effect on currents produced by M6G.
These results show that the relative efficacy of M6G is higher than morphine in locus coeruleus neurons, contrary to what has been shown using mu‐opioid receptors expressed in cell clones.

British Journal of Pharmacology (2000) 131, 1422–1428; doi:10.1038/sj.bjp.0703697
Modulation of ultraviolet‐induced hyperalgesia and cytokine upregulation by interleukins 10 and 13
Authors: Saadé Nayef E , Nasr Isam W , Massaad Cynthia A , Safieh‐Garabedian Bared , Jabbur Suhayl J , Kanaan Salim A 
Published: January 2005

Exposure to midrange ultraviolet radiation (UVB) is known to produce skin inflammation similar to sunburn. The aim of this study was to characterize the hyperalgesia and cytokine upregulation induced by UVB and their modulation by antiinflammatory cytokines.
Acute exposure of the dorsal skin of mice to UVB (200, 250 and 300 mJ cm2) resulted in a dose‐dependent decrease in the latencies of the hot plate and tail flick tests, without evident signs of skin lesions.
The observed hyperalgesia displayed a biphasic temporal evolution with an acute phase (3–6 h) and a late (48–96 h) phase.
Exposure to UVB (300 mJ cm2) elicited significant upregulation of interleukin (IL)‐1β, tumour necrosis factor (TNF)‐α and nerve growth factor (NGF), determined by ELISA in the exposed skin. This upregulation was more important during the acute phase of hyperalgesia.
Daily treatment of mice, with i.p. injections of either IL‐10 or IL‐13 (1.5, 7.5 and 15 ng in 100 μl saline) produced a dose‐dependent attenuation of the UVB‐induced hyperalgesia.
Treatment with the highest doses of either IL‐10 or IL‐13, produced significant attenuation of the levels of the cytokines and NGF by UVB, with relatively more pronounced effects by IL‐13.
Acute exposure to moderate amounts of UVB results in a systemic hyperalgesia related to the upregulation of cytokine and NGF levels, since both were prevented by treatment with antiinflammatory cytokines.

British Journal of Pharmacology (2000) 131, 1317–1324; doi:10.1038/sj.bjp.0703699
Cardiovascular and autonomic effects of ω‐conotoxins MVIIA and CVID in conscious rabbits and isolated tissue assays
Authors: Wright Christine E , Robertson Alan D , Whorlow Sarah L , Angus James A 
Published: January 2005

The effects of a novel N‐type voltage‐operated calcium channel antagonist, ω‐conotoxin CVID, were compared with ω‐conotoxin MVIIA on sympathetic‐evoked activation of right atria (RA), small mesenteric arteries (MA) and vasa deferentia (VD) isolated from the rat. Their effects were also compared on blood pressure and cardiovascular reflexes in conscious rabbits.
The pIC50 values for MVIIA and CVID, respectively, for inhibiting sympathetic‐evoked responses were equivalent in RA (8.7 and 8.7) and VD (9.0 and 8.7); however, in MA the values were 8.4 and 7.7. The cardiac to vascular (RA/MA) potency ratios, antilog (plog RA–plog MA), for MVIIA and CVID were 2 and 10. The offset rates for CVID and MVIIA were rapid, and peptide reapplication caused rapid onset of blockade, suggesting limited desensitization.
In the conscious rabbit, CVID and MVIIA (100 μg kg−1 i.v.) caused a similar fall in blood pressure and a tachycardia that rapidly reached maximum. Both peptides decreased the vagal‐ and sympathetic‐mediated components of the baroreflex, but had no effect on the vagal nasopharyngeal reflex. The orthostatic reflex to 90° tilt was blocked by MVIIA with sustained postural hypotension for 90 min after administration. In contrast, CVID caused postural hypotension at 30 min which recovered rapidly.
Neither CVID nor MVIIA (3 μg kg−1 i.t.) significantly altered cardiovascular variables or autonomic reflexes.
In conclusion, CVID appears to be relatively weak at inhibiting the reflex response to tilt consistent with its weaker inhibition of rat mesenteric artery constriction to perivascular nerve stimulation. This may point to subtype N‐type calcium channel selectivity.

British Journal of Pharmacology (2000) 131, 1325–1336; doi:10.1038/sj.bjp.0703701