bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repeated challenge with dinitrobenzene sulphonic acid in dinitrofluorobenzene‐sensitized mice results in vascular hyperpermeability in the trachea: a role for tachykinins
Authors: Van Houwelingen A H , Van Der Avoort L A , Van Heuven‐Nolsen D , Kraneveld A D , Nijkamp F P 
Published: January 2005

This study investigates the role of tachykinins in a repeated challenge with dinitrobenzene sulphonic acid (DNS) on the tracheal vascular permeability in dinitrofluorobenzene (DNFB)‐sensitized mice.
DNFB‐contact sensitization was followed by an intranasal (i.n.) challenge with DNS. A second challenge with DNS was administered 24 h after the first challenge. To assess changes in tracheal vascular permeability, Evans blue dye accumulation in tracheal tissue was measured.
A repeated challenge with DNS in DNFB‐sensitized mice led to a 2.8 fold increase in tracheal vascular permeability when compared to DNFB‐sensitized and vehicle‐challenged mice or a 2.5 fold increase when compared to DNFB‐sensitized single DNS‐challenged mice (P<0.001, ANOVA).
RP67580 (10−9 mol mouse−1 i.v.) reduced the increased tracheal vascular permeability induced by a second exposure to DNS in DNFB‐sensitized mice completely when injected 15 min before the second challenge (P<0.001, ANOVA).
The increased tracheal vascular permeability response induced by the second exposure to DNS could be mimicked with i.n. application of capsaicin (10−10 mol mouse−1) or substance P (SP) (10−12 mol mouse−1) to DNFB‐sensitized and single DNS‐challenged mice.
These results suggest that both tachykinin NK1 receptors and sensory nerves are involved in the development of vascular hyperpermeability changes found in the trachea of DNFB‐sensitized mice after a repeated DNS‐challenge.

British Journal of Pharmacology (1999) 127, 1583–1588; doi:10.1038/sj.bjp.0702707
A771726, the active metabolite of leflunomide, directly inhibits the activity of cyclo‐oxygenase‐2 in vitro and in vivo in a substrate‐sensitive manner
Authors: Hamilton Lorna C , Vojnovic Ivana , Warner Timothy D 
Published: January 2005

The immunosuppressive and anti‐inflammatory drug leflunomide has several sites of action, although its precise mode of action is unknown.
Here we show in vitro and in vivo that leflunomide and/or its active metabolite A771726, inhibit the activity of cyclo‐oxygenase (COX) at doses below those that affect protein expression.
In J774.2 macrophages treated with endotoxin for 24 h to induce COX‐2 and iNOS, leflunomide and A771726 inhibited more potently the accumulation of PGE2 (A771726, IC50 3.5 μg ml−1) than of NO2 (A771726, IC50 380 μg ml−1). At high concentrations (>300 μg ml−1) A771726 also exhibited the expression of COX‐2 and iNOS proteins.
In A549 cells treated for 24 h with interleukin‐1β, to induce COX‐2, A771726 potently inhibited PGE2 synthesis (IC50 0.13 μg ml−1). In the same cells, A771726 was notably less active (IC50, 52 μg ml−1) at inhibiting the formation of PGE2 stimulated by exposure to 30 μM arachidonic acid.
In a human whole blood assay, measuring the accumulation of TxB2 in response to calcium ionophore as a measure of COX‐1 activity and in response to incubation with bacterial endotoxin as a measure of COX‐2 activity, leflunomide inhibited COX‐1 and COX‐2 with IC50 values of 31 and 185 μg ml−1; for A771726 the corresponding values were 40 and 69 μg ml−1.
Pre‐treatment of rats with leflunomide or A771726 (10 mg kg−1, i.p.) inhibited the plasma accumulation of 6‐keto‐PGF1α but not NO2/NO3 following infusion of endotoxin. Injection of a bolus of arachidonic acid following 6 h infusion of endotoxin caused a marked acute rise in plasma 6‐keto‐PGF1α which was inhibited only by higher doses of A771726 (50 mg kg−1, i.p.).
In conclusion, leflunomide via A771726 can directly inhibit the activity of COX, an effect that appears blunted both by increases in substrate supply and possibly by plasma binding. Only at much higher drug levels does leflunomide and/or A771726 inhibit the induction of COX‐2 or iNOS proteins.

British Journal of Pharmacology (1999) 127, 1589–1596; doi:10.1038/sj.bjp.0702708
Evidence that the ATP‐induced increase in vasomotion of guinea‐pig mesenteric lymphatics involves an endothelium‐dependent release of thromboxane A2
Authors: Gao Jinnan , Zhao Jun , Rayner Sharyn E , Van Helden Dirk F 
Published: January 2005

Experiments were made to investigate mechanisms by which adenosine 5′‐trisphosphate (ATP) enhanced vasomotion in mesenteric lymphatic vessels isolated from young guinea‐pigs.
ATP (10−8–10−3 M) caused a concentration‐dependent increase of perfusion‐induced vasomotion with the endothelium mediating a fundamental role at low ATP concentrations (10−8–10−6 M).
The response to 10−6 M ATP showed tachyphylaxis when applied at intervals of 10 min but not at intervals of 20 or 30 min.
Suramin (10−4 M) or reactive blue 2 (3×10−5 M) but not PPADS (3×10−5 M) abolished the excitatory response to 10−6 M ATP confirming an involvement of P2 purinoceptors.
The excitatory response to 10−6 M ATP was abolished by treatment with either pertussis toxin (100 ng ml−1), antiflammin‐1 (10−9 M), indomethacin (3×10−6 M) or SQ29548 (3×10−7 M), inhibitors of specific G proteins, phospholipase A2, cyclo‐oxygenase and thromboxane A2 receptors respectively.
ATP simultaneously induced a suramin‐sensitive inhibitory response, which was normally masked by the excitatory response. ATP‐induced inhibition was mediated by endothelium‐derived nitric oxide (EDNO) as the response was abolished by NG‐nitro‐L‐arginine (L‐NOARG; 10−4 M), an inhibitor of nitric oxide synthase.
We conclude that ATP modulates lymphatic vasomotion by endothelium‐dependent and endothelium‐independent mechanisms. One of these is a dominant excitation caused through endothelial P2 purinoceptors which because of an involvement of a pertussis toxin sensitive G‐protein may be of the P2Y receptor subtype. Their stimulation increases synthesis of phospholipase A2 and production of thromboxane A2, an arachidonic acid metabolite which acts as an endothelium‐derived excitatory factor.

British Journal of Pharmacology (1999) 127, 1597–1602; doi:10.1038/sj.bjp.0702710
Microtubule cytoskeleton involvement in muscarinic suppression of voltage‐gated calcium channel current in guinea‐pig ileal smooth muscle
Authors: Unno T , Komori S , Ohashi H 
Published: January 2005

Effects of agents, which affect microtubule polymerization‐depolymerization cycle, on Ba2+ current (IBa) flowing through voltage‐gated Ca2+ channels and carbachol (CCh)‐induced sustained suppression of IBa were examined in whole‐cell voltage‐clamped smooth muscle cells of guinea‐pig ileum.
Colchicine (100 μM) and vinblastine (100 μM), microtubule depolymerizers, increased the ampitude of IBa. Lumicolchicine (100 μM), an inactive analogue of colchicine, had no effect on IBa.
Taxol (1–100 μM), a microtubule polymerizer, decreased IBa in a concentration‐dependent manner and accelerated the rate of inactivation of IBa. Baccatin III (100 μM), an inactive analogue of taxol, had no effect on IBa.
Colchicine (100 μM) and vinblastine (100 μM), but not lumicolchicine (100 μM), decreased or abolished the sustained component of CCh (10 μM)‐induced IBa suppression.
Pretreatment with taxol (10–100 μM) resulted in a concentration‐dependent decrease in IBa and the action of CCh on IBa. The inhibitory effects of taxol and CCh on IBa were not additive.
Colchicine (100 μM) or taxol (100 μM) had no effect on voltage‐gated K+ channel current or CCh‐induced non‐selective cationic channel current.
These results suggest that polymerization of microtubules leads to suppression of Ca2+ channel activity, and that muscarinic sustained suppression of Ca2+ channel current is mediated by a signal transduction element which involves microtubule cytoskeleton.

British Journal of Pharmacology (1999) 127, 1703–1711; doi:10.1038/sj.bjp.0702711
Block and modified gating of cardiac calcium channel currents by terodiline
Authors: Ogura Toshitsugu , Jones Stephen , Shuba Lesya M , McCullough John R , McDonald Terence F 
Published: January 2005

Terodiline, an anticholinergic/antispasmodic drug effective in the treatment of urinary incontinence, is presently restricted due to adverse side effects on cardiac function. To characterize its effects on cardiac L‐type Ca2+‐channel current carried by Ca2+ (ICa,L) and Ba2+ (IBa,L), concentrations ranging from 0.1 to 100 μM were applied to whole‐cell‐configured guinea‐pig ventricular myocytes.
Although sub‐micromolar concentrations of terodiline had no effect on ICa,L at 0 mV, 100 μM drug reduced its amplitude to ca. 10% of pre‐drug control. The estimated IC50 (15.2 μM in K+‐dialysed cells, 12.2 μM in Cs+‐dialysed cells; 0.1 Hz pulsing rate) is eight times higher than reported for ICa,L in bladder smooth muscle myocytes.
Terodiline affected ICa,L in a use‐dependent manner; block increased when the pulsing rate was increased from 0.1 to 2–3 Hz, and when holding potential was lowered from −43 mV. The drug accelerated the decay of ICa,L at 0 mV in a concentration‐dependent manner, and slowed the recovery of channels from inactivation.
Terodiline reduced peak IBa,L more effectively than peak ICa,L, and markedly accelerated the rate of inactivation of the current.
The results are discussed in terms of mechanisms of Ca2+ channel block and relation to the therapeutic and cardiotoxic effects of the drug.

British Journal of Pharmacology (1999) 127, 1837–1845; doi:10.1038/sj.bjp.0702713
Synthesis of nitric oxide in the dorsal motor nucleus of the vagus mediates the inhibition of gastric acid secretion by central bombesin
Authors: Beltrán Belén , Barrachina Ma Dolores , Méndez Asunción , Quintero Enrique , Esplugues Juan V 
Published: January 2005

Central administration of bombesin inhibits gastric acid production independently of the centrally or peripherally‐acting stimuli employed. This study evaluates the role and location of the cerebral nitric oxide (NO) implicated in the inhibitory effect of central bombesin on in vivo rat gastric acid secretion, as induced by distension with 15 cm H2O, insulin (0.75 u.i. kg−1 i.p.) TRH (1.2 μg kg−1, i.c.) or pentagastrin (100 μg kg−1, i.p.).
The acid‐inhibitory effect of i.c. bombesin (40 ng kg−1) was prevented by prior administration of L‐NAME (80 μg kg−1) in the dorsal motor nucleus of the vagus (DMN). This dose of L‐NAME when administered into the nucleus of the tractus solitarious (NTS) did not influence the effects of bombesin. Administration of L‐arginine (400 μg kg−1) into the DMN restored the acid‐inhibitory effect of i.c. bombesin in animals treated with L‐NAME.
Microinjection of bombesin (12 ng kg−1) into the paraventricular nucleus of the hypothalamus (PvN) inhibits acid secretion stimulated by pentagastrin. This inhibitory effect was prevented by a previous injection of L‐NAME (80 μg kg−1) into the DMN.
The release of NO in the DMN following i.c. administration of bombesin was confirmed by in vivo electrochemical detection.
Administration by microdialysis in the DMN of the NO‐donor SNAP (25 mM in 1.5 μl min−1) into the DMN inhibits pentagastrin‐stimulated gastric acid secretion.
The present study suggests that nNOS‐containing neurons in the DMN have an inhibitory role in the control of gastric acid responses.

British Journal of Pharmacology (1999) 127, 1603–1610; doi:10.1038/sj.bjp.0702717
Characterization of the 5‐hydroxytryptamine receptors mediating contraction in the intestine of Suncus murinus
Authors: Javid Farideh A , Naylor Robert J 
Published: January 2005

The effects of 5‐HT and 5‐HT agonists to induce contraction and the 5‐HT receptors mediating these effects were investigated in the proximal, central and terminal intestinal segments of Suncus murinus.
The contraction curves to 5‐HT (3 nM–30 μM) were shifted to the right by methysergide (1 μM) and ritanserin (0.1 μM), without affecting the maximum response.
In the central and terminal segments (but not the proximal segments) ondansetron (1 μM) and atropine (1 μM) significantly attenuated the contractions to higher concentrations of 5‐HT. The selective 5‐HT4 receptor antagonist SB204070 (1 nM), failed to modify 5‐HT induced contractions in any segment examined.
5‐carboxamidotryptamine, α‐methyl‐5‐HT and 5‐methoxytryptamine (0.003–3.0 μM) induced contractions but unlike 5‐HT, higher concentrations of these three agents failed to increase the response or were associated with a decrease in response. 2‐methyl‐5‐HT (0.03–1.0 μM) was ten times less potent than 5‐HT to induce contraction but achieved the same maximum response.
The contractions induced by the lower concentrations of 2‐methyl‐5‐HT (0.03–1.0 μM) in all segments were markedly reduced or abolished by methysergide (1.0 μM); the response to the higher concentrations of 2‐methyl‐5‐HT (3–30.0 μM) were markedly reduced by atropine (1.0 μM) and ondansetron (1.0 μM).
In all segments examined, tetrodotoxin (1 μM) significantly reduced the 5‐HT‐induced contraction.
It is concluded that the 5‐HT‐induced contraction was mediated via 5‐HT2 (ritanserin sensitive) receptors in all regions of the intestine, with 5‐HT3 (ondansetron sensitive) receptors mediating an additional major component in the central and terminal regions.

British Journal of Pharmacology (1999) 127, 1867–1875; doi:10.1038/sj.bjp.0702729
Alterations of insulin secretion from mouse islets treated with sulphonylureas: perturbations of Ca2+ regulation prevail over changes in insulin content
Authors: Anello Marcello , Gilon Patrick , Henquin Jean‐Claude 
Published: January 2005

To determine how pretreatment with sulphonylureas alters the β cell function, mouse islets were cultured (18–20 h) without (controls) or with (test) 0.01 μM glibenclamide. Acute responses to glucose were then determined in the absence of glibenclamide.
Test islets were insensitive to drugs (sulphonylureas and diazoxide) acting on K+‐ATP channels, and their [Ca2+]i was already elevated in the absence of stimulation.
Insulin secretion was increased in the absence of glucose, and mainly stimulated between 0–10 instead of 7–20 mM glucose in controls. The maximum response was halved, but this difference disappeared after correction for the 45% decrease in the islet insulin content.
The first phase of glucose‐induced insulin secretion was abrogated because of a paradoxical decrease of the high basal [Ca2+]i in β cells. The second phase was preserved but occurred with little rise of [Ca2+]i. These abnormalities did not result from alterations of glucose metabolism (NADPH fluorescence).
In islets cultured with 50 μM tolbutamide, glucose induced biphasic increases in [Ca2+]i and insulin secretion. The decrease in the secretory response was matched by the decrease in insulin content (45%) except at maximal glucose concentrations. Islets pretreated with tolbutamide, however, behaved like those cultured with glibenclamide if tolbutamide was also present during the acute functional tests.
In conclusion, treatment with a low glibenclamide concentration causes long‐lasting blockade of K+‐ATP channels and rise of [Ca2+]i in β cells. Glucose‐induced insulin secretion occurs at lower concentrations, is delayed and is largely mediated by a modulation of Ca2+ action on exocytosis. It is suggested that glucose regulation of insulin secretion mainly depends on a K+‐ATP channel‐independent pathway during in vivo sulphonylurea treatment.

British Journal of Pharmacology (1999) 127, 1883–1891; doi:10.1038/sj.bjp.0702731
Pharmacological characterization of ATP‐ and LPS‐induced IL‐1β release in human monocytes
Authors: Grahames C B A , Michel A D , Chessell I P , Humphrey P P A 
Published: January 2005

We have utilized the human monocytic cell line, THP‐1, and freshly isolated adherent human monocytes with the compounds pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disuphonic acid (PPADS), oxidized ATP, and 1‐(N,O‐bis{5‐isoquinolinesufonyll}‐N‐methyl‐L‐tyrosyl)‐4‐phenylpiperazine (KN‐62) to pharmacologically characterize the P2 receptor involved in ATP‐induced release of interleukin 1β (IL‐1β). We have also investigated the involvement of P2 receptors in lipopolysaccharide (LPS)‐induced IL‐1β release from both cell types.
ATP caused release of IL‐1β from LPS primed THP‐1 cells in both a time‐ and concentration‐dependent manner, with a minimal effective ATP concentration of 1 mM. Stimulation of cells with 5 mM ATP resulted in detectable concentrations of IL‐1β in cell supernatants within 30 min.
The ATP analogue benzoylbenzoyl ATP (DBATP), a P2X7 receptor agonist, was approximately 10 fold more potent than ATP at eliciting IL‐1β release.
KN‐62 (1 μM), PPADS (100 μM) or oxidized ATP (100 uM) significantly inhibited 5 mM ATP‐induced IL‐1β release by 81, 90 and 66% respectively, but failed to significantly inhibit LPS‐induced IL‐1β release in both THP‐1 cells and in freshly isolated human monocytes.
In both THP‐1 cells and freshly isolated human monocytes, addition of the ATP degrading enzyme apyrase (0.4 U ml−1) to cell supernatants prior to LPS activation failed to significantly inhibit the LPS‐induced IL‐1β release. In addition there was no correlation between extracellular ATP concentrations and IL‐1β release in THP‐1 cells when studied over a 6 h time period.
In conclusion our data confirm the involvement of P2X7 receptors in ATP‐induced IL‐1β release in human monocytes. However no evidence was obtained which would support the involvement of either endogenous ATP release or P2X7 receptor activation as the mechanism by which LPS‐induces IL‐1β release in either the THP‐1 cell line or in freshly isolated human monocytes.

British Journal of Pharmacology (1999) 127, 1915–1921; doi:10.1038/sj.bjp.0702732
In vitro functional evidence of different neurotensin‐receptors modulating the motor response of human colonic muscle strips
Authors: Croci Tiziano , Aureggi Giulio , Guagnini Fabio , Manara Luciano , Gully Danielle , Le Fur Gérard , Maffrand Jean‐Pierre , Mukenge Sylvain , Ferla Gianfranco , Ferrara Pascual , Chalon Pascale , Vita Natalio 
Published: January 2005

The newly developed non‐peptide neurotensin (NT)‐receptor antagonists SR 48692 and SR 142948 were used to challenge NT responses of human colonic circular smooth muscle strips in vitro. The presence of NT1 and NT2 receptor transcripts in this tissue was tested by reverse transcriptase polymerase chain reaction (RT–PCR) analysis.
NT potently and dose‐dependently contracted muscle strips, with significant regional differences in potency and efficacy between the transverse and distal colon: EC50, 3.6 and 7.5 nM; the maximal effect was 70 and 55% of 0.1 mM carbachol. Colonic responses to NT in both segments were virtually the same in the presence of atropine (1 μM), levocabastine (10 μM) or tetrodotoxin (1 μM).
SR 142948 (10 nM–1 μM) competitively antagonized NT responses in the transverse and distal colon with similar affinities: pA2 values 8.71 and 8.45, slopes 0.98 and 0.99. SR 48692 (10 nM–10 μM) antagonized the NT response competitively in the distal colon (pA2 6.55, slope 0.79) and non‐competitively in the transverse colon (pA2 8.0, slope 0.51). Neither compound had any agonist effect.
The fact that the specific antagonists prevented NT‐evoked atropine‐ and tetrodotoxin‐insensitive mechanical responses of colonic muscle strips is highly consistent with the presence in these tissues of non‐neuronal NT receptors, whose heterogeneity in the transverse segment is supported by the non‐competitive antagonism of SR 48692. The finding of NT1 receptor transcript in both transverse and distal colon suggests its identity with the lower affinity site disclosed functionally by SR 48692 in these segments.

British Journal of Pharmacology (1999) 127, 1922–1928; doi:10.1038/sj.bjp.0702734
Differentiated effects on splanchnic homeostasis by selective and non‐selective endothelin receptor antagonism in porcine endotoxaemia
Authors: Oldner Anders , Wanecek Michael , Weitzberg Eddie , Sundin Pierre , Sollevi Alf , Rubio Carlos , Hellström Per M , Alving Kjell , Rudehill Anders 
Published: January 2005

The non‐selective endothelin (ET) receptor antagonist bosentan has been shown to restore systemic and gut oxygen delivery and reverse intestinal mucosal acidosis in porcine endotoxin shock.
To further elucidate the specific role of the ETA as opposed to the ETB receptor and their effects in the splanchnic region a non‐selective (ETMIXra) A‐182086 and selective ETA (ETAra) PD155080 and ETB (ETBra) A‐192621 receptor antagonists were administered, separately or simultaneously (ETA+Bra) 2 h after onset of endotoxin shock. These four groups were compared to a control group receiving only endotoxin and vehicle.
Thirty‐nine pigs were anaesthetized and catheterized for measurement of central and regional haemodynamics. A tonometer in the distal ileum was used for measurement of mucosal PCO2. Blood gases and plasma ET‐1‐LI levels as well as histological samples from the gut were assessed. Intervention was started 2 h after onset of endotoxemia and the experiments were terminated after 5 h.
Endotoxin‐induced changes in systemic, gut oxygen delivery and portal hepatic vascular resistance and systemic acidosis were effectively counteracted by both ETA+Bra and ETMIXra. ETAra administration was not effective while ETBra proved to be fatal as all animals in this group died prior to full time of the experiment. While both ETA+Bra and ETMIXra improved gut oxygen delivery only the latter attenuated the profound endotoxin‐induced ileal mucosal acidosis.
The lethal effect seen from selective ETB receptor antagonism in the current study may be due to increased ETA receptor activity as plasma levels of ET‐1 is increased several fold by blocking the ETB receptor and thereby the plasma‐ET‐1‐clearing function. Furthermore, a loss of endothelial ETB receptor vasodilating properties may also have contributed to the lethal course in the ETBra group
The findings in this study suggest that ET is involved in the profound endotoxin‐induced disturbances in splanchnic homeostasis in porcine endotoxaemia. Furthermore, antagonism of both ETA and ETB receptors is necessary to effectively counteract these changes.

British Journal of Pharmacology (1999) 127, 1793–1804; doi:10.1038/sj.bjp.0702736
The ethanol metabolite acetaldehyde inhibits the induction of long‐term potentiation in the rat dentate gyrus in vivo
Authors: Abe Kazuho , Yamaguchi Shinichi , Sugiura Minoru , Saito Hiroshi 
Published: January 2005

Ethanol has been reported to inhibit the induction of long‐term potentiation (LTP) in the hippocampus. However, the correlation between the effects of ethanol in vivo and in vitro remained unclear. In addition, previous works have little considered the possibility that the effect of ethanol is mediated by its metabolites. To solve these problems, we investigated the effects of ethanol and acetaldehyde, the first metabolite in the metabolism of ethanol, on the induction of LTP at medial perforant path‐granule cell synapses in the dentate gyrus of anaesthetized rats in vivo.
Oral administration of 1 g kg−1 ethanol significantly inhibited the induction of LTP, confirming the effectiveness of ethanol in vivo.
A lower dose of ethanol (0.5 g kg−1) failed to inhibit the induction of LTP in intact rats, but significantly inhibited LTP in rats treated with disulfiram, an inhibitor of aldehyde dehydrogenase, demonstrating that LTP is inhibited by acetaldehyde accumulation following ethanol administration.
Intravenous injection of acetaldehyde (0.06 g kg−1) significantly inhibited the induction of LTP.
The inhibitory effect of acetaldehyde on LTP induction was also observed when it was injected into the cerebroventricules, suggesting that acetaldehyde has a direct effect on the brain. The intracerebroventricular dose of acetaldehyde effective in inhibiting LTP induction (0.1–0.15 mg brain−1) was approximately 10 fold lower than that of ethanol (1.0–1.5 mg brain−1).
It is possible that acetaldehyde is partly responsible for memory impairments induced by ethanol intoxication.

British Journal of Pharmacology (1999) 127, 1805–1810; doi:10.1038/sj.bjp.0702738