bluuebunny/crossref_metadata_2025_split huggingface dataset:
RSD1019 suppresses ischaemia‐induced monophasic action potential shortening and arrhythmias in anaesthetized rabbits
Authors: Barrett Terrance D , MacLeod Bernard A , Walker Michael J A 
Published: January 2005

The electrophysiological actions of lidocaine, tedisamil and RSD1019 were assessed on normal and ischaemic cardiac tissue using monophasic action potentials (MAPs) recorded from the epicardium of anaesthetized rabbits. Drug effects on ischaemia‐induced arrhythmias were assessed simultaneously in the same rabbits.
Lidocaine, infused at 2.5, 5 and 10 μmol kg−1 min−1 i.v., accelerated and worsened the electrophysiological derangement caused by ischaemia, had profibrillatory actions and reduced the time to the occurrence of ventricular fibrillation (VF) relative to controls.
Tedisamil, infused at 0.063, 0.125 and 0.25 μmol kg−1 min−1 i.v., prolonged MAP duration at 90% repolarization (MAPD90%) before induction of ischaemia in a dose‐related manner; however, this effect was not maintained 5 min after induction of ischaemia. Tedisamil had no significant antiarrhythmic actions over the dose‐range tested.
RSD1019, infused at 2, 4 and 8 μmol kg−1 min−1 i.v., produced a small increase in MAPD90% before induction of ischaemia and only at the highest dose tested. In contrast to tedisamil, RSD1019 suppressed ischaemia‐induced MAP shortening assessed 5 min after induction of ischaemia. This effect was dose‐related. RSD1019 completely prevented ischaemia‐induced tachyarrhythmias at the mid and highest infusion levels tested.
The results of this study illustrate a pathologically targeted approach for preventing ischaemia‐induced arrhythmias. Suppression of ischaemia‐induced MAP shortening, demonstrated herein for RSD1019, represents a novel antifibrillatory approach.

British Journal of Pharmacology (2000) 131, 405–414; doi:10.1038/sj.bjp.0703592
Effects of (+)‐pentazocine and 1,3‐di‐o‐tolylguanidine (DTG), sigma (σ) ligands, on micturition in anaesthetized rats
Authors: Shimizu Isao , Kawashima Katsuyoshi , Ishii Daisuke , Oka Makoto 
Published: January 2005

The effects of two sigma (σ) binding site ligands, (+)‐pentazocine and 1,3‐di‐o‐tolylguanidine (DTG), on bladder functions were examined in rats.
Cystometry using urethane‐anaesthetized rats showed that (+)‐pentazocine (1–5 mg kg−1, i.v.) and DTG (1–5 mg kg−1, i.v.) prolonged micturition intervals, indicating increased bladder capacity and raised the threshold pressure.
The effects of (+)‐pentazocine (2 mg kg−1, i.v.) on micturition were not influenced by naloxone (0.5 mg kg−1, i.v.), which antagonized similar effects of morphine (2 mg kg−1, i.v.).
When administered intracerebroventricularly (i.c.v.), DTG (1 μg) and (+)‐pentazocine (30 μg) prolonged micturition intervals with increased threshold pressure on the cystometrogram.
In isolated bladder detrusor strips of rats, (+)‐pentazocine (3 μM) and DTG (1 μM) did not affect contractile responses to electrical field stimulation. A higher concentration of DTG (3 μM) slightly suppressed the response induced by 30 Hz stimulation.
The effects of (+)‐pentazocine and DTG on micturition were abolished by pre‐treatment with pertussis toxin (PTX, 1 μg, i.c.v.).
These results indicate that typical σ ligands, such as (+)‐pentazocine and DTG, increase bladder capacity in anaesthetized rats. Moreover, the mechanism by which σ ligands change the urinary storage properties in rats may involve pathways in which the function of Gi/o proteins is necessary.

British Journal of Pharmacology (2000) 131, 610–616; doi:10.1038/sj.bjp.0703593
The effect of nucleotides and adenosine on stimulus‐evoked glutamate release from rat brain cortical slices
Authors: Bennett Gillian C , Boarder Michael R 
Published: January 2005

Evidence has previously been presented that P1 receptors for adenosine, and P2 receptors for nucleotides such as ATP, regulate stimulus‐evoked release of biogenic amines from nerve terminals in the brain. Here we investigated whether adenosine and nucleotides exert presynaptic control over depolarisation‐elicited glutamate release.
Slices of rat brain cortex were perfused and stimulated with pulses of 46 mM K+ in the presence of the glutamate uptake inhibitor L‐trans‐pyrrolidine‐2,4‐dicarboxylic acid (0.2 mM). High K+ substantially increased efflux of glutamate from the slices.
Basal glutamate release was unchanged by the presence of nucleotides or adenosine at concentrations of 300 μM.
Adenosine, ATP, ADP and adenosine 5′‐O‐(3‐thiotriphoshate) at 300 μM attenuated depolarisation‐evoked release of glutamate. However UTP, 2‐methylthio ATP, 2‐methylthio ADP, and α,β‐methylene ATP at 300 μM had no effect on stimulated glutamate efflux.
Adenosine deaminase blocked the effect of adenosine, but left the response to ATP unchanged.
The A1 antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine antagonised the inhibitory effect of both adenosine and ATP.
Cibacron blue 3GA inhibited stimulus‐evoked glutamate release when applied alone. When cibacron blue 3GA was present with ATP, stimulus‐evoked glutamate release was almost eliminated. However, this P2 antagonist had no effect on the inhibition by adenosine.
These results show that the release of glutamate from depolarised nerve terminals of the rat cerebral cortex is inhibited by adenosine and ATP. ATP appears to act directly and not through conversion to adenosine.

British Journal of Pharmacology (2000) 131, 617–623; doi:10.1038/sj.bjp.0703598
Suppression of the development of hypertension by the inhibitor of inducible nitric oxide synthase
Authors: Hong Hong‐Jye , Loh Shih‐Hurng , Yen Mao‐Hsiung 
Published: January 2005

Our previous study demonstrated that the aortic inducible nitric oxide synthase (iNOS) expression and the plasma nitrite level in spontaneously hypertensive rats (SHR) were greater than that in age‐matched Wistar‐Kyoto rats (WKY). We subsequently hypothesized that the over‐expression of iNOS might play an important role in the pathogenesis of hypertension in SHR.
In the present study, pyrrolidinedithiocarbamate (PDTC, 10 mg kg−1 day−1, p.o., antioxidant and nuclear factor‐κ B inhibitor) and aminoguanidine (15 mg kg−1 day−1, p.o., selective inhibitor of iNOS) was used to treat SHR and WKY from age of 5 weeks through 16 weeks.
We found that PDTC and aminoguanidine significantly suppressed the development of hypertension and improved the diminished vascular responses to acetylcholine in SHR but not in WKY. Likewise, the increase of iNOS expression, nitrotyrosine immunostaining, nitric oxide production and superoxide anion formation in adult SHR were also significantly suppressed by chronic treatment with PDTC and aminoguanidine.
In conclusion, this study demonstrated that both PDTC and aminoguanidine significantly attenuated the development of hypertension in SHR. The results suggest that PDTC suppresses iNOS expression due to its anti‐oxidant and/or nuclear factor‐κ B inhibitory properties. However, the effect of aminoguanidine was predominantly mediated by inhibition of iNOS activity, thereby reducing peroxynitrite formation. We propose that the development of a more specific and potent inhibitor of iNOS might be beneficial in preventing pathological conditions such as the essential hypertension.

British Journal of Pharmacology (2000) 131, 631–637; doi:10.1038/sj.bjp.0703603
Effect of the p38 kinase inhibitor, SB 203580, on allergic airway inflammation in the rat
Authors: Escott K J , Belvisi M G , Birrell M A , Webber S E , Foster M L , Sargent C A 
Published: January 2005

Tumour necrosis factor‐α (TNF‐α) and interleukin 1β (IL‐1β) have been implicated in the pathogenesis of asthma. The p38 kinase inhibitor, SB 203580 inhibits TNF‐α and IL‐1β production in vitro and in vivo. In this study the effect of SB 203580 on allergen‐induced airway TNF‐α production and inflammatory cell recruitment was investigated in sensitized Brown Norway rats. The allergen‐induced increase in bronchoalveolar lavage (BAL) TNF‐α was inhibited by SB 203580 at every dose tested (10–100 mg kg−1, p.o.). In contrast, neither ovalbumin‐induced eosinophilia or neutrophilia were inhibited by SB 203580 (10–100 mg kg−1, p.o.). In conclusion, SB 203580 inhibits BAL TNF‐α production by 95% without inhibiting either antigen‐induced airway eosinophilia or neutrophilia. This data suggests that either the residual TNF‐α is sufficent to drive allergen‐induced inflammatory cell recruitment into the lung or that TNF‐α is not involved in allergen‐induced inflammatory cell recruitment.British Journal of Pharmacology (2000) 131, 173–176; doi:10.1038/sj.bjp.0703605
Inhibition of acetylcholine muscarinic M1 receptor function by the M1‐selective ligand muscarinic toxin 7 (MT‐7)
Authors: Olianas Maria C , Maullu Carlo , Adem Abdu , Mulugeta Ezra , Karlsson Evert , Onali Pierluigi 
Published: January 2005

MT‐7 (1–30 nM), a peptide toxin isolated from the venom of the green mamba Dendroaspis angusticeps and previously found to bind selectively to the muscarinic M1 receptor, inhibited the acetylcholine (ACh)‐stimulated [35S]‐guanosine‐5′‐O‐(3‐thio)triphosphate ([35S]‐GTPγS) binding to membranes of Chinese hamster ovary (CHO) cells stably expressing the cloned human muscarinic M1 receptor subtype.
MT‐7 failed to affect the ACh‐stimulated [35S]‐GTPγS binding in membranes of CHO cells expressing either the M2, M3 or M4 receptor subtype.
In N1E‐115 neuroblastoma cells endogenously expressing the M1 and M4 receptor subtypes, MT‐7 (0.3–3.0 nM) inhibited the carbachol (CCh)‐stimulated inositol phosphates accumulation, but failed to affect the CCh‐induced inhibition of pituitary adenylate cyclase activating polypeptide (PACAP) 38‐stimulated cyclic AMP accumulation.
In both CHO/M1 and N1E‐115 cells the MT‐7 inhibition consisted in a decrease of the maximal agonist effect with minimal changes in the agonist EC50 value.
In CHO/M1 cell membranes, MT‐7 (0.05–25 nM) reduced the specific binding of 0.05, 1.0 and 15 nM [3H]‐N‐methylscopolamine ([3H]‐NMS) in a concentration‐dependent manner, but failed to cause a complete displacement of the radioligand. Moreover, MT‐7 (3 nM) decreased the dissociation rate of [3H]‐NMS by about 5 fold.
CHO/M1 cell membranes preincubated with MT‐7 (10 nM) and washed by centrifugation and resuspension did not recover control [3H]‐NMS binding for at least 8 h at 30°C.
It is concluded that MT‐7 acts as a selective noncompetitive antagonist of the muscarinic M1 receptors by binding stably to an allosteric site.

British Journal of Pharmacology (2000) 131, 447–452; doi:10.1038/sj.bjp.0703606
Oncostatin M synergises with house dust mite proteases to induce the production of PGE2 from cultured lung epithelial cells
Authors: Knight Darryl A , Asokananthan Nithiananthan , Watkins D Neil , Misso Neil L A , Thompson Philip J , Stewart Geoffrey A 
Published: January 2005

The release of PGE2 and nitric oxide (NO) from the respiratory epithelium may act to dampen inflammation. In other tissues, oncostatin M (OSM), a potent inducer of epithelial antiproteases, has also been shown to interact with IL‐1β to stimulate PGE2 release. However, whether OSM interacts with pro‐inflammatory cytokines and proteases in the production of anti‐inflammatory eicosanoids and NO from airway epithelium is unknown.
The effect of OSM and the related cytokine leukaemia inhibitory factor (LIF) on PGE2 and NO production by the respiratory epithelial cell line, A549 in response to pro‐inflammatory cytokines as well as protease‐rich house dust mite (HDM) fractions and a protease‐deficient rye grass pollen extract was examined by immunohistochemistry, cell culture, ELISA and enzyme‐immunoassay.
Cells treated with a mixture of IL‐1β, IFNγ and LPS for 48 h produced a 9 fold increase in PGE2 and a 3 fold increase in NO levels (both P<0.05). Both OSM and LIF were without effect. However, OSM added together with the cytokine mixture synergistically enhanced PGE2 production (22 fold, P<0.05). OSM also synergistically enhanced PGE2 production in response to a cysteine protease‐enriched, but not serine protease‐enriched HDM fraction (P<0.05). Rye grass extract, neither alone nor in combination with OSM, induced PGE2 or NO production, although it did induce the release of GM‐CSF.
These observations suggest that OSM is an important co‐factor in the release of PGE2 and NO from respiratory epithelial cells and may play a role in defense against exogenous proteases such as those derived from HDM.

British Journal of Pharmacology (2000) 131, 465–472; doi:10.1038/sj.bjp.0703612
Prodigiosin from the supernatant of Serratia marcescens induces apoptosis in haematopoietic cancer cell lines
Authors: Montaner Beatriz , Navarro Sira , Piqué Maria , Vilaseca Marta , Martinell Marc , Giralt Ernest , Gil Joan , Pérez‐Tomás Ricardo 
Published: January 2005

The effects of supernatant from the bacterial strain Serratia marcescens 2170 (CS‐2170) on the viability of different haematopoietic cancer cell lines (Jurkat, NSO, HL‐60 and Ramos) and nonmalignant cells (NIH‐3T3 and MDCK) was studied. We examined whether this cytotoxic effect was due to apoptosis, and we purified the molecule responsible for this effect and determined its chemical structure.
Using an MTT assay we showed a rapid (4 h) decrease in the number of viable cells. This cytotoxic effect was due to apoptosis, according to the fragmentation pattern of DNA, Hoechst 33342 staining and FACS analysis of the phosphatidylserine externalization. This apoptosis was blocked by using the caspase inhibitor Z‐VAD.fmk, indicating the involvement of caspases.
Prodigiosin is a red pigment produced by various bacteria including S. marcescens. Using mutants of S. marcescens (OF, WF and 933) that do not synthesize prodigiosin, we further showed that prodigiosin is involved in this apoptosis. This evidence was corroborated by spectroscopic analysis of prodigiosin isolated from S. marcescens.
These results indicate that prodigiosin, an immunosuppressor, induces apoptosis in haematopoietic cancer cells with no marked toxicity in nonmalignant cells, raising the possibility of its therapeutic use as an antineoplastic drug.

British Journal of Pharmacology (2000) 131, 585–593; doi:10.1038/sj.bjp.0703614
Identification of a novel nicotinic binding site in mouse brain using [125I]‐epibatidine
Authors: Whiteaker Paul , Jimenez Melissa , McIntosh J Michael , Collins Allan C , Marks Michael J 
Published: January 2005

[125I]‐Epibatidine binds to multiple nicotinic acetylcholine receptor (nAChR) subtypes with high affinity. In this study, [125I]‐epibatidine was used to label and characterize a novel nAChR subtype found in mouse brain inferior colliculus, interpeduncular nucleus, and olfactory bulb homogenates.
Binding of [125I]‐epibatidine was saturable and apparently monophasic in each brain region (KD=71±12 pM mean±s.e.mean across regions) but inhibition of [125I]‐epibatidine binding (200 pM) by A85380, cytisine and (−)‐nicotine was biphasic, indicating the presence of multiple binding sites.
The sites with lower agonist affinity comprised 30.0±2.2, 58.6±0.1 and 48.7±3.3% of specific [125I]‐epibatidine (200 pM) binding in inferior colliculus, interpeduncular nucleus, and olfactory bulb homogenates, respectively.
The affinity difference between A85380‐sensitive and ‐resistant binding sites was particularly marked (approximately 1000 fold). Thus A85380 was used to differentiate agonist‐sensitive and ‐resistant sites.
The pharmacological profiles of the A85380‐resistant sites in each region were assessed with inhibition binding experiments, using 14 agonists and five antagonists. The profiles were indistinguishable across regions, implying that A85380‐resistant [125I]‐epibatidine binding sites in inferior colliculus, interpeduncular nucleus, and olfactory bulb represent a single nAChR subtype.
The pharmacological profile of the A85380‐resistant sites is very different from that previously reported for high affinity (−)‐[3H]‐nicotine‐, [125I]‐α‐bungarotoxin‐, or [125I]‐α‐conotoxin MII‐binding sites, suggesting that they represent a novel nAChR population in mouse brain.

British Journal of Pharmacology (2000) 131, 729–739; doi:10.1038/sj.bjp.0703616
Regulation of the human prostanoid TPα and TPβ receptor isoforms mediated through activation of the EP1 and IP receptors
Authors: Walsh Marie‐Therese , Kinsella B Therese 
Published: January 2005

The intermolecular cross‐regulation mediated by the prostanoid IP‐receptor (IP)/EP1 receptor (EP1) agonists PGI2 and 17 phenyl trinor PGE2 on TP receptor (TP) signalling within platelets was compared to that which occurs to the individual TPα and TPβ receptors over‐expressed in human embryonic kidney (HEK) 293 cells. Ligand mediated TP receptor activation was monitored by analysing mobilization of intracellular calcium ([Ca2+]i) following stimulation with the selective thromboxane (TX) A2 mimetic U46619.
Consistent with previous studies, in platelets, PGI2 acting through endogenous IP receptors completely inhibited U46619‐mediated TP receptor signalling in a protein kinase (PK) A‐dependent, PKC‐independent manner.
In HEK 293 cells, PGI2, acting through endogenous AH6809 sensitive EP1 rather than IP receptors, and the selective EP1 receptor agonist 17 phenyl trinor PGE2 antagonized U46619‐mediated signalling by both TPα and TPβ receptors in a PKC‐dependent, PKA‐independent manner.
The maximum response induced by either ligand was significantly (P<0.005) greater for the TPα receptor than the TPβ receptor, pointing to possible physiologic differences between the TP isoforms, although the potency of each ligand was similar for both TP receptors.
TPΔ328, a truncated variant of TP receptor lacking the C‐tail sequences unique to TPα or TPβ receptors, was not sensitive to EP1 receptor‐mediated regulation by PGI2 or 17 phenyl trinor PGE2
In conclusion, these data confirm that TPα and TPβ receptors are subject to cross regulation by EP1 receptor signalling in HEK 293 cells mediated by PKC at sites unique to the individual TP receptors and that TPα receptor responses are significantly more reduced by EP1 receptor regulation than those of the TPβ receptor.

British Journal of Pharmacology (2000) 131, 601–609; doi:10.1038/sj.bjp.0703624
Neuroprotective abilities of resveratrol and other red wine constituents against nitric oxide‐related toxicity in cultured hippocampal neurons
Authors: Bastianetto Stéphane , Zheng Wen‐Hua , Quirion Rémi 
Published: January 2005

Animal and epidemiological studies suggest that polyphenol constituents of red wine possess antioxidant activities that favour protection against cardiovascular disease – the so‐called. ‘French paradox’ – and possibly, central nervous system disorders such as Alzheimer's disease (AD) and ischaemia.
In the present study, the potential of three major red wine derived‐polyphenols to protect against toxicity induced by the nitric oxide free radical donors sodium nitroprusside (SNP) and 3‐morpholinosydnonimine (SIN‐1) was examined in cultured rat hippocampal cells.
Both co‐ and post‐treatments with either the stilbene resveratrol (5–25 μM) or the flavonoids quercetin (5–25 μM) and (+)‐catechin (1–10 μM) were capable of attenuating hippocampal cell death and intracellular reactive oxygen species accumulation produced by SNP (100 μM and 1 mM, respectively). However, among the phenolic compounds tested, only the flavonoids afforded significant protection against 5 mM SIN‐1‐induced toxicity.
The effects of phenolic constituents were shared by Trolox (100 μM), a vitamin E analogue, but not by selective inhibitors of cyclo‐oxygenases (COX) and lipoxygenases (LOX).
Among the phenolic compounds tested, only quercetin (10 μM) inhibited 100 μM SNP‐stimulated protein kinase C (PKC) activation, whereas none of them were able to attenuate nitrite accumulation caused by SNP (100 μM).
Taken together, these data suggest that the neuroprotective abilities of quercetin, resveratrol, and (+)‐catechin result from their antioxidant properties rather than their purported inhibitory effects on intracellular enzymes such as COX, LOX, or nitric oxide synthase. Quercetin, however, may also act via PKC to produce its protective effects.

British Journal of Pharmacology (2000) 131, 711–720; doi:10.1038/sj.bjp.0703626
Bisphenol A diglycidyl ether (BADGE) is a PPARγ agonist in an ECV304 cell line
Authors: Bishop‐Bailey David , Hla Timothy , Warner Timothy D 
Published: January 2005

Peroxisome proliferator activated receptors (PPAR)s are nuclear transcription factors of the steroid receptor super‐family. One member, PPARγ, a critical transcription factor in adipogenesis, is expressed in ECV304 cells, and when activated participates in the induction of cell death by apoptosis. Here we describe a clone of ECV304 cells, ECV‐ACO.Luc, which stably expresses a reporter gene for PPAR activation. ECV‐ACO.Luc respond to the PPARγ agonists, 15‐deoxy‐Δ12,14 PGJ2, and ciglitizone, by inducing luciferase expression. Furthermore, using ECV‐ACO.Luc, we demonstrate that a newly described PPARγ antagonist, bisphenol A diglycidyl ether (BADGE) has agonist activities. Similar to 15‐deoxy‐Δ12,14 PGJ2, BADGE induces PPARγ activation, nuclear localization of the receptor, and induces cell death.British Journal of Pharmacology (2000) 131, 651–654; doi:10.1038/sj.bjp.0703628
Caspase‐1‐inhibitor ac‐YVAD‐cmk reduces LPS‐lethality in rats without affecting haematology or cytokine responses
Authors: Mathiak Guenther , Grass Guido , Herzmann Thomas , Luebke Thomas , Zetina Cecilia Cu , Boehm Sebastian A , Bohlen Heribert , Neville Lewis F , Hoelscher Arnulf H 
Published: January 2005

The effect of acetyl–tyrosyl‐valyl‐alanyl‐aspartyl–chloromethylketone (ac‐YVAD‐cmk), an irreversible caspase‐1 (IL‐1β converting enzyme, ICE) inhibitor on mortality, leukocyte and platelet counts and cytokine levels was investigated in a double‐blind rat model of endotoxaemia. Intravenous (i.v.) bolus administration of lipopolysaccharide (LPS) (25–75 mg kg−1, n=12 per group) to anaesthetized rats induced a dose dependent increase in mortality over 8 h (LD50=48 mg kg−1). During this period, animals became leukopenic and thrombocytopenic. Serum levels of IL‐β, IL‐6, and TNF‐α were highly elevated. Pretreatment of rats with ac‐YVAD‐cmk at a dose of 12.5 μmol kg−1 significantly reduced mortality from 83 to 33% using Log Rank analysis. However, ac‐YVAD‐cmk did not modify blood cell counts or cytokine profiles as compared with the LPS‐drug vehicle group. These data lay credence to the potential importance of caspase‐1‐inhibition in modifying the inflammatory response to endotoxin. Further investigations are warranted in understanding the relationship between caspase‐1 inhibition, cytokine production and animal survival in different experimental paradigms of sepsis.British Journal of Pharmacology (2000) 131, 383–386; doi:10.1038/sj.bjp.0703629