bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition by adenosine A2A receptors of NMDA but not AMPA currents in rat neostriatal neurons
Authors: Wirkner Kerstin , Assmann Heike , Köles Laszlo , Gerevich Zoltan , Franke Heike , Nörenberg Wolfgang , Boehm Rudolf , Illes Peter 
Published: January 2005

Whole‐cell patch clamp experiments were used to investigate the transduction mechanism of adenosine A2A receptors in modulating N‐methyl‐D‐aspartate (NMDA)‐induced currents in rat striatal brain slices. The A2A receptor agonist 2‐p‐(2‐carboxyethyl)phenethylamino‐5′‐N‐ethylcarboxamidoadenosine (CGS 21680) inhibited the NMDA, but not the (S)‐α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) current in a subset of striatal neurons.
Lucifer yellow‐filled pipettes in combination with immunostaining of A2A receptors were used to identify CGS 21680‐sensitive cells as typical medium spiny striatal neurons.
Dibutyryl cyclic AMP and the protein kinase A activator Sp‐cyclic AMPs, but not the protein kinase A inhibitors Rp‐cyclic AMPS or PKI(14–24)amide abolished the inhibitory effect of CGS 21680. The phospholipase C inhibitor U‐73122, but not the inactive structural analogue U‐73343 also interfered with CGS 21680. The activation of protein kinase C by phorbol 12‐myristate 13‐acetate or the blockade of this enzyme by staurosporine did not alter the effect of CGS 21680. Heparin, an antagonist of inositol 1,4,5‐trisphosphate (InsP3) and a more efficient buffering of intracellular Ca2+ by BAPTA instead of EGTA in the pipette solution, abolished the CGS 21680‐induced inhibition.
The calmodulin antagonist W‐7 and cytochalasin B which enhances actin depolymerization also prevented the effect of CGS 21680; the calmodulin kinase II inhibitors CaM kinase II(281–309) and KN‐93 but not the inactive structural analogue KN‐92 were also effective. The calcineurin inhibitor deltamethrin did not interfere with CGS 21680.
It is suggested that the transduction mechanism of A2A receptors to inhibit NMDA receptor channels is the phospholipase C/InsP3/calmodulin and calmodulin kinase II pathway. The adenylate cyclase/protein kinase A and phospholipase C/protein kinase C pathways do not appear to be involved.

British Journal of Pharmacology (2000) 130, 259–269; doi:10.1038/sj.bjp.0703234
Investigation of the role of intracellular Ca2+ stores in generation of the muscarinic agonist‐induced slow afterdepolarization (sADP) in guinea‐pig olfactory cortical neurones in vitro
Authors: Postlethwaite Michael , Constanti Andrew , Libri Vincenzo 
Published: January 2005

Intracellular recordings were made from guinea‐pig olfactory cortical brain slice neurones to assess the possible role of intracellular Ca2+ stores in the generation of the slow post‐stimulus afterdepolarization (sADP) and its underlying tail current (IADP), induced by muscarinic receptor activation.
Caffeine or theophylline (0.5–3 mM) reduced the amplitude of the IADP (measured under ‘hybrid’ voltage clamp) induced in the presence of the muscarinic agonist oxotremorine‐M (OXO‐M, 10 μM) by up to 96%, without affecting membrane properties or muscarinic depolarization of these neurones.
The L‐type Ca2+ channel blocker nifedipine (1, 10 μM) also inhibited IADP (by up to 46%), while ryanodine (10 μM) (a blocker of Ca2+ release from internal stores) produced a small (∼10%) reduction in IADP amplitude; however, neither 10 μM dantrolene (another internal Ca2+ release blocker) nor the intracellular Ca2+ store re‐uptake inhibitors thapsigargin (3 μM) or cyclopiazonic acid (CPA, 15 μM) affected IADP amplitude.
IBMX (100 μM), a phosphodiesterase inhibitor, also had no effect on IADP. Furthermore, inhibition of IADP by caffeine was not reversed by co‐application of 100 μM adenosine.
Caffeine (3 mM) or nifedipine (10 μM) reduced the duration of presumed Ca2+ spikes revealed by intracellular Cs+ loading. When applied in combination, nifedipine and caffeine effects were occlusive, rather than additive, suggesting a common site of action on L‐type calcium channels.
We conclude that Ca2+‐induced Ca2+ release (CICR) from internal stores does not contribute significantly to muscarinic IADP generation in olfactory cortical neurones. However caffeine and theophylline, which enhance CICR in other systems, blocked IADP induction. We suggest that this action might involve a combination of L‐type voltage‐gated Ca2+ channel blockade, and a direct inhibitory action on the putative IADP K+ conductance.

British Journal of Pharmacology (2000) 129, 1447–1457; doi:10.1038/sj.bjp.0703236
Upregulation of bradykinin B1‐receptor expression after myocardial infarction
Authors: Tschöpe Carsten , Heringer‐Walther Silvia , Koch Matthias , Spillmann Frank , Wendorf Michael , Leitner Eszter , Schultheiss Heinz‐Peter , Walther Thomas 
Published: January 2005

To determine the influence of the myocardial infarction (MI) on bradykinin B1‐receptor (B1R) regulation, we studied its expression in the left ventricle (LV) after MI. Rats were submitted to a permanent occlusion of the left coronary artery. Six hours, 24 h and 6 days after MI or after sham operation, left ventricular pressure (LVP) and dP/dtmax were measured. LV‐total RNA was extracted and B1R expression was analysed by a RNase‐protection assay (each group n=6). LVP and dP/dtmax were impaired at all time points after MI. Basal B1R expression was not detectable in controls. Six hours after MI, the B1R expression was upregulated and reached a maximum 24 h after MI (4 fold vs 6 h). Six days post‐MI, B1R expression returned to levels found 6 h after MI. These data are the first demonstration for an induced myocardial B1R expression in an in vivo model of MI.British Journal of Pharmacology (2000) 129, 1537–1538; doi:10.1038/sj.bjp.0703239
A redox‐based mechanism for nitric oxide‐induced inhibition of DNA synthesis in human vascular smooth muscle cells
Authors: Bundy Ruth E , Marczin Nándor , Chester Adrian H , Yacoub Magdi 
Published: January 2005

The current study explored potential redox mechanisms of nitric oxide (NO)‐induced inhibition of DNA synthesis in cultured human and rat aortic smooth muscle cells.
Exposure to S‐nitrosothiols, DETA‐NONOate and NO itself inhibited ongoing DNA synthesis and S phase progression in a concentration‐dependent manner, as measured by thymidine incorporation and flow cytometry. Inhibition by NO donors occurred by release of NO, as detected by chemiluminescence and judged by the effects of NO scavengers, haemoglobin and cPTIO.
Co‐incubation with redox compounds, N‐acetyl‐L‐cysteine, glutathione and L‐ascorbic acid prevented NO inhibition of DNA synthesis. These observations suggest that redox agents may alternatively attenuate NO bioactivity extracellularly, interfere with intracellular actions of NO on the DNA synthesis machinery or restore DNA synthesis after established inhibition by NO.
Recovery of DNA synthesis after inhibition by NO was similar with and without redox agents suggesting that augmented restoration of DNA synthesis is an unlikely mechanism to explain redox regulation.
Study of extracellular interactions revealed that all redox agents potentiated S‐nitrosothiol decomposition and NO release.
Examination of intracellular NO bioactivity showed that as opposed to attenuation of NO inhibition of DNA synthesis by redox agents, there was no inhibition (potentiation in the presence of ascorbic acid) of soluble guanylate cyclase (sGC) activation judged by cyclic GMP accumulation in rat cells.
These data provide evidence that NO‐induced inhibition of ongoing DNA synthesis is sensitive to redox environment. Redox processes might protect the DNA synthesis machinery from inhibition by NO, in the setting of augmented liberation of biologically active NO from NO donors.

British Journal of Pharmacology (2000) 129, 1513–1521; doi:10.1038/sj.bjp.0703240
GABAB receptor‐mediated effects on vagal pathways to the lower oesophageal sphincter and heart
Authors: Blackshaw L Ashley , Smid Scott D , O'Donnell Tracey A , Dent John 
Published: January 2005

GABAB receptors influencing vagal pathways to the lower oesophageal sphincter and heart were investigated.
In urethane‐anaesthetized ferrets, the GABAB agonist baclofen (7 μmol kg−1 i.v.) increased basal lower oesophageal sphincter (LOS) pressure. This was reversed by antagonism with CGP35348 (100 μmol kg−1 i.v.). Baclofen's effect was abolished by vagotomy, suggesting a central action, yet it was ineffective when given centrally (3–6 nmol i.c.v.).
Peripheral vagal stimulation (10 Hz, 5 s duration) caused LOS inhibition, followed by excitation, then prolonged inhibition. Bradycardia was also evoked during stimulation. Bradycardia and LOS responses were abolished after chronic supranodose vagotomy, indicating that they were due to stimulation of vagal pre‐ganglionic neurones, not antidromic stimulation of afferents.
Baclofen (1–10 μmol kg−1) reduced bradycardia and enhanced LOS excitation, which was also seen in animals pretreated with atropine (400 μg kg−1 i.v.) and guanethidine (5 mg kg−1 i.v.), but not in those pretreated with L‐NAME (100 mg kg−1 i.v.).
Effects of baclofen (7 μmol kg−1 i.v.) on vagal stimulation‐induced LOS and cardiac responses were unchanged by the GABAB antagonists CGP35348 or CGP36742 (up to 112 μmol kg−1 i.v.), but were reversed by CGP62349 (ED50 37 nmol kg−1 i.v.) or CGP54626 (ED50 100 nmol kg−1 i.v.).
Responses of isolated LOS strips to electrical stimulation, capsaicin, NK‐1, NK‐2 and nicotinic receptor agonists were all unaffected by baclofen (200 μ M).
We conclude that baclofen reduces vagal output at two peripheral sites: one presynaptically on pre‐ganglionic neurones (CGP35348‐insensitive), and another (CGP35348‐sensitive) that could not be identified. This demonstrates heterogeneity of GABAB receptors through differential sensitivity to antagonists.

British Journal of Pharmacology (2000) 130, 279–288; doi:10.1038/sj.bjp.0703244
Antihyperalgesic effects of δ opioid agonists in a rat model of chronic inflammation
Authors: Fraser Graeme L , Gaudreau Geneviève‐Anne , Clarke Paul B S , Ménard Daniel P , Perkins Martin N 
Published: January 2005

Opioid receptors in the brain activate descending pain pathways to inhibit the nociceptive response to acute noxious stimuli. The aim of the present study was to clarify the role of supraspinal opioid receptors in modulating the nociceptive response to persistent inflammation in rats.
Subcutaneous administration of 50 μl of complete Freund's Adjuvant (CFA) into the plantar surface of the hindpaw induced a significant decrease in paw withdrawal latency to thermal stimuli (P<0.01) at 24 h post‐injection.
Intracerebroventricular (i.c.v.) administration of the μ opioid receptor agonists, DAMGO and morphine, and the δ opioid receptor agonists, deltorphin II and SNC80, significantly reversed the hyperalgesic response associated with peripheral inflammation in a dose‐dependent manner (P<0.0001).
The μ and δ agonists also significantly attenuated the antinociceptive response to acute thermal stimulation in rats (P<0.001). However, deltorphin II and SNC80 were less potent, and in the case of SNC80 less efficacious, in modulating the response to acute thermal nociception in comparison to hyperalgesia associated with persistent inflammation.
These results indicate that μ and δ opioid receptors in the brain modulate descending pain pathways to attenuate the nociceptive response to acute thermal stimuli in both normal and inflamed tissues. The heightened response to δ agonists in the hyperalgesia model suggests that δ opioid receptors in the brain are promising targets for the treatment of pain arising from chronic inflammation.

British Journal of Pharmacology (2000) 129, 1668–1672; doi:10.1038/sj.bjp.0703248
Role of kynurenines in the neurotoxic actions of kainic acid
Authors: Behan W M H , Stone T W 
Published: January 2005

The neurotoxic actions of kainic acid can be partly suppressed by antagonists acting at N‐methyl‐D‐aspartate (NMDA) receptors. The present study examined the possible role of endogenous components of the kynurenine pathway to this phenomenon.
Administration of kainate (2 nmols) into the hippocampus of anaesthetized rats produced damage in the CA1 and CA3 regions. The involvement of NMDA receptors was confirmed by the ability of dizocilpine (1 mg kg−1) to reduce cell loss in the CA1 region from 92 to 42%.
The co‐administration of m‐nitrobenzoylalanine (20 nmols into the hippocampus), an inhibitor of kynurenine hydroxylase and kynureninase, together with a systemic injection of the compound (100 mg kg−1, i.p.), afforded some protection against kainate, reducing cell loss from 91 to 48%. Protection was not exerted against damage by quinolinic acid or NMDA, excluding a direct interaction between m‐nitrobenzoylalanine and NMDA receptors.
The protective effect of m‐nitrobenzoylalanine was not prevented by glycine, which would be expected to reverse protection caused by an elevation in the levels of endogenous kynurenic acid, arguing against a major role for increased levels of kynurenic acid.
The results indicate that inhibition of the kynurenine pathway offers protection against kainate‐induced damage. One possible mechanism for the protection is that an increased production of quinolinic acid in the brain, possibly from glial cells and macrophages activated by the initial kainate insult, normally contributes to the local activation of NMDA receptors and thus to kainate‐induced cerebral insults. This generation of endogenous quinolinic acid would be suppressed by m‐nitrobenzoylalanine.

British Journal of Pharmacology (2000) 129, 1764–1770; doi:10.1038/sj.bjp.0703250
Enhanced relaxation of porcine coronary arteries after acute exposure to a physiological level of 17β‐estradiol involves non‐genomic mechanisms and the cyclic AMP cascade
Authors: Teoh Hwee , Man Ricky Y K 
Published: January 2005

The present study extends our previous finding that the endothelium‐independent relaxation in porcine coronary artery rings is enhanced after short‐term (20 min) exposure to a physiological concentration (1 nM) of 17β‐estradiol and demonstrates that this effect may be attributable to activation of the cyclic AMP pathway.
Isometric tension was recorded in isolated rings of porcine coronary arteries.
Relaxation by levcromakalim and sodium nitroprusside, but not bradykinin and calcium ionophore A23187, were significantly potentiated following 20 min treatment with 1 nM 17β‐estradiol. This enhancing effect was insensitive to the transcriptional and translational inhibitors, actinomycin D and cycloheximide respectively and absent following repeated washing of the rings prior to construction of relaxation‐response curves.
The potentiating actions of 1 nM 17β‐estradiol on endothelium‐independent relaxation were mimicked by the cyclic AMP analogue 8‐Bromo‐cyclic AMP and the protein kinase A activator Sp‐cyclic AMPS but not by the cyclic GMP analogue 8‐Bromo‐cyclic GMP. The modulatory effect of 17β‐estradiol was increased in the presence of the phosphodiesterase inhibitor 3‐isobutyl‐1‐methylxanthine.
The cyclic AMP‐dependent protein kinase A inhibitor Rp‐cyclic AMPS, but not the cyclic GMP antagonist Rp‐8‐Bromo‐cyclic GMPS, effectively inhibited the enhancing effects 1 M 17β‐estradiol had on the relaxation responses of levcromakalim and sodium nitroprusside.
These data support our earlier findings that physiologically relevant concentrations of 17β‐estradiol can acutely modify vasorelaxation in vitro. Furthermore, we report that this short‐term effect of 17β‐estradiol on vasorelaxation appears to be mediated via non‐genomic pathways and involves the cyclic AMP cascade.

British Journal of Pharmacology (2000) 129, 1739–1747; doi:10.1038/sj.bjp.0703252
ATP‐induced [Ca2+]i changes and depolarization in GH3 cells
Authors: Chung Hae Sook , Park Kyu Sang , Cha Seung Kyu , Kong In Deok , Lee Joong Woo 
Published: January 2005

Extracellular ATP is a neurotransmitter and mediates a variety of responses. In the endocrine system, there are data suggesting a physiological role for ATP in Ca2+ signalling and hormone secretion. However, the ATP receptor subtype involved has not been clearly elucidated in GH3 cells, a rat anterior pituitary cell line.
BzATP‐ and ATP‐induced [Ca2+]i responses had EC50 values of 18 and 651 μM, respectively. The maximal response to ATP was only 59±8% of that for BzATP. The BzATP‐induced [Ca2+]i increase was dependent upon the extracellular Ca2+ concentration. Preincubation with oxidized ATP (oATP) nearly abolished the ATP‐ and BzATP‐induced [Ca2+]i increases.
Both BzATP and ATP induced depolarization in GH3 cells, with EC50 values of 31 μM and 1 mM, respectively. The maximal depolarization to BzATP and ATP were 152±21 and 146±16% of that elicited by 30 mM KCl.
The rank order of agonist potency for [Ca2+]i and depolarization responses was BzATP ≫ ATP >2‐MeSATP and purine derivatives such as ADP, AMP, adenosine were ineffective. Neither UTP nor α, β‐methylene ATP showed any effect.
In low‐divalent conditions BzATP evoked non‐desensitizing inward currents, which were reversed at ∼0 mV. This nonselective cationic conductance was increased by repeated applications of BzATP and the cells became very permeable to NMDG. Longer applications (30 min) of BzATP stimulated ethidium bromide influx in low divalent conditions, suggesting increased permeability to larger molecules. We also identified the existence of P2X7 mRNA on GH3 cells by using reverse transcriptase (RT)‐polymerase chain reaction (PCR).
These results suggest that the GH3 cells have an endogenous P2X7 receptor and purinergic stimulation may play a potential role in neuroendocrine modulation on these cells.

British Journal of Pharmacology (2000) 130, 1843–1852; doi:10.1038/sj.bjp.0703253
An improved in vitro bioassay for the study of 5‐HT4 receptors in the human isolated large intestinal circular muscle
Authors: Prins N H , Shankley N P , Welsh N J , Briejer M R , Lefebvre R A , Akkermans L M A , Schuurkes J A J 
Published: January 2005

Recently, it was demonstrated that 5‐HT induces relaxation of human colon circular muscle through activation of 5‐HT4 receptors and 5‐HT7 receptors. The aim of the current study was to develop a new in vitro bioassay of human colon that would facilitate the pharmacological analysis of 5‐HT responses mediated solely by 5‐HT4 receptors.
Contracting circular muscle strips with KCl (80 mM) yielded a stable contractile tension and, in contrast to muscarinic cholinoceptor agonists and histamine, a profound reduction of spontaneous contractility. This allowed the establishment of reproducible, fully‐defined, agonist concentration‐response curves by cumulative dosing. Under these conditions, 5‐HT induced a concentration‐dependent relaxation (pEC50 7.31, Hill slope 0.91).
Neither methysergide (10 μM) nor granisetron (1 μM) affected the 5‐HT‐induced relaxation, suggesting that 5‐HT1, 5‐HT2, 5‐HT3, 5‐ht5, 5‐HT6 or 5‐HT7 receptors are not involved. The lack of effect of tetrodotoxin (0.3 μM) indicated a direct effect of 5‐HT on the smooth muscle.
The selective 5‐HT4 receptor antagonists GR 113808, GR 125487 and RS 39604 competitively antagonized the 5‐HT‐induced relaxation (pKB 9.43, 10.12 and 8.53, respectively). SB 204070 (1 nM) produced a rightward shift (pA2 10.34) and depression of the 5‐HT curve. These affinity estimates are similar to those previously reported for 5‐HT4 receptors.
The selective 5‐HT4 receptor agonists, prucalopride and R076186, induced relaxations (pEC50 7.50 and 7.57, respectively), that were blocked by GR 113808 (3 nM), yielding pA2 estimates of 9.31 and 9.21, respectively.
To summarise, in KCl (80 mM)‐contracted muscle strips, 5‐HT induces relaxation through activation of a homogeneous smooth muscle 5‐HT4 receptor population. This new bioassay allows the focused, pharmacological characterization of human colonic 5‐HT4 receptors in vitro.

British Journal of Pharmacology (2000) 129, 1601–1608; doi:10.1038/sj.bjp.0703254
Suppression of apoptosis by glucocorticoids in glomerular endothelial cells: effects on proapoptotic pathways
Authors: Meßmer Udo K , Winkel Gundula , Briner Verena A , Pfeilschifter Josef 
Published: January 2005

Tumour necrosis factor‐α (TNF‐α)‐ and lipopolysaccharide (LPS)‐induced apoptosis of bovine glomerular endothelial cells is now recognized as an important part in the pathogenesis of glomerulonephritis characterized by early mitochondrial cytochrome c release, mitochondrial permeability transition, Bak protein upregulation, Bcl‐XL protein downregulation and caspase‐3 activation.
Co‐treatment of cells with 10 nM dexamethasone and TNF‐α or LPS blocked roughly 90% of apoptotic cell death in glomerular endothelial cells. The action of glucocorticoids could be documented in that they prevented all apoptotic markers such as DNA laddering, DNA fragmentation measured by the diphenylamine assay as well as morphological alterations.
To mechanistically elucidate the action of glucocorticoids we evaluated whether glucocorticoids elicit a time‐dependent effect. For dexamethasone, to maximally inhibit DNA fragmentation a preincubation period was not required. Even if dexamethasone was supplemented 6 h following TNF‐α or LPS we observed a maximal inhibitory effect.
Concerning its influence on TNF‐α and LPS signal transduction, we found that dexamethasone only partially prevented cytochrome‐c‐release as a first sign of apoptotic cell death but efficiently blocked mitochondrial permeability transition. Moreover, TNF‐α‐ and LPS‐induced Bak upregulation, Bcl‐XL‐downregulation, and the activation of caspase‐3‐like proteases, measured fluorometrically using DEVD‐AMC and PARP cleavage, were efficiently blocked by dexamethasone.
We postulate that glucocorticoids exert their inhibitory action upstream of the terminal death pathways but downstream of primary receptor mediated signals by blocking pro‐apoptotic signals pre‐ and/or post cytochrome c release and mitochondrial signalling.

British Journal of Pharmacology (2000) 129, 1673–1683; doi:10.1038/sj.bjp.0703255
The hypocretins are weak agonists at recombinant human orexin‐1 and orexin‐2 receptors
Authors: Smart D , Jerman J C , Brough S J , Neville W A , Jewitt F , Porter R A 
Published: January 2005

The pharmacology of the orexin‐like peptides, hypocretin‐1 and hypocretin‐2, was studied in Chinese hamster ovary (CHO) cells stably expressing orexin‐1 (OX1) or orexin‐2 (OX2) receptors by measuring intracellular calcium ([Ca2+]i) using Fluo‐3AM. Orexin‐A and orexin‐B increased [Ca2+]i in CHO‐OX1 (pEC50=7.99±0.05 and 7.00±0.10 respectively, n=8) and CHO‐OX2 (pEC50=8.30±0.05 and 8.21±0.07 respectively, n=5). However, hypocretin‐1 and hypocretin‐2 were markedly less potent, with pEC50 values of 5.31±0.04 and 5.41±0.04 respectively in CHO‐OX2 cells (n=5). In CHO‐OX1 cells 10 μM hypocretin‐1 only elicited a 37.5±3.4% response whilst 10 μM hypocretin‐2 elicited a 18.0±2.1% response (n=8). Desensitisation of OX1 or OX2 with orexin‐A (100 nM) abolished the response to orexin‐A (10 nM) and the hypocretins (10 μM), but not to UTP (3 μM). In conclusion, the hypocretins are only weak agonists at the orexin receptors.British Journal of Pharmacology (2000) 129, 1289–1291; doi:10.1038/sj.bjp.0703257