bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of cyclopiazonic acid on contraction and intracellular Ca2+ in oesophageal striated muscle of normotensive and spontaneously hypertensive rats
Authors: Sekiguchi Fumiko , Shimamura Keiichi , Kawata Kyoko , Nakazawa Yumi , Saitoh Ritsuko , Yanagitani Yoshiko , Sunano Satoru 
Published: January 2005

The effects of cyclopiazonic acid (CPA), a selective inhibitor of sarcoplasmic reticulum (SR) Ca2+‐ATPase, on twitch contraction and on the resting state of tension and intracellular Ca2+ level ([Ca2+]i) of the oesophageal striated muscle of stroke‐prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar Kyoto rats (WKY) were compared.
CPA (10 μM) augmented the twitch contraction of oesophageal striated muscle preparations from both SHRSP and WKY, reducing the rate of relaxation (−dT/dt), and thus resulting in the prolongation of the time to 80% relaxation. The effect was significantly smaller in the SHRSP preparations.
In the resting state, CPA caused a sustained elevation of [Ca2+]i. The elevation was greater in the WKY preparations. Tension development accompanied by the elevation was observed in WKY preparations, but not in SHRSP preparations.
The sustained elevation of [Ca2+]i induced by CPA was eliminated by the removal of extracellular Ca2+. Both the elevated [Ca2+]i and tension in the preparations from WKY were reduced by flufenamic acid (100 μM), mefenamic acid (100 μM), lanthanum (La3+, 100 μM), gadolinium (Gd3+, 100 μM) and SK&F 96365 (100 μM) but not by verapamil (10 μM).
Thapsigargin (3 μM), another SR Ca2+‐ATPase inhibitor, produced similar effects on basal tension to those of CPA, although it reduced the amplitude of twitch contraction.
These results suggest that in the rat oesophageal striated muscle, (1) CPA extends the sequestrating time of Ca2+ into the SR, (2) CPA induces a Ca2+ influx mediated through verapamil‐insensitive pathways, possibly nonselective cation channels, and (3) the mechanism of [Ca2+]i modulation due to CPA‐sensitive SR Ca2+‐ATPase is deteriorated in the oesophageal striated muscle from SHRSP as compared with WKY preparations.

British Journal of Pharmacology (1999) 128, 961–968; doi:10.1038/sj.bjp.0702867
Inhibition of vascular KATP channels by U‐37883A: a comparison with cardiac and skeletal muscle
Authors: Wellman G C , Barrett‐Jolley R , Köppel H , Everitt D , Quayle J M 
Published: January 2005

The aim of this study was to investigate the selectivity of the ATP‐sensitive potassium (KATP) channel inhibitor U‐37883A (4‐morpholinecarboximidine‐N‐1‐adamantyl‐N′‐1‐cyclohexyl). Membrane currents through KATP channels were recorded in single muscle cells enzymatically isolated from rat mesenteric artery, cardiac ventricle and skeletal muscle (flexor digitorum brevis). KATP currents were induced either by cell dialysis with 0.1 mM ATP and 0.1 mM ADP, or by application of synthetic potassium channel openers (levcromakalim or pinacidil).
U‐37883A inhibited KATP currents in smooth muscle cells from rat mesenteric artery. Half inhibition of 10 μM levcromakalim‐induced currents occurred at a concentration of 3.5 μM.
Relaxations of rat mesenteric vessels caused by levcromakalim were reversed by U‐37883A. 1 μM levcromakalim‐induced relaxations were inhibited at a similar concentration of U‐37883A (half inhibition, 1.1 μM) to levcromakalim‐induced KATP currents.
KATP currents activated by 100 μM pinacidil were also studied in single myocytes from rat mesenteric artery, skeletal muscle and cardiac ventricle. 10 μM U‐37883A substantially inhibited KATP currents in vascular cells, but had little effect in skeletal or cardiac myocytes. Higher concentrations of U‐37883A (100 μM) caused a modest decrease in KATP currents in skeletal and cardiac muscle. The sulphonylurea KATP channel antagonist glibenclamide (10 μM) abolished currents in all muscle types.
The effect of U‐37883A on vascular inward rectifier (KIR) and voltage‐dependent potassium (KV) currents was also examined. While 10 μM U‐37883A had little effect on these currents, some inhibition was apparent at higher concentrations (100 μM) of the compound.
We conclude that U‐37883A inhibits KATP channels in arterial smooth muscle more effectively than in cardiac and skeletal muscle. Furthermore, this compound is selective for KATP channels over KV and KIR channels in smooth muscle cells.

British Journal of Pharmacology (1999) 128, 909–916; doi:10.1038/sj.bjp.0702868
Domains determining agonist selectivity in chimaeric VIP2 (VPAC2)/PACAP (PAC1) receptors
Authors: Lutz E M , MacKenzie C J , Johnson M , West K , Morrow J A , Harmar A J , Mitchell R 
Published: January 2005

The VPAC2 and PAC1 receptors are closely related members of the Group II G protein‐coupled receptor family. At the VPAC2 receptor, VIP is equipotent to PACAP‐38 in stimulating cyclic AMP production, whereas at the PAC1 receptor PACAP‐38 is many fold more potent than VIP. In this study, domains which confer this selectivity were investigated by constructing four chimaeric receptors in which segments of the VPAC2 receptor were exchanged with the corresponding segment from the PAC1 receptor.
When expressed in COS 7 cells all the chimaeric receptors bound the common ligand [125I]PACAP‐27 and produced cyclic AMP in response to agonists.
Relative selectivity for agonists was determined primarily by the amino terminal extracellular domain of the PAC1 receptor and the VPAC2 receptor. The interchange of other domains had little effect on the potency of PACAP‐38 or PACAP‐27.
For chimaeric constructs with a PAC1 receptor amino terminal domain, the substitution of increasing portions of the VPAC2 receptor decreased the potency of VIP yet increased that of helodermin.
This suggests that the interaction of VIP/helodermin but not PACAP with the PAC1 receptor may be influenced (and differentially so) by additional receptor domains.

British Journal of Pharmacology (1999) 128, 934–940; doi:10.1038/sj.bjp.0702872
Elevated concentrations of morphine 6‐beta‐D‐glucuronide in brain extracellular fluid despite low blood–brain barrier permeability
Authors: Stain‐Texier Frédérique , Boschi Gabrielle , Sandouk Pierre , Scherrmann Jean‐Michel 
Published: January 2005

This study was done to find out how morphine 6‐beta‐D‐glucuronide (M6G) induces more potent central analgesia than morphine, despite its poor blood–brain barrier (BBB) permeability. The brain uptake and disposition of these compounds were investigated in plasma and in various brain compartments: extracellular fluid (ECF), intracellular space (ICS) and cerebrospinal fluid (CSF).
Morphine or M6G was given to rats at 10 mg kg−1 s.c. Transcortical microdialysis was used to assess their distributions in the brain ECF. Conventional tissue homogenization was used to determine the distribution in the cortex and whole brain. These two procedures were combined to estimate drug distribution in the brain ICS. The blood and CSF pharmacokinetics were also determined.
Plasma concentration data for M6G were much higher than those of morphine, with Cmax and AUC 4–5 times more higher, Tmax shorter, and VZf−1 (volume of distribution) and CL f−1 (clearance) 4–6 times lower. The concentrations of the compounds in various brain compartments also differed: AUC values for M6G were lower than those of morphine in tissue and CSF and higher in brain ECF. AUC values in brain show that morphine levels were four times higher in ICS than in ECF, whereas M6G levels were 125 higher in ECF than in ICS.
Morphine entered brain cells, whereas M6G was almost exclusively extracellular. This high extracellular concentration, coupled with extremely slow diffusion into the CSF, indicates that M6G was predominantly trapped in the extracellular fluid and therefore durably available to bind at opioid receptors.

British Journal of Pharmacology (1999) 128, 917–924; doi:10.1038/sj.bjp.0702873
Diinosine pentaphosphate (IP5I) is a potent antagonist at recombinant rat P2X1 receptors
Authors: King B F , Liu M , Pintor J , Gualix J , Miras‐Portugal M T , Burnstock G 
Published: January 2005

The antagonist activity of a series of diinosine polyphosphates (IpnI, where n=3, 4, 5) was assessed against ATP‐activated inward currents at rat P2X1–4 receptors expressed in Xenopus oocytes and studied under voltage‐clamp conditions.
Diinosine polyphosphates were prepared by the enzymatic degradation of their corresponding diadenosine polyphosphates (e.g., Ap5A into Ip5I) using 5′‐adenylic deaminase, and purified using reverse‐phase chromatography.
Against ATP‐responses at rP2X1 receptors, the potency order for antagonism was (pIC50): Ip5I (8.5)>Ip4I (6.3)>Ip3I (>4.5). Ip5I (10–100 nM) caused a concentration‐dependent rightwards displacement of the ATP concentration‐response curve without reducing the maximum ATP effect. However, the Schild plot was non‐linear which indicated Ip5I is not a competitive antagonist. Blockade by micromolar concentrations of Ip5I was not surmountable. Ip4I also behaved as a non‐surmountable antagonist.
Against ATP‐responses at rP2X3 receptors, the potency order for antagonism was (pIC50): Ip4I (6.0)>Ip5I (5.6)>Ip3I (>4.5). Blockade by Ip4I (pA2, 6.75) and Ip5I (pA2, 6.27) was surmountable at micromolar concentrations.
Diinosine polyphosphates failed to inhibit ATP‐responses at rP2X2 receptors, whereas agonist responses at rP2X4 were reversibly potentiated by Ip4I and Ip5I. None of the parent diadenosine polyphosphates behave as antagonists at rP2X1–4 receptors.
Thus, Ip5I acted as a potent and relatively‐selective antagonist at the rP2X1 receptor. This dinucleotide pentaphosphate represents a high‐affinity antagonist for the P2X1 receptor, at which it acts in a competitive manner at low (100 nM) concentrations but has more complex actions at higher (>100 nM) concentrations.

British Journal of Pharmacology (1999) 128, 981–988; doi:10.1038/sj.bjp.0702876
Role of L‐arginine in the deficiency of nitric oxide and airway hyperreactivity after the allergen‐induced early asthmatic reaction in guinea‐pigs
Authors: De Boer Jacob , Duyvendak Michiel , Schuurman Fineke E , Pouw F May H , Zaagsma Johan , Meurs Herman 
Published: January 2005

Using a guinea‐pig model of allergic asthma, we investigated the role of L‐arginine limitation in the allergen‐induced deficiency of nitric oxide (NO) and airway hyperreactivity (AHR) after the early asthmatic reaction, by examining the effects of various concentrations of the NO synthase (NOS) substrate on the responsiveness to methacholine of isolated perfused tracheae from unchallenged (control) animals and from animals 6 h after ovalbumin challenge.
Preparations from ovalbumin‐challenged guinea‐pigs showed a 1.9 fold increase in the maximal response (Emax) to intraluminal (IL) administration of methacholine compared to controls (P<0.001). A similar 2.0 fold (P<0.05) increase in Emax to methacholine was observed in control airways incubated with the NOS inhibitor Nω‐nitro‐L‐arginine methyl ester (L‐NAME; 0.1 mM, IL), while L‐NAME had no further effect on the airways from ovalbumin‐challenged animals.
In control airways, extraluminal (EL) administration of 0.3, 1.0 and 5.0 mM L‐arginine all suppressed the Emax for methacholine by approximately 40% (P<0.01 all), whereas 5.0 mM D‐arginine (EL) had no effect.
L‐Arginine dose‐dependently reduced the AHR to methacholine in tracheae from ovalbumin‐challenged guinea‐pigs, the responsiveness being normalized in the presence of 5.0 mM L‐arginine. As in controls, 5.0 mM D‐arginine was without effect.
The results demonstrate that deficiency of endogenous NO contributes to the allergen‐induced AHR to methacholine after the early asthmatic reaction, which is reversed by exogenous administration of L‐arginine. This indicates that limitation of substrate may underly the reduced cNOS activity and subsequent AHR after the acute asthmatic response.

British Journal of Pharmacology (1999) 128, 1114–1120; doi:10.1038/sj.bjp.0702882
Effect of the umami peptides on the ligand binding and function of rat mGlu4a receptor might implicate this receptor in the monosodium glutamate taste transduction
Authors: Monastyrskaia Katherine , Lundstrom Kenneth , Plahl Doris , Acuna Gonzalo , Schweitzer Christophe , Malherbe Pari , Mutel Vincent 
Published: January 2005

The effect of several metabotropic ligands and di‐ or tripeptides were tested on the binding of [3H]‐L(+)‐2‐amino‐4‐phosphonobutyric acid ([3H]‐L‐AP4) on rat mGlu4 receptor. For selected compounds, the functional activity was determined on this receptor using the guanosine‐5′[γ‐35S]‐thiotriphosphate [γ‐35S]‐GTP binding assay.
Using the scintillation proximity assay, [3H]‐L‐AP4 saturation analysis gave binding parameters KD and Bmax values of 150 nM and 9.3 pmoles mg−1 protein, respectively. The specific binding was inhibited concentration‐dependently by several mGlu receptor ligands, and their rank order of affinity was established.
Several peptides inhibited the [3H]‐L‐AP4 binding with the following rank order of potency: glutamate‐glutamate>glutamate‐glutamate‐leucine=aspartate ‐ glutamate>>glutamate ‐ glutamate‐aspartate>lactoyl‐glutamate>>aspartate‐aspartate. Aspartate‐phenylalanine‐methyl ester (aspartame) was inactive up to 1 mM and guanosine‐5′‐monophosphate and inosine‐5′‐monophosphate were inactive up to 100 μM.
The [γ‐35S]‐GTP binding functional assay was used to determine the agonist activities of the different compounds. For the rat mGlu4 agonists, L‐AP4 and L‐glutamate, the correlation between their occupancy and activation of the receptor was close to one. The peptides, Glu‐Glu, Asp‐Glu and Glu‐Glu‐Asp failed to stimulate the [γ‐35S]‐GTP binding at receptor occupancy greater than 80% and Glu‐Glu‐Leu appeared to be a weak partial agonist. These peptides did not elicit a clear dose‐dependent umami perception. However, Glu‐lac showed a good correlation between its potency to stimulate the [γ‐35S]‐GTP binding and its affinity for displacement of [3H]‐L‐AP4 binding. These data are in agreement with the peptide taste assessment in human subjects, which showed that the acid derivatives of glutamate had characteristics similar to umami.

British Journal of Pharmacology (1999) 128, 1027–1034; doi:10.1038/sj.bjp.0702885
Cardioprotective effects of N‐hydroxyguanidine PR5 in myocardial ischaemia and reperfusion in rats
Authors: Veveris Maris , Dambrova Maija , Cirule Helena , Meirena Dainuvite , Kalvinsh Ivars , Wikberg Jarl E S 
Published: January 2005

The potential for the N‐hydroxyguanidine compound PR5 (N‐(3,4‐dimethoxy‐2‐chlorobenzylideneamino)‐N′‐hydroxyguanidine) as a cardioprotective agent in heart ischaemia and reperfusion injury was investigated using rat models.
Administration of 1–10 mg kg−1 of PR5 5 min before 10 min of left coronary artery occlusion, followed by 20 min reperfusion, strongly inhibited reperfusion burst of arrhythmias and markedly improved the survival of the animals (e.g. ventricular fibrillation incidence 93 vs 43% (P<0.05); mortality 47 vs 0% (P<0.05), for controls and for 3 mg kg−1 of PR5, respectively).
Administration of 3 mg kg−1 of PR5 1 min before reperfusion to rats subjected to 10 min occlusion, 20 min reperfusion was most effective in reducing arrhythmias and decreasing mortality (43 vs 0%, P<0.05), but effects were also seen when PR5 was administered 0, 1 and 5 min after start of reperfusion.
Coronary occlusion/reperfusion (10–20 min) increased malondialdehyde (MDA) of rat hearts (0.88±0.13 for sham vs 1.45±0.12 nmol mg−1 protein for ischaemic; P<0.05). In rats where 3 mg kg−1 PR5 were administered 1 min before reperfusion the increase was attenuated (MDA being 1.04±0.12; P<0.05 vs ischaemic).
PR5 caused a substantial reduction of the infarction size in rats subjected to 180 min left coronary artery occlusion, followed by 120 min of reperfusion; the necrotic zone being 326±32 mg for controls vs 137±21 mg for animals treated with 3×3 mg kg−1 of PR5 (P<0.01).
PR5 reduced the elevation of the ST‐segment of the ECGs, as well as caused pronounced attenuation of the rapid blood pressure drop seen at the start of reperfusion following coronary artery occlusion.
We conclude that the N‐hydroxyguanidine PR5 provides remarkable protection against ischaemia and reperfusion induced myocardial necrosis and life‐threatening arrhythmias. These effects of PR5 are discussed in relation to a recently discovered ability of N‐hydroxyguanidines to function as electron acceptors at the xanthine oxidase enzyme.

British Journal of Pharmacology (1999) 128, 1089–1097; doi:10.1038/sj.bjp.0702887
Effect of A2A adenosine receptor stimulation and antagonism on synaptic depression induced by in vitro ischaemia in rat hippocampal slices
Authors: Latini Serena , Bordoni Francesca , Corradetti Renato , Pepeu Giancarlo , Pedata Felicita 
Published: January 2005

In the present study we investigated the role of A2A adenosine receptors in hippocampal synaptic transmission under in vitro ischaemia‐like conditions.
The effects of adenosine, of the selective A2A receptor agonist, CGS 21680 (2‐[p‐(2‐carboxyethyl)‐phenethylamino]‐5′‐N‐ethylcarboxamidoadenosine), and of selective A2A receptor antagonists, ZM 241385 (4‐(2‐[7‐amino‐2‐(2‐furyl)‐{1,2,4}‐triazolo{2,3‐a}{1,3,5}triazin‐5‐ylamino]ethyl)phenol) and SCH 58261 (7‐(2‐phenylethyl)‐5‐amino‐2‐(2‐furyl)‐pyrazolo‐[4,3‐e]‐1,2,4‐triazolo[1,5‐c]pyrimidine), have been evaluated on the depression of field e.p.s.ps induced by an in vitro ischaemic episode.
The application of 2 min of in vitro ischaemia brought about a rapid and reversible depression of field e.p.s.ps, which was completely prevented in the presence of the A1 receptor antagonist DPCPX (1,3‐dipropyl‐8‐cyclopentylxanthine) (100 nM). On the other hand both A2A receptor antagonists, ZM 241385 and SCH 58261, by themselves did not modify the field e.p.s.ps depression induced by in vitro ischaemia.
A prolonged application of either adenosine (100 μM) or CGS 21680 (30, 100 nM) before the in vitro ischaemic episode, significantly reduced the synaptic depression. These effects were antagonized in the presence of ZM 241385 (100 nM).
SCH 58261 (1 and 50 nM) did not antagonize the effect of 30 nM CGS 21680 on the ischaemia‐induced depression.
These results indicate that in the CA1 area of the hippocampus the stimulation of A2A adenosine receptors attenuates the A1‐mediated depression of synaptic transmission induced by in vitro ischaemia.

British Journal of Pharmacology (1999) 128, 1035–1044; doi:10.1038/sj.bjp.0702888
‘Outside‐in’ signalling mechanisms underlying CD11b/CD18‐mediated NADPH oxidase activation in human adherent blood eosinophils
Authors: Lynch Oonagh T , Giembycz Mark A , Barnes Peter J , Hellewell Paul G , Lindsay Mark A 
Published: January 2005

Incubation of human eosinophils in BSA‐coated tissue culture plates resulted in time‐dependent adhesion and attendant activation of the NADPH oxidase that were both inhibited (by >85%) by blocking antibodies raised against CD11b and CD18.
SB 203580, an inhibitor of p38 mitogen‐activated protein (MAP) kinase, did not influence adhesion but inhibited superoxide anion generation (pIC50=−6.57).
PP1, an inhibitor of the src‐family of protein tyrosine kinases, inhibited adhesion and CD11b/CD18‐mediated superoxide anion generation with similar potencies (pEC50s=−5.53 and −5.99 respectively) suggesting that inhibition of the NADPH oxidase was a direct consequence of blocking adhesion.
The protein kinase C (PKC) inhibitors Ro‐31 8220 (broad spectrum inhibitor), GF 109203X (inhibitor of conventional and novel isoforms) and Gö 6976 (inhibitor of conventional isoforms) suppressed adhesion‐dependent NADPH oxidase activation (pIC50s=−6.61, −6.05 and −4.89 respectively) without affecting adhesion. Based upon the selectivity of these drugs PKCδ and PKCε are implicated in the suppression of oxidant production.
Wortmannin, an inhibitor of phosphatidylinositol 3‐kinase (PtdIns 3‐kinase), abolished superoxide anion production in adherent eosinophils (pEC50=−9.06). Similarly, CD11b/CD18‐dependent adhesion was suppressed with the same potency (pEC50=−9.29) although the maximum effect did not exceed 50% implying that wortmannin also had an affect on those processes that govern adhesion‐driven oxidase activation.
PD 098059 and piceatannol, inhibitors of MAP kinase kinase‐1 and the syk tyrosine kinase respectively, had no effect on CD11b/CD18‐mediated adhesion or NADPH oxidase activation.
The results of this study demonstrate that human eosinophils adhere to BSA‐coated plastic by a CD11b/CD18‐dependent mechanism, which is responsible for activation of the NADPH oxidase. Although the signalling pathway(s) utilized by CD11b/CD18 is still to be elucidated, the data presented herein implicate p38 MAP kinase, novel PKCs and PtdIns 3‐kinase.

British Journal of Pharmacology (1999) 128, 1149–1158; doi:10.1038/sj.bjp.0702892
Cyclo‐oxygenase‐2: pharmacology, physiology, biochemistry and relevance to NSAID therapy
Authors: Mitchell Jane A , Warner Timothy D 
Published: January 2005

Cyclo‐oxygenase is expressed in cells in two distinct isoforms. Cyclo‐oxygenase‐1 is present constitutively whilst cyclo‐oxygenase‐2 is expressed primarily after inflammatory insult. The activity of cyclo‐oxygenase‐1 and ‐2 results in the production of a variety of potent biological mediators (the prostaglandins) that regulate homeostatic and disease processes. Inhibitors of cyclo‐oxygenase include the nonsteroidal anti‐inflammatory drugs (NSAIDs) aspirin, ibuprofen and diclofenac. NSAIDs inhibit cyclo‐oxygenase‐2 at the site of inflammation, to produce their therapeutic benefits, as well as cyclo‐oxygenase‐1 in the gastric mucosa, which produces gastric damage. Most recently selective inhibitors of cyclo‐oxygenase‐2 have been developed and introduced to man for the treatment of arthritis. Moreover, recent epidemiological evidence suggests that cyclo‐oxygenase inhibitors may have important therapeutic relevance in the prevention of some cancers or even Alzheimer's disease. This review will discuss how the new advancements in NSAIDs research has led to the development of a new class of NSAIDs that has far reaching implications for the treatment of disease.British Journal of Pharmacology (1999) 128, 1121–1132; doi:10.1038/sj.bjp.0702897