bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of cyclo‐oxygenase‐2 expression by methyl arachidonyl fluorophosphonate in murine J774 macrophages: roles of protein kinase C, ERKs and p38 MAPK
Authors: Lin Wan‐W , Chen Bing‐C 
Published: January 2005

Methyl arachidonyl fluorophosphonate (MAFP), an inhibitor of phospholipase A2 (PLA2), has been widely used to assess the roles of PLA2 in various cell functions. Here, we report on a novel action of this compound at concentrations similar to those used for PLA2 inhibition.
The murine macrophage J774 released a large amount of prostaglandin E2 (PGE2) by MAFP (1–30 μM), which was abolished by indomethacin and NS‐398 but not by valeryl salicylate, and results from increased cyclo‐oxygenase‐2 (COX‐2) protein levels and gene expression.
This PGE2 release was blocked by inhibitors of tyrosine kinase (genistein), protein kinase C (PKC) (Ro 31–8220, Go 6976 or LY 379196), mitogen‐activated protein kinase kinase (MEK) (PD 098059) or p38 mitogen‐activated protein kinase (MAPK) (SB 203580).
Consistent with these results, MAFP caused membrane translocation of PKCβI and βII isoforms and activated extracellular signal‐regulated kinase (ERK) and p38 MAPK.
In accordance with these effects of MAFP, PKC activator phorbol 12‐myristate 13‐acetate (PMA) increased PGE2 release and caused activation of PKCβ, ERKs and p38 MAPK.
This is the first report that the PLA2 inhibitor, MAFP, can induce COX‐2 gene expression and PGE2 synthesis via the PKC‐, ERK‐ and p38 MAPK‐dependent pathways. Thus, the use of MAFP as a PLA2 inhibitor should be treated with caution.

British Journal of Pharmacology (1999) 126, 1419–1425; doi:10.1038/sj.bjp.0702436
Cytosolic Ca2+ movements of endothelial cells exposed to reactive oxygen intermediates: Role of hydroxyl radical‐mediated redox alteration of cell‐membrane Ca2+ channels
Authors: Az‐ma Toshiharu , Saeki Noboru , Yuge Osafumi 
Published: January 2005

The mode of action of reactive oxygen intermediates in cysosolic Ca2+ movements of cultured porcine aortic endothelial cells exposed to xanthine/xanthine oxidase (X/XO) was investigated.
Cytosolic Ca2+ movements provoked by X/XO consisted of an initial Ca2+ release from thapsigargin‐sensitive intracellular Ca2+ stores and a sustained Ca2+ influx through cell‐membrane Ca2+ channels. The Ca2+ movements from both sources were inhibited by catalase, cell‐membrane permeable iron chelators (o‐phenanthroline and deferoxamine), a •OH scavenger (5,5‐dimethyl‐1‐pyrroline‐N‐oxide), or an anion channel blocker (disodium 4, 4′‐diisothiocyano‐2, 2′‐stilbenedisulphonic acid), suggesting that •O2− influx through anion channels was responsible for the Ca2+ movements, in which •OH generation catalyzed by intracellular transition metals (i.e., Haber‐Weiss cycle) was involved.
After an initial Ca2+ elevation provoked by X/XO, cytosolic Ca2+ concentration decreased to a level higher than basal levels. Removal of X/XO slightly enhanced the Ca2+ decrease. Extracellular addition of sulphydryl (SH)‐reducing agents, dithiothreitol or glutathione, after the removal of X/XO accelerated the decrement. A Ca2+ channel blocker, Ni2+, abolished the sustained increase in Ca2+, suggesting that Ca2+ influx through cell‐membrane Ca2+ channels was extracellularly regulated by the redox state of SH‐groups.
The X/XO‐provoked change in cellular respiration was inhibited by Ni2+ or dithiothreitol as well as inhibitors of Haber‐Weiss cycle, suggesting that Ca2+ influx was responsible for •OH‐mediated cytotoxicity. We concluded that intracellular •OH generation was involved in the Ca2+ movements in endothelial cells exposed to X/XO. Cytosolic Ca2+ elevation was partly responsible for the oxidants‐mediated cytotoxicity.

British Journal of Pharmacology (1999) 126, 1462–1470; doi:10.1038/sj.bjp.0702438
Inhibitory effect of 4‐aminopyridine on responses of the basilar artery to nitric oxide
Authors: Sobey Christopher G , Faraci Frank M 
Published: January 2005

Voltage‐dependent K+ channels are present in cerebral arteries and may modulate vascular tone. We used 200 μM 4‐aminopyridine (4‐AP), thought to be a relatively selective inhibitor of voltage‐dependent K+ channels at this concentration, to test whether activation of these channels may influence baseline diameter of the basilar artery and dilator responses to nitric oxide (NO) and cyclic GMP in vivo.
Using a cranial window in anaesthetized rats, topical application of 4‐AP to the basilar artery (baseline diameter=240±5 μm, mean±s.e.mean) produced 10±1% constriction. Sodium nitroprusside (a NO donor), acetylcholine (which stimulates endothelial release of NO), 8‐bromo cyclic GMP (a cyclic GMP analogue), cromakalim (an activator of ATP‐sensitive K+ channels) and papaverine (a non‐NO, non‐K+ channel‐related vasodilator) produced concentration‐dependent vasodilator responses that were reproducible.
Responses to 10 and 100 nM nitroprusside were inhibited by 4‐AP (20±4 vs 8±2% and 51±5 vs 33±5%, respectively, n=10; P<0.05). Responses to acetylcholine and 8‐bromo cyclic GMP were also partially inhibited by 4‐AP. In contrast, 4‐AP had no effect on vasodilator responses to cromakalim or papaverine. These findings suggest that NO/cyclic GMP‐induced dilator responses of the basilar artery are selectively inhibited by 4‐aminopyridine.
Responses to nitroprusside were also markedly inhibited by 10 μM 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (an inhibitor of soluble guanylate cyclase; 16±4 vs 1±1% and 44±7 vs 7±1%; n=10; P<0.05).
Thus, dilator responses of the rat basilar artery to NO appear to be mediated by activation of soluble guanylate cyclase and partially by activation of a 4‐aminopyridine‐sensitive mechanism. The most likely mechanism would appear to be activation of voltage‐dependent K+ channels by NO/cyclic GMP.

British Journal of Pharmacology (1999) 126, 1437–1443; doi:10.1038/sj.bjp.0702439
Kinetics of rate‐dependent shortening of action potential duration in guinea‐pig ventricle; effects of IK1 and IKr blockade
Authors: Williams Beatrice A , Dickenson David R , Beatch Gregory N 
Published: January 2005

The kinetics of shortening of action potential duration (APD) following an increase in pacing rate, from 2 to 3.3 Hz, was characterized in guinea‐pig ventricular preparations. Terikalant (RP62719), an inhibitor of the inwardly rectifying K+ current (IK1), and dofetilide, a specific inhibitor of the rapidly activating delayed‐rectifier current (IKr), were applied to determine the effect of inhibition of these ion currents on slow APD shortening.
Action potentials were recorded from isolated guinea‐pig ventricular myocytes using the perforated‐patch patch‐clamp technique, and monophasic action potentials were recorded from Langendorff‐perfused guinea‐pig ventricles using a contact epicardial probe.
Under control conditions, after an increase in pacing rate, APD immediately decreased, and then shortened slowly with an exponential time course. In ventricular myocytes, the time constant of this exponential shortening was 28±4 s and the amount of slow shortening was 21.9±0.9 ms (n=8) for an increase in rate from 2 to 3.3 Hz. Similar values were observed in Langendorff‐perfused ventricles.
Terikalant dose‐dependently increased APD and the increase was enhanced by rapid pacing (‘positive’ rate‐dependence). The drug dose‐dependently decreased the time constant of shortening and amount of slow APD shortening. In contrast, dofetilide, an inhibitor of IKr, which shows ‘reverse’ rate‐dependent APD widening, had no significant effect on the time constant or amount of slow shortening.
These observations suggest that IK1 plays a role in rate‐dependent shortening of APD. The results appear to support the hypothesis that ‘reverse’ rate‐dependent effects of IKr blockers are due to these drugs not affecting the ion current(s) mediating intrinsic rate‐dependent slow shortening of APD.

British Journal of Pharmacology (1999) 126, 1426–1436; doi:10.1038/sj.bjp.0702443
Dural vasodilation causes a sensitization of rat caudal trigeminal neurones in vivo that is blocked by a 5‐HT1B/1D agonist
Authors: Cumberbatch M J , Williamson D J , Mason G S , Hill R G , Hargreaves R J 
Published: January 2005

Migraine headache pain is thought to result from an abnormal distention of intracranial, extracerebral blood vessels and the consequent activation of the trigeminal nervous system. Migraine is also often accompanied by extracranial sensory disturbances from facial tissues. These experiments investigate whether meningeal dilation produces central sensitization of neurones that receive convergent input from the face.
Single unit extracellular activity was recorded from the trigeminal nucleus caudalis of anaesthetized rats in response to either noxious stimulation of the dura mater, innocuous stimulation of the vibrissae or to a transient dilation of the meningeal vascular bed.
Rat α‐CGRP (calcitonin gene‐related peptide; 1 μg kg−1, i.v.) caused a dilation of the middle meningeal artery and facilitated vibrissal responses by 36±7%.
The 5‐HT1B/1D agonist, L‐741,604 (3 mg kg−1, i.v.), inhibited responses to noxious stimulation of the dura mater (16±7% of control) and, in a separate group of animals, blocked the CGRP‐evoked facilitation of vibrissal responses.
L‐741,604 (3 mg kg−1, i.v.) also inhibited responses to innocuous stimulation of the vibrissa (14±10% of control) with neurones that received convergent input from the face and from the dura mater, but not with cells that received input only from the face (70±12% of control).
These data show that dilation of meningeal blood vessels causes a sensitization of central trigeminal neurones and a facilitation of facial sensory processing which was blocked by activation of pre‐synaptic 5‐HT1B/1D receptors.
Sustained dural blood vessel dilation during migraine may cause a sensitization of trigeminal neurones. This may underlie some of the symptoms of migraine, such as the headache pain and the extracranial allodynia. Inhibition of this central sensitization may therefore offer a novel strategy for the development of acute and/or prophylactic anti‐migraine therapies.

British Journal of Pharmacology (1999) 126, 1478–1486; doi:10.1038/sj.bjp.0702444
Characterization of the binding of a novel radioligand to CCKB/gastrin receptors in membranes from rat cerebral cortex
Authors: Harper E A , Shankley N P , Black J W 
Published: January 2005

We have investigated the binding of a novel radiolabelled CCKB/gastrin receptor ligand, [3H]‐JB93182 (5[[[(1S)‐[[(3,5‐dicarboxyphenyl)amino]carbonyl]‐2‐phenylethylamino]‐carbonyl]‐6‐[[(1‐adamantylmethyl) amino]carbonyl]‐indole), to sites in rat cortex membranes.
The [3H]‐JB93182 was 97% radiochemically pure as assessed by reverse‐phase HPLC (RP‐HPLC) and was not degraded by incubation (150 min) with rat cortex membranes.
Saturation analysis indicated that [3H]‐JB93182 labelled a homogeneous population of receptors in rat cortex membranes (pKD=9.48±0.08, Bmax=3.61∼plusmn;0.65 pmol g−1 tissue, nH=0.97±0.02, n=5). The pKD was not significantly different when estimated by association‐dissociation analysis (pKD=9.73±0.11; n=10).
In competition studies, the low affinity of the CCKA receptor antagonists, L‐364,718; SR27897 and 2‐NAP, suggest that, under the assay conditions employed, [3H]‐JB93182 (0.3 nM) does not label CCKA receptors in the rat cortex.
The affinity estimates obtained for reference CCKB/gastrin receptor antagonists were indistinguishable from one of the affinity values obtained when a two site model was used to interpret [125I]‐BH‐CCK8S competition curves obtained in the same tissue (Harper et al., 1999).
This study provides further evidence for the existence of two CCKB/gastrin sites in rat cortex. [3H]‐JB93182 appears to label selectively sites previously designated as gastrin‐G1 and therefore it may be a useful compound for the further discrimination and characterization of these putative receptor subtypes.

British Journal of Pharmacology (1999) 126, 1504–1512; doi:10.1038/sj.bjp.0702447
Rapid actions of calcitriol and its side chain analogues CB1093 and GS1500 on intracellular calcium levels in skeletal muscle cells: a comparative study
Authors: Vazquez Guillermo , Sellés Juana , De Boland Ana Russo , Boland Ricardo 
Published: January 2005

The ability of synthetic analogues of the secosteroid hormone 1α,25‐dihydroxy‐vitamin‐D3 [calcitriol, CT; 1,25(OH)2D3] to exert non‐genomic (rapid) effects on target cells has been scarcely studied. To evaluate the pharmacological potential of the CT side‐chain analogues CB1093 and GS1500, we compared their fast effects on intracellular calcium concentration ([Ca2+]i) in chick skeletal muscle cells with those elicited by the natural hormone.
Both analogues, similarly to CT, specifically induced rapid (30–60 s) and sustained rises in [Ca2+]i levels. CB1093 and GS1500 were more potent than the natural hormone at concentrations as low as 10−13 M (4.5 fold stimulation) and 10−12 M (2.5 fold), respectively, whereas higher concentrations (10−9–10−8 M) of CT were more effective than the analogues in elevating [Ca2+]i. Cyclic AMP was markedly increased by both analogues pointing for a role of this messenger in the fast actions of the synthetic compounds.
In Ca2+ free medium CT and analogues elicited a transient elevation in [Ca2+]i. The PLC inhibitors U73122 (2 μM) and neomycin (0.5 mM), as well as depletion of intracellular stores with thapsigargin (1 μM), completely prevented CB1093/GS1500‐dependent changes in [Ca2+]i suggesting that, similarly to CT, these analogues mobilized Ca2+ from an IP3/thapsigargin‐sensitive store.
The voltage‐dependent calcium channel (VDCC) blocker nifedipine (2 μM) reduced by 50–60% the influx phase of the [Ca2+]i response to CB1093 and GS1500, indicating that VDCC contributed partially to Ca2+ entry. The Ca2+ readdition protocol suggested that analogue‐dependent activation of a SOC entry pathway accounted, to the same extent as for CT, for the remaining non‐VDCC mediated Ca2+ influx.

British Journal of Pharmacology (1999) 126, 1815–1823; doi:10.1038/sj.bjp.0702451
Involvement of CB1 cannabinoid receptors in the EDHF‐dependent vasorelaxation in rabbits
Authors: Niederhoffer Nathalie , Szabo Bela 
Published: January 2005

It was recently suggested that an endogenous cannabinoid could represent an endothelium‐derived hyperpolarizing factor (EDHF). The aim of the present study was to clarify whether CB1 cannabinoid receptors are involved in the nitric oxide (NO)‐ and prostanoid‐independent vasodilation produced by acetylcholine in rabbits.
Pithed rabbits received indomethacin. Noradrenaline was infused to raise blood pressure, and vasodilation was elicited by bolus injections of acetylcholine. The NO‐synthase inhibitor Nω‐nitro‐L‐arginine methylester inhibited the acetylcholine‐evoked vasodilation by about 40%. The remaining vasodilation was unaffected by the CB1 cannabinoid receptor antagonist SR141716A, but was inhibited by the potassium channel blocker tetraethylammonium. In addition, the mixed CB1/CB2 cannabinoid receptor agonist WIN55212‐2 did not elicit vasodilation.
No CB1 cannabinoid receptors were involved in the prostanoid‐ and NO‐independent vasodilation produced by acetylcholine. An exogenous cannabinoid also did not cause vasodilation. Therefore, it is unlikely that an endogenous cannabinoid serves as an EDHF acting at smooth muscle CB1 cannabinoid receptors in the rabbit.

British Journal of Pharmacology (1999) 126, 1383–1386; doi:10.1038/sj.bjp.0702452
Effects of dexamethasone on airway hyper‐responsiveness to the adenosine A1 receptor agonist cyclo‐pentyl adenosine in an allergic rabbit model
Authors: El‐Hashim Ahmed Z , Banner Katharine H , Paul William , Page Clive P 
Published: January 2005

New Zealand White (NZW) rabbits were immunized within 24 h of birth with Alternaria tenuis in aluminium hydroxide (Al (OH)3) (i.p.) or sham immunized (saline plus Al (OH)3 i.p.) and subsequently injected with the allergen (i.p.) or sham‐immunized for the next 3 months. At 3 months of age, baseline airway responsiveness was assessed using cyclo‐pentyl adenosine (CPA). Bronchoalveolar lavage (BAL) was performed in all animals and samples of peripheral blood were collected from some animals for estimation of dexamethasone levels. In some animals, blood was collected at the end of the experiment and cellular function was assessed by measurement of ex vivo proliferation of mononuclear cells in response to phytohaemagglutinin (PHA).
Allergen immunization significantly increased baseline airway responsiveness to inhaled CPA (P<0.05) in comparison with sham‐immunized animals, at 3 months after immunization. Dexamethasone (0.5 mg kg−1 day−1) treatment for 1 month did not modify this established airway hyper‐responsiveness to CPA. Dexamethasone treatment did not affect either total or differential cell numbers in BAL fluid during the 4 week period, although significant plasma levels of dexamethasone were achieved in dexamethasone treated animals.
Treatment of rabbits with dexamethasone (0.1 mg kg−1 i.p.), 6 h prior to each allergen injection from the neonatal stage, significantly reduced baseline airway hyper‐responsiveness to CPA measured at 3 months (P<0.05). There was no significant difference in either total or differential cell numbers in BAL fluid, or any difference in mitogen‐induced proliferation of mononuclear cells between dexamethasone and vehicle treated rabbits.
These results suggest that introduction of glucocorticosteroids in early life can prevent baseline airway hyper‐responsiveness to inhaled CPA in allergic rabbits. However, once established, such underlying airway hyper‐responsiveness is difficult to resolve, even with prolonged treatment with glucocorticosteroids.

British Journal of Pharmacology (1999) 126, 1513–1521; doi:10.1038/sj.bjp.0702455
Interaction of amiodarone and triiodothyronine on the expression of β‐adrenoceptors in brown adipose tissue of rat
Authors: Adli Houria , Bazin Raymond , Perret Gérard Y 
Published: January 2005

This study was undertaken to evaluate in vivo the influence of amiodarone on the effects of triiodothyronine (T3) in brown adipose tissue (BAT) which are independent of thyroid hormone synthesis and of the conversion of thyroxine (T4) to T3. Thyroidectomized rats were given a replacement dose of T3 (0.5 mg kg−1 p.o. daily for 3 days) with or without amiodarone (50 mg kg−1 p.o. daily for 1 week).
As assessed by RT–PCR, treatment of thyroidectomized rats with T3 caused a 2 fold decrease in β3‐adrenoceptor (β3‐AR) mRNA levels and a 2 fold increase in β1‐AR mRNA levels.
Binding studies using [3H]‐CGP 12177 as a ligand showed that treatment of thyoidectomized rats with T3 resulted in a 70% decrease in β3‐AR number and in an 80% increase in β1‐AR in BAT membranes.
T3‐treatment abolished the increase in BAT adenylyl cyclase (AC) activity induced by CGP12177 in thyroidectomized rats. It also decreased the amount of Gi protein (ADP‐ribosylation) by 30%.
At variance with the literature on the heart, amiodarone administration did not inhibit the positive effect of T3 on β1‐AR expression in BAT in thyroidectomized rats. However, it antagonized the effect of T3 on β3‐AR number, but not on AC activity or on Gi expression.
These results indicate that the effects of thyroid hormones on the responsiveness of BAT to catecholamines involves both receptor and post‐receptor mechanisms, they also suggest that interaction between amiodarone and thyroid hormones is highly tissue‐specific and depends on the β‐AR subtype.

British Journal of Pharmacology (1999) 126, 1455–1461; doi:10.1038/sj.bjp.0702456
The antifungal antibiotic clotrimazole potently inhibits L‐type calcium current in guinea‐pig ventricular myocytes
Authors: Thomas George P , Karmazyn Morris , Zygmunt Andrew C , Antzelevitch Charles , Narayanan Njanoor 
Published: January 2005

The antimycotic agent clotrimazole (CLT) is a promising potential therapeutic agent for a variety of diseases including cancer. Although it is known that CLT alters calcium homeostasis in many cell types, its cardiac effects are virtually unknown. We investigated the effects of CLT on L‐type calcium current (ICa,L) and action potentials in guinea‐pig ventricular myocytes. CLT (5, 25 and 50 μM) inhibited basal ICa,L by 16, 59 and 93%, respectively. The inhibitory effect of CLT was rapid and the peak effect was attained within 3 min. At a concentration of 25 μM, the inhibitory effect of CLT was partially reversible whereas the response to 50 μM CLT persisted following drug withdrawal. CLT abbreviated action potential duration at 50 and 90% of repolarization and suppressed the plateau significantly. These results indicate that CLT may have important cardiac effects at concentrations used to induce the antiproliferative action of the drug.British Journal of Pharmacology (1999) 126, 1531–1533; doi:10.1038/sj.bjp.0702475
UK‐78,282, a novel piperidine compound that potently blocks the Kv1.3 voltage‐gated potassium channel and inhibits human T cell activation
Authors: Hanson Douglas C , Nguyen Angela , Mather Robert J , Rauer Heiko , Koch Kevin , Burgess Laurence E , Rizzi James P , Donovan Carol B , Bruns Matthew J , Canniff Paul C , Cunningham Ann C , Verdries Kimberly A , Mena Edward , Kath John C , Gutman George A , Cahalan Michael D , Grissmer Stephan , Chandy K George 
Published: January 2005

UK‐78,282, a novel piperidine blocker of the T lymphocyte voltage‐gated K+ channel, Kv1.3, was discovered by screening a large compound file using a high‐throughput 86Rb efflux assay. This compound blocks Kv1.3 with a IC50 of ∼200 nM and 1 : 1 stoichiometry. A closely related compound, CP‐190,325, containing a benzyl moiety in place of the benzhydryl in UK‐78,282, is significantly less potent.
Three lines of evidence indicate that UK‐78,282 inhibits Kv1.3 in a use‐dependent manner by preferentially blocking and binding to the C‐type inactivated state of the channel. Increasing the fraction of inactivated channels by holding the membrane potential at −50 mV enhances the channel's sensitivity to UK‐78,282. Decreasing the number of inactivated channels by exposure to ∼160 mM external K+ decreases the sensitivity to UK‐78,282. Mutations that alter the rate of C‐type inactivation also change the channel's sensitivity to UK‐78,282 and there is a direct correlation between τh and IC50 values.
Competition experiments suggest that UK‐78,282 binds to residues at the inner surface of the channel overlapping the site of action of verapamil. Internal tetraethylammonium and external charybdotoxin do not compete UK‐78,282's action on the channel.
UK‐78,282 displays marked selectivity for Kv1.3 over several other closely related K+ channels, the only exception being the rapidly inactivating voltage‐gated K+ channel, Kv1.4.
UK‐78,282 effectively suppresses human T‐lymphocyte activation.

British Journal of Pharmacology (1999) 126, 1707–1716; doi:10.1038/sj.bjp.0702480