bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduction by gabapentin of K+‐evoked release of [3H]‐glutamate from the caudal trigeminal nucleus of the streptozotocin‐treated rat
Authors: Maneuf Y P , Blake R , Andrews N A , McKnight A T 
Published: February 2004

Recently, we showed that gabapentin can inhibit a facilitatory effect of substance P (SP) on K+‐evoked glutamate release in rat trigeminal slices (Maneuf et al., 2001), and we have now examined the effect of gabapentin on glutamate release in the trigeminal slice from the streptozotocin (STZ)‐treated rat.

At 4 weeks following STZ treatment (50 mg kg−1 i.p.), blood glucose was increased in the majority of cases, compared to the control level. All the treated animals showed a significant degree (P<0.001) of tactile allodynia (assessed using von Frey filaments) that did not appear to correlate with blood glucose levels.
In this study, we demonstrated that, after STZ treatment, 30 μM gabapentin reduced K+‐evoked release of [3H]‐glutamate in either normal (11 mM) or high (30 mM) glucose conditions by 24 and 22%, respectively. In the normal rat, gabapentin (up to 100 μM) is ordinarily unable to affect release of glutamate from the trigeminal slice.
The uptake of glutamate in Sp5C punches from streptozotocin‐treated rats was reduced under normal glucose conditions (41.7% of control), whereas high glucose restored uptake to normal (84.7% of control).
The addition of 1 μM substance P potentiated the evoked release of glutamate in both normal (40% increase) and high glucose (28%), and this was blocked by gabapentin (30 μM) in both conditions. It is interesting to speculate that this ability of gabapentin to reduce the release of glutamate in the trigeminal nucleus after streptozotocin treatment may be of relevance to the antihyperalgesic‐allodynic actions of the drug.

British Journal of Pharmacology (2004) 141, 574–579. doi:10.1038/sj.bjp.0705579
Activation of VPAC1 receptors by VIP and PACAP‐27 in human bronchial epithelial cells induces CFTR‐dependent chloride secretion
Authors: Dérand Renaud , Montoni Alicia , Bulteau‐Pignoux Laurence , Janet Thierry , Moreau Bertrand , Muller Jean‐Marc , Becq Frédéric 
Published: February 2004

In the human airway epithelium, VIP/PACAP receptors are distributed in nerve fibers and in epithelial cells but their role in transepithelial ion transport have not been reported. Here, we show that human bronchial epithelial Calu‐3 cells expressed the VPAC1 receptor subtype which shares similar high affinity for VIP and PACAP‐27.
The stoichiometric binding parameters characterizing the 125I‐VIP and 125I‐PACAP‐27 binding to these receptors were determined.
We found that VIP (EC50∼7.6 nM) and PACAP‐27 (EC50∼10 nM) stimulated glibenclamide‐sensitive and DIDS‐insensitive iodide efflux in Calu‐3 cells.
The protein kinase A (PKA) inhibitor, H‐89 and the protein kinase C (PKC) inhibitor, chelerythrine chloride prevented activation by both peptides demonstrating that PKA and PKC are part of the signaling pathway. This profile corresponds to the pharmacological signature of CFTR.
In the cystic fibrosis airway epithelial IB3‐1 cell lacking functional CFTR but expressing VPAC1 receptors, neither VIP, PACAP‐27 nor forskolin stimulated chloride transport.
Ussing chamber experiments demonstrated stimulation of CFTR‐dependent short‐circuit currents by VIP or PACAP‐27 applied to the basolateral but not to the apical side of Calu‐3 cells monolayers.
This study shows the stimulation in human bronchial epithelial cells of CFTR‐dependent chloride secretion following activation by VIP and PACAP‐27 of basolateral VPAC1 receptors.

British Journal of Pharmacology (2004) 141, 698–708. doi:10.1038/sj.bjp.0705597
Lymphocyte function antigen‐1 mediates leukocyte adhesion and subsequent liver damage in endotoxemic mice
Authors: Li Xiang , Klintman Daniel , Weitz‐Schmidt Gabriele , Schramm René , Thorlacius Henrik 
Published: February 2004

Sepsis is associated with leukocyte activation and recruitment in the liver. We investigated the role of lymphocyte function antigen‐1 (LFA‐1) in endotoxin‐induced leukocyte–endothelium interactions, microvascular perfusion failure, hepatocellular injury and apoptosis in the liver by use of gene‐targeted mice, blocking antibodies and a synthetic inhibitor of LFA‐1 (LFA703). For this purpose, mice were challenged with lipopolysaccharide (LPS)+D‐galactosamine (Gal), and intravital microscopy of the liver microcirculation was conducted 6 h later.
The number of firmly adherent leukocytes in response to LPS/Gal was reduced by 48% in LFA‐1‐deficient mice. Moreover, endotoxin‐induced increases of apoptosis and enzyme markers of hepatocellular injury were decreased by 64 and 69–90%, respectively, in LFA‐1‐deficient mice. Furthermore, sinusoidal perfusion was improved in endotoxemic mice lacking LFA‐1.
A similar protective pattern was observed in endotoxemic mice pretreated with an antibody against LFA‐1. Thus, immunoneutralization of LFA‐1 reduced endotoxin‐induced leukocyte adhesion by 55%, liver enzymes by 64–66% and apoptosis by 42%, in addition to the preservation of microvascular perfusion.
Administration of a novel statin‐derived inhibitor of LFA‐1, LFA703, significantly decreased leukocyte adhesion (more than 56%) and the subsequent liver injury in endotoxemic mice.
Thus, this study demonstrates a pivotal role of LFA‐1 in supporting leukocyte adhesion in the liver. Moreover, interference with LFA‐1‐mediated leukocyte adhesion protects against endotoxemic liver damage, and may constitute a potential therapeutic strategy in sepsis.

British Journal of Pharmacology (2004) 141, 709–716. doi:10.1038/sj.bjp.0705634
Kinin B2 receptor is not involved in enalapril‐induced apoptosis and regression of hypertrophy in spontaneously hypertensive rat aorta: possible role of B1 receptor
Authors: Duguay David , Sarkissian Shant Der , Kouz Rémi , Ongali Brice , Couture Réjean , DeBlois Denis 
Published: February 2004

Treatment with enalapril induces smooth muscle cell apoptosis and regression of aortic hypertrophy in spontaneously hypertensive rats (SHRs), whereas combined blockade of angiotensin II AT1 and AT2 receptors does not. We postulated that vascular apoptosis with enalapril involves enhanced half‐life of bradykinin (BK) and kinin B2 receptor stimulation.
SHR, 11‐weeks old, were treated for 4 weeks with enalapril (30 mg kg−1 day−1), Hoe 140 (500 μg kg−1 day−1; B2 receptor antagonist), alone or in combination. Controls received vehicle.
The half‐life of hypotensive responses to intra‐arterial bolus injections of BK were significantly increased in SHR anesthetized after 4 weeks of enalapril, an effect prevented by Hoe 140. The magnitude of BK‐induced hypotension was significantly attenuated in all rats treated with Hoe 140.
As compared to placebo, enalapril treatment significantly reduced blood pressure (−34±2%), aortic hypertrophy (−20±3%), hyperplasia (−37±5%) and DNA synthesis (−61±8%), while it increased aortic DNA fragmentation by two‐fold. Hoe 140 given alone or in combination with enalapril affected none of these parameters.
As a possible alternative mechanism, aortae isolated during the second week of enalapril treatment showed a transient upregulation of contractile responses to des‐Arg9BK (EC50<1 nM), which were significantly reduced by [Leu8]des‐Arg9BK (10 μM). Moreover, in vitro receptor autoradiography revealed an increase in expression of B1 and B2 receptor binding sites by 8–11 days of enalapril treatment.
Aortic apoptosis induction and hypertrophy regression with enalapril do not involve kinin B2 receptors in SHR. Kinins acting via B1 receptors remains a candidate mechanism.

British Journal of Pharmacology (2004) 141, 728–736. doi:10.1038/sj.bjp.0705642
EP4 prostanoid receptor‐mediated vasodilatation of human middle cerebral arteries
Authors: Davis Richard J , Murdoch Colin E , Ali Mozam , Purbrick Stuart , Ravid Rivka , Baxter Gordon S , Tilford Nick , Sheldrick Robert L G , Clark Kenneth L , Coleman Robert A 
Published: February 2004

Dilatation of the cerebral vasculature is recognised to be involved in the pathophysiology of migraine. Furthermore, elevated levels of prostaglandin E2 (PGE2) occur in the blood, plasma and saliva of migraineurs during an attack, suggestive of a contributory role. In the present study, we have characterised the prostanoid receptors involved in the relaxation and contraction of human middle cerebral arteries in vitro.
In the presence of indomethacin (3 μM) and the TP receptor antagonist GR32191 (1 μM), PGE2 was found to relax phenylephrine precontracted cerebral arterial rings in a concentration‐dependent manner (mean pEC50 8.0±0.1, n=5).
Establishment of a rank order of potency using the EP4>EP2 agonist 11‐deoxy PGE1, and the EP2>EP4 agonist PGE1‐OH (mean pEC50 of 7.6±0.1 (n=6) and 6.4±0.1 (n=4), respectively), suggested the presence of functional EP4 receptors. Furthermore, the selective EP2 receptor agonist butaprost at concentrations <1 μM failed to relax the tissues.
Blockade of EP4 receptors with the EP4 receptor antagonists AH23848 and EP4A caused significant rightward displacements in PGE2 concentration–response curves, exhibiting pA2 and pKB values of 5.7±0.1, n=3, and 8.4, n=3, respectively.
The IP receptor agonists iloprost and cicaprost relaxed phenylephrine precontracted cerebral arterial rings (mean pEC50 values 8.3±0.1 (n=4) and 8.1±0.1 (n=9), respectively). In contrast, the DP and FP receptor agonists PGD2 and PGF2α failed to cause appreciable relaxation or contraction at concentrations of up to 30 μM. In the absence of phenylephrine contraction and GR32191, the TP receptor agonist U46619 caused concentration‐dependent contraction of cerebral artery (mean pEC50 7.4±0.3, n=3).
These data demonstrate the presence of prostanoid EP4 receptors mediating PGE2 vasodilatation of human middle cerebral artery. IP receptors mediating relaxation and TP receptors mediating contraction were also functionally demonstrated.

British Journal of Pharmacology (2004) 141, 580–585. doi:10.1038/sj.bjp.0705645
Potential mechanisms for the enhancement of HERG K+ channel function by phospholipid metabolites
Authors: Wang Jingxiong , Zhang Yiqiang , Wang Huizhen , Han Hong , Nattel Stanley , Yang Baofeng , Wang Zhiguo 
Published: February 2004

Phospholipid metabolites lysophospholipids cause extracellular K+ accumulation and action potential shortening with increased risk of arrhythmias during myocardial ischemia. Here we studied effects of several lysophospholipids with different lengths of hydrocarbon chains and charged headgroups on HERG K+ currents (IHERG) expressed in HEK293 cells and the potential mechanisms using whole‐cell patch‐clamp techniques.
Only the lipids with 16 hydrocarbons such as 1‐palmitoyl‐lysophosphatidylcholine (LPC‐16) and 1‐palmitoyl‐lysophosphatidylglycerol (LPG‐16) were found to produce significant enhancement of IHERG and negative shifts of HERG activation, although the voltage dependence of the effects was different between LPC‐16 and LPG‐16 which have differently charged headgroups. The lipid with 18 hydrocarbons modestly increased IHERG. The lipids with 6 or 24 hydrocarbons had no effect or slightly decreased IHERG.
Inhibition or activation of protein kinase C did not alter the effects of LPC‐16 and LPG‐16. Participation of phosphatidylinositol‐4,5‐bisphosphate in IHERG enhancement by LPC‐16/LPG‐16 was also excluded.
Vitamin E augmented the effects of LPC‐16/LPG‐16 whereas xanthine/xanthine oxidase reduced IHERG: indicating that LPC‐16/LPG‐16 produced dual effects on IHERG: direct enhancement of IHERG and indirect suppression via production of superoxide anion.
We conclude that enhancement of HERG function by lysophospholipids is specific to the lipids with 16‐hydrocarbon chain structure and the pattern of voltage dependence is determined by the polar headgroups. The increase in IHERG is best described by direct interactions between lipid molecules and HERG proteins, which is consistent with lack of effects via membrane destabilization or modulation by intracellular signaling pathways.

British Journal of Pharmacology (2004) 141, 586–599. doi:10.1038/sj.bjp.0705646
Comparison of U46619‐, endothelin‐1‐ or phenylephrine‐induced changes in cellular Ca2+ profiles and Ca2+ sensitisation of constriction of pressurised rat resistance arteries
Authors: Shaw Linda , O'Neill Stephen , Jones Carolyn J P , Austin Clare , Taggart Michael J 
Published: February 2004

In pressurised rat mesenteric small arteries (50 mmHg), we examined the effects of stimulation with U46619, endothelin‐1 (ET‐1) or phenylephrine (PE) on changes in vessel diameter, global [Ca2+]i, individual smooth muscle cell [Ca2+]i and Ca2+‐sensitisation of contraction.
U46619 or ET‐1 gave tonic diameter reductions, whereas PE‐stimulated vessels gave tonic contractions or initial vasoconstrictions followed by diameter oscillations. Global [Ca2+]i changes were transient for each agonist, with tonic constrictions being accompanied by maintained submaximal global [Ca2+]i levels.
U46619, ET‐1 or PE tonic constrictions were accompanied by apparently asynchronous [Ca2+]i waves in individual smooth muscle cells of the vessel wall, as examined by confocal fluorescent microscopy. In vessels exhibiting vasomotion to PE, some apparent synchrony of activation of individual cells was evident; however, this was incomplete with many cells responding out of phase with their neighbours.
In α‐toxin‐permeabilised preparations, agonist‐induced Ca2+‐sensitisation of constriction at submaximal Ca2+ (pCa6.7) in the presence of GTP was greater with U46619 or ET than PE.
We conclude that, in pressurised mesenteric arteries, (i) a general feature of receptor‐coupled constriction is the generation of periodic smooth muscle [Ca2+]i waves; (ii) complete synchrony of Ca2+ oscillations between smooth muscle cells is not a prerequisite for receptor‐coupled vasomotion; (iii) varied Ca2+‐sensitising actions of agonists may partly determine tonic or phasic vessel responses to different stimuli.

British Journal of Pharmacology (2004) 141, 678–688. doi:10.1038/sj.bjp.0705647
E‐Ring 8‐isoprostanes inhibit ACh release from parasympathetic nerves innervating guinea‐pig trachea through agonism of prostanoid receptors of the EP3‐subtype
Authors: Clarke Deborah L , Giembycz Mark A , Patel Hema J , Belvisi Maria G 
Published: February 2004

In the present study, we examined the effect of E‐ring 8‐isoprostanes on cholinergic neurotransmission in guinea‐pig trachea and identified the receptor(s) involved. As isoprostanes are isomeric with prostaglandins, PGE2 and sulprostone (a selective EP3‐receptor agonist) were examined in parallel.
8‐Iso‐PGE1, 8‐iso‐PGE2 (0.1 nM–1 μM), sulprostone (1 nM–1 μM) and PGE2 (1 μM) suppressed EFS‐evoked [3H]ACh release from guinea‐pig trachea in a concentration‐dependent manner, producing 39.5, 53.9, 61.2 and 59.9% inhibition, respectively, at 1 μM. It should be noted that an established maximum effective concentration was not determined.
Neither SQ 29,548 (1 μM; a TP‐receptor antagonist) nor AH 6809 (10 μM; an EP1‐/EP2‐/DP‐receptor antagonist) reversed the inhibitory effect of these compounds.
L‐798,106, a novel and highly selective EP3‐receptor antagonist, produced a parallel shift to the right of the concentration–response curves that described the inhibitory action of sulprostone on EFS‐evoked contractile responses in guinea‐pig vas deferens (an established EP3‐receptor‐expressing tissue), from which a mean pA2 of 7.48 was derived. On guinea‐pig trachea, L‐798,106 also antagonised sulprostone‐induced inhibition of EFS‐induced twitch responses, with similar potency (mean pA2=7.82).
The inhibitory effects of 8‐iso‐PGE1, 8‐iso‐PGE2, sulprostone and PGE2 on EFS‐induced [3H]ACh release was blocked by L‐798,106 at a concentration (10 μM) that binds only weakly to human recombinant EP1‐, EP2‐ and EP4‐receptor subtypes expressed in HEK 293 cells.
These data suggest that E‐ring 8‐isoprostanes, PGE2 and sulprostone inhibit EFS‐evoked [3H]ACh release from cholinergic nerves innervating guinea‐pig trachea, by interacting with prejunctional prostanoid receptors of the EP3‐subtype.

British Journal of Pharmacology (2004) 141, 600–609. doi:10.1038/sj.bjp.0705648
Particular sensitivity to calcium channel blockers of the fast inward voltage‐dependent sodium current involved in the invasive properties of a metastastic breast cancer cell line
Authors: Roger Sébastien , Guennec Jean‐Yves Le , Besson Pierre 
Published: February 2004

A voltage‐dependent sodium current has been described in the highly invasive breast cancer cell line MDA‐MB‐231. Its activity is associated with the invasive properties of the cells. The aim of our study was to test whether this current (INa) is sensitive to three representative calcium channel blockers: verapamil, diltiazem and nifedipine. INa was studied in patch‐clamp conditions.
INa was sensitive to verapamil (IC50=37.6±2.5 μM) and diltiazem (53.2±3.6 μM), while it was weakly sensitive to nifedipine.
The tetrodotoxin (TTX) concentration, which fully blocks INa (30 μM), did not affect cell proliferation. Diltiazem and verapamil, at concentrations that do not fully block INa, strongly reduced cell proliferation, suggesting, regarding proliferation, that these molecules act on targets distinct from sodium channels. These targets are probably not other ionic channels, since the current measured at the end of a 500 ms long pulse in the voltage range between −60 and +40 mV was unaffected by verapamil and diltiazem.
We conclude that the sodium channel expressed in MDA‐MB‐231 cells is sensitive to several calcium channel blockers. The present study also underlines the danger of concluding to the possible involvement of membrane channel proteins in any phenomenon on the sole basis of pharmacology, and without an electrophysiological confirmation.

British Journal of Pharmacology (2004) 141, 610–615. doi:10.1038/sj.bjp.0705649
Circadian rhythm of dihydrouracil/uracil ratios in biological fluids: a potential biomarker for dihydropyrimidine dehydrogenase levels
Authors: Jiang Hao , Lu Jing , Ji Jiang 
Published: February 2004

In many cancer patients, 5‐fluorouracil (5‐FUra) treatment is toxic and even causes death. Nevertheless, all patients are subjected to a standard therapy regimen because there is no reliable way to identify beforehand those patients who are predisposed to 5‐FUra‐induced toxicity. In this study, we identified the dihydrouracil/uracil (UH2/Ura) ratio in plasma or urine as a potential biomarker reflecting the activity of dihydropyrimidine dehydrogenase (DPD), the rate‐limiting enzyme in 5‐FUra metabolism.
UH2/Ura ratios were measured by high‐performance liquid chromatography tandem triple quadrupole mass spectrometry (HPLC‐MS/MS) in both healthy subjects (n=55) and in patients (n=20) diagnosed with grade I/II gestational trophoblastic tumours. In addition, rats (n=18) were used as an animal model to verify a correlation between UH2/Ura ratios and DPD levels in the liver.
A significant circadian rhythm was observed in UH2/Ura ratios in healthy subjects, whereas a disrupted rhythm occurred in cancer patients who were continuously infused with a high dose of 5‐FUra. In rats, UH2/Ura ratios, liver DPD levels and PBMC DPD levels showed a definite circadian rhythm. Significant linear correlations with liver DPD levels were demonstrated for plasma UH2/Ura ratios (r=0.883, P<0.01), urine UH2/Ura ratios (r=0.832, P<0.01) and PBMC DPD levels (r=0.859, P<0.01).
The UH2/Ura ratio in biological fluid was significantly correlated with liver DPD levels; hence, this ratio could be a potential biomarker to identify patients with a deficiency in DPD.

British Journal of Pharmacology (2004) 141, 616–623. doi:10.1038/sj.bjp.0705651
Characterization of the mouse cold‐menthol receptor TRPM8 and vanilloid receptor type‐1 VR1 using a fluorometric imaging plate reader (FLIPR) assay
Authors: Behrendt H‐J , Germann T , Gillen C , Hatt H , Jostock R 
Published: February 2004

TRPM8 (CMR1) is a Ca2+‐permeable channel, which can be activated by low temperatures, menthol, eucalyptol and icilin. It belongs to the transient receptor potential (TRP) family, and therefore is related to vanilloid receptor type‐1 (VR1, TRPV1). We tested whether substances which are structurally related to menthol, or which produce a cooling sensation, could activate TRPM8, and compared the responses of TRPM8 and VR1 to these ligands.
The effects of 70 odorants and menthol‐related substances on recombinant mouse TRPM8 (mTRPM8), expressed in HEK293 cells, were examined using a FLIPR® assay. In all, 10 substances (linalool, geraniol, hydroxycitronellal, WS‐3, WS‐23, FrescolatMGA, FrescolatML, PMD38, CoolactP and Cooling Agent 10) were found to be agonists.
The EC50 values of the agonists defined their relative potencies: icilin (0.2±0.1 μM)>FrescolatML (3.3±1.5 μM) > WS‐3 (3.7±1.7 μM) >(−)menthol (4.1±1.3 μM) >frescolatMAG (4.8±1.1 μM) > cooling agent 10 (6±2.2 μM) >(+)menthol (14.4±1.3 μM) > PMD38 (31±1.1 μM) > WS‐23 (44±7.3 μM) > Coolact P (66±20 μM) > geraniol (5.9±1.6 mM) > linalool (6.7±2.0 mM) > eucalyptol (7.7±2.0 mM) > hydroxycitronellal (19.6±2.2 mM).
Known VR1 antagonists (BCTC, thio‐BCTC and capsazepine) were also able to block the response of TRPM8 to menthol (IC50: 0.8±1.0, 3.5±1.1 and 18±1.1 μM, respectively).
The Ca2+ response of hVR1‐transfected HEK293 cells to the endogenous VR1 agonist N‐arachidonoyl‐dopamine was potentiated by low pH. In contrast, menthol‐ and icilin‐activated TRPM8 currents were suppressed by low pH.
In conclusion, in the present study, we identified 10 new agonists and three antagonists of TRPM8. We found that, in contrast to VR1, TRPM8 is inhibited rather than potentiated by protons.

British Journal of Pharmacology (2004) 141, 737–745. doi:10.1038/sj.bjp.0705652
Nicotine attenuates β‐amyloid peptide‐induced neurotoxicity, free radical and calcium accumulation in hippocampal neuronal cultures
Authors: Liu Qiang , Zhao Baolu 
Published: February 2004

Recent studies indicate that neuronal loss in Alzheimer's disease (AD) is accompanied by the deposition of β‐amyloid protein (Aβ) in senile plaques. Nicotine as a major component of cigarette smoke has been suggested to have a protective effect for neurons against Aβ neurotoxicity.
Our present study demonstrates that nicotine protected cultured hippocampal neurons against the Aβ‐induced apoptosis. Nicotine effectively inhibits apoptosis in hippocampal cultures caused by Aβ25–35 or Aβ1–40 treatment and increase of caspase activity induced by Aβ25–35 or Aβ1–40.
Measurements of cellular oxidation and intracellular free Ca2+ showed that nicotine suppressed Aβ‐induced accumulation of free radical and increase of intracellular free Ca2+.
Cholinergic antagonist mecamylamine inhibited nicotine‐induced protection against Aβ‐induced caspase‐3 activation and ROS accumulation.
The data show that the protection of nicotine is partly via nicotinic receptors. Our results suggest that nicotine may be beneficial in retarding the neurodegenerative diseases such as AD.

British Journal of Pharmacology (2004) 141, 746–754. doi:10.1038/sj.bjp.0705653