bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of inflammatory mediators in lipid A analogue (ONO‐4007)‐induced vascular permeability change in mouse skin
Authors: Ishida Hiroyasu , Fujii Emiko , Irie Kaoru , Yoshioka Toshimasa , Muraki Takamura , Ogawa Ryou 
Published: January 2005

Endotoxin shock is accompanied by an increase in peripheral vascular permeability. It has been postulated that most biological activities of LPS are derived from lipid A moiety. Here we examined the effect of lipid A analogue ONO‐4007 in increasing vascular permeability and the possible mediators in mouse skin by a dye leakage method.
Subcutaneous injection of ONO‐4007 (1–2 mg site−1) induced a dose‐dependent increase in vascular permeability which was evident after 120 min.
ONO‐4007‐induced dye leakage was significantly attenuated by pretreatments with anti‐tumour necrosis factor‐α (TNF‐α) and anti‐interleukin‐1α (IL‐1α) antibodies, but not with indomethacin (5 mg kg−1) or diphenhydramine (10 mg kg−1). ONO‐4007‐induced dye leakage was significantly inhibited by a pretreatment with NG‐nitro‐L‐arginine methyl ester (L‐NAME) (10 mg kg−1) but not with aminoguanidine (50 mg kg−1). In inducible nitric oxide synthase (iNOS)‐deficient mice, ONO‐4007 significantly increased the dye leakage, while ONO‐4007 dilated rat thoracic aortic rings pre‐contracted with phenylephrine, and the L‐NAME pretreatment inhibited the dilation.
Thus, TNF‐α, IL‐1α and constitutive NOSs‐derived nitric oxide but not prostaglandins or histamine play a role in ONO‐4007‐induced increase in vascular permeability. Although ONO‐4007 mimics LPS in increasing vascular permeability, mechanisms of permeability change elicited by ONO‐4007 were not identical to those of LPS.

British Journal of Pharmacology (2000) 130, 1235–1240; doi:10.1038/sj.bjp.0703425
[3H]‐8‐OH‐DPAT binding in the rat brain raphe area: involvement of 5‐HT1A and non‐5‐HT1A receptors
Authors: Assié Marie‐Bernadette , Koek Wouter 
Published: January 2005

The 5‐HT1A agonist 8‐OH‐DPAT has been shown to have additional 5‐HT uptake inhibiting properties. The present work was undertaken to examine further the binding of [3H]‐8‐OH‐DPAT in the raphe area of the rat brain, a region rich in 5‐HT1A receptors and 5‐HT uptake sites.
5‐HT inhibited [3H]‐8‐OH‐DPAT binding in a biphasic manner (pKi1: 8.82±0.01, pKi2: 6.07±0.05, n=4) with the low affinity site representing 36±4% of the total population. A biphasic inhibition curve was found also with the 5‐HT1A antagonist, WAY 100635 (pKi1: 8.65±0.17, pKi2: 4.26±0.38, n=3). In the presence of 1 μM WAY 100635 to mask 5‐HT1A receptors, 5‐HT inhibited [3H]‐8‐OH‐DPAT binding in a monophasic manner (pKi: 6.04±0.07, n=3).
The affinities of various compounds for sites labelled by [3H]‐8‐OH‐DPAT in the presence of 1 μM WAY 100635 and for sites labelled by [3H]‐citalopram (a selective 5‐HT uptake inhibitor) were determined. There was a significant correlation between pKi values at 5‐HT uptake sites and at non‐5HT1A sites labelled by [3H]‐8‐OH‐DPAT (r=0.80, P<0.001, n=17), suggesting these latter sites to be 5‐HT uptake sites.
Whereas the affinities of R(+) and S(−) enantiomers of 8‐OH‐DPAT for the 5‐HT uptake site are similar, R(+)8‐OH‐DPAT has 10 times higher affinity for the non‐5‐HT1A site than S(−)8‐OH‐DPAT and was considered as an outlier in the correlation. It is suggested that [3H]‐8‐OH‐DPAT labels other, as yet unknown binding sites in the raphe.

British Journal of Pharmacology (2000) 130, 1348–1352; doi:10.1038/sj.bjp.0703426
Selective agonist of group II glutamate metabotropic receptors, LY354740, inhibits tolerance to analgesic effects of morphine in mice
Authors: Popik Piotr , Kozela Ewa , Pilc Andrzej 
Published: January 2005

Antagonists of glutamate N‐methyl‐D‐aspartate (NMDA) subtype receptor inhibit the development of tolerance to the antinociceptive effects of opioids. Another way to inhibit the function of glutamate receptors is the stimulation of presynaptic metabotropic group II (mGluRII) receptors. Because LY354740 ((+)‐2‐aminobicyclo [3,1,0] hexane‐2,6‐dicarboxylic acid) is the first systemically active agonist of group II mGlu receptors, we investigated if this compound might inhibit the development of tolerance to antinociceptive effects of morphine and fentanyl.
As assessed by cumulative dose‐response approach in the tail‐flick test, administration of 10 mg kg−1 morphine bid s.c. to male Albino Swiss mice for 6 days, right‐shifted morphine dose‐response curve by ∼4 fold. In a separate group of mice, 12 injections of 0.04 mg kg−1 of fentanyl over 3 days, right‐shifted fentanyl dose‐response curve by ∼3.3 fold.
In experiment 1, LY354740 (1 and 10, but not 0.1 mg kg−1) as well as the reference compound, an uncompetitive NMDA receptor antagonist memantine (7.5 mg kg−1) inhibited the development of morphine tolerance. Neither LY354740 (10 mg kg−1) nor memantine (7.5 mg kg−1) affected the development of tolerance to fentanyl. In experiment 2, neither LY354740 (1 and 10 mg kg−1) nor memantine (7.5 mg kg−1) affected the tail‐flick antinociceptive response, or the acute antinociceptive effect of morphine.
The present results are the first to suggest that the development of antinociceptive morphine tolerance may be inhibited by metabotropic group II glutamate agonist.

British Journal of Pharmacology (2000) 130, 1425–1431; doi:10.1038/sj.bjp.0703438
Effects of combined neutral endopeptidase 24‐11 and angiotensin‐converting enzyme inhibition on femoral vascular conductance in streptozotocin‐induced diabetic rats
Authors: Arbin V , Claperon N , Fournié‐Zaluski M ‐C , Roques B P , Peyroux J 
Published: January 2005

The successive effects of the angiotensin‐converting enzyme inhibitor captopril (CAP, 2 mg kg−1+1 mg kg−1 30 min−1 infusion) and the neutral endopeptidase 24‐11 inhibitor retrothiorphan (RT, 25 mg kg−1+12.5 mg kg−1 30 min−1 infusion) were studied on femoral vascular conductance (FVC) in streptozotocin‐induced diabetic (STZ‐SD) and control Sprague‐Dawley (C‐SD) rats. The role of the kinin‐nitric oxide (NO) pathway was assessed by (1) using pre‐treatments: a bradykinin (BK) B2 receptor antagonist (Hoe‐140, 300 μg kg−1), a NO‐synthase inhibitor (Nω‐nitro‐L‐arginine methyl ester, L‐NAME, 10 mg kg−1), a kininase I inhibitor (DL‐2‐mercaptomethyl‐3‐guanidinoethylthiopropanoic acid, MGTA, 10 mg kg−1+20 mg kg−1 20 min−1 infusion) and (2) comparing the effects in STZ‐induced diabetic (STZ‐BN) and control Brown‐Norway kininogen‐deficient (C‐BN) rats.
In C‐SDs, CAP and CAP+RT increased FVC similarly. In STZ‐SDs, FVC and FBF were decreased compared to C‐SDs. CAP+RT increased them more effectively than CAP alone.
In both C‐SDs and STZ‐SDs, the femoral bed vasodilatation elicited by CAP was inhibited by Hoe‐140 and L‐NAME. The FVC increase elicited by CAP+RT was not significantly reduced by Hoe‐140 but was inhibited by L‐NAME and Hoe‐140+MGTA.
In C‐BNs, the vasodilatator responses to CAP and CAP+RT were abolished and highly reduced, respectively. In STZ‐BNs, these responses were abolished.
These results show that in STZ‐SDs, CAP+RT improve FBF and FVC more effectively than CAP alone. These effects are linked to an increased activation of the kinin‐NO pathway. BK could lead to NO production by BK B2 receptor activation and another pathway in which kininase I may be involved.

British Journal of Pharmacology (2000) 130, 1297–1304; doi:10.1038/sj.bjp.0703442
Comparative effects of continuous infusion of mCPP, Ro 60‐0175 and d‐fenfluramine on food intake, water intake, body weight and locomotor activity in rats
Authors: Vickers S P , Benwell K R , Porter R H , Bickerdike M J , Kennett G A , Dourish C T 
Published: January 2005

The aim of the study was to compare the effects of 14 day subcutaneous infusion of the 5‐HT2C receptor agonists, m‐chlorophenylpiperazine (mCPP, 12 mg kg−1 day−1) and Ro 60‐0175 (36 mg kg−1 day−1) and the 5‐HT releasing agent and re‐uptake inhibitor, d‐fenfluramine (6 mg kg−1 day−1), on food and water intake, body weight gain and locomotion in lean male Lister hooded rats.
Chronic infusion of all three drugs significantly reduced food intake and attenuated body weight gain. In contrast, drug infusion did not lead to significant reductions in locomotor activity in animals assessed 2 and 13 days after pump implantation.
In a subsequent 14 day study that was designed to identify possible tolerance during days 7–14, animals were given a subcutaneous infusion of mCPP (12 mg kg−1 day−1) or d‐fenfluramine (6 mg kg−1 day−1) for either 7 or 14 days. During the first 7 days both drugs significantly reduced body weight gain compared to saline‐infused controls; however, from day 7 onwards animals withdrawn from drug treatment exhibited an increase in body weight such that by day 14 they were significantly heavier than their 14‐day drug‐treated counterparts.
Both mCPP and d‐fenfluramine reduced daily food intake throughout the infusion periods. For 14‐day treated animals this hypophagia was marked during the initial week of the study but only minor during the second week. In light of the sustained drug effect on body weight, the data suggest that weight loss by 5‐HT2C receptor stimulation may be only partly dependent on changes in food consumption and that 5‐HT2C receptor agonists may have effects on thermogenesis.
These data suggest tolerance does not develop to the effects of d‐fenfluramine, mCPP and Ro 60‐0175 on rat body weight gain.

British Journal of Pharmacology (2000) 130, 1305–1314; doi:10.1038/sj.bjp.0703443
Direct effects of propylthiouracil on testosterone secretion in rat testicular interstitial cells
Authors: Chiao Yu‐Chung , Lin Ho , Wang Shyi‐Wu , Wang Paulus S 
Published: January 2005

The aim of this study was to investigate the mechanism by which propylthiouracil (PTU) exerts its inhibitory effects on the production of testosterone by rat testicular interstitial cells.
The plasma testosterone concentration was decreased 60 and 120 min after an intravenous infusion of PTU (10 or 20 mg kg−1), but the concentration of plasma T4 was unaffected by the drug treatment.
Exposure of anterior pituitary tissue to PTU (3–12 mM) in vitro did not affect either basal or gonadotropin‐releasing hormone (GnRH)‐stimulated luteinizing hormone (LH) release.
PTU (3–12 mM) inhibited both the basal and the human chorionic gonadotropin (hCG, 0.05 iu ml−1)‐stimulated release of testosterone from rat testicular tissue in vitro; at the highest concentration tested (12 mM), it also inhibited the forskolin or 8‐bromo‐adenosine 3′:5′‐cyclic monophosphate (8‐Br‐cyclic AMP)‐stimulated release of testosterone.
The 25‐OH‐cholesterol (10−7–10−5 M)‐stimulated release of pregnenolone and testosterone by the testicular interstitial cells was inhibited by PTU (12 mM, P<0.05).
The results suggest that the inhibitory actions of PTU on testosterone secretion are exerted, at least in part, at the testicular level through a mechanism which is independent of thyroid status and which involves a reduction in P450scc activity and, hence, in the conversion of cholesterol to pregnenolone.

British Journal of Pharmacology (2000) 130, 1477–1482; doi:10.1038/sj.bjp.0703444
Antidepressant drugs inhibit glucocorticoid receptor‐mediated gene transcription – a possible mechanism
Authors: Budziszewska Bogusława , Jaworska‐Feil Lucylla , Kajta Małgorzata , Lasoń Władysław 
Published: January 2005

Antidepressant drugs are known to inhibit some changes evoked by glucocorticoids, as well as a hyperactivity of hypothalamic‐pituitary‐adrenal (HPA) axis, often observed in depression.
The aim of present study was to investigate effects of various antidepressant drugs on the glucocorticoid‐mediated gene transcription in fibroblast cells, stably transfected with an MMTV promoter (LMCAT cells).
The present study have shown that antidepressants (imipramine, amitriptyline, desipramine, fluoxetine, tianeptine, mianserin and moclobemide), but not cocaine, inhibit the corticosterone‐induced gene transcription in a concentration‐ and a time‐dependent manner.
Drugs which are known to augment clinical effects of medication in depressed patients (lithium chloride, amantadine, memantine), do not affect the inhibitory effects of imipramine on the glucocorticoid receptor (GR)‐mediated gene transcription.
Inhibitors of phospholipase C (PLC), protein kinase C (PKC), Ca2+/calmodulin‐dependent protein kinase (CaMK) and antagonists of the L‐type Ca2+ channel also inhibit the corticosterone‐induced gene transcription.
Inhibitors of protein kinase A (PKA) and protein kinase G (PKG) are without effect on the GR‐induced gene transcription.
Phorbol ester (an activator of PKC) attenuates the inhibitory effect of imipramine on the GR‐induced gene transcription.
Imipramine decreases binding of corticosterone‐receptor complex to DNA.
It is concluded that antidepressant drugs inhibit the corticosterone‐induced gene transcription, and that the inhibitory effect of imipramine depends partly on the PLC/PKC pathway.

British Journal of Pharmacology (2000) 130, 1385–1393; doi:10.1038/sj.bjp.0703445
Effects of dronedarone on Acetylcholine‐activated current in rabbit SAN cells
Authors: Altomare Claudia , Barbuti Andrea , Viscomi Carlo , Baruscotti Mirko , DiFrancesco Dario 
Published: January 2005

The effect of the antiarrhythmic drug dronedarone on the Acetylcholine‐activated K+ current (IK(ACh)) was investigated in single cells isolated from sinoatrial node (SAN) tissue of rabbit hearts.
Externally perfused dronedarone (0.001–1 μM) caused a potent, voltage independent block of IK(ACh). Fitting of the dose response curve of IK(ACh) block yielded an IC50 value of 63 nM, a value over one order of magnitude lower than those reported for dronedarone block of other cardiac currents.
IK(ACh) block was not due to an inhibitory action of dronedarone on the muscarinic M2 receptor activation, since the drug was effective on IK(ACh) constitutively activated by intracellular perfusion with GTP‐γS.
External cell perfusion with dronedarone inhibited the activity of IK(ACh) channels recorded from cell‐attached patches by reducing the channel open probability (from 0.56 to 0.11) without modification of the single‐channel conductance.
These data suggest that dronedarone blocks IK(ACh) channels either by disrupting the G‐protein‐mediated activation or by a direct inhibitory interaction with the channel protein.

British Journal of Pharmacology (2000) 130, 1315–1320; doi:10.1038/sj.bjp.0703446
Cytoplasmic binding and disposition kinetics of diclofenac in the isolated perfused rat liver
Authors: Weiss Michael , Kuhlmann Olaf , Hung Daniel Y , Roberts Michael S 
Published: January 2005

The binding kinetics of diclofenac to hepatocellular structures were evaluated in the perfused rat liver using the multiple indicator dilution technique and a stochastic model of organ transit time density.
The single‐pass, in situ rat liver preparation was perfused with buffer solution (containing 2% albumin) at 30 ml min−1. Diclofenac and [14C]‐sucrose (extracellular reference) were injected simultaneously as a bolus dose into the portal vein (six experiments in three rats). An analogous series of experiments was performed with [14C]‐diclofenac and [3H]‐sucrose.
The diclofenac outflow data were analysed using three models of intracellular distribution kinetics, assuming (1) instantaneous distribution and binding (well‐mixed model), (2) ‘slow’ binding at specific intracellular sites after instantaneous distribution throughout the cytosol (slow binding model), and (3) ‘slowing’ of cytoplasmic diffusion due to instantaneous binding (slow diffusion model).
The slow binding model provided the best description of the data. The rate constants for cellular influx and sequestration were 0.126±0.026 and 0.013±0.009 s−1, respectively. The estimated ratio of cellular initial distribution volume to extracellular volume of 2.82 indicates an almost instantaneous distribution in the cellular water space, while the corresponding ratio of 5.54 estimated for the apparent tissue distribution volume suggests a relatively high hepatocellular binding. The non‐instantaneous intracellular equilibration process was characterized by time constants of the binding and unbinding process of 53.8 and 49.5 s, respectively. The single‐pass availability of diclofenac was 86%. The results obtained with [14C]‐diclofenac and [3H]‐sucrose were not statistically different.

British Journal of Pharmacology (2000) 130, 1331–1338; doi:10.1038/sj.bjp.0703448
Lack of nitric oxide‐ and guanosine 3′:5′‐cyclic monophosphate‐dependent regulation of α‐thrombin‐induced calcium transient in endothelial cells of spontaneously hypertensive rat hearts
Authors: Failli Paola , Fazzini Alessandro , Ruocco Carlo , Mazzetti Luca , Cecchi Enrica , Giovannelli Lisa , Marra Fabio , Milani Stefano , Giotti Alberto 
Published: January 2005

While the expression and/or activity of endothelial nitric oxide synthase (eNOS) has been characterized in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rat (WKY) hearts, in coronary endothelial cells (ECs) from both strains, the effect of NO on intracellular calcium concentration ([Ca2+]i) is still unknown.
Coronary microvascular ECs were isolated from SHR and WKY and characterized. Immunocytochemistry and Western blot analysis showed that eNOS was similarly expressed in ECs from both strains.
Measuring [Ca2+]i by imaging analysis of fura‐2‐loaded cells, we demonstrated that α‐thrombin (3−180 U l−1) induced a superimposable dose‐dependent calcium transient in ECs from both strains.
In WKY ECs, S‐nitroso‐N‐acetyl‐DL‐penicillamine (SNAP) dose‐dependently (10–100 μM) and 0.1 μM atrial natriuretic factor (ANF) reduced the maximum and the decay time of α‐thrombin‐induced calcium transient. The inhibitory effects of SNAP and ANF were prevented by blocking cyclic GMP‐dependent protein kinase. Non selective eNOS inhibitors prolonged the decay time of α‐thrombin‐induced calcium transient, while the selective inducible NOS inhibitor 1400 W was ineffective. SNAP (100 μM) and 0.1 μM ANF increased cyclic GMP content up to 22.9 and 42.3 fold respectively.
In SHR ECs, α‐thrombin‐induced calcium transient was not modified by SNAP, ANF or eNOS inhibition. SNAP (100 μM) and 0.1 μM ANF increased cyclic GMP content up to 9.3 and 51 fold respectively.
In WKY ECs, SNAP dose‐dependently (10–100 μM) reduced also bradykinin‐induced calcium transient, while in SHR ECs was ineffective.
We concluded that in SHR ECs, the cyclic GMP‐dependent regulation of calcium transient is lost.

British Journal of Pharmacology (2000) 130, 1468–1476; doi:10.1038/sj.bjp.0703453
Vanilloid receptors on capsaicin‐sensitive sensory nerves mediate relaxation to methanandamide in the rat isolated mesenteric arterial bed and small mesenteric arteries
Authors: Ralevic V , Kendall D A , Randall M D , Zygmunt P M , Movahed P , Högestätt E D 
Published: January 2005

In the present study, the vasodilator actions of methanandamide and capsaicin in the rat isolated mesenteric arterial bed and small mesenteric arterial segments were investigated.
Methanandamide elicited concentration‐dependent relaxations of preconstricted mesenteric arterial beds (pEC50=6.0±0.1, Emax=87±3%) and arterial segments (pEC50=6.4±0.1, Emax=93±3%).
In arterial beds, in vitro capsaicin pre‐treatment blocked vasorelaxation to 1 and 3 μM methanandamide, and reduced to 12±7% vasorelaxation to 10 μM methanandamide. Methanandamide failed to relax arterial segments pre‐treated in vitro with capsaicin.
In arterial beds from rats treated as neonates with capsaicin to cause destruction of primary afferent nerves, methanandamide at 1 and 3 μM did not evoke vasorelaxation, and relaxation at 10 μM methanandamide was reduced to 26±4%.
Ruthenium red (0.1 μM), an inhibitor of vanilloid responses, attenuated vasorelaxation to methanandamide in arterial beds (pEC50=5.6±0.1, Emax=89±1%). Ruthenium red at 1 μM abolished the response to 1 μM methanandamide, and greatly attenuated relaxation at 3 and 10 μM methanandamide in arterial beds. In arterial segments, ruthenium red (0.15 μM) blocked vasorelaxation to methanandamide, but not to CGRP.
In arterial segments, the vanilloid receptor antagonist capsazepine (1 μM) inhibited, and the calcitonin gene‐related peptide (CGRP) receptor antagonist CGRP8–37 (3 μM) abolished, methanandamide‐induced relaxations. CGRP8–37, but not capsazepine, attenuated significantly relaxation to exogenous CGRP.
These data show that capsaicin and ruthenium red attenuate vasorelaxation to methanandamide in the rat isolated mesenteric arterial bed and small mesenteric arterial segments. In addition, CGRP8–37 and capsazepine antagonize responses to methanandamide in mesenteric arterial segments. In conclusion, vanilloid receptors on capsaicin‐sensitive sensory nerves play an important role in the vasorelaxant action of methanandamide in the rat isolated mesenteric arterial bed and small mesenteric arterial segments.

British Journal of Pharmacology (2000) 130, 1483–1488; doi:10.1038/sj.bjp.0703456
Characterization of [125I]‐SB‐258585 binding to human recombinant and native 5‐HT6 receptors in rat, pig and human brain tissue
Authors: Hirst Warren D , Minton Jayne A L , Bromidge Steven M , Moss Stephen F , Latter Alison J , Riley Graham , Routledge Carol , Middlemiss Derek N , Price Gary W 
Published: January 2005

SB‐258585 (4‐Iodo‐N‐[4‐methoxy‐3‐(4‐methyl‐piperazin‐1‐yl)‐phenyl]‐benzenesulphonamide) is a high affinity ligand at 5‐HT6 receptors. It displays over 100 fold selectivity for the 5‐HT6 receptor over all other 5‐HT receptors tested so far. SB‐258585 has been radiolabelled, to high specific activity, for its characterization as a 5‐HT6 receptor selective radioligand.
[125I]‐SB‐258585 bound, with high affinity, to a single population of receptors in a cell line expressing human recombinant 5‐HT6 receptors. Kinetic and saturation binding experiments gave pKD values of 9.01±0.09 and 9.09±0.02, respectively.
In membranes derived from rat or pig striatum and human caudate putamen, [125I]‐SB‐258585 labelled a single site with high levels (>60%) of specific binding. Saturation analysis revealed pKD values of 8.56±0.07 for rat, 8.60±0.10 for pig and 8.90±0.02 for human. Bmax values for the tissues ranged from 173±23 and 181±25 fmol mg−1 protein in rat and pig striatum, respectively, to 215±41 fmol mg−1 protein in human caudate putamen.
The pKi rank order of potency for a number of compounds, determined in competition binding assays with [125I]‐SB‐258585, at human caudate putamen membranes was: SB‐271046>SB‐258585>SB‐214111>methiothepin>clozapine>5‐Me‐OT>5‐HT>Ro 04‐6790>mianserin>ritanserin=amitriptyline>5‐CT>mesulergine. Similar profiles were obtained from pig and rat striatal membranes and recombinant 5‐HT6 receptors; data from the latter correlated well with [3H]‐LSD binding.
Thus, [125I]‐SB‐258585 is a high affinity, selective radioligand which can be used to label both recombinant and native 5‐HT6 receptors and will facilitate further characterization of this receptor subtype in animal and human tissues.

British Journal of Pharmacology (2000) 130, 1597–1605; doi:10.1038/sj.bjp.0703458