bluuebunny/crossref_metadata_2025_split huggingface dataset:
Respective role of lipoxygenase and nitric oxide‐synthase pathways in plasma histamine‐induced macromolecular leakage inconscious hamsters
Authors: Gimeno G , Carpentier P H , Desquand‐Billiald S , Finet M , Hanf R 
Published: January 2005

Intravital microscopy technique was used to determine the distribution of a fluorescent plasma marker (fluorescein‐isothiocyanate‐dextran, 150 kD; FD‐150) into venular and interstitial compartments of dorsal skin fold preparations in conscious hamsters.
One mg kg−1 histamine (i.v.) caused a biphasic decrease in venular fluorescence due to FD‐150 extravasation in all organs (general extravasation). Immediately after injection, the venular fluorescence decreased and plateaued in 60 min. Ninety minutes after histamine injection, venular fluorescence further decreased until 180 min. Prior treatment with indomethacin (0.1 mg kg−1, i.v.) did not modify the time‐course of general extravasation but prevented histamine‐induced venule dilatation.
Prior treatment with the 5‐lipoxygenase activating protein (FLAP) inhibitor, 3‐[1‐(p‐chlorobenzyl)‐5‐(isopropyl)‐3‐t‐butylthioindol‐2‐yl]‐2,2‐dimethyl‐propanoic acid sodium (MK‐886)(10 μg kg−1, i.v.), the leukotriene receptor antagonist, benzenemethanol a‐pentyl‐3‐(2‐quinolinylmethoxy) (REV‐5901)(1 mg kg−1, i.v.), or the glutathione‐S‐transferase inhibitor, ethacrynic acid (1 mg kg−1, i.v.), delayed by 60 min the onset of general extravasation caused by 1 mg kg−1 histamine.
Prior treatment with lipoxygenase pathway inhibitors and NG‐nitro‐L‐arginine‐methylester (L‐NAME)(100 mg kg−1, i.v.) abolished the general extravasation and venule dilatation induced by 1 mg kg−1 histamine.
Injection of 1 μg kg−1 (i.v.), of leukotriene‐C4 (LTC4) or ‐D4 (LTD4) induced immediate and sustained general extravasation and reduction in venule diameter, these effects being blocked by REV‐5901.
Histamine (1 mg kg−1, i.v.) induced biphasic decline in mean arterial blood pressure (MAP). An initial phase (from 0 to 60 min) was followed by a late phase beginning 90 min after histamine injection. L‐NAME (100 mg kg−1, i.v.) and aminoguanidine (1 mg kg−1, i.v.) prevented the late phase of histamine‐induced hypotension.
Thus, plasma histamine can trigger both an immediate cysteinyl‐leukotriene (Cys‐LT)‐dependent and a late nitric oxide (NO)‐mediated inflammatory cascade. Although the cyclo‐oxygenase (COX) pathway might account for histamine‐induced venule dilatation, it would not influence histamine‐induced extravasation.

British Journal of Pharmacology (1999) 126, 1801–1809; doi:10.1038/sj.bjp.0702380
Inhibition of the production of endothelium‐derived hyperpolarizing factor by cannabinoid receptor agonists
Authors: Fleming I , Schermer B , Popp R , Busse R 
Published: January 2005

The endogenous cannabinoid, anandamide, has been reported to induce an 'endothelium‐derived hyperpolarizing factor (EDHF)‐like' relaxation in vitro. We therefore investigated the effects of cannabinoid CB1 receptor agonists; HU 210, Δ9‐tetrahydrocannabinol (Δ9‐THC) and anandamide, and a CB1 antagonist/inverse agonist, SR 141716A, on nitric oxide (NO) and EDHF‐mediated relaxation in precontracted rings of porcine coronary, rabbit carotid and mesenteric arteries.
In rings of mesenteric artery HU 210 and Δ9‐THC induced endothelium‐ and cyclo‐oxygenase‐independent relaxations which were sensitive to SR 141716A. Anandamide (0.03–30 μM) induced a slowly developing, endothelium‐independent relaxation which was abolished by diclofenac and was therefore mediated by cyclo‐oxygenase product(s). None of the CB1 agonists tested affected the tone of precontracted rings of rabbit carotid or porcine coronary artery.
In endothelium‐intact segments, HU 210, Δ9‐THC and anandamide did not affect NO‐mediated responses but under conditions of continuous NO synthase/cyclo‐oxygenase blockade, significantly inhibited acetylcholine and bradykinin‐induced relaxations which are attributed to the production of EDHF. The effects of HU 210 and Δ9‐THC were not observed when experiments were performed in the presence of SR 141716A suggesting the involvement of the CB1 receptor.
In a patch clamp bioassay of EDHF production, HU 210 decreased the EDHF‐mediated hyperpolarization of detector smooth muscle cells when applied to the donor segment but was without effect on the membrane potential of detector cells. The inhibition of EDHF production was unrelated to alterations in Ca2+‐signalling or cytochrome P450 activity.
These results suggest that the activation of endothelial CB1 receptors appears to be negatively coupled to the production of EDHF.

British Journal of Pharmacology (1999) 126, 949–960; doi:10.1038/sj.bjp.0702381
Effect of cerivastatin sodium, a new inhibitor of HMG‐CoA reductase, on plasma lipid levels, progression of atherosclerosis, and the lesional composition in the plaques of WHHL rabbits
Authors: Shiomi Masashi , Ito Takashi 
Published: January 2005

The aim of this study was to examine whether cerivastatin sodium, a new inhibitor of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase, affects the lesional composition of spontaneously developed atherosclerosis due to hypercholesterolaemia and delays progression of the lesions.
We administered cerivastatin to 2‐month‐old WHHL rabbits, a low‐density lipoprotein receptor‐deficient animal model, at a dose of 0.6 mg kg−1 day−1 for 32 weeks. We examined the plasma lipid levels, the severity of atherosclerosis, and composition of atherosclerotic lesions. Lesional composition was determined using immunohistostaining for macrophages and smooth muscle cells, and Azan‐Mallory staining for collagen fibres and extracellular lipid deposits.
Compared to the control group, the plasma cholesterol levels were decreased in the treated group by 39% (12.7±0.6 mmol L−1 versus 20.9±1.0 mmol L−1, P<0.001). Atherosclerosis was suppressed by about 37% as measured by the thickness of the aortic lesions (158±13 μm versus 250±15 μm, P<0.001), and by 28% as measured by coronary stenosis (62.7±11.4 versus 86.9±12.2, P<0.05). In the cerivastatin group, regarding the per cent areas of lesional components in the lesion area, the macrophages (21.0±1.5% versus 27.9±1.9%, P<0.01) and extracellular lipid deposits (3.2±0.4% versus 5.1±0.4%, P<0.001) were decreased in the aortic lesions, and the per cent area of macrophages in the coronary lesions was also decreased (4.9±1.4% versus, 11.6±2.4%, P<0.05). The per cent area of smooth muscle cells and collagen fibres did not significantly decrease.
These results indicate that cerivastatin contributed to the plaque stabilization and delayed progression of early atherosclerosis in young WHHL rabbits, in addition to the potent hypolipidemic effects.

British Journal of Pharmacology (1999) 126, 961–968; doi:10.1038/sj.bjp.0702382
Mode of action of ICS 205,930, a novel type of potentiator of responses to glycine in rat spinal neurones
Authors: Chesnoy‐Marchais D 
Published: January 2005

The effect of a novel potentiator of glycine responses, ICS 205,930, was studied by whole‐cell recordings from spinal neurones, and compared with that of other known potentiators, in an attempt to differentiate their sites of action.
The ability of ICS 205,930 (0.2 μM) to potentiate glycine responses persisted in the presence of concentrations of Zn2+ (5–10 μM) that were saturating for the potentiating effect of this ion.
Preincubation with 10 μM Zn2+ before application of glycine plus Zn2+ had an inhibitory effect, which did not result from Zn2+ entry into the neurone, since it persisted with either 10 mM internal EGTA or 10 μM internal Zn2+. To test whether the potentiating effects of ICS 205,930 and Zn2+ interact, both compounds were applied without preincubation.
The potentiating effect of ICS 205,930 was similar for responses to glycine and for responses to glycine plus Zn2+, provided the concentrations of agonist were adjusted so as to induce control responses of identical amplitudes.
ICS 205,930 remained able to potentiate glycine responses in the presence of ethanol (200 mM).
ICS 205,930 also retained its potentiating effect in the presence of the anaesthetic propofol (30–90 μM), which strongly potentiated glycine responses but, in contrast with ICS 205,930, also markedly increased the resting conductance.
The anticonvulsant chlormethiazole (50–100 μM) neither potentiated glycine responses nor prevented the effect of ICS 205,930, even though it increased the resting conductance and potentiated GABAA responses.
The mechanism of action of ICS 205,930 appears to be different from those by which Zn2+, propofol or ethanol potentiate glycine responses.

British Journal of Pharmacology (1999) 126, 801–809; doi:10.1038/sj.bjp.0702384
Identification of novel polymorphisms within the promoter region of the human β2 adrenergic receptor gene
Authors: Scott Mark G H , Swan Caroline , Wheatley Amanda P , Hall Ian P 
Published: January 2005

By screening the 1470 bp 5′ to the start codon of the human β2 adrenergic receptor gene, we have identified a total of eight polymorphisms (−20 T→C, −47 T→C, −367 T→C, −468 C→G, −654 G→A, −1023 G→A, −1343 A→G and −1429 T→A c.f. β2 adrenergic receptor start codon). Transient transfection of 5′ flanking deletion luciferase reporter constructs demonstrated the majority of activity of the human β2 adrenergic gene 5′ flanking region to be present within a 549 bp fragment immediately upstream from the start codon. Because of linkage disequilibrium, some combinations of polymorphisms were particularly frequent. We transiently transfected COS‐7 cells with luciferase constructs under the control of the 549 bp of 5′ flanking DNA containing the two most frequent extended haplotypes in this region. Luciferase activity was significantly reduced in cells transfected with the ‘mutant’ construct (−20C, −47C, −367C, −468G) c.f. the ‘wild‐type’ construct (−20T, −47T, −367T, −468C). These data suggest that polymorphisms have the potential to alter human β2 adrenergic receptor gene expression.British Journal of Pharmacology (1999) 126, 841–844; doi:10.1038/sj.bjp.0702385
The effects of phosphodiesterase type 4 inhibitors on tumour necrosis factor‐α and leukotriene B4 in a novel human whole blood assay
Authors: Brideau Christine , Van Staden Carlo , Styhler Angela , Rodger Ian W , Chan Chi‐Chung 
Published: January 2005

The aim of this study was to assess the inhibitory activities of phosphodiesterase type 4 (PDE4) inhibitors on tumour necrosis factor‐α (TNF‐α) and leukotriene B4 (LTB4) production in a novel human whole blood assay.
Lipopolysaccharide (LPS) stimulation of human whole blood caused a time dependent increase in TNF‐α and prostaglandin E2 (PGE2) plasma levels. Inhibition of LPS‐induced TNF‐α by the selective PDE4 inhibitor RP73401 was proportionally enhanced with endogenous PGE2 (maximal after 24 h). In contrast, blocking endogenous PGE2 production with indomethacin in blood stimulated with LPS for 24 h decreased the potency of RP73401 to that observed with a 4 h LPS incubation.
Non‐selective and selective PDE4 inhibitors showed greater inhibition of LPS‐induced TNF‐α after 24 h compared to 4 h. Stereoselectivity was only achieved in the 24 h method.
LPS‐stimulation of whole blood for either 30 min or 24 h followed by N‐formyl‐Met‐Leu‐Phe (fMLP) activation resulted in low plasma LTB4 levels. Combination of both treatments resulted in a greater than 7 fold increase in plasma LTB4 levels. Inhibition of the double LPS and fMLP‐activated LTB4 production was observed with non‐selective and PDE4‐selective inhibitors. Their LTB4 inhibitory potencies were similar to that observed in the 24 h LPS‐induced TNF‐α assay. Thus, stimulation of human whole blood with two LPS stimulations followed by fMLP gives rise to both TNF‐α and LTB4 and their inhibition by various compounds can be assessed in the same blood sample.
Calcium ionophore (A23187) stimulation of whole blood resulted in plasma LTB4 levels similar to the double LPS and fMLP method. Inhibition of A23187‐induced LTB4 biosynthesis was also achieved by PDE4‐selective inhibitors as well as the direct 5‐lipoxygenase (5‐LO) inhibitor L‐739,010.
These results confirm the anti‐inflammatory properties of PDE4 inhibitors. Thus, this novel human whole blood can be used to assess the biochemical efficacy of PDE4 inhibitors in human subjects.

British Journal of Pharmacology (1999) 126, 979–988; doi:10.1038/sj.bjp.0702387
Effect of low‐dose treatment with selegiline on dopamine transporter (DAT) expression and amphetamine‐induced dopamine release in vivo
Authors: Lamensdorf Itschak , Porat Shai , Simantov Rabi , Finberg John P M 
Published: January 2005

Chronic treatment with low doses of the selective monoamine oxidase (MAO) type B inhibitors selegiline [(−)‐deprenyl] and rasagiline, causes elevation in extracellular level of 3,4‐dihydroxyphenylethylamine (dopamine) in the rat striatum in vivo (Lamensdorf et al., 1996). The present study was carried out to determine whether this effect of selegiline could be the result of an inhibition of the high‐affinity dopamine neuronal transport process.
Changes in activity of the dopamine transporter (DAT) in vivo following selegiline treatment were evaluated indirectly by microdialysis technique in the rat, from the change in striatal dopamine extracellular concentration following systemic amphetamine administration (4 mg kg−1, i.p.). Striatal levels of the DAT molecule were determined by immunoblotting. Uptake of [3H]‐dopamine was determined in synaptosomes from selegiline‐treated animals.
Amphetamine‐induced increase in striatal extracellular dopamine level was attenuated by one day and by chronic (21 days) treatment with selegiline (0.25 mg kg−1, s.c.).
Striatal levels of DAT were elevated after 1 and 21 days treatment with selegiline, but were not affected by clorgyline, rasagiline, nomifensine or amphetamine.
The increase in DAT expression, and attenuation of amphetamine‐induced dopamine release, were not accompanied by a change in [3H]‐dopamine uptake in synaptosomes of selegiline‐treated animals.
The results suggest that a reversible inhibition of dopamine uptake occurs following chronic low dose selegiline treatment in vivo which may be mediated by an increase in endogenous MAO‐B substrates such as 2‐phenylethylamine, rather than by the inhibitor molecule or its metabolites. Increased DAT expression appears to be a special property of the selegiline molecule, since it occurs after one low dose of selegiline, and is not seen with other inhibitors of MAO‐A or MAO‐B. The new DAT molecules formed following selegiline treatment appear not to be functionally active.

British Journal of Pharmacology (1999) 126, 997–1002; doi:10.1038/sj.bjp.0702389
Prostanoid receptors involved in the relaxation of human bronchial preparations
Authors: Norel Xavier , Walch Laurence , Labat Carlos , Gascard Jean‐Pierre , Dulmet Elisabeth , Brink Charles 
Published: January 2005

Iloprost and cicaprost (IP‐receptor agonists) induced relaxations in the histamine‐ (50 μM) contracted human bronchial preparations (pD2 values, 6.63±0.12 and 6.86±0.08; Emax values, 90±04 and 65±08% of the papaverine response for iloprost (n=6) and cicaprost (n=3), respectively).
Prostaglandin E2 (PGE2) and misoprostol (EP‐receptor agonist) relaxed the histamine‐contracted human bronchial preparations (pD2 values, 7.13±0.07 and 6.33±0.28; Emax values, 67±04 and 57±08% of the papaverine response for PGE2 (n=14) and misoprostol (n=4), respectively). In addition, both relaxations were inhibited by AH6809 (DP/EP1/EP2‐receptor antagonist; 3 μM; n=5–6).
The PGE2‐induced relaxations of human bronchial preparations were not modified by treatment with AH23848B (TP/EP4‐receptor antagonist; 30 μM; n=4).
The contracted human bronchial preparations were significantly relaxed by prostaglandin D2 (PGD2) or by BW245C a DP‐receptor agonist. However, these responses did not exceed 40% of the relaxation induced by papaverine. In addition, the relaxations induced by PGD2 were significantly inhibited by treatment with a DP‐receptor antagonist BWA868C (0.1 μM; n=3).
These data suggest that the relaxation of human isolated bronchial preparations induced by prostanoids involved IP‐, EP2‐ and to a lesser extent DP‐receptors but not EP4‐receptor.

British Journal of Pharmacology (1999) 126, 867–872; doi:10.1038/sj.bjp.0702392
Role of potassium channels in the antinociception induced by agonists of α2‐adrenoceptors
Authors: Galeotti Nicoletta , Ghelardini Carla , Vinci Maria Cristina , Bartolini Alessandro 
Published: January 2005

The effect of the administration of pertussis toxin (PTX) as well as modulators of different subtypes of K+ channels on the antinociception induced by clonidine and guanabenz was evaluated in the mouse hot plate test.
Pretreatment with pertussis toxin (0.25 μg per mouse i.c.v.) 7 days before the hot‐plate test, prevented the antinociception induced by both clonidine (0.08–0.2 mg kg−1, s.c.) and guanabenz (0.1–0.5 mg kg−1, s.c.).
The administration of the KATP channel openers minoxidil (10 μg per mouse, i.c.v.), pinacidil (25 μg per mouse, i.c.v.) and diazoxide (100 mg kg−1, p.o.) potentiated the antinociception produced by clonidine and guanabenz whereas the KATP channel blocker gliquidone (6 μg per mouse, i.c.v.) prevented the α2 adrenoceptor agonist‐induced analgesia.
Pretreatment with an antisense oligonucleotide (aODN) to mKv1.1, a voltage‐gated K+ channel, at the dose of 2.0 nmol per single i.c.v. injection, prevented the antinociception induced by both clonidine and guanabenz in comparison with degenerate oligonucleotide (dODN)‐treated mice.
The administration of the Ca2+‐gated K+ channel blocker apamin (0.5–2.0 ng per mouse, i.c.v.) never modified clonidine and guanabenz analgesia.
At the highest effective doses, none of the drugs used modified animals' gross behaviour nor impaired motor coordination, as revealed by the rota‐rod test.
The present data demonstrate that both KATP and mKv1.1 K+ channels represent an important step in the transduction mechanism underlying central antinociception induced by activation of α2 adrenoceptors.

British Journal of Pharmacology (1999) 126, 1214–1220; doi:10.1038/sj.bjp.0702395
Adenosine 5′‐triphosphate and neuropeptide Y are co‐transmitters in conjunction with noradrenaline in the human saphenous vein
Authors: Racchi Héctor , Irarrázabal Manuel J , Howard Michel , Morán Sergio , Zalaquett Ricardo , Huidobro‐Toro J Pablo 
Published: January 2005

Human saphenous veins were used to assess the cooperative participation of adenosine 5‐triphosphate (ATP), neuropeptide Y (NPY), and noradrenaline (NA) in the vasomotor responses elicited following electrical depolarization of the perivascular nerve terminals. Rings from recently dissected human biopsies were mounted to record isometric muscular contractions; the motor activity elicited in the circular muscle layer following electrical depolarization (2.5–20 Hz, 50 V, 0.5 msec) were recorded.
Incubation of the biopsies with either 100 nM tetrodotoxin (TTX) or 1 μM guanethidine abolished the vasomotor response elicited by electrical nerve depolarization. The independent application of either ATP or NA to vein rings induced concentration‐dependent contractions.
Tissue incubation with 30 μM suramin or 10 nM prazosin produced 10 fold rightward displacements of the α,β‐methylene ATP and NA concentration‐response curves respectively. NPY contracted a limited number of biopsies, the vasoconstriction elicited was completely blocked by 1 μM BIBP 3226. A 5 min incubation of the biopsies with 10–100 nM NPY synergized, in a concentration‐dependent fashion, both the ATP and the ATP analogue‐induced contractions. Likewise, tissue preincubation with 10 nM NPY potentiated the vasomotor responses evoked with 20–60 nM NA.
Neither suramin, BIBP 3226, nor prazosin was individually able to significantly modify the derived frequency‐tension curves. In contrast, the co‐application of 30 μM suramin and 10 nM prazosin or 30 μM suramin and 1 μM BIBP 3226, elicited a significant (P<0.01) downward displacement of the respective frequency‐tension curves.
The simultaneous application of the three antagonists–30 μM suramin, 1 μM BIBP 3226 and 10 nM prazosin–caused a significantly greater displacement of the frequency‐tension curve than that achieved in experiments using two of these antagonists.
Electrically‐evoked vasomotor activity is blocked to a larger extent by tissue incubation with 2.5 μM chloroethylclonidine and 30 μM suramin rather than with 10 nM 5 methyl urapidil and 30 μM suramin. As a result, the α1‐adrenoceptor involved in the vasomotor activity has tentatively been associated with the α1B adrenoceptor family subtype.
Results support the physiological role of ATP in sympathetic neurotransmission. The present results are consistent with the working hypothesis that human sympathetic vasomotor reflexes involve the coordinated motor action of ATP, NPY, and NA acting on vascular smooth muscle cells. The present results support the concept of sympathetic co‐transmission in the human saphenous vein.

British Journal of Pharmacology (1999) 126, 1175–1185; doi:10.1038/sj.bjp.0702396
Inhibition by simvastatin, but not pravastatin, of glucose‐induced cytosolic Ca2+ signalling and insulin secretion due to blockade of L‐type Ca2+ channels in rat islet β‐cells
Authors: Yada Toshihiko , Nakata Masanori , Shiraishi Tomoko , Kakei Masafumi 
Published: January 2005

Hypercholesterolaemia often occurs in patients with type 2 diabetes, who therefore encounter administration of HMG‐CoA reductase inhibitors. Alteration of pancreatic β‐cell function leading to an impaired insulin secretory response to glucose plays a crucial role in the pathogenesis of type 2 diabetes. Therefore, it is important to examine the effects of HMG‐CoA reductase inhibitors on β‐cell function.
Cytosolic Ca2+ concentration ([Ca2+]i) plays a central role in the regulation of β‐cell function. The present study examined the effects of HMG‐CoA reductase inhibitors on the glucose‐induced [Ca2+]i signalling and insulin secretion in rat islet β‐cells.
Simvastatin, a lipophilic HMG‐CoA reductase inhibitor, at 0.1–3 μg ml−1 concentration‐dependently inhibited the first phase increase and oscillation of [Ca2+]i induced by 8.3 mM glucose in single β‐cells. The less lipophilic inhibitor, simvastatin‐acid, inhibited the first phase [Ca2+]i increase but was two orders of magnitude less potent. The hydrophilic inhibitor, pravastatin (100 μg ml−1), was without effect on [Ca2+]i.
Simvastatin (0.3 μg ml−1), more potently than simvastatin‐acid (30 μg ml−1), inhibited glucose‐induced insulin secretion from islets, whereas pravastatin (100 μg ml−1) had no effect.
Whole‐cell patch clamp recordings demonstrated a reversible inhibition of the β‐cell L‐type Ca2+ channels by simvastatin, but not by pravastatin. Simvastatin also inhibited the [Ca2+]i increases by L‐arginine and KCl, agents that act via opening of L‐type Ca2+ channels.
In conclusion, lipophilic HMG‐CoA reductase inhibitors can inhibit glucose‐induced [Ca2+]i signalling and insulin secretion by blocking L‐type Ca2+ channels in β‐cells, and their inhibitory potencies parallel their lipophilicities. Precaution should be paid to these findings when HMG‐CoA reductase inhibitors are used clinically, particularly in patients with type 2 diabetes.

British Journal of Pharmacology (1999) 126, 1205–1213; doi:10.1038/sj.bjp.0702397