bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sibutramine reduces feeding, body fat and improves insulin resistance in dietary‐obese male Wistar rats independently of hypothalamic neuropeptide Y
Authors: Brown Michael , Bing Chen , King Peter , Pickavance Lucy , Heal David , Wilding John 
Published: January 2005

We studied the effects of the novel noradrenaline and serotonin (5‐HT) reuptake inhibitor sibutramine on feeding and body weight in a rat model of dietary obesity, and whether it interacts with hypothalamic neuropeptide Y (NPY) neurones.
Chow‐fed and dietary‐obese (DIO) male Wistar rats were given sibutramine (3 mg kg−1 day−1 p.o.) or deionized water for 21 days.
Sibutramine decreased food intake throughout the treatment period in both dietary‐obese rats (P<0.0001) and lean rats (P<0.0001). Weight gain was reduced so that final body weight was 10% lower in dietary‐obese (P<0.005) and 8% lower in lean (P<0.05) rats versus their untreated controls. Plasma leptin concentration was lower in sibutramine‐treated dietary‐obese rats (P<0.05), and in treated lean rats (P<0.05). Using the homeostasis model assessment (HOMA) as a measure of insulin resistance, untreated DIO rats were significantly more insulin resistant than controls (P<0.005), and this was corrected by sibutramine treatment (P<0.05). Neither hypothalamic NPY mRNA nor NPY peptide levels in a number of hypothalamic nuclei were significantly altered by sibutramine compared to untreated controls.
The hypophagic and anti‐obesity effects of sibutramine in dietary‐obese Wistar rats appear not to be mediated by inhibition of ARC NPY neurones.

British Journal of Pharmacology (2001) 132, 1898–1904; doi:10.1038/sj.bjp.0704030
Contribution of α2 receptor subtypes to nerve injury‐induced pain and its regulation by dexmedetomidine
Authors: Malmberg Annika B , Hedley Linda R , Jasper Jeffrey R , Hunter John C , Basbaum Allan I 
Published: January 2005

There is evidence that noradrenaline contributes to the development and maintenance of neuropathic pain produced by trauma to a peripheral nerve. It is, however, unclear which subtype(s) of α adrenergic receptors (AR) may be involved. In addition to pro‐nociceptive actions of AR stimulation, α2 AR agonists produce antinociceptive effects.
Here we studied the contribution of the α2 AR subtypes, α2A, α2B and α2C to the development of neuropathic pain. We also examined the antinociceptive effect produced by the α2 AR agonist dexmedetomidine in nerve‐injured mice.
The studies were performed in mice that carry either a point (α2A) or a null (α2B and α2C) mutation in the gene encoding the α2 AR. To induce a neuropathic pain condition, we partially ligated the sciatic nerve and measured changes in thermal and mechanical sensitivity.
Baseline mechanical and thermal withdrawal thresholds were similar in all mutant and wild‐type mice; and, after peripheral nerve injury, all mice developed comparable hypersensitivity (allodynia) to thermal and mechanical stimulation.
Dexmedetomidine reversed the allodynia at a low dose (3 μg kg−1, s.c.) and produced antinociceptive effects at higher doses (10 – 30 μg kg−1) in all groups except in α2A AR mutant mice. The effect of dexmedetomidine was reversed by intrathecal, but not systemic, injection of the α2 AR antagonist RS 42206.
These results suggest that neither α2A, α2B nor α2C AR is required for the development of neuropathic pain after peripheral nerve injury, however, the spinal α2A AR is essential for the antinociceptive effects of dexmedetomidine.

British Journal of Pharmacology (2001) 132, 1827–1836; doi:10.1038/sj.bjp.0704032
The effects of the statins lovastatin and cerivastatin on signalling by the prostanoid IP‐receptor
Authors: Lawler Orlaith A , Miggin Sinead M , Kinsella B Therese 
Published: January 2005

The prostanoid‐IP receptor may be unique among G protein coupled receptors in that it is isoprenylated. In this study, we investigated the effects of the statins lovastatin and cerivastatin on signalling by the mouse (m) IP and the human (h) IP receptors, over‐expressed in human embryonic kidney (HEK) 293 cells and by the hIP receptor, endogenously expressed in human erythroleukaemia cells.
Both statins significantly reduced IP receptor‐mediated cyclic AMP generation and intracellular calcium ([Ca2+]i) mobilization in a time and concentration dependent manner but had no effect on signalling by the non‐isoprenylated β2 adrenergic receptor or by the human prostanoid‐TP receptor isoforms.
Cerivastatin (IC50, 50 – 90 nM) was significantly more potent than lovastatin (IC50, 0.80 – 4.2 μM) in inhibiting IP receptor signalling.
Whereas IC50 values indicated that the hIP receptor was significantly more sensitive than the mIP receptor to the statins, the extent of inhibition of cyclic AMP generation by the mIP receptor was significantly greater than that of the hIP receptor to either statin, even at the highest concentrations used.
Pretreatment with either statin significantly reduced IP receptor mediated desensitization of signalling by the h.TPα, but not by the h.TPβ, receptor isoform.
These data generated in whole cells point to the possibility that statin therapy may interfere with IP receptor signalling in vivo; such interference may be extenuated under conditions where circulating statin levels are elevated and may account, in part, for some of the pleiotropic affects of the statins not attributed solely to their lipid lowering properties.

British Journal of Pharmacology (2001) 132, 1639–1649; doi:10.1038/sj.bjp.0704033
Functional characterization of a human receptor for neuropeptide FF and related peptides
Authors: Kotani Masato , Mollereau Catherine , Detheux Michel , Le Poul Emmanuel , Brézillon Stéphane , Vakili Jalal , Mazarguil Honoré , Vassart Gilbert , Zajac Jean‐Marie , Parmentier Marc 
Published: January 2005

Neuropeptides FF (NPFF) and AF (NPAF) are involved in pain modulation and opioid tolerance. These peptides were known to act through uncharacterized G protein‐coupled receptors (GPCR). We describe here, using an aequorin‐based assay as screening tool, that an orphan GPCR, previously designated HLWAR77, is a functional high affinity receptor for NPFF and related peptides. This receptor is further designated as NPFFR.
Binding experiments were performed with a new radioiodinated probe, [125I]‐EYF, derived from the EFW‐NPSF sequence of the rat NPFF precursor. Chinese hamster ovary (CHO) cell membranes expressing NPFFR bound [125I]‐EYF with a Kd of 0.06 nM. Various NPFF analogues and related peptides inhibited [125I]‐EYF specific binding with the following rank order (Ki): human NPAF (0.22 nM), SQA‐NPFF (0.29 nM), NPFF (0.30 nM), 1DMe (0.31 nM), EYW‐NPSF (0.32 nM), QFW‐NPSF (0.35 nM), 3D (1.12 nM), Met‐enk‐RF‐NH2 (3.25 nM), FMRF‐NH2 (10.5 nM) and NPSF (12.1 nM).
The stimulatory activity of the same set of peptides was measured by a functional assay based on the co‐expression of NPFFR, Gα16 and apoaequorin. The rank order of potency was consistent with the results of the binding assay.
Membranes from NPFFR expressing CHO cells bound GTPγ[35S] in the presence of SQA‐NPFF. This functional response was prevented by pertussis toxin treatment, demonstrating the involvement of Gi family members.
SQA‐NPFF inhibited forskolin induced cyclic AMP accumulation in recombinant CHO cells in a dose dependent manner. This response was abolished as well by pertussis toxin pre‐treatment.
RT – PCR analysis of human tissues mRNA revealed that expression of NPFFR was mainly detected in placenta, thymus and at lower levels in pituitary gland, spleen and testis.

British Journal of Pharmacology (2001) 133, 138–144; doi:10.1038/sj.bjp.0704038
Dual action of ZD6169, a novel K+ channel opener, on ATP‐sensitive K+ channels in pig urethral myocytes
Authors: Teramoto Noriyoshi , Yunoki Takakazu , Takano Makoto , Yonemitsu Yoshikazu , Masaki Ichiro , Sueishi Katsuo , Brading Alison F , Ito Yushi 
Published: January 2005

The effects of ZD6169, a novel K+ channel opener, on both membrane and unitary currents in pig urethra were investigated using patch‐clamp techniques. Its effect was also examined on currents in inside‐out patches of COS7 cells expressing carboxy terminus truncated inwardly rectifying K+ channel (Kir6.2) subunits (Kir6.2ΔC36) which form ATP‐sensitive K+ channels (KATP channels).
In current‐clamp mode, ZD6169 (10 μM) induced a concentration‐dependent membrane hyperpolarization. Higher concentrations (30 μM) caused a transient membrane hyperpolarization, followed by a gradual membrane depolarization. On removal of ZD6169, an after hyperpolarization was observed.
In conventional voltage‐clamp configuration, at −50 mV in symmetrical 140 mM K+ conditions, ZD6169 (100 μM) caused a transient inward current which gradually decayed. Removal of ZD6169 evoked a much larger amplitude K+ current with a similar time course.
ZD6169 produced an inward glibenclamide‐sensitive K+ current, demonstrating a bell‐shaped concentration‐response relationship.
In cell‐attached configuration in symmetrical 140 mM K+ conditions, ZD6169 (30 μM) activated an KATP channel which was reversibly suppressed by application of glibenclamide. In contrast, ZD6169 (100 μM) inhibited the activity of the levcromakalim‐induced KATP channels.
ZD6169 (100 μM) had no significant effect on the channel activity of Kir6.2ΔC36 in inside‐out configuration, although cibenzoline greatly suppressed the channel activity.
These results demonstrate that ZD6169 possesses a dual effect on the activity of the KATP channel; activating at low concentration and inhibiting at higher concentration.

British Journal of Pharmacology (2001) 133, 154–164; doi:10.1038/sj.bjp.0704042
The role of α1‐adrenoceptors and 5‐HT1A receptors in the control of the micturition reflex in male anaesthetized rats
Authors: Conley Rachel K , Williams Timothy J , Ford Anthony P D W , Ramage Andrew G 
Published: January 2005

The effects of the α1‐adrenoceptor antagonists doxazosin (0.1 – 2 mg kg−1), RS‐100329 (α1A; 0.01 – 1 mg kg−1), RS‐513815 (Ro 151‐3815, α1B; 0.3 – 3 mg kg−1) and BMY 7378 (α1D; 0.1 – 1 mg kg−1), the 5‐HT1A receptor agonist, 8‐OH‐DPAT (0.03 – 0.3 mg kg−1) and antagonist WAY‐100635 (0.03 – 0.3 mg kg−1) were investigated (i.v.) on the ‘micturition reflex’ in the urethane anaesthetized male rat.
Reflex‐evoked urethra contractions were most sensitive to the inhibitory action of RS‐100329, followed by doxazosin, BMY 7378 and WAY‐100635 and then RS‐513815. The maximum inhibition was 66, 63, 54, 46 and 22% at doses of 0.3, 0.5, 0.3, 0.3 and 3 mg kg−1 respectively.
BMY 7378 and 8‐OH‐DPAT decreased, while WAY‐100635 increased, the pressure threshold to induce bladder contraction. WAY‐100635 (0.01 mg kg−1) blocked the effects of BMY 7378 (1 mg kg−1) on bladder pressure and volume threshold.
Doxazosin, RS‐100329 and BMY 7378 had a similar potency in inducing a fall in arterial blood pressure while WAY‐100635 only caused a fall at the highest dose.
Therefore, reflex‐evoked urethral contraction involves the activation of α1A/1D‐adrenoceptors, as BMY 7378 and RS‐100329 are similarly potent in attenuating this effect. The ability of WAY‐100635 to attenuate this contraction may suggest that 5‐HT1A receptors are also involved. However, as this inhibition occurred at the highest dose of WAY‐100635, which also caused a fall in arterial blood pressure; this effect is considered to be due to blockade of α1‐adrenoceptors not 5‐HT1A receptors. Nevertheless the initiation of the ‘micturition reflex’ involves the activation of 5‐HT1A receptors.

British Journal of Pharmacology (2001) 133, 61–72; doi:10.1038/sj.bjp.0704043
Agonist and antagonist activities on human NPFF2 receptors of the NPY ligands GR231118 and BIBP3226
Authors: Mollereau Catherine , Gouardères Christine , Dumont Yvan , Kotani Masato , Detheux Michel , Doods Henri , Parmentier Marc , Quirion Rémi , Zajac Jean‐Marie 
Published: January 2005

Neuropeptide FF (NPFF) is a part of a neurotransmitter system acting as a modulator of endogenous opioid functions. At this time, no non‐peptide or peptide NPFF‐antagonists have been discovered. Here, we demonstrate that Neuropeptide Y (NPY) ligands, in fact possess significant ability to interact with the human NPFF2 receptors. NPY Y1 antagonist BIBP3226 and mixed Y1 antagonist/Y4 agonist GR231118 are able to displace with low affinity, 50 – 100 nM, the specific binding on NPFF receptors expressed in CHO cells as well as in rat dorsal spinal cord, an affinity however superior to those determined against Y2, Y4 or Y5 receptors. Furthermore, BIBP3226 which is unable to inhibit the forskolin‐stimulated cyclic AMP production mediated by NPFF2 receptors, antagonizes the effect of NPFF, revealing the first antagonist of NPFF receptors. These properties of NPY ligands on Neuropeptide FF receptors must be considered when evaluating pharmacological activities of these drugs. British Journal of Pharmacology (2001) 133, 1–4; doi:10.1038/sj.bjp.0704049
Involvement of accumulated endogenous NOS inhibitors and decreased NOS activity in the impaired neurogenic relaxation of the rabbit proximal urethra with ischaemia
Authors: Masuda Hitoshi , Tsujii Toshihiko , Okuno Tetsuo , Kihara Kazunori , Goto Moritaka , Azuma Hiroshi 
Published: January 2005

We examined the effect of ischaemia on the neurogenic and nitric oxide (NO)‐mediated urethral relaxation.
Rabbits were divided into control and urethral ischaemia (UI) groups, which was prepared by the partial occlusion of bilateral iliac arteries using blood vessel occluders.
Neurogenic and NO‐mediated proximal urethral relaxation induced by electrical field stimulation (EFS) was greatly impaired in the UI group, while relaxation by sodium nitroprusside (SNP) as a NO donor showed no difference between the two groups. Pretreatment with L‐arginine significantly improved but did not normalize the impaired relaxation in the UI group. Not only basal level, but also stimulated production of cyclic GMP with EFS, were significantly decreased in the UI group.
The tissue contents of NG‐methyl‐L‐arginine (L‐NMA) and asymmetric NG, NG‐dimethyl‐L‐arginine (ADMA) in the proximal urethra were increased following ischaemia. While L‐arginine and symmetric NG, N′G‐dimethyl‐L‐arginine (SDMA) contents remained unchanged. Exogenously applied authentic L‐NMA and ADMA (1 – 100 μM) concentration‐dependently inhibited the EFS‐induced urethral relaxation in the control group. The inhibition with L‐NMA and ADMA was undetectable in the presence of 3 mM L‐arginine.
The Ca2+‐dependent NOS activity in the urethra from the UI group was significantly lower than that from the control group and was not restored by an addition of 3 mM L‐arginine.
These results suggest that the impaired neurogenic and NO‐mediated urethral relaxation with ischaemia is closely related to the increased accumulation of L‐NMA and ADMA and decreased NOS activity, which would result in an accelerated reduction in NO production/release.

British Journal of Pharmacology (2001) 133, 97–106; doi:10.1038/sj.bjp.0704050
Role of bradykinin and eNOS in the anti‐ischaemic effect of trandolapril
Authors: Cargnoni Anna , Comini Laura , Bernocchi Palmira , Bachetti Tiziana , Ceconi Claudio , Curello Salvatore , Ferrari Roberto 
Published: January 2005

Angiotensin converting enzyme (ACE) inhibitors are under study in ischaemic heart diseases, their mechanism of action being still unknown.
The anti‐ischaemic effect of trandolapril and the possible involvement of a bradykinin‐modulation on endothelial constitutive nitric oxide synthase (eNOS) in exerting this effect, were investigated.
Three doses of trandolapril, chronically administered in vivo, were studied in isolated perfused rat hearts subjected to global ischaemia followed by reperfusion.
Trandolapril has an anti‐ischaemic effect. The dose of 0.3 mg kg−1 exerted the best effect reducing diastolic pressure increase during ischaemia (from 33.0±4.5 to 14.0±5.2 mmHg; P<0.05 vs control) and reperfusion (from 86.1±9.4 to 22.2±4.1 mmHg; P<0.01 vs control), improving functional recovery, counteracting creatine phosphokinase release and ameliorating energy metabolism after reperfusion.
Trandolapril down‐regulated the baseline developed pressure.
Trandolapril increased myocardial bradykinin content (from 31.8±6.1 to 54.8±7.5 fmol/gww; P<0.05, at baseline) and eNOS expression and activity in aortic endothelium (both P<0.01 vs control) and in cardiac myocytes (from 11.3±1.5 to 17.0±2.0 mUOD μg protein−1 and from 0.62±0.05 to 0.80±0.06 pmol mg prot−1 min−1; both P<0.05 vs control).
HOE 140 (a bradykinin B2 receptor antagonist) and NOS inhibitors counteracted the above‐reported effects.
There was a negative correlation between myocyte's eNOS up‐regulation and myocardial contraction down‐regulation.
Our findings suggest that the down‐regulation exerted by trandolapril on baseline cardiac contractility, through a bradykinin‐mediated increase in NO production, plays a crucial role in the anti‐ischaemic effect of trandolapril by reducing energy breakdown during ischaemia.

British Journal of Pharmacology (2001) 133, 145–153; doi:10.1038/sj.bjp.0704052
Transfection of annexin 1 in monocytic cells produces a high degree of spontaneous and stimulated apoptosis associated with caspase‐3 activation
Authors: Solito Egle , De Coupade Catherine , Canaider Silvia , Goulding Nicolas J , Perretti Mauro 
Published: January 2005

Transfection of the pre‐monomyelocytic U937 cell line with a plasmid coding for full‐length annexin 1 (ANX1, 347 amino acid) leads to cell death by promoting apoptosis. In addition, over‐expression of the N‐terminal and the first domain of the protein (144 amino acids, clone ANX1‐S), which does not contain the Ca2+ binding sites, gives susceptibility to cell apoptosis following activation by either 5 ng ml−1 tumour necrosis factor (TNF)‐α or 1 – 40 μg ml−1 etoposide. This was demonstrated by using the fluorescent labelled annexin V, cell cycle and nuclear staining analyses.
Transfection with an empty plasmid (clone CMV) or with a plasmid carrying the cDNA antisense for ANX1 (clone ANX1‐AS) did not alter U937 cells to the degree of apoptosis promoted by either stimulant.
Treatment of CMV U937 cells with TNF‐α increased ANX1 mRNA and protein expression in a time‐dependent manner, with maximal increases at 3 and 6 h, respectively.
Clone ANX1‐S showed higher constitutive (more than 2 fold) and activated caspase‐3 activity, associated with higher phospholipase A2 (PLA2) activity (in the region of +50 – 100%), whereas expression of cytosolic PLA2 Bax and Bcl‐2 were similar in all cell clones, as determined by Western blotting.
In conclusion, this study demonstrates a complex regulatory role of cell apoptosis for ANX1, at least with regards to cells of the myelo‐monocytic lineage.

British Journal of Pharmacology (2001) 133, 217–228; doi:10.1038/sj.bjp.0704054
Glimepiride block of cloned β‐cell, cardiac and smooth muscle KATP channels
Authors: Song Dae‐Kyu , Ashcroft Frances M 
Published: January 2005

We examined the effect of the sulphonylurea glimepiride on three types of recombinant ATP‐sensitive potassium (KATP) channels.
KATP channels share a common pore‐forming subunit, Kir6.2, which associates with different sulphonylurea receptor isoforms (SUR1 in β‐cells, SUR2A in heart and SUR2B in smooth muscle).
Kir6.2 was coexpressed with SUR1, SUR2A or SUR2B in Xenopus oocytes and macroscopic KATP currents were recorded from giant inside‐out membrane patches. Glimepiride was added to the intracellular membrane surface.
Glimepiride inhibited Kir6.2/SUR currents by interaction with two sites: a low‐affinity site on Kir6.2 (IC50=∼400 μM) and a high‐affinity site on SUR (IC50=3.0 nM for SUR1, 5.4 nM for SUR2A and 7.3 nM for SUR2B). The potency of glimepiride at the high‐affinity site is close to that observed for glibenclamide (4 nM for SUR1, 27 nM for SUR2A), which has a similar structure.
Glimepiride inhibition of Kir6.2/SUR2A and Kir6.2/SUR2B currents, but not Kir6.2/SUR1 currents, reversed rapidly.
Our results indicate that glimepiride is a high‐affinity sulphonylurea that does not select between the β‐cell, cardiac and smooth muscle types of recombinant KATP channel, when measured in inside‐out patches. High‐affinity inhibition is mediated by interaction of the drug with the sulphonylurea receptor subunit of the channel.

British Journal of Pharmacology (2001) 133, 193–199; doi:10.1038/sj.bjp.0704062
Antihypertensive effects of the flavonoid quercetin in spontaneously hypertensive rats
Authors: Duarte Juan , Pérez‐Palencia Raquel , Vargas Felix , Angeles Ocete Maria , Pérez‐Vizcaino Francisco , Zarzuelo Antonio , Tamargo Juan 
Published: January 2005

The effects of an oral daily dose (10 mg kg−1) of the flavonoid quercetin for 5 weeks in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY) were analysed.
Quercetin induced a significant reduction in systolic (−18%), diastolic (−23%) and mean (−21%) arterial blood pressure and heart rate (−12%) in SHR but not in WKY rats.
The left ventricular weight index and the kidney weight index in vehicle‐treated SHR were significantly greater than in control WKY and these parameters were significantly reduced in quercetin‐treated SHR in parallel with the reduction in systolic blood pressure.
Quercetin had no effect on the vasodilator responses to sodium nitroprusside or to the vasoconstrictor responses to noradrenaline or KCl but enhanced the endothelium‐dependent relaxation to acetylcholine (Emax=58±5%vs 78±5%, P<0.01) in isolated aortae.
The 24 h urinary isoprostane F2α excretion and the plasma malonyldialdehyde (MDA) levels in SHR rats were increased as compared to WKY rats. However, in quercetin‐treated SHR rats both parameters were similar to those of vehicle‐treated WKY.
These data demonstrate that quercetin reduces the elevated blood pressure, the cardiac and renal hypertrophy and the functional vascular changes in SHR rats without effect on WKY. These effects were associated with a reduced oxidant status due to the antioxidant properties of the drug.

British Journal of Pharmacology (2001) 133, 117–124; doi:10.1038/sj.bjp.0704064
Short‐ and long‐term influences of calcitonin gene‐related peptide on the synthesis of acetylcholinesterase in mammalian myotubes
Authors: Da Costa Valter Luiz , Lapa Antonio José , Godinho Rosely O 
Published: January 2005

The present study analyses the short‐ (15 min – 2 h) and long‐term (24 – 48 h) influences of calcitonin gene‐related peptide (CGRP) on acetylcholinesterase (AChE) expression in the rat cultured skeletal muscle and the signal transduction events underlying CGRP actions.
To assess the effect of CGRP on AChE synthesis, myotubes were pre‐exposed to the irreversible AChE inhibitor diisopropyl fluorophosphate (DFP) and treated with CGRP or forskolin, an adenylyl cyclase (AC) activator. Treatment of myotubes with 1 – 100 nM CGRP for 2 h increased by up to 42% the synthesis of catalytically active AChE with a parallel increase in the intracellular cyclic AMP.
The stimulation of AChE synthesis induced by CGRP was mimicked by direct activation of AC with 3 – 30 μM forskolin. In contrast, pre‐treatment of cultures with 100 nM CGRP for 20 h reduced by 37% the subsequent synthesis of AChE, resulting in a 15% decrease in total AChE activity after 48 h CGRP treatment.
Moreover, 24 h treatment of myotubes with 100 nM CGRP reduced by 54% the accumulation of cyclic AMP induced by a subsequent CGRP treatment.
These findings indicate that, in skeletal muscle cells, CGRP modulates the AChE expression in a time‐dependent manner, initially stimulating the enzyme synthesis through a cyclic AMP‐dependent mechanism. The decreased AChE synthesis observed after long‐term CGRP treatment suggests that CGRP signalling system is subject to desensitization or down‐regulation, that might function as an important adaptative mechanism of the muscle fibre in response to long‐term changes in neuromuscular transmission.

British Journal of Pharmacology (2001) 133, 229–236; doi:10.1038/sj.bjp.0704069