bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic fluoxetine treatment selectively uncouples raphe 5‐HT1A receptors as measured by [35S]‐GTPγS autoradiography
Authors: Pejchal Tina , Foley Melissa A , Kosofsky Barry E , Waeber Christian 
Published: January 2005

Selective Serotonin Reuptake Inhibitors (SSRIs) are thought to have a delay in therapeutic efficacy because of the need to overcome the inhibitory influence of raphe 5‐HT1A autoreceptors. Prolonged SSRI administration has been reported to desensitize these autoreceptors. We have used [35S]‐GTPγS autoradiography to determine whether this desensitization occurs at the level of receptor/G protein coupling.
Male mice were injected intraperitoneally once a day with saline or 20 mg kg−1 fluoxetine for either 2 days or 14 days. 5‐HT1A receptor binding and coupling to G proteins were assessed using [3H]‐8‐OH‐DPAT and [35S]‐GTPγS autoradiography, respectively.
The 5‐HT receptor agonist 5‐carboxamidotryptamine (5‐CT) stimulated [35S]‐GTPγS binding in the substantia nigra, as well as in hippocampus and dorsal raphe nucleus. The 5‐HT1A receptor antagonist p‐MPPF (4‐fluoro‐N‐(2‐[4‐(2‐methoxyphenyl)1‐piperazinyl]ethyl)‐N‐(2‐pyridinyl)benzamide) blocked this effect in the latter regions, whereas the 5‐HT1B/D antagonist GR‐127,935 (2′‐methyl‐4′‐(5‐methyl‐[1,2,4]oxadiazol‐3‐yl)‐biphenyl‐4‐carboxylic acid [4‐methoxy‐3‐(4‐methyl‐piperazin‐l‐yl)‐phenyl]‐amide) only decreased labelling in substantia nigra.
Fourteen‐day fluoxetine treatment decreased 5‐CT‐stimulated [35S]‐GTPγS binding in dorsal raphe (saline: 112±12% stimulation; fluoxetine: 66±13%), but not in substantia nigra (99±14% vs 103±7%) or hippocampus (157±3% vs 148±18%). Two‐day fluoxetine treatment did not alter 5‐CT‐stimulated [35S]‐GTPγS binding in any of the brain areas investigated.
Decreased [35S]‐GTPγS binding was not due to receptor down‐regulation, since the density of raphe [3H]‐8‐OH‐DPAT binding sites was unaffected by fluoxetine treatment.
These results suggest that the desensitization of presynaptic 5‐HT1A receptor function occurs at the level of receptor‐G protein interaction on dorsal raphe neurons, and may underlie the therapeutic efficacy of long‐term SSRI treatment.

British Journal of Pharmacology (2002) 135, 1115–1122; doi:10.1038/sj.bjp.0704555
Effect of agmatine on locus coeruleus neuron activity: possible involvement of nitric oxide
Authors: Ruiz‐Durántez Eduardo , Ruiz‐Ortega José A , Pineda Joseba , Ugedo Luisa 
Published: January 2005

To investigate whether agmatine (the proposed endogenous ligand for imidazoline receptors) controls locus coeruleus neuron activity and to elucidate its mechanism of action, we used single‐unit extracellular recording techniques in anaesthetized rats.
Agmatine (10, 20 and 40 μg, i.c.v.) increased in a dose‐related manner the firing rate of locus coeruleus neurons (maximal increase: 95±13% at 40 μg).
I1‐imidazoline receptor ligands stimulate locus coeruleus neuron activity through an indirect mechanism originated in the paragigantocellularis nucleus via excitatory amino acids. However, neither electrolytic lesions of the paragigantocellularis nucleus nor pretreatment with the excitatory amino acid antagonist kynurenic acid (1 μmol, i.c.v.) modified agmatine effect (10 μg, i.c.v.).
After agmatine administration (20 μg, i.c.v.), dose‐response curves for the effect of clonidine (0.625 – 10 μg kg−1 i.v.) or morphine (0.3 – 4.8 mg kg−1 i.v.) on locus coeruleus neurons were not different from those obtained in the control groups.
Pretreatment with the nitric oxide synthase inhibitors Nω‐nitro‐L‐arginine (10 μg, i.c.v.) or Nω‐nitro‐L‐arginine methyl ester (100 μg, i.c.v.) but not with the less active stereoisomer Nω‐nitro‐D‐arginine methyl ester (100 μg, i.c.v.) completely blocked agmatine effect (10 and 40 μg, i.c.v.).
Similarly, when agmatine (20 pmoles) was applied into the locus coeruleus there was an increase that was blocked by Nω‐nitro‐L‐arginine methyl ester (100 μg, i.c.v.) in the firing rate of the locus coeruleus neurons (maximal increase 53±11% and 14±10% before and after nitric oxide synthase inhibition, respectively).
This study demonstrates that agmatine stimulates the firing rate of locus coeruleus neurons via a nitric oxide synthase‐dependent mechanism located in this nucleus.

British Journal of Pharmacology (2002) 135, 1152–1158; doi:10.1038/sj.bjp.0704556
Evidence of a novel site mediating anandamide‐induced negative inotropic and coronary vasodilatator responses in rat isolated hearts
Authors: Ford William R , Honan Stuart A , White Richard , Hiley C Robin 
Published: January 2005

Cannabinoids are known to cause coronary vasodilatation and reduce left ventricular developed pressure (LVDP) in isolated hearts although the identity of the receptor(s) mediating these responses is unknown. Our objective was to pharmacologically characterize cannabinoid receptors mediating cardiac responses to the endocannabinoid, anandamide.
Dose‐response curves for coronary perfusion pressure (CPP) and LVDP were constructed to anandamide, R‐(+)‐methanandamide, palmitoylethanolamide (PEA) and JWH015 in isolated Langendorff‐perfused rat hearts. Anandamide dose‐response curves were also constructed in the presence of antagonists selective for CB1, CB2 or VR1 receptors.
Anandamide and methanadamide significantly reduced CPP and LVDP but the selective CB2 receptor agonists, PEA and JWH015 had no significant effect, compared with equivalent vehicle doses.
Single bolus additions of the selective CB1‐receptor agonist, ACEA (5 nmol), decreased LVDP and CPP. When combined with JWH015 (5 nmol) these responses were not augmented.
Anandamide‐mediated reductions in CPP were significantly blocked by the selective CB1 receptor antagonists SR 141716A (1 μM) and AM251 (1 μM) and the selective CB2 receptor antagonist SR 144528 (1 μM) but not by another selective CB2 receptor antagonist AM630 (10 μM) nor the vanilloid VR1 receptor antagonist capsazepine (10 μM).
SR 141716A, AM281 and SR 144528 significantly blocked negative inotropic responses to anandamide that were not significantly affected by AM251, AM630 and capsazepine.
One or more novel sites mediate negative inotropic and coronary vasodilatatory responses to anandamide. These sites can be distinguished from classical CB1 and CB2 receptors, as responses are sensitive to both SR 141716A and SR 144528.

British Journal of Pharmacology (2002) 135, 1191–1198; doi:10.1038/sj.bjp.0704565
Ca2+ signalling by recombinant human CXCR2 chemokine receptors is potentiated by P2Y nucleotide receptors in HEK cells
Authors: Werry Tim D , Christie Mark I , Dainty Ian A , Wilkinson Graeme F , Willars Gary B 
Published: January 2005

Human embryonic kidney (HEK)‐293 cells expressing recombinant Gαi‐coupled, human CXC chemokine receptor 2 (CXCR2) were used to study the elevation of the intracellular [Ca2+] ([Ca2+]i) in response to interleukin‐8 (IL‐8) following pre‐stimulation of endogenously expressed P2Y1 or P2Y2 nucleotide receptors.
Pre‐stimulation of cells with adenosine 5′‐triphosphate (ATP) revealed a substantial Ca2+ signalling component mediated by IL‐8 (Emax=83±8% of maximal ATP response, pEC50 of IL‐8 response=9.7±0.1).
1 μM 2‐methylthioadenosine 5′‐diphosphate (2MeSADP; P2Y1 selective) and 100 μM uridine 5′‐triphosphate (UTP; P2Y2 selective) stimulated equivalent maximal increases in [Ca2+]i elevation. However, UTP caused a sustained elevation, whilst following 2MeSADP [Ca2+]i rapidly returned to basal levels.
Both UTP and 2MeSADP increased the potency and magnitude of IL‐8‐mediated [Ca2+]i elevation but the effects of UTP (Emax of IL‐8 response increased to 50±1% of the maximal response to ATP, pEC50 increased to 9.8±0.1) were greater than those of 2MeSADP (Emax increased to 36±2%, pEC50 increased to 8.7±0.2).
The potentiation of IL‐8‐mediated Ca2+ signalling by UTP was not dependent upon the time of IL‐8 addition following UTP but was dependent on the continued presence of UTP. Potentiated IL‐8 Ca2+ signalling was apparent in the absence of extracellular Ca2+, demonstrating the release of Ca2+ from intracellular stores.
Activation of P2Y1 and P2Y2 receptors also revealed Ca2+ signalling by an endogenously expressed, Gαs‐coupled β‐adrenoceptor.
In conclusion, pre‐stimulation of P2Y nucleotide receptors, particularly P2Y2, facilitates Ca2+ signalling by either recombinant CXCR2 or endogenous β‐adrenoceptors.

British Journal of Pharmacology (2002) 135, 1199–1208; doi:10.1038/sj.bjp.0704566
Tachykinins via Tachykinin NK2 receptor activation mediate ozone‐induced increase in the permeability of the tracheal mucosa in guinea‐pigs
Authors: Fu Li , Kaneko Takeshi , Ikeda Hirotada , Nishiyama Harumi , Suzuki Shunsuke , Okubo Takao , Trevisani Marcello , Geppetti Pierangelo , Ishigatsubo Yoshiaki 
Published: January 2005

Acute exposure to ozone is known to cause airway hyperresponsiveness, which, at least in part, seems to result from an increase in the permeability of the airway mucosa. Recently, we demonstrated that depletion of sensory neuropeptides inhibits the ozone‐induced increase in the permeability of the tracheal mucosa in guinea‐pigs. The aim of this study was to determine whether tachykinins mediate ozone‐induced increase in the permeability of the tracheal mucosa in guinea‐pigs.
Anaesthetized guinea‐pigs were exposed to either 3 p.p.m. ozone or filtered air for 30 min. Immediately after exposure, a tracheal segment was isolated in vivo and administered with horseradish peroxidase (HRP). The permeability was assessed by monitoring the appearance of HRP in the blood.
A low dose of NKA increased the permeability of the tracheal mucosa, whereas a low dose of SP was without effect. Low and high doses of the selective NK3 receptor agonist, senktide, were also without effect. The effect of a low dose of NKA was abolished by the NK2 receptor antagonist, SR‐48,968. A high dose of SP increased the permeability in a manner reversible by the NK1 receptor antagonist, CP‐96,345.
Pretreatment with SR‐48,968 completely inhibited the ozone‐induced increase in the permeability, whereas CP‐96,345 had no effect.
It is thus concluded that endogenous tachykinins mediate the ozone‐induced increase in the permeability of the tracheal mucosa in guinea‐pigs mainly via NK2 receptor activation.

British Journal of Pharmacology (2002) 135, 1331–1335; doi:10.1038/sj.bjp.0704572
Enhancement of 1α,25‐dihydroxyvitamin D3‐induced differentiation of human leukaemia HL‐60 cells into monocytes by parthenolide via inhibition of NF‐κB activity
Authors: Kang S N , Kim S H , Chung S W , Lee M H , Kim H J , Kim T S 
Published: January 2005

Transcription factors such as NF‐κB provide powerful targets for drugs to use in the treatment of cancer. In this report parthenolide (PT), a sesquiterpene lactone of herbal remedies such as feverfew (Tanacetum parthenium) with NF‐κB inhibitory activity, markedly increased the degree of human leukaemia HL‐60 cell differentiation when simultaneously combined with 5 nM 1α,25‐dihydroxyvitamin D3 (1,25‐(OH)2D3). PT by itself did not induce HL‐60 cell differentiation.
Cytofluorometric analysis indicated that PT stimulated 1,25‐(OH)2D3‐induced differentiation of HL‐60 cells predominantly into monocytes.
Pretreatment of HL‐60 cells with PT before the 1,25‐(OH)2D3 addition also potentiated the 1,25‐(OH)2D3‐induced HL‐60 cell differentiation in both a dose‐ and a time‐dependent manner, in which the enhanced levels of cell differentiation closely correlated with the inhibitory levels of NF‐κB binding activity by PT.
In contrast, santonin, a sesquiterpene lactone without an inhibitory activity of NF‐κB binding to the κB sites, did not enhance the 1,25‐(OH)2D3‐induced HL‐60 cell differentiation.
In transfection experiments, PT enhanced 1,25‐(OH)2D3‐induced VDRE‐dependent promoter activity. Furthermore, PT restored 1,25‐(OH)2D3‐induced VDRE‐dependent promoter activity inhibited by TNF‐α, an activator of NF‐κB signalling pathway.
These results indicate that PT strongly potentiates the 1,25‐(OH)2D3‐induced HL‐60 cell differentiation into monocytes via the inhibition of NF‐κB activity and provide evidence that inhibition of NF‐κB activation can be a pre‐requisite to the efficient entry of promyelocytic leukaemia cells into a differentiation pathway.

British Journal of Pharmacology (2002) 135, 1235–1244; doi:10.1038/sj.bjp.0704573
Adenosine A2A receptors in portal hypertension: their role in the abnormal response to adenosine of the cranial mesenteric artery in rabbits
Authors: Villa de Brito M T , Canto A , Duarte Correia J H , Cunha R A , Marques M C 
Published: January 2005

Adenosine is a regulator of mesenteric vasodilation involved in auto‐regulation and post‐prandial hyperemia, but the adenosine receptor subtype involved in this relaxant effect is poorly characterized. We have now pharmacologically characterized this receptor in rabbit mesenteric arteries and investigated how this adenosine receptor response changes in portal hypertensive animals since the adenosine response is decreased.
The closest non‐metabolisable adenosine analogue, 2‐chloroadenosine (CADO), the mixed A1/A2 receptor agonist, 5′‐ethylcarboxamidoadenosine (NECA), and the selective A2A receptor agonist, 2‐[4‐(2‐p‐carbonyethyl)phenylamino]‐5′‐N‐ethylcarboxamidoadenosine (CGS 21680) (1 pM – 1 mM) relaxed noradrenaline pre‐contracted arteries with a rank order of potency of CGS 21680 (EC50=20 nM)NECA (60 nM)>>CADO (640 nM).
The selective A2A receptor antagonist, 4‐(2‐[7‐amino‐2‐(2‐furyl)‐[1,2,4]‐triazolo[2,3‐a][1,3,5]‐triazin‐5‐ylamino]ethyl)phenol (ZM 241385, 100 nM), shifted to the right the CADO concentration‐response curve.
In portal hypertensive animals, there was mainly a decreased potency but also a decreased efficacy of all tested adenosine agonists compared to normal animals. Concomitantly, there was a decreased adenosine plasma level and a decreased binding density of [3H]‐CGS 21680 and [3H]‐ZM 241385 to mesenteric artery membranes from portal hypertensive compared to normal rabbits.
These results indicate that A2A receptor activation is required for the adenosine‐induced mesenteric relaxation and that the decreased density of A2A receptors may contribute to the decreased relaxation induced by adenosine of mesenteric arteries in portal hypertensive animals.

British Journal of Pharmacology (2002) 135, 1324–1330; doi:10.1038/sj.bjp.0704575
Systemic pre‐treatment with a group II mGlu agonist, LY379268, reduces hyperalgesia in vivo
Authors: Sharpe E F , Kingston A E , Lodge D , Monn J A , Headley P M 
Published: January 2005

Previous studies investigating the role of metabotropic glutamate (mGlu) receptors in nociceptive processing have been hampered by the lack of systemically active, selective, ligands. This study investigates the possible analgesic and/or anti‐hyperalgesic properties of the most potent compound to date that has systemic agonist activity at group II mGlu receptors, LY379268.
In testing the drug in rats as an analgesic to acute noxious stimuli, LY379268 (in doses up to 3 mg kg−1 i.p.) did not affect withdrawal latencies to either mechanical or thermal stimulation.
However, when a 3 mg kg−1 dose was given prior to an intraplantar injection of carrageenan, the inflammatory hyperalgesia that developed was significantly delayed compared to saline pre‐treated controls, without affecting the inflammation of the paw. A similar dose of the mGlu‐inactive enantiomer, LY379267, was not anti‐hyperalgesic.
In a model of mouse tail withdrawal to warm water, LY379268 (12 mg kg−1 i.p.), given before a subcutaneous tail injection of capsaicin, reduced the subsequent neurogenic hyperalgesia.
Rota‐rod testing showed that the drug did not produce a motor impairment in rats at antihyperalgesic doses.
The results indicate that systemic activation of this group of mGlu receptors reduces both inflammatory and neurogenic thermal hyperalgesia.

British Journal of Pharmacology (2002) 135, 1255–1262; doi:10.1038/sj.bjp.0704583
A comparison of the efficacy of carbamazepine and the novel anti‐epileptic drug levetiracetam in the tetanus toxin model of focal complex partial epilepsy
Authors: Doheny H C , Whittington M A , Jefferys J G R , Patsalos P N 
Published: January 2005

The tetanus toxin seizure model, which is associated with spontaneous and intermittent generalized and non‐generalized seizures, is considered to reflect human complex partial epilepsy. The purpose of the present study was to investigate and compare the anticonvulsant effects of carbamazepine with that of levetiracetam, a new anti‐epileptic drug in this model.One μl of tetanus toxin solution (containing 12 mLD50 μl−1of tetanus toxin) was placed stereotactically into the rat left hippocampus resulting in generalized and non‐generalized seizures. Carbamazepine (4 mg kg−1 h−1) and levetiracetam (8 and 16 mg kg−1 h−1) were administered during a 7 day periodviaan osmotic minipump which was placed in the peritoneal cavity.Carbamazepine (4 mg kg−1 h−1) exhibited no significant anticonvulsant effect, compared to control, when the entire 7 day study period was evaluated but the reduction in generalized seizures was greater (35.5%) than that for non‐generalized seizures (12.6%). However, during the first 2 days of carbamazepine administration a significant reduction in both generalized seizure frequency (90%) and duration (25%) was observed. Non‐generalized seizures were unaffected. This time‐dependent anticonvulsant effect exactly paralleled the central (CSF) and peripheral (serum) kinetics of carbamazepine in that steady‐state concentrations declined over time, with the highest concentrations achieved during the first 2 days. Also there was a significant 27.3% reduction in duration of generalized seizures during the 7 day study period (P=0.0001).Levetiracetam administration (8 and 16 mg kg−1 h−1) was associated with a dose‐dependent reduction in the frequency of both generalized (39 v 57%) and non‐generalized (36 v 41%) seizures. However, seizure suppression was more substantial for generalized seizures. Also a significant dose‐dependent reduction in overall generalized seizure duration was observed.These data provide experimental evidence for the clinical efficacy of levetiracetam for the management of patients with complex partial seizures. Furthermore, levetiracetam probably does not act by preventing ictogenesisper sebut acts to reduce seizure severity and seizure generalization.British Journal of Pharmacology(2002)135, 1425–1434; doi:10.1038/sj.bjp.0704606
Endothelial dysfunction in aging animals: the role of poly(ADP‐ribose) polymerase activation
Authors: Pacher Pál , Mabley Jon G , Soriano Francisco G , Liaudet Lucas , Komjáti Katalin , Szabó Csaba 
Published: January 2005

Recent work has demonstrated the production of reactive oxygen and nitrogen species in the vasculature of aging animals. Oxidant induced cell injury triggers the activation of nuclear enzyme poly(ADP ribose) polymerase (PARP) leading to endothelial dysfunction in various pathophysiological conditions (reperfusion, shock, diabetes). Here we studied whether the loss of endothelial function in aging rats is dependent upon the PARP pathway within the vasculature. Young (3 months‐old) and aging (22 months‐old) Wistar rats were treated for 2 months with vehicle or the PARP inhibitor PJ34. In the vehicle‐treated aging animals there was a significant loss of endothelial function, as measured by the relaxant responsiveness of vascular rings to acetylcholine. Treatment with PJ34, a potent PARP inhibitor, restored normal endothelial function. There was no impairment of the contractile function and endothelium‐independent vasodilatation in aging rats. Furthermore, we found no deterioration in the myocardial contractile function in aging animals. Thus, intraendothelial PARP activation may contribute to endothelial dysfunction associated with aging.British Journal of Pharmacology (2002) 135, 1347–1350; doi:10.1038/sj.bjp.0704627
Aponecrotic, antiangiogenic and antiproliferative effects of a novel dextran derivative on breast cancer growth in vitro and in vivo
Authors: Benedetto Mélanie Di , Starzec Anna , Colombo Bruno M , Briane Dominique , Perret Gérard Y , Kraemer Michel , Crépin Michel 
Published: January 2005

1 Since the sodium phenylacetate (NaPa) was reported to enhance the inhibitory effect of carboxymethyl benzylamide dextran (CMDB) on the breast cancer growth, we performed the esterification of CMDB with NaPa to obtain a new drug carrying the characteristics of these two components. A new molecule, phenylacetate carboxymethyl benzylamide dextran, was named NaPaC.
We investigated in vitro and in vivo the effects of NaPaC on MCF‐7ras cell growth as well as its apoptotic and antiangiogenic effects in comparison to NaPa and CMDB. In addition, we assessed in vitro the antiproliferative effects of these drugs on other breast cancer cells, including MDA‐MB‐231, MDA‐MB‐435 and MCF‐7.
In vitro, NaPaC inhibited MCF‐7ras cell proliferation by 40% at concentration lower than that of CMDB and NaPa (12 μM vs 73 μM and 10 mM). IC50s were 6 and 28 μM for NaPaC and CMDB, respectively. The similar results were obtained for three other breast cancer cell lines. NaPaC reduced the DNA replication and induced cell recruitment in G0/G1 phase more efficiently than its components. Moreover, it induced a cell death at concentration 1000‐fold lower than NaPa.
In vivo, CMDB (150 mg kg−1) and NaPa (40 mg kg−1) inhibited the MCF‐7ras tumour growth by 37 and 57%, respectively, whereas NaPaC (15 mg kg−1) decreased tumour growth by 66% without toxicity.
NaPa or CMDB reduced the microvessel number in tumour by 50% after 7 weeks of treatment. NaPaC had the same effect after only 2 weeks. After 7 weeks, it generated a large necrosis area without detectable microvessels. In vitro, NaPaC inhibited human endothelial cell proliferation more efficiently than CMDB or NaPa. NaPaC interacts with vascular endothelial growth factor as observed by affinity electrophoresis.
NaPaC acts like NaPa and CMDB but in more potent manner than components used separately. Its antiproliferative, aponecrotic and anti‐angiogenic actions make it a good candidate for a new anti‐cancer drug.

British Journal of Pharmacology (2002) 135, 1859–1871; doi:10.1038/sj.bjp.0704645