bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temporal variation in endotoxin‐induced vascular hyporeactivity in a rat mesenteric artery organ culture model
Authors: O'Brien A J , Wilson A J , Sibbald R , Singer M , Clapp L H 
Published: January 2005

Endotoxin‐induced vascular hyporeactivity to phenylephrine (PE) is well described in rodent aorta, but has not been investigated in smaller vessels in vitro.
Segments of rat superior mesenteric artery were incubated in culture medium with or without foetal bovine serum (10%) for 6, 20 or 46 h in the presence or absence of bacterial lipopolysaccharide (LPS; 1 – 100 μg ml−1).
Contractions to PE were measured with or without nitric oxide synthase (NOS) inhibitors: L‐NAME (300 μM), aminoguanidine (AMG; 400 μM) 1400W (10 μM) and GW273629 (10 μM); the guanylyl cyclase inhibitor, ODQ (3 μM); the COX‐2 inhibitor, NS‐398 (10 μM). Contractile responses to the thromboxane A2 mimetic, U46619 were also assessed.
In the presence of serum, LPS induced hyporeactivity at all time points. In its absence, hyporeactivity only occurred at 6 and 20 h.
L‐NAME and AMG fully reversed hyporeactivity at 6 h, whereas they were only partially effective at 20 h and not at all at 46 h. In contrast partial reversal of peak contraction was observed with 1400W (62% at 46 h), GW273629 (57% at 46 h) and ODQ (75% at 46 h). COX‐2 inhibition produced no reversal.
In contrast to PE, contractions to U46619 were substantially less affected by LPS.
We describe a well‐characterized reproducible model of LPS‐induced hyporeactivity, which is largely mediated by the NO‐cyclic GMP‐dependent pathway. Importantly, long‐term (2‐day) production of NO via iNOS is demonstrated. Moreover, conventional doses of L‐NAME and AMG became increasingly ineffective over time. Thus, the choice of inhibitor merits careful consideration in long‐term models.

British Journal of Pharmacology (2001) 133, 351–360; doi:10.1038/sj.bjp.0704079
Differential prevention of morphine amnesia by antisense oligodeoxynucleotides directed against various Gi‐protein α subunits
Authors: Galeotti Nicoletta , Ghelardini Carla , Bartolini Alessandro 
Published: January 2005

The effect of the i.c.v. administration of pertussis toxin (PTX) and antisense oligodeoxynucleotide directed against the α subunit of different Gi‐proteins (anti‐Giα1, anti‐Giα2, anti‐Giα3) on amnesia induced by morphine was evaluated in the mouse passive avoidance test.
The administration of morphine (6 – 10 mg kg−1 i.p.) immediately after the training session produced amnesia that was prevented by PTX (0.25 μg per mouse i.c.v.) administered 7 days before the passive avoidance test.
Anti‐Giα1 (6.25 μg per mouse i.c.v.) and anti‐Giα3 (12.5 μg per mouse i.c.v.), administered 18 and 24 h before the training session, prevented the morphine amnesia. By contrast, pretreatment with anti‐Giα2 (3.12 – 25 μg per mouse i.c.v.) never modified the impairment of memory processes induced by morphine.
At the highest effective doses, none of the compounds used impaired motor coordination, as revealed by the rota rod test, nor modified spontaneous motility and inspection activity, as revealed by the hole board test.
These results suggest the important role played by Gi1 and Gi3 protein subtypes in the transduction mechanism involved in the impairment of memory processes produced by morphine.

British Journal of Pharmacology (2001) 133, 267–274; doi:10.1038/sj.bjp.0704081
CXC chemokines, MIP‐2 and KC, induce P‐selectin‐dependent neutrophil rolling and extravascular migration in vivo
Authors: Zhang Xiao Wei , Liu Qing , Wang Yusheng , Thorlacius Henrik 
Published: January 2005

The purpose of this study was to examine the impact of CXC chemokines, i.e. macrophage inflammatory protein‐2 (MIP‐2) and KC, on leukocyte‐endothelium interactions in detail and to evaluate the role of P‐selectin by use of intravital microscopy in the mouse cremaster muscle.
Administration of MIP‐2 and KC provoked a dose (5 – 500 ng)‐ and time (0 – 4 h)‐dependent increase in leukocyte rolling, adhesion and tissue recruitment. Neutrophils comprised more than 92% of the leukocyte response. Pretreatment with an antibody directed against P‐selectin (RB40.34) significantly inhibited MIP‐2‐ and KC‐induced leukocyte rolling by more than 96%. This marked decrease in rolling abolished firm adhesion and extravascular accumulation of neutrophils (>89% reduction), suggesting that CXC chemokines induce P‐selectin‐dependent rolling, which in turn apparently is a precondition for the subsequent stationary adhesion and extravasation of neutrophils.
Moreover, the extravascular recruitment of leukocytes was evaluated in whole‐mounts of the cremaster muscle without preceding intravital microscopy. Using this approach, it was again observed that MIP‐2‐ and KC‐induced neutrophil accumulation was completely dependent onP‐selectin function. In contrast to the CXC chemokines, administration of the classical chemoattractant formyl‐methionyl leucyl phenylalanine (fMLP) did not provoke extravascular tissue accumulation of neutrophils.
We could not detect gene expression of CXCR2 in murine endothelial cells, whereas neutrophils were positive, indicating that the stimulatory effect of CXC chemokines on leukocyte‐endothelium interactions is not a direct effect on the endothelium but rather an indirect effect via activation of an intermediary tissue cell. However, challenge with MIP‐2 and KC did not increase the number of degranulated mast cells.
In conclusion, our data demonstrate that CXC chemokines induce all steps in the extravasation process of leukocytes, including rolling, adhesion and transmigration in vivo. Moreover, these results show that P‐selectin plays a critical role in MIP‐2 and KC provoked neutrophil recruitment as a critical mediator of initial leukocyte rolling. Additionally, our study suggest that a restricted action of MIP‐2 and KC on neutrophils is far too simplistic to explain the complex mechanisms of action of CXC chemokines on neutrophil infiltration in vivo.

British Journal of Pharmacology (2001) 133, 413–421; doi:10.1038/sj.bjp.0704087
Acute effect of the dual angiotensin‐converting enzyme and neutral endopeptidase 24‐11 inhibitor mixanpril on insulin sensitivity in obese Zucker rat
Authors: Arbin V , Claperon N , Fournié‐Zaluski M ‐C , Roques B P , Peyroux J 
Published: January 2005

The aim of this study was to determine whether acute dual angiotensin‐converting enzyme (ACE)/neutral endopeptidase 24‐11 (NEP) inhibition could improve whole body insulin‐mediated glucose disposal (IMGD) more than ACE inhibition alone and whether this effect was mediated by the kinin‐nitric oxide (NO) pathway activation.
We therefore compared in anaesthetized obese (fa/fa) Zucker rats (ZOs) the effects of captopril (2 mg kg−1, i.v.+2 mg kg−1 h−1), retrothiorphan (25 mg kg−1, i.v. +25 mg  kg−1 h−1), a selective NEP inhibitor, and mixanpril (25 mg kg−1, i.v.+25 mg kg−1 h−1), a dual ACE/NEP inhibitor, on IMGD using hyperinsulinaemic euglycaemic clamp technique. The role of the kinin‐NO pathway in the effects of mixanpril was tested using a bradykinin B2 receptor antagonist (Hoe‐140, 300 μg kg−1) and a NO‐synthase inhibitor (Nω‐nitro‐L‐arginine methyl ester, L‐NAME, 10 mg kg−1 i.v. +10 mg kg−1 h−1) as pretreatments.
Insulin sensitivity index (ISI) was lower in ZO controls than in lean littermates. Increases in ISI were observed in captopril‐ and retrothiorphan‐treated ZOs. In mixanpril‐treated ZOs, ISI was further increased, compared to captopril‐ and retrothiorphan‐treated ZOs.
In ZOs, Hoe‐140 and L‐NAME alone did not significantly alter and slightly reduced the ISI respectively. Hoe‐140 and L‐NAME markedly inhibited the ISI improvement induced by mixanpril.
These results show that in obese insulin‐resistant Zucker rats, under acute conditions, NEP or ACE inhibition can improve IMGD and that dual ACE/NEP inhibition improves IMGD more effectively than does either single inhibition. This effect is linked to an increased activation of the kinin‐NO pathway.

British Journal of Pharmacology (2001) 133, 495–502; doi:10.1038/sj.bjp.0704098
HET0016, a potent and selective inhibitor of 20‐HETE synthesizing enzyme
Authors: Miyata Noriyuki , Taniguchi Kazuo , Seki Takayuki , Ishimoto Tsuyoshi , Sato‐Watanabe Mariko , Yasuda Yoshiko , Doi Mariko , Kametani Shunichi , Tomishima Yasumitsu , Ueki Tomokazu , Sato Masakazu , Kameo Kazuya 
Published: January 2005

The present study examined the inhibitory effects of N‐Hydroxy‐N′‐(4‐butyl‐2‐methylphenyl)‐formamidine (HET0016) on the renal metabolism of arachidonic acid by cytochrome P450 (CYP) enzymes. HET0016 exhibited a high degree of selectivity in inhibiting the formation of 20‐hydroxy‐5,8,11,14‐eicosatetraenoic acid (20‐HETE) in rat renal microsomes. The IC50 value averaged 35±4 nM, whereas the IC50 value for inhibition of the formation of epoxyeicosatrienoic acids by HET0016 averaged 2800±300 nM. In human renal microsomes, HET0016 potently inhibited the formation of 20‐HETE with an IC50 value of 8.9±2.7 nM. Higher concentrations of HET0016 also inhibited the CYP2C9, CYP2D6 and CYP3A4‐catalysed substrates oxidation with IC50 values of 3300, 83,900 and 71,000 nM. The IC50 value for HET0016 on cyclo‐oxygenase activity was 2300 nM. These results indicate that HET0016 is a potent and selective inhibitor of CYP enzymes responsible for the formation of 20‐HETE in man and rat.British Journal of Pharmacology (2001) 133, 325–329; doi:10.1038/sj.bjp.0704101
Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone
Authors: Varró András , Takács János , Németh Miklós , Hála Ottó , Virág László , Iost Norbert , Baláti Beáta , Ágoston Márta , Vereckei András , Pastor Gilbert , Delbruyère Martine , Gautier Patrick , Nisato Dino , Papp Julius Gy 
Published: January 2005

The electrophysiological effects of dronedarone, a new nonionidated analogue of amiodarone were studied after chronic and acute administration in dog Purkinje fibres, papillary muscle and isolated ventricular myocytes, and compared with those of amiodarone by applying conventional microelectrode and patch‐clamp techniques.
Chronic treatment with dronedarone (2×25 mg−1 kg−1 day p.o. for 4 weeks), unlike chronic administration of amiodarone (50 mg−1 kg−1 day p.o. for 4 weeks), did not lengthen significantly the QTc interval of the electrocardiogram or the action potential duration (APD) in papillary muscle. After chronic oral treatment with dronedarone a small, but significant use‐dependent Vmax block was noticed, while after chronic amiodarone administration a strong use‐dependent Vmax depression was observed.
Acute superfusion of dronedarone (10 μM), similar to that of amiodarone (10 μM), moderately lengthened APD in papillary muscle (at 1 Hz from 239.6±5.3 to 248.6±5.3 ms, n=13, P<0.05), but shortened it in Purkinje fibres (at 1 Hz from 309.6±11.8 to 287.1±10.8 ms, n=7, P<0.05).
Both dronedarone (10 μM) and amiodarone (10 μM) superfusion reduced the incidence of early and delayed afterdepolarizations evoked by 1 μM dofetilide and 0.2 μM strophantidine in Purkinje fibres.
In patch‐clamp experiments 10 μM dronedarone markedly reduced the L‐type calcium current (76.5±0.7 %, n=6, P<0.05) and the rapid component of the delayed rectifier potassium current (97±1.2 %, n=5, P<0.05) in ventricular myocytes.
It is concluded that after acute administration dronedarone exhibits effects on cardiac electrical activity similar to those of amiodarone, but it lacks the ‘amiodarone like’ chronic electrophysiological characteristics.

British Journal of Pharmacology (2001) 133, 625–634; doi:10.1038/sj.bjp.0704106
The synthetic cannabinoid WIN55,212‐2 attenuates hyperalgesia and allodynia in a rat model of neuropathic pain
Authors: Bridges Daniel , Ahmad Kamran , Rice Andrew S C 
Published: January 2005

The analgesic properties of the synthetic cannabinoid WIN55,212‐2 were investigated in a model of neuropathic pain. In male Wistar rats, bilateral hind limb withdrawal thresholds to cold, mechanical and noxious thermal stimuli were measured. Following this, unilateral L5 spinal nerve ligation was performed. Seven days later, sensory thresholds were reassessed and the development of allodynia to cold and mechanical stimuli and hyperalgesia to a noxious thermal stimulus confirmed.
The effect of WIN55,212‐2 (0.1 – 5.0 mg kg−1, i.p.) on the signs of neuropathy was then determined; there was a dose related reversal of all three signs of painful neuropathy at doses which did not generally alter sensory thresholds in the contralateral unligated limb. This effect was prevented by co‐administration of the CB1 receptor antagonist SR141716a, but not by co‐administration of the CB2 receptor antagonist SR144528, suggesting this action of WIN55,212‐2 is mediated via the CB1 receptor. Administration of SR141716a alone had no affect on the observed allodynia and hyperalgesia, which does not support the concept of an endogenous analgesic tone.
These data indicate that cannabinoids may have therapeutic potential in neuropathic pain, and that this effect is mediated through the CB1 receptor.

British Journal of Pharmacology (2001) 133, 586–594; doi:10.1038/sj.bjp.0704110
Generation of 8‐epi‐prostaglandin F2α in isolated rat kidney glomeruli by a radical‐independent mechanism
Authors: Klein Thomas , Neuhaus Katrin , Reutter Felix , Nüsing Rolf M 
Published: January 2005

Isoprostanes comprise a group of free radical‐catalyzed products of arachidonic acid. However, there is recent evidence pointing towards an enzyme‐dependent formation of isoprostanes.
With the use of isolated rat glomeruli we addressed the mechanisms of isoprostane generation. Synthesis of prostanoids and isoprostanes, including 8‐epi‐PGF2α, was studied under conditions favouring radical formation.
Cultured glomeruli formed different prostanoids including 8‐epi‐PGF2α. Upon LPS challenge cyclo‐oxygenase (COX)‐2 expression was enhanced, and this was paralleled by a 2–9‐fold increase in prostanoid formation, including isoprostanes. Addition of COX‐isoform unselective inhibitors (diclofenac, indomethacin) or a selective inhibitor (NS‐398) suppressed the synthesis of prostanoids, 8‐epi‐PGF2α and total isoprostane fraction; however, inhibition of the latter was less pronounced.
Antioxidants such as butylated hydroxytoluene (BHT), nordihydroguaiaretic acid (NDGA), or dimethylurea exhibited an only minimal inhibitory effect on 8‐epi‐PGF2α synthesis. Moreover, ROS‐generating drugs (menadione, methylviologen) or NADPH‐driven radical formation were unable to cause the generation of significant amounts of 8‐epi‐PGF2α by rat glomeruli. In contrast, the total isoprostane fraction could be increased by menadione addition.
These data provide further evidence for a radical‐independent, but COX‐dependent formation of 8‐epi‐PGF2α in renal tissue. Regarding the other isoprostanes, both radicals and COX enzymes contribute to their formation. Based on our data we assume that elevated release of vasoactive 8‐epi‐PGF2α has to be expected under conditions when the prostanoid system in the kidney is stimulated, e.g. under inflammatory conditions. Regarding renal oxidative injuries, the usefulness of 8‐epi‐PGF2α as a representative marker molecule of oxidative stress has to be questioned.

British Journal of Pharmacology (2001) 133, 643–650; doi:10.1038/sj.bjp.0704111
Blockade by ruthenium red of tissue factor‐initiated coagulation
Authors: Chu Arthur J , Wang Zhen‐Guo , Nwobi Obioma I , Beydoun Salwa 
Published: January 2005

The ability of ruthenium red (RuR) to inhibit tissue factor (TF)‐initiated blood coagulation was demonstrated at the protein and cellular levels as well as in human plasma.
In a single‐stage clotting assay, RuR concentration‐dependently inhibited rabbit brain thromboplastin (rbTF)‐induced coagulation and offset bacterial endotoxin (LPS)‐induced monocytic TF (mTF) hypercoagulation; the IC50s were estimated at 7.5 and 12.3 μM, respectively.
A 15‐min preincubation of RuR with rbTF or monocyte suspension resulted in the pronounced inhibition with a significantly lowered IC50 at 1.8 or 7.7 μM for rbTF or mTF procoagulation, respectively. The differences in IC50s between rbTF and mTF without or with the preincubation indicated that TF was a primary target for RuR action.
The effect of RuR on the physiological function of TF in FVII activation was demonstrated by the proteolytic cleavage of FVII zymogen to its active forms of serine protease on Western blotting analyses. RuR readily blocked TF‐catalyzed FVII activation (diminished FVIIa formation), thus down regulating the initiation of blood coagulation.
Inclusion of RuR into human plasma samples in vitro significantly prolonged prothrombin time, indicating the depressed coagulation. FVII activity was inhibited by 30–60% depending on the dose; as a result, FX activity also decreased. However, RuR showed no effect on thrombin time. Thus, RuR inhibited FVII activation to block the initiation of coagulation.

British Journal of Pharmacology (2001) 133, 659–664; doi:10.1038/sj.bjp.0704116
Dominant role of L‐ and P‐selectin in mediating CXC chemokine‐induced neutrophil migration in vivo
Authors: Miotla Jadwiga M , Ridger Victoria C , Hellewell Paul G 
Published: January 2005

The role of selectins in neutrophil emigration in response to the CXC chemokines KC and MIP‐2 was investigated in wild type and P‐selectin deficient mice.
Intrapleural injection of KC or MIP‐2 induced a rapid and specific neutrophil accumulation. Emigration 2 h after KC or MIP‐2 was reduced 83 – 88% by anti‐L‐selectin mAb and 53 – 63% by anti‐P‐selectin mAb. Co‐administration of anti‐L‐ and P‐selectin mAbs abolished neutrophil migration induced by either chemokine.
An anti‐E‐selectin mAb tested alone did not affect KC‐induced neutrophil migration after 2 or 4 h. Moreover, anti‐E‐selectin did not have an additive inhibitory effect on KC‐induced neutrophil migration compared with P‐selectin blockade alone. This was found when neutrophil migration was measured at 2 and 4 h after KC.
Despite a blood neutrophilia, neutrophil migration at 2 and 4 h after KC was markedly smaller (by approximately 90%) in P‐selectin deficient mice compared with wild type animals. Responses at both time points were not decreased further in animals given E‐selectin mAb but were reduced to the PBS control level in the presence of anti‐L‐selectin.
In vitro study of cultured murine endothelial cells demonstrated that KC can directly increase cell surface P‐selectin expression.
These data suggest that CXC chemokine‐induced neutrophil accumulation is dependent on both neutrophil L‐selectin and a rapid upregulation of endothelial P‐selectin but there is no evidence for E‐selectin induction.

British Journal of Pharmacology (2001) 133, 550–556; doi:10.1038/sj.bjp.0704118
Identification and quantification of phosphodiesterase 4 subtypes in CD4 and CD8 lymphocytes from healthy and asthmatic subjects
Authors: Landells L J , Szilagy C M , Jones N A , Banner K H , Allen J M , Doherty A , O'Connor B J , Spina D , Page C P 
Published: January 2005

In the present study, for the first time, PDE4 subtypes were identified and semi‐quantified in both CD4 and CD8 lymphocytes from healthy and asthmatic individuals.
CD4 and CD8 lymphocytes from healthy and mild asymptomatic asthmatic subjects (receiving β‐agonist therapy only) were isolated from peripheral venous blood using appropriate antibody coated paramagnetic beads. PDE4 subtypes and β‐actin were identified by digoxigenin (DIG)‐labelling reverse transcriptase‐polymerase chain reaction and semi‐quantified by DIG‐detection enzyme‐linked immunosorbance assay.
In CD4 and CD8 lymphocytes PDE4A, PDE4B and PDE4D were detected, with no significant differences observed between healthy and asthmatic groups. In CD8 lymphocytes, enzyme subtype expression was lower and showed more intersubject variability.
In functional studies investigating the effects of various PDE inhibitors on PHA‐induced proliferation of mononuclear cells from healthy and asthmatic subjects, CDP840 (0.03–10 μM), rolipram (0.1–10 μM) and theophylline (10 μM–1 mM) inhibited PHA‐induced proliferation of mononuclear cells from healthy and asthmatic subjects in a concentration‐dependent manner, although no significant difference was observed between the groups investigated.
In additional studies, total monocyte cyclic AMP PDE activity was investigated in cells isolated from asthmatic subjects both prior to and 24 h after allergen challenge. Total monocyte cyclic AMP PDE activity remained unaffected following challenge of asthmatic subjects with either house dust mite or cat dander and was inhibited in a concentration‐dependent manner by rolipram (0.01–100 μM) both before and after allergen challenge.

British Journal of Pharmacology (2001) 133, 722–729; doi:10.1038/sj.bjp.0704120
The mechanism for the contraction induced by leukotriene C4 in guinea‐pig taenia coli
Authors: Ieiri Satoshi , Nishimura Junji , Hirano Katsuya , Suita Sachiyo , Kanaide Hideo 
Published: January 2005

The mechanism underlying the LTC4‐induced contraction of guinea‐pig taenia coli was determined using the simultaneous measurements of [Ca2+]i and force in whole muscle preparations. Additional experiments were performed in receptor coupled permeabilized preparation. For comparison purposes, the contraction which was induced by a typical G‐protein mediated agonist, carbachol was also characterized.
LTC4 induced a contraction in the guinea‐pig taenia coli in a concentration‐dependent manner. The maximal response was obtained at 100 nM and the EC50 value was 5.4±1.9 nM.
Both LTC4 and carbachol induced increases in [Ca2+]i and force. The maximum force induced by 100 nM LTC4 was significantly smaller than that induced by 10 μM carbachol, although an increase in [Ca2+]i produced by both agonists was similar. In the permeabilized preparations, carbachol, but not LTC4, induced an additional force development at a fixed Ca2+ concentration.
LTC4 induced no increase in [Ca2+]i and force in the Ca2+‐free solution, while carbachol induced transient increases in both [Ca2+]i and force in a Ca2+‐free solution.
Both diltiazem and SK&F 96365 significantly inhibited the LTC4− and carbachol‐induced increases in [Ca2+]i and force in normal PSS. The inhibitory pattern of [Ca2+]i by these drugs was also similar.
We thus conclude that LTC4 induces the contraction of the guinea‐pig taenia coli mainly through Ca2+ influx via both the diltiazem‐sensitive and SK&F 96365‐sensitive Ca2+ channels, without affecting either the Ca2+‐sensitivity or the intracellular Ca2+ release. These results indicated that the mechanism underlying the LTC4‐induced contraction differs greatly from that for conventional G‐protein mediated agonists, such as carbachol.

British Journal of Pharmacology (2001) 133, 529–538; doi:10.1038/sj.bjp.0704122
Y‐27632, an inhibitor of Rho‐kinase, antagonizes noradrenergic contractions in the rabbit and human penile corpus cavernosum
Authors: Rees Rowland W , Ralph David J , Royle Michael , Moncada Salvador , Cellek Selim 
Published: January 2005

We have examined the effect of an inhibitor of Rho‐kinase, (+)‐(R)‐trans‐4‐(1‐aminoethyl)‐N‐(4‐pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate (Y‐27632), on the contractions elicited by noradrenergic nerve stimulation and by phenylephrine in the human and rabbit penile corpus cavernosum. In both tissues, after treatment with scopolamine (10 μM) and NG‐nitro‐L‐arginine methyl ester (L‐NAME; 300 μM), electrical field stimulation (EFS) elicited noradrenergic contractions. These contractions were inhibited by Y‐27632 in a concentration‐dependent manner. The compound caused concentration‐dependent relaxation of phenylephrine‐contracted tissues, which were treated with scopolamine (10 μM), guanethidine (10 μM) and L‐NAME (300 μM). These results suggest that Rho‐kinase is involved in noradrenergic contractile pathway in the cavernosal smooth muscle of the penis.British Journal of Pharmacology (2001) 133, 455–458; doi:10.1038/sj.bjp.0704124