bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypoxia‐induced down‐regulation of CYP1A1/1A2 and up‐regulation of CYP3A6 involves serum mediators
Authors: Fradette Caroline , Bleau Anne‐Marie , Pichette Vincent , Chauret Nathalie , Du Souich Patrick 
Published: November 2002

Acute moderate hypoxia modifies the catalytic activity and expression of certain isoenzymes of hepatic cytochrome P450 (P450). The aim of this study was to document whether hypoxia affects hepatic P450 directly or through the release of serum mediators.Rabbits were subjected to a FiO2of 8% for 48 h, sacrificed, and serum and hepatocytes were isolated; hepatocytes from control and rabbits with hypoxia were incubated with serum from control and hypoxic rabbits for 4 and 24 h, and total P450 content, CYP1A1, 1A2 and 3A6 activities and expressions were assessed. Sera were fractionated by size exclusion chromatography and fractions tested for their ability to modify activity and amount of P450, and serum mediators were identified through neutralization experiments.Total serum and fractions with proteins of 15–23 and 65–94 kDa of Mrreduced P450 content and expression of CYP1A1, 1A2 and 3A6, as well asCYP1A1,1A2and3A6mRNA. Total serum and the fraction with 32–44 kDa proteins increased CYP3A6 activity and protein and mRNA. The serum mediators implicated in the decrease in activity and expression of CYP1A1, 1A2 and 3A6 were interferon‐γ (IFN‐γ), interleukin‐1β (IL‐1β) and IL‐2. Erythropoietin (Epo) was partly responsible for the increase in P450 content and CYP3A6 expression.In conclusion, acute moderate hypoxia diminishes the activity and expression of CYP1A1, 1A2 andCYP1A1,1A2mRNA, and increases CYP3A6 protein, activity andCYP3A6mRNA. Several mechanisms contribute to these changes in P450, among them the release of cytokines acting as serum mediators.British Journal of Pharmacology(2002)137, 881–891. doi:10.1038/sj.bjp.0704933
Inhibitors of poly(ADP‐ribose) polymerase‐1 suppress transcriptional activation in lymphocytes and ameliorate autoimmune encephalomyelitis in rats
Authors: Chiarugi Alberto 
Published: November 2002

In the presence of genotoxic stress poly(ADP‐ribose) polymerase‐1 (PARP‐1) leads to NAD+ and ATP depletion, participating in the pathogenesis of several disorders including inflammation. Accordingly, chemical inhibitors of PARP‐1 are efficacious anti‐inflammatories, albeit the underlying molecular mechanisms are still under debate.
This study investigated the effect of the PARP‐1 inhibitors 6(5H)‐phenanthridinone and benzamide as well as that of benzoic acid, an inactive analogue of benzamide, on development of experimental allergic encephalomyelitis (EAE) in rats. Both 6(5H)‐phenanthridinone and benzamide attenuated development of EAE, reducing clinical score, neuroimmune infiltration and expression of inflammatory mediators such as inducible nitric oxide synthase, interleukin‐1β and ‐2, cyclooxygenase‐2, tumour necrosis factor‐α and interferon‐γ in the spinal cord of myelin‐immunized rats. Importantly, no evidence of NAD+ and ATP depletion as well as poly(ADP‐ribose) formation was detected in the spinal cord.
By contrast, a robust formation of poly(ADP‐ribose) occurred in B‐ and T‐cell areas in lymph nodes of myelin‐immunized rats and was suppressed by the treatment with 6(5H)‐phenanthridinone and benzamide. In cultures of activated rat lymphocytes, 6(5H)‐phenanthridinone and benzamide reduced the DNA‐binding activity of NF‐κB and AP‐1 and transcription of pro‐inflammatory cytokines such as interleukin‐2, interferon‐γ and tumour necrosis factor‐α.
Notably, benzoic acid did not reproduce the in vivo and in vitro effects of its parent compound.
These findings indicate that PARP‐1 promotes transcriptional activation in lymphocytes and inhibitors of its enzymatic activity are useful for the treatment of autoimmune disorders of the central nervous system.

British Journal of Pharmacology (2002) 137, 761–770. doi:10.1038/sj.bjp.0704934
Selective inhibitors of cyclo‐oxygenase‐2 (COX‐2) induce hypoalgesia in a rat paw model of inflammation
Authors: Francischi J N , Chaves C T , Moura A C L , Lima A S , Rocha O A , Ferreira‐Alves D L , Bakhle Y S 
Published: November 2002

It is well‐established that inhibitors of cyclo‐oxygenase (COX) and hence of prostaglandin (PG) biosynthesis reverse inflammatory hyperalgesia and oedema in both human and animal models of inflammatory pain.
Paw oedema and hyperalgesia in rats were induced by injecting carrageenan (250 μg paw−1) into a hindpaw. Both inflammatory responses were followed for 24 h after the injection, measuring hyperalgesia by decreased pain threshold in the paws and oedema by plethysmography.
Three selective inhibitors of cyclo‐oxygenase‐2 (COX‐2), celecoxib, rofecoxib and SC 236, given systemically in a range of doses, before the inflammatory stimulus, abolished carrageenan‐induced hyperalgesia with little reduction of oedema. These inhibitors also induced hypoalgesia, increasing nociceptive thresholds in the inflamed paw above normal, non‐inflamed levels. This hypoalgesia was lost at the higher doses of the selective inhibitors, although hyperalgesia was still prevented.
In paws injected with saline only, celecoxib, given at the dose inducing the maximum hypoalgesia after carrageenan, did not alter the nociceptive thresholds.
Two non‐selective inhibitors of COX‐2, indomethacin and piroxicam, abolished hyperalgesia and reduced oedema but did not induce hypoalgesia.
Celecoxib given locally into the paw also abolished inflammatory hyperalgesia and induced hypoalgesia without reducing oedema.
We conclude that hypoalgesia is expressed only over a critical range of COX‐2 inhibition and that concomitant inhibition of COX‐1 prevents expression of hypoalgesia, although hyperalgesia is still prevented.
Our results suggest a novel anti‐nociceptive pathway mediating hypoalgesia, involving COX‐2 selectively and having a clear peripheral component. This peripheral component can be further explored for therapeutic purposes.

British Journal of Pharmacology (2002) 137, 837–844. doi:10.1038/sj.bjp.0704937
The mechanisms for tachykinin‐induced contractions of the rabbit corpus cavernosum
Authors: Takahashi Ryosuke , Nishimura Junji , Hirano Katsuya , Naito Seiji , Kanaide Hideo 
Published: November 2002

This study was designed to investigate the mechanisms for the contractions induced by tachykinins (substance P (SP), neurokinin A (NKA) and neurokinin B (NKB)) in the rabbit corpus cavernosum strips, using fura‐PE3 fluorimetry and α‐toxin permeabilization.
Tachykinins induced contractions in the rabbit corpus cavernosum in a concentration‐dependent manner. The potency order was SP>NKA>NKB.
The tachykinin‐induced contractions were enhanced by phosphoramidon (PPAD), an endopeptidase inhibitor, but not by Nω‐nitro‐L‐arginine methylester (L‐NAME).
The NK1 receptor selective antagonist, SR 140333 significantly inhibited the tachykinin‐induced contractions. Although the NK2 receptor selective antagonist, SR 48968 alone did not influence the effects of tachykinins, it potentiated the inhibitory effect of SR 140333. The NK3 receptor selective antagonist, SR142801 had no effect.
In the rabbit corpus cavernosum, tachykinins induced sustained increases in [Ca2+]i and tension in normal PSS, while only small transient increases in [Ca2+]i and tension were observed in Ca2+‐free solution.
In α‐toxin permeabilized preparations, tachykinins induced an additional force development at a constant [Ca2+]i.
These results indicated that in the rabbit corpus cavernosum: (1) Tachykinins induced contractions by increasing both the [Ca2+]i and myofilament Ca2+ sensitivity; (2) The tachykinin‐induced [Ca2+]i elevations were mainly due to the Ca2+ influx; (3) Tachykinin‐induced contractions were mainly mediated through the activation of NK1 receptor expressed in the rabbit corpus cavernosum smooth muscle, and affected by the endopeptidase activity and (4) Tachykinins may thus play a role in controlling the corpus cavernosum tone.

British Journal of Pharmacology (2002) 137, 845–854. doi:10.1038/sj.bjp.0704938
A novel phenoxazine derivative suppresses surface IgM expression in DT40 B cell line
Authors: Gao Sanyang , Takano Tomoko , Sada Kiyonao , He Jinsong , Noda Chiseko , Hori‐Tamura Naoko , Tomoda Akio , Yamamura Hirohei 
Published: November 2002

2‐amino‐4, 4α‐dihydro‐4α, 7‐dimethyl‐3H‐phenoxazine‐3‐one (Phx) has been demonstrated to be an actinomycin D‐like phenoxazine, and to display anti‐tumour activity.
In this study, we report on the effect of Phx on B cell antigen receptor (BCR) and receptor‐mediated signalling in DT40 B cells.
Treatment of B cells with Phx for 12 h inhibited BCR‐stimulated tyrosine phosphorylation of cellular proteins.
B cells exposed to Phx exhibited down‐regulation of surface IgM which is part of BCR. In contracts with actinomycin D, Phx rapidly reduced the expression of IgM without decreasing the expression of other signalling molecules.
Analysis with confocal microscopy demonstrated that Phx treatment reduced IgM expression both at the cell surface and inside the cell.
Treatment of B cells with Phx resulted in the reduction of IgM secretion. Since MG‐132, a proteasomal inhibitor, restored IgM contents to the control levels, Phx has the specific effect of accelerating IgM degradation.
These results suggest that Phx down‐regulates the expression of IgM and inhibits BCR‐mediated signalling and IgM secretion. Phx may be useful as an immunosuppressive agent for therapeutic purposes.

British Journal of Pharmacology (2002) 137, 749–755. doi:10.1038/sj.bjp.0704939
Guanidinoethyl sulphonate is a glycine receptor antagonist in striatum
Authors: Sergeeva Olga A , Chepkova Aisa N , Haas Helmut L 
Published: November 2002

Guanidinoethyl sulphonate (GES) is an analogue of taurine and an inhibitor of taurine transport. Interactions of GES with GABAA and glycine receptors are studied by whole cell recording and fast drug application in isolated striatal neurons of the mouse.
We confirm that GES is a weak agonist at GABAA receptors, and is able to antagonize GABA‐evoked responses. GES did not gate GlyR.
GES antagonized glycine responses in a concentration‐dependent and surmountable manner. Glycine dose–response curves were shifted to the right by GES (0.5 mM), yielding EC50s and Hill coefficients of 62 μM and 2.5 in control, 154 μM and 1.3 in the presence of GES.
GlyR‐mediated taurine responses were competitively antagonized by GES. Taurine dose–response curves, in contrast to the glycine dose–response curves were shifted by GES to the right in a parallel manner.
The GlyR‐block by GES was not voltage‐dependent.
In contrast to our findings in the mouse, in rat striatal neurons which lack expression of the α3 GlyR subunit, GES shifted the glycine dose–response curve to the right in a parallel way without affecting the maximal response. Subtype‐specificity of the GES action at GlyR must await further investigation in artificial expression systems.
We conclude that GES is a competitive antagonist at GlyR. The antagonistic action of GES at inhibitory ionotropic receptors can explain its epileptogenic action. Care must be taken with the interpretation of data on GES evoked taurine release.

British Journal of Pharmacology (2002) 137, 855–860. doi:10.1038/sj.bjp.0704940
Modulation of reflexly evoked vagal bradycardias by central 5‐HT1A receptors in anaesthetized rabbits
Authors: Skinner Matthew R , Ramage Andrew G , Jordan David 
Published: November 2002

The role of central 5‐HT1A receptors in the control of the bradycardia and changes in central respiratory drive, renal nerve activity and blood pressure evoked by stimulating cardiopulmonary afferents with phenylbiguanide, baroreceptors by electrical stimulation of the aortic nerve and chemoreceptors by injections of sodium cyanide (NaCN) in atenolol‐pretreated anaesthetized rabbits were studied.
Buspirone (100 μg kg−1; i.c.) potentiated the bradycardia (increase in R‐R interval) and the changes in blood pressure and renal nerve activity evoked by all three reflexes. These effects could be attenuated by pretreatment with the 5‐HT1A receptor antagonist WAY‐100635 (100 μg kg−1); i.v.), which alone had no effect on these reflex‐evoked changes. However, WAY‐100635 (100 μg kg−1; i.c.) did attenuate these reflex‐evoked responses produced by activation of cardiopulmonary and aortic baroreceptors but not that caused by stimulation of chemoreceptors. When given i.v., buspirone was less effective in modulating the responses evoked by these three reflexes.
The present data are consistent with the view that central 5‐HT1A receptors play a role in the reflex activation of cardiac preganglionic vagal motoneurones. However, although antagonists of 5‐HT1A receptors affected the responses evoked by cardiopulmonary and aortic nerve afferents, they were not effective on chemoreceptor reflex‐evoked changes. This suggests that 5‐HT1A receptors play a different role in chemoreceptor pathways compared to that for the other reflexes. This may relate to the fact that the chemoreceptor afferents travel in the IXth (glossopharyngeal) nerve whilst the other afferents travel in the Xth (vagus) nerve and thus may use different central circuitry and neurotransmitters.

British Journal of Pharmacology (2002) 137, 861–873. doi:10.1038/sj.bjp.0704941
Involvement of T‐type calcium channels in excitatory junction potentials in rat resistance mesenteric arteries
Authors: Xi Qi , Ziogas James , Roberts Jonathan A , Evans Richard J , Angus James A 
Published: November 2002

We investigated the role of voltage‐operated calcium channels in sympathetic transmission and depolarization‐induced contractions in the rat mesenteric artery. In particular, we investigated the role of the T‐type voltage‐operated calcium channels (T‐channels) in mediating excitatory junction potentials (EJPs).
EJPs were evoked by electrical field stimulation (trains of five stimuli at 0.9 Hz) in small mesenteric arteries. The average resting membrane potential was −59.8±0.5 mV (n=65). Trains of stimuli evoked individual EJPs with the peak EJP of 6±0.2 mV (n=34) occurring with the second stimulus. Trains of EJPs were inhibited 90% by tetrodotoxin (0.1 μM) or by ω‐conotoxin GVIA (GVIA, 10 nM) indicating their neural origin.
The EJPs were not inhibited by the L‐type calcium channel blocker nicardipine at 0.1 μM, a concentration sufficient to abolish the contraction to potassium depolarization. However, mibefradil (3 μM), considered a relatively selective T‐channel antagonist, inhibited the EJPs by about 50%. This concentration of mibefradil did not inhibit GVIA‐sensitive electrically‐evoked twitches of the rat vas deferens. Thus the action of mibefradil in reducing EJPs is unlikely to be due to either inhibition of L‐ or N‐type channels but is probably due to inhibition of T‐channels.
The finding that Ni2+ (300 μM), an inhibitor of T‐type calcium channels, also reduced EJP amplitude by about 80% but did not block electrically‐evoked twitches in the rat vas deferens, further supports an important role of T‐channels in mediating small depolarizations associated with the EJPs evoked by sympathetic nerve stimulation.

British Journal of Pharmacology (2002) 137, 805–812. doi:10.1038/sj.bjp.0704943
Impact of ageing on the antinociceptive effect of reference analgesics in the Lou/c rat
Authors: Jourdan Didier , Pickering Gisèle , Marchand Fabien , Gaulier Jean‐Michel , Alliot Josette , Eschalier Alain 
Published: November 2002

Research on the evolution of experimental pain perception and on the achievement of analgesia with ageing has led so far to contradictory results.
This study investigated in the rat the impact of ageing on the antinociceptive effect of reference analgesics, acetaminophen (50, 100, 200, 400 mg kg−1 po), aspirin (50, 100, 200, 400 mg kg−1 sc), clomipramine (5, 10, 20, 40 mg kg−1 sc) and morphine (1.25, 2.5, 5, 10 mg kg−1 sc).
Lou/c rats were chosen because they provide a model of healthy ageing and they do not develop obesity with age. Three groups of 40 rats each (mature (4 months), middle‐aged (18 months) and old (26 months)), were treated with each drug at 14 days interval. Two tests were used: a thermal test (tail immersion in 48°C water and measurement of reaction latency) and a mechanical test (paw pressure and measurement of struggle threshold).
Results confirm the increased mechanical sensitivity to pain and no change in thermal sensitivity for old rats compared to mature and middle‐aged animals. They show a marked decrease in the effect of morphine with age and no age‐related effect for acetaminophen, aspirin or clomipramine. Plasma levels of morphine and metabolites are not different in the three age groups.
It is likely that the influence of age on morphine analgesia is linked mainly to pharmacodynamic rather than pharmacokinetic changes.

British Journal of Pharmacology (2002) 137, 813–820. doi:10.1038/sj.bjp.0704944
Effects of pharmacological preconditioning with U50488H on calcium homeostasis in rat ventricular myocytes subjected to metabolic inhibition and anoxia
Authors: Ho J C S , Wu S , Kam K W L , Sham J S K , Wong T M 
Published: November 2002

The effects of pharmacological preconditioning with U50488H (U50), a selective κ‐opioid receptor agonist, on Ca2+ homeostasis in rat ventricular myocytes subjected for 9 min to metabolic inhibition (MI) and anoxia (A), consequences of ischaemia, were studied and compared with those of preconditioning with brief periods of MI/A.
Precondition with 30 μM of U50 for three cycles of 1 min each cycle separated by 3 min of recovery (UP) significantly increased the percentage of non‐blue cells following MI/A. The effect of UP is the same as that of preconditioning with an inhibitor of glycolysis and an oxygen scavenger for three 1‐min cycles separated by three‐minute recovery (MI/AP). The results indicate that like MI/AP, UP also confers cardioprotection.
MI/A increased intracellular Ca2+ ([Ca2+]i) and reduced the amplitude of caffeine‐induced [Ca2+]i transients, an indication of Ca2+ content in the sarcoplasmic reticulum (SR). MI/A also reduced the electrically‐induced [Ca2+]i transient, that indicates Ca2+‐release during excitation‐contraction coupling, and Ca2+ sparks in unstimulated myocytes, that indicates spontaneous Ca2+‐release from SR. It also prolonged the decline of the electrically‐induced [Ca2+]i transient and slowed down the recovery of the electrically‐induced [Ca2+]i transient after administration of caffeine. In addition, MI/A prolonged the decline of caffeine induced [Ca2+]i transient, an indication of Na+–Ca2+ exchange activity, and UP prevented it. So UP, that confers cardioprotection, prevented the changes induced by MI/A. With the exception of Ca2+‐spark, which was not studied, the effects of MI/AP are the same as those of UP.
It is concluded that pharmacological preconditioning with U50, that confers immediate cardioprotection, prevents changes of Ca2+ homeostasis altered by MI/A in the rat heart. This may be responsible, at least partly, for the cardioprotective action.
The study also provided evidence that MI/A causes mobilization of Ca2+ from SR to cytoplasm causing Ca2+‐overload which may be due to reduced Ca2+‐uptake by SR. MI/A also reduces spontaneous and electrically induced Ca2+ release from SR.

British Journal of Pharmacology (2002) 137, 739–748. doi:10.1038/sj.bjp.0704945
Possible role of histamine (H1‐ and H2‐) receptors in the regulation of meningeal blood flow
Authors: Dux Mária , Schwenger Nina , Messlinger Karl 
Published: November 2002

Vasodilatation in the dura mater has been suggested to play an important role in the pathophysiology of vascular headaches. Histamine may contribute to these vascular changes. The aim of the present study was to examine the role of different histamine receptors in histamine‐induced meningeal hyperperfusion using laser Doppler flowmetry.
The blood flow in the medial meningeal artery was monitored in the exposed parietal dura mater encephali of barbiturate anaesthetized rats. Local application of histamine (10−5 and 10−4 M) onto the dura caused increases in flow to 114.2±9.6 and 135.1±19.1%, respectively, of the basal flow.
Flow increases induced by topical application of histamine (10−4 M) were reduced by local pretreatment with the H2‐receptor antagonist cimetidine (0.4 and 4 mM) to 63.4±17 and 37.8±18.8%, respectively. Systemic pre‐administration of cimetidine (5 mg kg−1 i.v.) did not change histamine‐induced flow increases.
Local pretreatment with the H1‐receptor antagonist cetirizine (2 μM) further increased the flow evoked by topical histamine administration (10−4 M) to 123.5±14.7% of the histamine control.
Increases in blood flow induced by i.v. administration of histamine (10 μg kg−1) were reduced by i.v. pre‐injection of cetirizine (50 μg kg−1) to 31.9±9% but not by i.v. cimetidine (5 mg kg−1).
We conclude that histamine‐induced relaxation of dural arterial vessels is mediated by H2‐receptors, most likely located on vascular smooth muscle cells, and by endothelial H1‐receptors. In addition, H1‐receptors on smooth muscle cells may mediate vasoconstriction.

British Journal of Pharmacology (2002) 137, 874–880. doi:10.1038/sj.bjp.0704946
Nitric oxide inhibits capacitative Ca2+ entry by suppression of mitochondrial Ca2+ handling
Authors: Thyagarajan Baskaran , Malli Roland , Schmidt Kurt , Graier Wolfgang F , Groschner Klaus 
Published: November 2002

Nitric oxide (NO) is a key modulator of cellular Ca2+ signalling and a determinant of mitochondrial function. Here, we demonstrate that NO governs capacitative Ca2+ entry (CCE) into HEK293 cells by impairment of mitochondrial Ca2+ handling.
Authentic NO as well as the NO donors 1‐[2‐(carboxylato)pyrrolidin‐1‐yl]diazem‐1‐ium‐1,2‐diolate (ProliNO) and 2‐(N,N‐diethylamino)‐diazenolate‐2‐oxide (DEANO) suppressed CCE activated by thapsigargin (TG)‐induced store depletion. Threshold concentrations for inhibition of CCE by ProliNO and DEANO were 0.3 and 1 μM, respectively.
NO‐induced inhibition of CCE was not mimicked by peroxynitrite (100 μM), the peroxynitrite donor 3‐morpholino‐sydnonimine (SIN‐1, 100 μM) or 8‐bromoguanosine 3′,5′‐cyclic monophosphate (8‐BrcGMP, 1 mM). In addition, the guanylyl cyclase inhibitor 1H‐[1,2,4] oxadiazole[4,3‐a] quinoxalin‐1‐one (ODQ, 30 μM) failed to antagonize the inhibitory action of NO on CCE.
DEANO (1–10 μM) suppressed mitochondrial respiration as evident from inhibition of cellular oxygen consumption. Experiments using fluorescent dyes to monitor mitochondrial membrane potential and mitochondrial Ca2+ levels, respectively, indicated that DEANO (10 μM) depolarized mitochondria and suppressed mitochondrial Ca2+ sequestration. The inhibitory effect of DEANO on Ca2+ uptake into mitochondria was confirmed by recording mitochondrial Ca2+ during agonist stimulation in HEK293 cells expressing ratiometric‐pericam in mitochondria.
DEANO (10 μM) failed to inhibit Ba2+ entry into TG‐stimulated cells when extracellular Ca2+ was buffered below 1 μM, while clear inhibition of Ba2+ entry into store depleted cells was observed when extracellular Ca2+ levels were above 10 μM. Moreover, buffering of intracellular Ca2+ by use of N,N′‐[1,2‐ethanediylbis(oxy‐2,1‐phenylene)] bis [N‐[25‐[(acetyloxy) methoxy]‐2‐oxoethyl]]‐, bis[(acetyloxy)methyl] ester (BAPTA/AM) eliminated inhibition of CCE by NO, indicating that the observed inhibitory effects are based on an intracellular, Ca2+ dependent‐regulatory process.
Our data demonstrate that NO effectively inhibits CCE cells by cGMP‐independent suppression of mitochondrial function. We suggest disruption of local Ca2+ handling by mitochondria as a key mechanism of NO induced suppression of CCE.

British Journal of Pharmacology (2002) 137, 821–830. doi:10.1038/sj.bjp.0704949