bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characteristics of the Ca2+‐dependent inhibition of cyclic AMP accumulation by histamine and thapsigargin in human U373 MG astrocytoma cells
Authors: Wong M‐P Mabel , Cooper Dermot M F , Young Kenneth W , Young J Michael 
Published: January 2005

Histamine, acting on H1‐receptors, caused a Ca2+‐dependent inhibition of forskolin‐ and isoprenaline‐induced cyclic AMP accumulation in monolayers of human U373 MG cells (IC50 1.3±0.3 μM, maximum inhibition 66±3%). The inhibition was not reversed by the protein kinase inhibitor K‐252A.
Thapsigargin also inhibited cyclic AMP accumulation (IC50 6.0±0.3 nM, maximum inhibition 72±1%). In the absence of extracellular Ca2+ 5 μM thapsigargin caused only a 12±2% inhibition of cyclic AMP accumulation.
The inhibitory effect of 100 nM thapsigargin on forskolin‐stimulated cyclic AMP accumulation was blocked by La3+ (best‐fit maximum inhibition 81±4%, IC50 125±8 nM). In contrast, the inhibitory action of 10 μM histamine was much less sensitive to reversal by 1 μM La3+ (33±5% reversal, compared with 78±6% reversal of the inhibition by thapsigargin measured concurrently). However, in the presence of both thapsigargin and histamine the inhibition of cyclic AMP accumulation was reversed by 1 μM La3+ to the same extent as the inhibition by thapsigargin alone.
Thapsigargin (5 μM)+1 μM La3+ caused only a 20±1% inhibition of histamine‐stimulated phosphoinositide hydrolysis.
There was no indication from measurement of intracellular Ca2+ of any persistent La3+‐insensitive Ca2+ entry component activated by histamine.
The results provide evidence that Ca2+ entry is required for the inhibition by histamine and thapsigargin of drug‐induced cyclic AMP accumulation in U373 MG astrocytoma cells. The differential sensitivity of the inhibitory action of the two agents to block by La3+ suggests that more than one pathway of Ca2+ entry is involved.

British Journal of Pharmacology (2000) 130, 1021–1030; doi:10.1038/sj.bjp.0703411
D2 dopamine receptors enable Δ9‐tetrahydrocannabinol induced memory impairment and reduction of hippocampal extracellular acetylcholine concentration
Authors: Nava F , Carta G , Battasi A M , Gessa G L 
Published: January 2005

The systemic administration of Δ9‐tetrahydrocannabinol (2.5–7.5 mg kg−1) reduced hippocampal extracellular acetylcholine concentration and impaired working memory in rats.
Both effects were antagonized not only by the CB1 cannabinoid receptor antagonist SR141716A (0.5 mg kg−1, i.p.) but also unexpectedly by the D2 dopamine receptor antagonist S(−)‐sulpiride (5, 10 and 25 mg kg−1, i.p.). Conversely, Δ9‐tetrahydrocannabinol‐induced memory impairment and inhibition of hippocampal extracellular acetylcholine concentration were potentiated by the subcutaneous administration of the D2 dopamine receptor agonist (−)‐quinpirole (25 and 500 μg kg−1). The inhibition of hippocampal extracellular acetylcholine concentration and working memory produced by the combination of (−)‐quinpirole and Δ9‐tetrahydrocannabinol was suppressed by either SR141716A or S(−)‐sulpiride.
Our findings suggest that impairment of working memory and inhibition of hippocampal extracellular acetylcholine concentration are mediated by the concomitant activation of D2 dopamine and CB1 cannabinoid receptors, and that D2 dopamine receptor antagonists may be useful in the treatment of the cognitive deficits induced by marijuana.

British Journal of Pharmacology (2000) 130, 1201–1210; doi:10.1038/sj.bjp.0703413
Effect of amygdala kindling on the central nervous system effects of tiagabine: EEG effects versus brain GABA levels
Authors: Cleton A , Altorf B A , Voskuyl R A , Danhof M 
Published: January 2005

The objective of this investigation was to determine the influence of amygdala kindling on the pharmacodynamics of tiagabine in vivo, using quantitative EEG parameters and extracellular GABA concentrations as pharmacodynamic endpoints. In integrated pharmacokinetic/pharmacodynamic (PK/PD) studies the time course of these effects was determined in conjunction with plasma concentrations following intravenous administration of 10 mg kg−1. An ‘effect compartment’ model was used to derive individual concentration–effect relationships.
Tiagabine produced an increase in the amplitude of the 11.5–30 Hz frequency band of the EEG. The relationship between concentration and EEG effect was non‐linear and described by the Hill equation. In kindled rats the EC50 was reduced to 291 ng ml−1 from the original value of 521 ng ml−1 in controls. The values of all other parameters were unchanged.
In kindled rats the baseline extracellular GABA concentration was increased to 1.58 μM from 0.74 μM in controls. The relationships between tiagabine concentration and extracellular GABA concentration were again non‐linear and described by the Hill equation. No differences were observed between kindled rats and controls. In the synaptoneurosmal preparation in vitro no changes in the functioning of the GABA transporter were observed.
It is concluded that unlike the situation with midazolam, there is no resistance to the EEG effect of tiagabine in the kindling model of experimental epilepsy. The observed shift in the concentration–EEG effect relationship to lower concentrations can presumably be explained by the increase in the baseline GABA levels.

British Journal of Pharmacology (2000) 130, 1037–1044; doi:10.1038/sj.bjp.0703417
Inhibition of NFκB‐mediated pro‐inflammatory gene expression in rat mesangial cells by the enolized 1,3‐dioxane‐4,6‐dione‐5‐carboxamide, CGP‐43182
Authors: Scholz‐Pedretti Kirsten , Eberhardt Wolfgang , Rupprecht Gerhard , Beck Karl‐Friedrich , Spitzer Silke , Pfeilschifter Josef , Kaszkin Marietta 
Published: January 2005

CGP‐43182 has been described as a potent inhibitor of group IIA secreted phospholipase A2 (group IIA sPLA2) activity in vitro. In rat mesangial cells, inhibition of group IIA sPLA2 activity by CGP‐43182 results in a 70% reduction of cytokine‐stimulated prostaglandin E2 biosynthesis, suggesting that group IIA sPLA2 participates in arachidonic acid release and eicosanoid formation. Under these conditions the cytosolic phospholipase A2 is not affected.
In mesangial cells, in addition to inhibition of catalytic activity, the membrane‐permeant CGP‐43182 completely blocked interleukin 1β (IL1β)‐stimulated group IIA sPLA2 gene expression.
A further action of CGP‐43182 was a complete inhibition of cyclo‐oxygenase‐2 gene expression, resulting in a drastic reduction of prostaglandin formation in mesangial cells.
Moreover, CGP‐43182 completely blocked IL1β‐induced gene expression of the inducible nitric oxide synthase, leading to an inhibition of cytokine‐stimulated nitric oxide formation.
In contrast, the stimulatory effect of the cell‐permeant cyclic AMP‐analogue, dibutyryl‐cAMP, on the induction of these enzymes was not inhibited by CGP‐43182. These data indicate that CGP‐43182 interferes with IL1β‐ but not cyclic AMP‐activated transcriptional regulation.
By studying components of the upstream transcription machinery, we observed an inhibition of NFκB activation by CGP‐43182 in IL1β‐treated cells. Moreover, we observed that CGP‐43182 prevented the phosphorylation and proteolytic degradation of the endogenous NFκB inhibitor, IκB, a process necessary for NFκB activation.
From our data, we propose that CGP‐43182 is a potent anti‐inflammatory drug useful for preventing the consequences of a concerted action of cytokine‐stimulated pro‐inflammatory genes mediated by NFκB.

British Journal of Pharmacology (2000) 130, 1183–1190; doi:10.1038/sj.bjp.0703419
Stimulus‐specific alteration of the relationship between cytosolic Ca2+ transients and nitric oxide production in endothelial cells ex vivo
Authors: Mizuno Osamu , Kobayashi Sei , Hirano Katsuya , Nishimura Junji , Kubo Chiharu , Kanaide Hideo 
Published: January 2005

To investigate the quantitative relationship between elevation in the intracellular Ca2+ concentration ([Ca2+]i) and nitric oxide (NO) production, the changes in [Ca2+]i and NO production were determined in parallel, using fluorimetry of fura‐2 and 2,3‐diaminonaphthalene, respectively, in endothelial cells ex vivo of pig aortic valves.
The extent of [Ca2+]i elevation was quantitatively assessed by two parameters: the level of peak [Ca2+]i elevation and the area under the [Ca2+]i curve during treatment (the integrated [Ca2+]i elevation). The amount of NO production was expressed as a percentage of that obtained with 10 μM ATP for 3 min.
ATP, bradykinin, thrombin, and ionomycin were used as stimulation to induce NO production, and all these caused [Ca2+]i increases and NO production in a concentration‐dependent manner.
The relationships between the peak [Ca2+]i and NO production or between the integrated [Ca2+]i elevation and NO production were well described by a straight line. However, the slope value of the linear relationship in both cases varied with the type of stimulation, with thrombin giving the greatest value, followed by ATP, bradykinin and ionomycin.
These data suggest that in endothelial cells ex vivo: (1) [Ca2+]i elevation regulates NO production, but (2) the peak [Ca2+]i elevation‐ or the integrated [Ca2+]i elevation‐NO production relationships varies depending on the type of agonists. Our results thus demonstrate the presence of the agonists‐dependent modulation of the relationship between [Ca2+]i elevation and NO production in endothelial cells ex vivo.

British Journal of Pharmacology (2000) 130, 1140–1146; doi:10.1038/sj.bjp.0703420
Comparison of enalapril and valsartan in cyclosporine A‐induced hypertension and nephrotoxicity in spontaneously hypertensive rats on high‐sodium diet
Authors: Lassila Markus , Finckenberg Piet , Pere Anna‐Kaisa , Krogerus Leena , Ahonen Juhani , Vapaatalo Heikki , Nurminen Marja‐Leena 
Published: January 2005

We compared the effects of the angiotensin converting enzyme (ACE) inhibitor enalapril and the angiotensin AT1 receptor antagonist valsartan in cyclosporine A (CsA)‐induced hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR).
SHR (8–9 weeks old) on high‐sodium diet were given CsA (5 mg kg−1d −1 s.c.) for 6 weeks. The rats were treated concomitantly either with enalapril (30 mg kg−1d −1 p.o.) or valsartan (3 or 30 mg kg−1 d −1 p.o.). To evaluate the role of bradykinin in the action of enalapril, some rats received a bradykinin B2 receptor antagonist icatibant (HOE 140, 500 μg kg−1 d −1 s.c.) during the last 2 weeks of enalapril treatment.
Blood pressure was recorded every second week by tail cuff method. Renal function was measured by serum creatinine, creatinine clearance and urinary excretion of proteins at the end of the experiment. The activity of the renal kallikrein‐kinin system was estimated by urinary kallikrein excretion.
CsA caused hypertension, impaired renal function and induced morphological nephrotoxicity with glomerular damage and interstitial fibrosis.
Enalapril and the lower dose of valsartan attenuated the CsA‐induced hypertension to the same extent, while the higher dose of valsartan totally abolished it. Icatibant did not reduce the antihypertensive effect of enalapril. Urinary kallikrein excretion was similar in all groups. Enalapril and valsartan equally prevented the CsA‐induced deterioration of kidney function and morphology.
The renin‐angiotensin but not the kallikrein‐kinin system plays a crucial role in CsA‐toxicity during high intake of sodium in SHR.

British Journal of Pharmacology (2000) 130, 1339–1347; doi:10.1038/sj.bjp.0703422
On the mechanism of ADP‐induced alteration of sulphonylurea sensitivity in cardiac ATP‐sensitive K+ channels
Authors: Miyamura Akihiro , Kakei Masafumi , Ichinari Kotaro , Okamura Midori , Oketani Naoya , Tei Chuwa 
Published: January 2005

To study the mechanism of regulation of sulphonylurea sensitivity in ATP‐sensitive K+ (KATP) channels, we used the inside‐out patch clamp technique in guinea‐pig ventricular myocytes.
In the absence of nucleotides, the half maximal concentration of tolbutamide inhibition of KATP channels (IC50) was 0.4 mM, and it decreased to 0.1 mM when 0.1 mM ATP was added.
Increasing the ADP concentration from 0 to 0.1 and 0.3 mM in the absence of ATP shifted the IC50 from 0.4 to 5.3 and 11.4 mM, respectively. Increasing the ADP concentration further to 1 and 3 mM conversely reduced the IC50 to 9.5 and 4.4 mM, respectively.
In the absence of Mg2+ and ADP, the IC50 was calculated to 16.6 mM which was found to be less, 12.3, 5.1 and 2.5 mM, respectively, when the ADP concentration was increased to 0.1, 0.3 and 1 mM.
The IC50s for tolbutamide obtained at various concentrations of ADP in the presence of Mg2+ were best fitted by equations reflecting a model that assumed two binding sites for ADP; one is a high affinity site that reduces the sensitivity to the sulphonylurea, while the other is a low affinity site that increases such sensitivity. Dissociation constants calculated for ADP to sites 1 and 2 were 2.6 μM and 46.7 mM, respectively. In the absence of Mg2+, data were fitted by equations corresponding to a single site model (site 2); the dissociation constant for ADP was 25.0 mM.
It is concluded that ADP modifies tolbutamide sensitivity by binding to two sites. The high affinity site is strongly Mg2+‐dependent, whereas the low affinity site is Mg2+‐independent.

British Journal of Pharmacology (2000) 130, 1411–1417; doi:10.1038/sj.bjp.0703423
The emetic and anti‐emetic effects of the capsaicin analogue resiniferatoxin in Suncus murinus, the house musk shrew
Authors: Andrews P L R , Okada F , Woods A J , Hagiwara H , Kakaimoto S , Toyoda M , Matsuki N 
Published: January 2005

In Suncus murinus the ultrapotent capsaicin analogue resiniferatoxin (RTX) induced an emetic response in the dose range 1–1000 μg kg−1, s.c. The latency was inversely related to dose and ranged from 41.2±4.4 min. (1 μg kg−1, s.c.) to 2.7±0.6 min. (1000 μg kg−1, s.c.).
The emetic response to RTX (10 or 100 μg kg−1, s.c.) was blocked or markedly reduced by pre‐treatment with RTX (100 μg kg−1, s.c.), 8‐OH‐DPAT (100 μg kg−1, s.c.), morphine (2 mg kg−1, s.c.), neonatal capsaicin (100 mg kg−1, s.c.) and the NK1 receptor antagonist CP‐99,994 (10–20 mg kg−1, s.c.) but not by the 5‐HT3 receptor antagonist tropisetron (200 μg kg−1, s.c.).
RTX (100 μg kg−1, s.c.) induced c‐fos‐like immunoreactivity in the area postrema and parts of the nucleus tractus solitarius. This pattern is consistent with the proposal that the emetic effect is mediated via one or both of these structures and an involvement of substance P is discussed.
RTX (10 and 100 μg kg−1, s.c.) had broad‐spectrum antiemetic effects in Suncus as indicated by its ability to block or markedly reduce the emetic response to motion (1 Hz, 4 cm lateral, 10 min.), cisplatin (20 mg kg−1, i.p.), intragastric copper sulphate (40 mg kg−1, p.o.), nicotine (10 mg kg−1, s.c.) and RTX (100 μg kg−1, s.c.) itself.
It is proposed that the site of the anti‐emetic effect is in the nucleus tractus solitarius and mechanisms involving the modulation of substance P release are discussed.
The general utility of Suncus for investigations of vanilloid receptors is reviewed in the light of the exquisite sensitivity of the emetic reflex in this species to resiniferatoxin.

British Journal of Pharmacology (2000) 130, 1247–1254; doi:10.1038/sj.bjp.0703428
Effect of furanocoumarin derivatives in grapefruit juice on the uptake of vinblastine by Caco‐2 cells and on the activity of cytochrome P450 3A4
Authors: Ohnishi Ayako , Matsuo Hirotami , Yamada Shiho , Takanaga Hitomi , Morimoto Satoshi , Shoyama Yukihiro , Ohtani Hisakazu , Sawada Yasufumi 
Published: January 2005

The presence of inhibitors of drug efflux transporters, such as P‐glycoprotein (P‐gp), in grapefruit juice (GFJ) was confirmed based on the uptake of [3H]‐vinblastine (VBL) by Caco‐2 cells.
The uptake of [3H]‐VBL by Caco‐2 cells was significantly increased by the ethyl acetate extract of GFJ as well as by cyclosporin A. The extract was separated on a Cosmosil column and the eluate with 60% methanol increased [3H]‐VBL uptake, while the activity to inhibit CYP3A4 was greatest in the 70 and 80% eluates.
These results show that the major inhibitor of efflux transport of VBL is different from that of CYP3A4.
Further separation of the 60% methanol eluate afforded dihydroxybergamottin (DHBG). Both ethyl acetate extract of GFJ and DHBG increased steady‐state [3H]‐VBL uptake by LLC‐GA5‐COL300 cells. Besides DHBG, other furanocoumarins contained in GFJ, such as bergamottin, FC726, bergaptol and bergapten, increased the steady‐state uptake of [3H]‐VBL by Caco‐2 cells.
The order of inhibitory potency of these compounds was FC726>DHBG>bergamottin>bergapten>bergaptol. While, the IC50 values for inhibition of CYP3A4 were 0.075, 0.45, 1.0, 1.0 and >20 μM, respectively. Bergaptol specifically inhibited VBL efflux.
DHBG was thus identified as a candidate for inhibitors of VBL transport, together with other furanocoumarins. Moreover, partly involvement of the P‐gp inhibition was suggested.
Therefore, the inhibition of efflux transport of drugs as well as of drug metabolism by CYP3A4 could be an important cause of drug‐GFJ interaction.

British Journal of Pharmacology (2000) 130, 1369–1377; doi:10.1038/sj.bjp.0703433
Inhibition by ethanol of rat P2X4 receptors expressed in Xenopus oocytes
Authors: Xiong Keming , Li Chaoying , Weight Forrest F 
Published: January 2005

The effect of ethanol on the function of P2X4 receptors expressed in Xenopus oocytes was studied using two‐electrode voltage‐clamp recording.
The amplitude of current activated by 1 μM ATP was decreased by ethanol in a concentration‐dependent manner over the concentration range 1–500 mM. The concentration of ethanol that produced 50% inhibition (IC50) of current activated by 1 μM ATP was 58 mM.
Ethanol inhibition of ATP‐activated current was not dependent on membrane potential from −60 to +20 mV, and ethanol did not change the reversal potential of ATP‐activated current.
Ethanol, 50 mM, shifted the ATP concentration‐response curve to the right, increasing the EC50 for ATP from 9.1 to 16.0 μM, but did not reduce the maximal response to ATP.
The results suggest that ethanol may inhibit P2X4 receptors by decreasing the apparent affinity of the binding site for ATP.
Since the P2X4 receptor is the most abundant P2X subunit in the brain, these receptors could be important effectors of ethanol action in the central nervous system.

British Journal of Pharmacology (2000) 130, 1394–1398; doi:10.1038/sj.bjp.0703439
Voltage‐dependent blockade of normal and mutant muscle sodium channels by benzylalcohol
Authors: Haeseler G , Mamarvar M , Bufler J , Dengler R , Hecker H , Aronson J K , Piepenbrock S , Leuwer M 
Published: January 2005

We studied the effects of benzylalcohol on heterologously expressed wild type (WT), paramyotonia congenita (R1448H) and hyperkalaemic periodic paralysis (M1360V) mutant α‐subunits of human skeletal muscle sodium channels.
Benzylalcohol blocked rested channels at −150 mV membrane potential, with an ECR50 of 5.3 mM in wild type, 5.1 mM in R1448H, and 6.2 mM in M1360V. When blockade was assessed at −100 mV, the ECR50 was reduced in R1448H (2 mM) compared with both wild type (4.3 mM; P<0.01) and M1360V (4.3 mM).
Membrane depolarization before the test depolarization significantly promoted benzylalcohol‐induced sodium channel blockade. The values of KD for the fast‐inactivated state derived from benzylalcohol‐induced shifts in steady‐state availability curves were 0.66 mM in wild type and 0.58 mM in R1448H. In the presence of slow inactivation induced by 2.5 s depolarizing prepulses, the ECI50 for benzylalcohol‐induced current inhibition was 0.59 mM in wild type and 0.53 mM in R1448H.
Recovery from fast inactivation was prolonged in the presence of drug in all clones.
Benzylalcohol induced significant frequency‐dependent block at stimulating frequencies of 10, 50, and 100 Hz in all clones.
Our results clearly show that benzylalcohol is an effective blocker of muscle sodium channels in conditions that are associated with membrane depolarization. Mutants that enter voltage‐dependent inactivation at more hyperpolarized membrane potentials compared with wild type are more sensitive to inhibitory effects at the normal resting potential.

British Journal of Pharmacology (2000) 130, 1321–1330; doi:10.1038/sj.bjp.0703447
NO‐naproxen modulates inflammation, nociception and downregulates T cell response in rat Freund's adjuvant arthritis
Authors: Cicala Carla , Ianaro Angela , Fiorucci Stefano , Calignano Antonio , Bucci Mariarosaria , Gerli Roberto , Santucci Luca , Wallace John L , Cirino Giuseppe 
Published: January 2005

Anti‐inflammatory non steroidal drugs releasing NO (NO‐NSAIDs) are a new class of anti‐inflammatory drugs to which has been added an NO‐releasing moiety. These compounds have been shown to retain the anti‐inflammatory, analgesic and antipyretic activity of the parent compound but to be devoid of gastrointestinal (GI) toxicity.
Freund's adjuvant (FA) arthritis was induced in rats by a single intraplantar injection into the right hindpaw of 100 μl of mycobacterium butirricum (6 mg ml−1). The effect of equimolar doses of naproxen (1, 3 and 10 mg kg−1) and NO‐naproxen (1.5, 4.5 and 16 mg kg−1) was evaluated using two dosage regimen protocols: (i) preventive, starting oral administration of the drugs at the time of induction of arthritis and for the following 21 days (day 1–21); (ii) therapeutic, starting oral administration of the drugs 7 days after adjuvant injection and for the following 14 days (day 7–21).
Hindpaw swelling (days 3, 7, 11, 14, 17, 21) and nociception (days 15 and 21) were measured. On day 22 rats were sacrificed, draining lymph nodes were removed and T cells isolated. In vitro proliferation of T cells following stimulation with concanavalin A (0.5–5 μg ml−1) was measured using a tritiated thymidine incorporation assay. IL‐2 receptor expression on T cells was measured by FACS analysis.
Naproxen and NO‐naproxen showed similar activity in reducing oedema formation in the non‐injected (controlateral) hindpaw. Both drugs showed anti‐nociceptive effect. NO‐naproxen was anti‐nociceptive at a dose of 4.5 mg kg−1 while naproxen showed the same extent of inhibition only at a dose of 10 mg kg−1.
T cells were isolated and characterized by FACS analysis. Stimulation of isolated T cells with concanavallin A in vitro caused a significant increase in thymidine uptake. NO‐naproxen at a dose of 4.5 mg kg−1 inhibited T cell proliferation to the same extent as 10 mg kg−1 of naproxen.
Inhibition of T cell proliferation was well correlated with reduced IL‐2 receptor expression on T cells. In addition, NO‐naproxen reduced both IL‐1β and TNFα plasma levels whilst naproxen reduced IL‐1β levels only.
In conclusion, both naproxen and NO‐naproxen reduce inflammation and nociception associated with arthritis. In addition NO‐naproxen interferes to a larger extent with cellular mechanism involved in T cell activation in rat adjuvant arthritis indicating that introduction of the NO moiety in the naproxen structure increases the effect at the level of the immune system.

British Journal of Pharmacology (2000) 130, 1399–1405; doi:10.1038/sj.bjp.0703449