bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of redox compounds on nitrovasodilator‐induced relaxations of rat coronary arteries
Authors: Murphy Michael E 
Published: January 2005

Various classes of nitrovasodilators release nitric oxide (NO) through distinct reaction pathways, many of which involve endogenous reductants and/or oxidants. This study examined relaxations of isolated rat coronary arteries induced by spermine NONOate (SPNO), 3‐morpholinosydnonimine (SIN‐1), nitroprusside (NP), S‐nitroso‐N‐acetylpenicillamine (SNAP) and nitroglycerin (NTG) in order to assess whether their potency was influenced by any of six redox compounds: 1 mM ascorbate, 1 mM dehydroascorbate, 0.1 mM dithiothreitol, 10 μM diamide, 0.1 mM ferrocyanide, and 0.1 mM ferricyanide.
Only SPNO spontaneously generated NO at measurable levels. These levels were decreased by the presence of ascorbate and dithiothreitol, which likewise decreased the potency of SPNO.
The potency of SIN‐1 was unaffected by any redox compound except ferricyanide, which increased the potency not only of SIN‐1, but also of other nitrovasodilators and NO‐independent vasodilators.
The potency of NP was decreased by two structurally similar multivalent anions, ferrocyanide and ferricyanide, suggesting that NP metabolism requires ionic binding to tissue.
SNAP lost its potency in solutions containing ascorbate or dehydroascorbate. SNAP potency was also decreased by the glutathione oxidant, diamide, and by ferrocyanide and ferricyanide, suggesting that glutathione and ionic binding may be required for NO release.
NTG appeared to relax arteries via two pathways. One required only low concentrations of NTG and a labile endogenous factor that was preserved by dithiothreitol and eliminated by ferricyanide. A distinct second pathway required higher concentrations of NTG.
These distinct attributes of nitrovasodilator metabolism may underlie differences in regional specificity or tolerance development, and therefore might eventually be exploited in the development and use of nitrovasodilators.

British Journal of Pharmacology (1999) 128, 435–443; doi:10.1038/sj.bjp.0702777
Recovery of dopamine neuronal transporter but lack of change of its mRNA in substantia nigra after inactivation by a new irreversible inhibitor characterized in vitro and ex vivo in the rat
Authors: Do Régo Jean‐Claude , Syringas Maria , Leblond Bertrand , Costentin Jean , Bonnet Jean‐Jacques 
Published: January 2005

In vitro, the ability of DEEP‐NCS {1‐[2‐(diphenylmethoxy)ethyl]‐4‐[2‐(4‐isothiocyanatophenyl)ethyl]‐piperazine} to inhibit [3H]‐dopamine uptake by rat striatal synaptosomes was concentration‐dependent and inversely related to the protein concentration. This inhibition was irreversible and resulted from changes in Vmax and KM. DEEP‐NCS was less potent on noradrenaline, serotonin and choline transport.
One day after intrastriatal injections of DEEP‐NCS (100 and 1000 pmol) in 20% dimethylsulphoxide, moderate decreases in the ex vivo dopamine uptake were observed in synaptosomes obtained from striatum injected with DEEP‐NCS or solvent, and the contralateral uninjected striatum.
In similar conditions, 300 pmol DEEP‐NCS in 45% 2 hydroxypropyl‐γ‐cyclodextrin–0.5% dimethylsulphoxide solution sub‐totally reduced ex vivo dopamine uptake and mazindol binding, and moderately decreased choline and serotonin transport. These reductions were specific to DEEP‐NCS‐injected striata. A clomipramine pretreatment (16 mg kg−1 i.p. 1 h before) was performed in following experiments, since it reduced the DEEP‐NCS‐elicited decrease in serotonin uptake without affecting other indices.
One day after intrastriatal injection, DEEP‐NCS elicited similar dose‐dependent decreases in ex vivo dopamine uptake and mazindol binding (ID50=6.9‐8 ng striatum−1). Changes in KM and Vmax for ex vivo dopamine transport produced by DEEP‐NCS disappeared according to similar time‐courses.
The t½ for transporter recovery was 6.1 days. This value should correspond to its actual turnover rate in vivo, since no change in transporter mRNA level was observed in substantia nigra ipsilateral to 300 pmol DEEP‐NCS‐injected striatum.
The results indicate that DEEP‐NCS behaves as a potent, quite selective, irreversible inhibitor of the DAT, in vitro and in vivo. Its use in vivo suggests that the physiological half‐life of the rat striatal DAT is close to 6 days.

British Journal of Pharmacology (1999) 128, 51–60; doi:10.1038/sj.bjp.0702784
Nepalolide A inhibits the expression of inducible nitric oxide synthase by modulating the degradation of IκB‐α and IκB‐β in C6 glioma cells and rat primary astrocytes
Authors: Wang Chuen‐Neu , Shiao Young‐Ji , Lin Yun‐Lian , Chen Chieh‐Fu 
Published: January 2005

The effects of nepalolide A on the expression of inducible nitric oxide synthase (iNOS) caused by incubation with lipopolysaccharide/interferon‐γ (LPS/IFN‐γ) or tumour necrosis factor‐α/interleukin‐1β/IFN‐γ (TNF‐α/IL‐1β/IFN‐γ, mixed cytokines) in C6 glioma cells and primary astrocytes of rat were investigated. The mechanisms by which nepalolide A confers its effect on iNOS expression were also elucidated.
Treatment with LPS/IFN‐γ and mixed cytokines for 24 h elicited the induction of iNOS activity as determined by nitrite accumulation in the culture medium and assay of enzyme activity. Nepalolide A at 10 μM abrogated the LPS/IFN‐γ‐ and mixed cytokines‐mediated induction of iNOS by more than 90% in C6 glioma cells, and by 80% for mixed cytokines‐induced induction of iNOS in primary astrocytes. The effect of nepalolide A (2–10 μM) was concentration‐dependent.
The inhibition of iNOS induction by nepalolide A was attributed to decreases in the content of iNOS protein and the level of iNOS mRNA, as measured by immunoblotting and reverse transcriptase‐polymerase chain reaction.
Electrophoretic mobility shift assay was used to evaluate the effect of nepalolide A on the activation of nuclear factor‐κB (NF‐κB). Results showed that nepalolide A diminished the LPS/IFN‐γ‐mediated association of NF‐κB with consensus oligonucleotide in a concentration‐dependent manner. The activation of NF‐κB by mixed cytokines was modulated both in the extent of activation and in its time‐course by nepalolide A.
The ability of nepalolide A to inhibit NF‐κB activation was further confirmed by studies on the degradation of the inhibitor of NF‐κB, IκB, as measured by immunoblotting.
The present study demonstrates that the attenuation of NF‐κB activation by nepalolide A was mediated by blockade of the degradation of IκB, leading to suppression of the expression of iNOS.

British Journal of Pharmacology (1999) 128, 345–356; doi:10.1038/sj.bjp.0702785
Potent depression of stimulus evoked field potential responses in the medial entorhinal cortex by serotonin
Authors: Schmitz Dietmar , Gloveli Tengis , Empson Ruth M , Heinemann Uwe 
Published: January 2005

The entorhinal cortex (EC), main input structure to the hippocampus, gets innervated by serotonergic terminals from the raphe nuclei and expresses 5‐HT‐receptors at high density. Using extra‐ and intracellular recording techniques we here investigated the effects of serotonin on population and cellular responses within the EC.
Stimulation in the lateral entorhinal cortex resulted in complex field potential responses in the superficial EC. The potentials are composed of an early antidromic and a late orthodromic component reflecting the efferent and afferent circuitry.
Serotonin (5‐HT) reduced synaptic potentials of the stimulus evoked extracellular field potential at all concentrations tested (0.1–100 μM; 59%‐depression by 10 μM serotonin), while the antidromic response was not significantly changed by up to 50 μM 5‐HT. Depression of field potential responses by serotonin was associated with a significant increase in paired‐pulse facilitation from 1.15 to 1.88.
The effects of serotonin on field potential responses were mimicked by 5‐HT1A‐receptor agonists (8‐OH‐DPAT, 5‐CT) and partially prevented by the 5‐HT1A‐receptor antagonist (S‐UH‐301). Moreover, the 5‐HT1A‐receptor antagonist WAY100635 reduced the effect of 5‐CT.
Fenfluramine, a serotonin releaser, mimics the effects of serotonin on stimulus‐evoked field potential responses, indicating that synaptically released serotonin can produce the changes in reactivity to afferent stimulation.
Depression of isolated AMPA‐receptor mediated EPSCs by serotonin as well as fenfluramine was associated with an increase in paired pulse facilitation, indicating a presynaptic locus of action.
We conclude that physiological concentrations of serotonin potently suppresses excitatory synaptic transmission in the superficial entorhinal cortex by a presynaptic mechanism.

British Journal of Pharmacology (1999) 128, 248–254; doi:10.1038/sj.bjp.0702788
The influence of allopurinol on kidney haemodynamic and excretory responses to renal ischaemia in anaesthetized rats
Authors: Hestin Dominique , Johns Edward J 
Published: January 2005

This study examined the impact of allopurinol on the renal functional responses to a 30 min period of ischaemia in anaesthetized rats.
Immediately on reperfusion, blood pressure rose transiently, while renal blood flow remained stable throughout at control values. Glomerular filtration rate was decreased by some 90% over the first and 80% over the sixth hour (P<0.001).
Allopurinol, 50 or 100 mg kg−1, had no effect on the blood pressure or renal blood flow responses over the 6 h reperfusion period but glomerular filtration decreased by 60% initially, and to less than 30% of basal at 6 h.
Urine flow and absolute sodium excretion increased 2–3 fold in the first 2 h but decreased thereafter. Fractional sodium excretion was 30 times higher for the first 2 h but decreased reaching some 10 fold higher at 6 h. In the presence of allopurinol, urine flow and absolute sodium excretion increased by 5–6 fold in the first 2 h, and fell by half by 6 h which was greater than in the vehicle group (P<0.01). Fractional sodium excretion increased 20 fold in the allopurinol animals in the first 2 h period, but fell at a faster rate (P<0.01) than in untreated rats.
Potassium excretion decreased (P<0.05) by one half for the 6 h reperfusion period but in the allopurinol animals it was minimally altered.
Allopurinol largely ameliorated the decrease in kidney haemodynamic and excretory function following an ischeamic period for the initial few hours of reperfusion.

British Journal of Pharmacology (1999) 128, 255–261; doi:10.1038/sj.bjp.0702789
Inhibitory effect of nociceptin on [3H]‐5‐HT release from rat cerebral cortex slices
Authors: Siniscalchi Anna , Rodi Donata , Beani Lorenzo , Bianchi Clementina 
Published: January 2005

The effect of nociceptin (NC) on 5‐hydroxytryptamine (5‐HT) release was studied in rat cerebral cortex slices preincubated with [3H]‐5‐HT and electrically stimulated (3 Hz, for 2 min) at the 45th (St1) and the 75th (St2) min of superfusion.
NC (0.1–3 μM), present in the medium from the 70th min onward, concentration‐dependently reduced electrically evoked [3H]‐5‐HT efflux (pEC50=6.54, Emax −54%). The inhibition was not antagonized by naloxone (1 μM) ruling out the involvement of opioid receptors.
Phe1ψ(CH2‐NH2)Gly2]NC(1‐13)NH2, which acts as an opioid‐like receptor (ORL1) antagonist at the peripheral level, behaved as a partial agonist in cerebral cortex slices i.e. it inhibited [3H]‐5‐HT efflux when added before St2, however, when present in the medium throughout the whole experiment, [Phe1ψ(CH2‐NH2)Gly2]NC(1‐13)NH2 prevented the action of NC added at the 70th min.
The non‐selective ORL1 receptor antagonist, naloxone benzoylhydrazone (3 μM), in the presence of 10 μM naloxone, did not modify the St2/St1 ratio but completely abolished the NC effect.
These findings demonstrate that NC inhibits 5‐HT release from rat cerebral cortex slices via ORL1 receptors, suggesting its involvement in central processes mediated by 5‐HT.

British Journal of Pharmacology (1999) 128, 119–123; doi:10.1038/sj.bjp.0702793
Inhibition of uptake, steady‐state currents, and transient charge movements generated by the neuronal GABA transporter by various anticonvulsant drugs
Authors: Eckstein‐Ludwig Ursula , Fei Jian , Schwarz Wolfgang 
Published: January 2005

We have expressed the GABA transporter (GAT1) of mouse brain in Xenopus oocytes and have investigated the effects of four antiepileptic drugs, tiagabine (TGB), vigabatrin (VGB), gabapentin (GBP) and valproate (VAL), on GAT1 transporter function by measurements of 3H‐labelled GABA uptake and GAT1‐mediated currents.
Not only TGB, a well‐known inhibitor of GAT1‐mediated transport, but also the other drugs efficiently inhibit the uptake of [3H]‐GABA by GAT1. Inhibition at 50% is obtained for VGB, TGB, GBP, and VAL at concentrations of about 1 nM, 1 μM, 50 μM and 100 μM, respectively.
However, GAT1‐mediated steady‐state and transient currents are nearly unaffected by VGB, GBP, and VAL at even five times higher concentrations. Only TGB blocks the uptake and steady‐state and transient currents at micromolar concentrations.
VGB exhibits a complex interaction with GAT1; at concentrations about 1 nM, the inhibition of uptake is released, but at millimolar concentrations the uptake is inhibited again, and also the GAT1‐mediated current is finally inhibited at these concentrations with a KI value of 0.5 mM. The concentration dependency of inhibition of uptake can be explained by two interaction sites with different affinities, a blocking site and a transport site.
The differences in effects of VAL, GBP, and VGB on uptake and currents can be attributed to the fact that GAT1 has the capability to operate in an electrogenic mode without uptake of GABA. We suggest that inhibition occurs only when GAT1 operates in the GABA‐uptake mode.
The inhibition of GABA uptake by these four drugs will result in an elevation of the GABA concentration in the synaptic cleft, which will enhance synaptic inhibition and thereby contribute to their antiepileptic effects.

British Journal of Pharmacology (1999) 128, 92–102; doi:10.1038/sj.bjp.0702794
21‐Aminosteroids prevent the down‐regulation of hepatic cytochrome P450 induced by hypoxia and inflammation in conscious rabbits
Authors: Galal Ahmed , Du Souich Patrick 
Published: January 2005

This study was conducted to assess whether a 21‐aminosteroid, U74389G, could prevent the down‐regulation of hepatic cytochrome P450 (P450) induced by acute moderate hypoxia or an inflammatory reaction.
The rabbits of two groups (n=6 per group) were subjected to acute moderate hypoxia (PaO2∼35 mmHg), one pre‐treated with U74389G (3 mg kg−1 i.v. every 6 h, for 48 h). The rabbits of two other groups received 5 ml of turpentine s.c., one of them being pre‐treated with U74389G (3 mg kg−1 i.v. every 6 h, for 72 h). The kinetics of theophylline (2.5 mg kg−1) were assessed to evaluate the activity of the P450. Once the rabbits were sacrificed, the P450 content and the amount of thiobarbituric acid reactive substances (TBARS), a marker of lipid peroxidation, were estimated in the liver.
Compared with control rabbits, hypoxia and inflammation increased theophylline plasma concentrations, as a result of a decrease in theophylline systemic clearance (P<0.05). Both experimental conditions reduced hepatic content of P450 by 40–50% (P<0.05) and increased the amount of hepatic TBARS by around 50% (P<0.05). Pre‐treatment with U74389G prevented the hypoxia‐ and inflammation‐induced decrease in theophylline systemic clearance, the down‐regulation of hepatic P450, and the increase in liver TBARS.
It is concluded that in the rabbit, U74389G prevents hepatic P450 depression produced by acute moderate hypoxia and a turpentine‐induced inflammatory reaction, possibly by eliciting a radical quenching antioxidant activity.

British Journal of Pharmacology (1999) 128, 374–379; doi:10.1038/sj.bjp.0702796
The role of P‐glycoprotein in blood‐brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (−/−) and mdr1a (+/+) mice
Authors: Xie Rujia , Hammarlund‐Udenaes Margareta , De Boer Albertus G , De Lange Elizabeth C M 
Published: January 2005

The aim of this study was to investigate whether blood‐brain barrier transport of morphine was affected by the absence of mdr1a‐encoded P‐glycoprotein (Pgp), by comparing mdr1a (−/−) mice with mdr1a (+/+) mice.
Mdr1a (−/−) and (+/+) mice received a constant infusion of morphine for 1, 2 or 4 h (9 nmol/min/mouse). Microdialysis was used to estimate morphine unbound concentrations in brain extracellular fluid during the 4 h infusion. Two methods of estimating in vivo recovery were used: retrodialysis with nalorphine as a calibrator, and the dynamic‐no‐net‐flux method.
Retrodialysis loss of morphine and nalorphine was similar in vivo. Unbound brain extracellular fluid concentration ratios of (−/−)/(+/+) were 2.7 for retrodialysis and 3.6 for the dynamic‐no‐net‐flux at 4 h, with corresponding total brain concentration ratios of (−/−)/(+/+) being 2.3 for retrodialysis and 2.6 for the dynamic‐no‐net‐flux. The total concentration ratios of brain/plasma were 1.1 and 0.5 for mdr1a (−/−) and (+/+) mice, respectively.
No significant differences in the pharmacokinetics of the metabolite morphine‐3‐glucoronide were observed between (−/−) and (+/+) mice.
In conclusion, comparison between mdr1a (−/−) and (+/+) mice indicates that Pgp participates in regulating the amount of morphine transport across the blood‐brain barrier.

British Journal of Pharmacology (1999) 128, 563–568; doi:10.1038/sj.bjp.0702804
Cannabinoid agonists and antagonists discriminated by receptor binding in rat cerebellum
Authors: Griffin Graeme , Wray Emma J , Martin Billy R , Abood Mary E 
Published: January 2005

The effect of allosteric regulators on the binding affinity of a number of cannabinoid receptor ligands of varying efficacy in the rat cerebellum was investigated.
Radioligand ([3H]‐SR141716A) competition curves were constructed in the presence or absence of sodium ions, magnesium ions and guanine nucleotides.
It was found that the presence of these allosteric regulators did not affect the affinity of the two antagonists used but did cause a significant decrease in the affinity of full and partial agonists.
This reduction in affinity ranged from a 3.67 fold rightward shift of the displacement curve of a mixed agonist/antagonist (3‐(6‐cyano‐2‐hexynyl)‐delta‐8‐tetrahydrocannabinol‐O‐823) to a 38 fold rightward shift for 3‐(1,1‐dimethyl‐6‐dimethylcarboxamide)‐delta‐8‐tetrahydrocannabinol (O‐1125), a full agonist.
In summary, the results of this study suggest a simple method for the inference of functional data using the classical radioligand binding assay.

British Journal of Pharmacology (1999) 128, 684–688; doi:10.1038/sj.bjp.0702806
The molecular interaction of the high affinity reversal agent XR9576 with P‐glycoprotein
Authors: Martin Catherine , Berridge Georgina , Mistry Prakash , Higgins Christopher , Charlton Peter , Callaghan Richard 
Published: January 2005

The kinetics and nature of equilibrium binding were used to characterize the molecular interaction of the anthranilic acid derivative [3H]‐XR9576 with the multidrug resistance P‐glycoprotein (P‐gp). XR9576 displayed specific high‐affinity binding to P‐gp (Bmax=275 pmol mg−1, Kd=5.1 nM). The transport substrates [3H]‐vinblastine and [3H]‐paclitaxel displayed 4 fold and 20 fold lower affinity respectively for P‐gp. The duration of action of XR9576 with P‐gp was increased in comparison to that of vinblastine which displayed a slower rate of association and a faster dissociation rate.
The relative affinities of several modulators and transport substrates to interact with P‐gp were determined from displacement drug equilibrium binding assays. Vinblastine and paclitaxel could only fractionally displace [3H]‐XR9576 binding, displaying Ki values significantly different from their measured Kd values. This suggests a non‐competitive interaction between XR9576 and the P‐gp substrates vinblastine and paclitaxel.
XR9576 was shown to be a potent modulator of P‐gp mediated [3H]‐vinblastine and [3H]‐paclitaxel transport as it increased the steady‐state accumulation of these cytotoxics in CHrB30 cells to levels observed in non‐P‐gp‐expressing AuxB1 cells (EC50=487±50 nM). This inhibition of drug transport is not mediated through competition for transport since [3H]‐XR9576 accumulation was not influenced by P‐gp expression or function.
These results demonstrate that the P‐gp modulator XR9576 exhibits greater selectivity, duration of inhibition and potency of interaction with this transporter than any other reported modulators. Several lines of evidence suggest that XR9576 inhibits P‐gp function by binding at a site which is distinct from the site of interaction of transport substrates. The two sites may be classified as serving modulatory or transport functions.

British Journal of Pharmacology (1999) 128, 403–411; doi:10.1038/sj.bjp.0702807
Different receptors mediating the inhibitory action of exogenous ATP and endogenously released purines on guinea‐pig intestinal peristalsis
Authors: Heinemann Ákos , Shahbazian Anaid , Barthó Loránd , Holzer Peter 
Published: January 2005

Adenosine 5′‐triphosphate (ATP) is an enteric neurotransmitter which acts at purine receptors on intestinal nerve and muscle. This study set out to shed light on the receptor mechanisms by which exogenous and endogenous ATP influences intestinal peristalsis.
Peristalsis in isolated segments of the guinea‐pig small intestine was triggered by a perfusion‐induced rise of the intraluminal pressure. Motor changes were quantified by alterations of the peristaltic pressure threshold (PPT) at which propulsive muscle contractions were elicited.
ATP (3 μM) increased PPT and abolished peristalsis at concentrations of 100–300 μM. Adenosine 5′‐O‐2‐thiodiphosphate (ADPβS, 3–100 μM) was more potent, whereas α,β‐methylene ATP (α,β‐meATP, 3–100 μM) was less potent, than ATP in depressing peristalsis.
8‐Phenyltheophylline (10 μM) attenuated the anti‐peristaltic effect of 10 and 30 μM ATP but not that of higher ATP concentrations. Apamin (0.5 μM) counteracted the ability of ATP, ADPβS and α,β‐meATP to enhance PPT. Suramin (300 μM) and pyridoxal phosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS, 150 μM) antagonized the inhibitory effect of α,β‐meATP on peristalsis but did not alter the effect of ATP and ADPβS.
PPADS (50–150 μM) reduced PPT by as much as 50%. This stimulant effect on peristalsis was prevented by suramin (300 μM) but left unaltered by apamin (0.5 μM) and NG‐nitro‐L‐arginine methyl ester (300 μM).
These data show that exogenous and endogenous ATP inhibits intestinal peristalsis via different apamin‐sensitive purinoceptor mechanisms. Exogenous ATP depresses peristalsis mostly via suramin‐ and PPADS‐insensitive P2 receptors, whereas endogenous purines act via P2 receptors sensitive to both suramin and PPADS.

British Journal of Pharmacology (1999) 128, 313–320; doi:10.1038/sj.bjp.0702808
Long‐term deprivation of oestrogens by ovariectomy potentiates β‐amyloid‐induced working memory deficits in rats
Authors: Yamada Kiyofumi , Tanaka Tomoko , Zou Li‐Bo , Senzaki Kouji , Yano Kohji , Osada Takashi , Ana Olariu , Ren Xiuhai , Kameyama Tsutomu , Nabeshima Toshitaka 
Published: January 2005

In the present study, we examined whether deprivation of oestrogens by ovariectomy could modify learning and memory deficits caused by a continuous intracerebroventricular (i.c.v.) infusion of amyloid β‐peptide (Aβ), the major constituent of senile plaques in AD.
Neither long‐term (3 months) nor short‐term (1 month), deprivation of oestrogens by ovariectomy caused a significant impairment in spatial learning and memory in a water maze and spontaneous alternation behaviour in a Y‐maze.
A continuous i.c.v. infusion of Aβ‐(1‐42) caused spatial learning and memory deficits in both ovariectomized and sham‐operated rats.
The Aβ‐induced working memory deficits were significantly potentiated in ovariectomized rats compared with sham‐operated rats when mnemonic ability was examined 3 months after ovariectomy.
These results suggest that long‐term deprivation of oestrogens induced by ovariectomy increases susceptibility to memory deficits produced by Aβ‐(1‐42) in rats.

British Journal of Pharmacology (1999) 128, 419–427; doi:10.1038/sj.bjp.0702811