bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determination of effects of antiepileptic drugs on SNAREs‐mediated hippocampal monoamine release using in vivo microdialysis
Authors: Murakami Takuya , Okada Motohiro , Kawata Yuko , Zhu Gan , Kamata Akihisa , Kaneko Sunao 
Published: January 2005

To elucidate possible mechanisms underlying the effects of carbamazepine (CBZ), valproate (VPA) and zonisamide (ZNS) on neurotransmitter exocytosis, the interaction between these three antiepileptic drugs (AEDs) and botulinum toxins (BoNTs) on basal, Ca2+‐ and K+‐evoked release of dopamine (DA) and serotonin (5‐HT) were determined by microdialysis in the hippocampus of freely moving rats.
Basal release of monoamine was decreased by pre‐microinjection of the syntaxin inhibitor, BoNT/C, but only weakly affected by the synaptobrevin inhibitor, BoNT/B. Ca2+‐evoked release was inhibited by BoNT/C selectively. K+‐evoked release was reduced by BoNT/B predominantly and BoNT/C weakly.
Perfusion with low and high concentrations of CBZ and ZNS increased and decreased basal monoamine release, respectively. Perfusion with VPA increased basal 5‐HT release concentration‐dependently, whereas basal DA release was affected by VPA biphasic concentration‐dependently, similar to CBZ and ZNS. This stimulatory action of AEDs on basal release was inhibited by BoNT/C predominantly.
Ca2+‐evoked monoamine release was increased by low concentrations of CBZ, ZNS and VPA, but decreased by high concentrations. These effects of the AEDs on Ca2+‐evoked release were inhibited by BoNT/C, but not by BoNT/B.
K+‐evoked monoamine release was reduced by AEDs concentration‐dependently. The inhibitory effect of these three AEDs on K+‐evoked release was inhibited by BoNT/B, but not by BoNT/C,
These findings suggest that the therapeutic‐relevant concentration of CBZ, VPA and ZNS affects exocytosis of DA and 5‐HT, the enhancement of syntaxin‐mediated monoamine release during resting stage, and the inhibition of synaptobrevin‐mediated release during depolarizing stage.

British Journal of Pharmacology (2001) 134, 507–520; doi:10.1038/sj.bjp.0704285
Selective inhibition of thapsigargin‐induced contraction and capacitative calcium entry in mouse anococcygeus by trifluoromethylphenylimidazole (TRIM)
Authors: Gibson Alan , Fernandes Filomena , Wallace Pat , McFadzean Ian 
Published: January 2005

This study examined the effects of trifluoromethylphenylimidazole (TRIM) on tone, and calcium entry, in mouse anococcygeus stimulated by either thapsigargin (Tg; 100 nM) which activates capacitative calcium entry (CCE), or high K (60 mM) which activates voltage‐operated calcium channels. TRIM (1 – 333 μM) produced concentration‐related relaxation of Tg‐induced tone (EC50, 42 μM) but was much less effective against high K. In single smooth muscle cells loaded with FURA‐2, TRIM reduced the increase in fluorescence ratio produced by Tg but had no effect on that produced by high K. The relaxations of Tg‐induced tone, and reduction in fluorescence ratio, were obtained in the presence of L‐NG‐nitroarginine and were thus independent of nitric oxide synthase inhibition; further, TRIM had no discernible effect on nitrergic responses. TRIM provides a novel drug for the selective inhibition of CCE and a template for the development of more potent inhibitors.British Journal of Pharmacology (2001) 134, 233–236; doi:10.1038/sj.bjp.0704286
The KATP channel opener diazoxide protects cardiac myocytes during metabolic inhibition without causing mitochondrial depolarization or flavoprotein oxidation
Authors: Lawrence C L , Billups B , Rodrigo G C , Standen N B 
Published: January 2005

The KATP channel opener diazoxide has been proposed to protect cardiac muscle against ischaemia by opening mitochondrial KATP channels to depolarize the mitochondrial membrane potential, ΔΨm. We have used the fluorescent dye TMRE to measure ΔΨm in adult rat freshly isolated cardiac myocytes exposed to diazoxide and metabolic inhibition.
Diazoxide, at concentrations that are highly cardioprotective (100 or 200 μM), caused no detectable increase in TMRE fluorescence (n=27 cells). However, subsequent application of the protonophore FCCP, which should collapse ΔΨm, led to large increases in TMRE fluorescence (>300%).
Metabolic inhibition (MI: 2 mM NaCN+1 mM iodoacetic acid (IAA) led to an immediate partial depolarization of ΔΨm, followed after a few minutes delay by complete depolarization which was correlated with rigor contracture. Removal of metabolic inhibition led to abrupt mitochondrial repolarization followed in many cells by hypercontracture, indicated by cell rounding and loss of striated appearance.
Prior application of diazoxide (100 μM) reduced the number of cells that hypercontracted after metabolic inhibition from 63.7±4.7% to 24.2±1.8% (P<0.0001). 5‐hydroxydeanoate (100 μM) reduced the protection of diazoxide (46.8±2.7% cells hypercontracted, P<0.0001 vs diazoxide alone).
Diazoxide caused no detectable change in flavoprotein autofluorescence (n=26 cells).
Our results suggest that mitochondrial depolarization and flavoprotein oxidation are not inevitable consequences of diazoxide application in intact cardiac myocytes, and that they are also not essential components of the mechanism by which it causes protection.

British Journal of Pharmacology (2001) 134, 535–542; doi:10.1038/sj.bjp.0704289
Cannabinoid CB1‐receptor mediated regulation of gastrointestinal motility in mice in a model of intestinal inflammation
Authors: Izzo Angelo A , Fezza Filomena , Capasso Raffaele , Bisogno Tiziana , Pinto Luisa , Iuvone Teresa , Esposito Giuseppe , Mascolo Nicola , Di Marzo Vincenzo , Capasso Francesco 
Published: January 2005

We have studied the effect of cannabinoid agonists (CP 55,940 and cannabinol) on intestinal motility in a model of intestinal inflammation (induced by oral croton oil in mice) and measured cannabinoid receptor expression, endocannabinoids (anandamide and 2‐arachidonylglycerol) and anandamide amidohydrolase activity both in physiological and pathophysiological states.
CP 55,940 (0.03 – 10 nmol mouse−1) and cannabinol (10 – 3000 nmol mouse−1) were more active in delaying intestinal motility in croton oil‐treated mice than in control mice. These inhibitory effects were counteracted by the selective cannabinoid CB1 receptor antagonist SR141716A (16 nmol mouse−1). SR141716A (1 – 300 nmol mouse−1), administered alone, increased intestinal motility to the same extent in both control and croton oil‐treated mice
Croton oil‐induced intestinal inflammation was associated with an increased expression of CB1 receptor, an unprecedented example of up‐regulation of cannabinoid receptors during inflammation.
High levels of anandamide and 2‐arachidonylglycerol were detected in the small intestine, although no differences were observed between control and croton oil‐treated mice; by contrast anandamide amidohydrolase activity increased 2 fold in the inflamed small intestine.
It is concluded that inflammation of the gut increases the potency of cannabinoid agonists possibly by ‘up‐regulating’ CB1 receptor expression; in addition, endocannabinoids, whose turnover is increased in inflamed gut, might tonically inhibit intestinal motility.

British Journal of Pharmacology (2001) 134, 563–570; doi:10.1038/sj.bjp.0704293
Reduction of oxidative stress and AT1 receptor expression by the selective oestrogen receptor modulator idoxifene
Authors: Bäumer Anselm T , Wassmann Sven , Ahlbory Katja , Strehlow Kerstin , Müller Cornelius , Sauer Heinrich , Böhm Michael , Nickenig Georg 
Published: January 2005

The beneficial vasoprotective effects of oestrogens are hampered by their side effects on secondary sexual organs. Selective oestrogen receptor modulators (SERM) such as idoxifene may exert beneficial vascular effects without influencing cancerogenesis in breast or uterus.
In order to investigate vascular effects of selective oestrogen receptor modulators, we examined the impact of idoxifene on production of reactive oxygen species as well as AT1 receptor expression in vascular smooth muscle cells (VSMC).
Idoxifene caused a concentration‐ and time‐dependent down‐regulation of AT1 receptor mRNA expression, as assessed by Northern analysis. The maximal effect was reached with 10 μmol l−1 idoxifene after a 4 h incubation period (33±7% of control levels). Western blots showed a similar down‐regulation of AT1 receptor protein to 36±11% of control levels.
Confocal laserscanning microscopy using the redox sensitive marker 2′,7′‐dichlorofluorescein (DCF) and measurement of NAD(P)H oxidase activity in cell homogenates revealed that idoxifene effectively blunted the angiotensin II‐induced production of reactive oxygen species.
In order to investigate the signal transduction involved in SERM‐induced modulation of AT1 receptor expression, VSMC were preincubation with PD98059, genistein, wortmannin, or Nω‐Nitro‐L‐arginine. The results suggested that idoxifene caused AT1 receptor down‐regulation through nitric oxide‐dependent pathways.
In conclusion, idoxifene reduces angiotensin II‐evoked oxidative stress in VSMC. This could in part be explained by idoxifene‐induced down‐regulation of AT1 receptor expression. These results demonstrate that the selective oestrogen receptor modulator idoxifene may exert beneficial vascular effects which could be useful for therapeutic regimen in postmenopausal women at risk for cardiovascular diseases.

British Journal of Pharmacology (2001) 134, 579–584; doi:10.1038/sj.bjp.0704299
Glycosylation and the activation of proteinase‐activated receptor 2 (PAR2) by human mast cell tryptase
Authors: Compton Steven J , Renaux Bernard , Wijesuriya Suranga J , Hollenberg Morley D 
Published: January 2005

Human mast cell tryptase appears to display considerable variation in activating proteinase‐activated receptor 2 (PAR2). We found tryptase to be an inefficient activator of wild‐type rat‐PAR2 (wt‐rPAR2) and therefore decided to explore the factors that may influence tryptase activation of PAR2.
Using a 20 mer peptide (P20) corresponding to the cleavage/activation sequence of wt‐rPAR2, tryptase was as efficient as trypsin in releasing the receptor‐activating sequence (SLIGRL…). However, in the presence of either human‐PAR2 or wt‐r PAR2 expressing cells, tryptase could only activate PAR2 by releasing SLIGRL from the P20 peptide, suggesting that PAR2 expressed on the cells was protected from tryptase activation.
Three approaches were employed to test the hypothesis that PAR2 receptor glycosylation restricts tryptase activation. (a) pretreatment of wt‐rPAR2 expressing cells or human embryonic kidney cells (HEK293) with vibrio cholerae neuraminidase to remove oligosaccharide sialic acid, unmasked tryptase‐mediated PAR2 activation. (b) Inhibiting receptor glycosylation in HEK293 cells with tunicamycin enabled tryptase‐mediated PAR2 activation. (c) Wt‐rPAR2 devoid of the N‐terminal glycosylation sequon (PAR2T25−), but not rPAR2 devoid of the glycosylation sequon located on extracellular loop‐2 (PAR2T224A), was selectively and substantially (>30 fold) more sensitive to tryptase compared with the wt‐rPAR2.
Immunocytochemistry using antisera that specifically recognized the N‐terminal precleavage sequence of PAR2 demonstrated that tryptase released the precleavage domain from PAR2T25− but not from wt‐rPAR2.
Heparin : tryptase molar ratios of greater than 2 : 1 abrogated tryptase activation of PAR2T25−.
Our results indicate that glycosylation of PAR2 and heparin‐inhibition of PAR2 activation by tryptase could provide novel mechanisms for regulating receptor activation by tryptase and possibly other proteases.

British Journal of Pharmacology (2001) 134, 705–718; doi:10.1038/sj.bjp.0704303
Properties of Ca2+ release induced by clofibric acid from the sarcoplasmic reticulum of mouse skeletal muscle fibres
Authors: Ikemoto Takaaki , Endo Makoto 
Published: January 2005

To characterize the effect of clofibric acid (Clof) on the Ca2+ release mechanism in the sarcoplasmic reticulum (SR) of skeletal muscle, we analysed the properties of Clof‐induced Ca2+ release under various conditions using chemically skinned skeletal muscle fibres of the mouse.
Clof (>0.5 mM) released Ca2+ from the SR under Ca2+‐free conditions buffered with 10 mM EGTA (pCa >8).
Co‐application of ryanodine and Clof at pCa >8 but not ryanodine alone reduced the Ca2+ uptake capacity of the SR. Thus, Ca2+ release induced by Clof at pCa >8 must be a result of the activation of the ryanodine receptor (RyR).
At pCa >8, (i) Clof‐induced Ca2+ release was inhibited by adenosine monophosphate (AMP), (ii) the inhibitory effect of Mg2+ on the Clof‐induced Ca2+ release was saturated at about 1 mM, and (iii) Clof‐induced Ca2+ release was not inhibited by procaine (10 mM). These results indicate that Clof may activate the RyR‐Ca2+ release channels in a manner different from Ca2+‐induced Ca2+ release (CICR).
In addition to this unique mode of opening, Clof also enhanced the CICR mode of opening of RyR‐Ca2+ release channels.
Apart from CICR, a high concentration of Ca2+ might also enhance the unique mode of opening by Clof.
These results suggest that some features of Ca2+ release activated by Clof are similar to those of physiological Ca2+ release (PCR) in living muscle cells and raise the possibility that Clof may be useful in elucidating the mechanism of PCR in skeletal muscle.

British Journal of Pharmacology (2001) 134, 719–728; doi:10.1038/sj.bjp.0704306
Thrombin‐induced platelet endostatin release is blocked by a proteinase activated receptor‐4 (PAR4) antagonist
Authors: Ma Li , Hollenberg Morley D , Wallace John L 
Published: January 2005

Endostatin is a potent endogenous inhibitor of angiogenesis that was recently shown to be stored in platelets and released in response to thrombin, but not ADP. In the present study, we have tested the hypothesis that thrombin‐induced endostatin release from rat platelets is mediated via proteinase‐activated receptor‐4 (PAR4). Immunoprecipitation and Western blotting confirmed that endostatin is contained within rat platelets. Aggregation and release of endostatin could be elicited by thrombin (0.5 – 1.0 U ml−1) or by specific PAR4 agonist (AYPGKF‐NH2; AY‐NH2; 15 – 50 μM). Significant release of endostatin could be induced by a dose of thrombin below that necessary for induction of aggregation. An adenosine diphosphate (ADP) scavenger, apyrase, inhibited the platelet aggregation induced by thrombin, but not the release of endostatin. In contrast, a selective PAR4 antagonist (trans‐cinnamoyl‐YPGKF‐NH2; tcY‐NH2) prevented endostatin release and aggregation induced by thrombin or by AY‐NH2. We conclude that thrombin‐induced endostatin release from rat platelets is PAR4‐mediated via an ADP‐independent mechanism that can occur independently of platelet aggregation.British Journal of Pharmacology (2001) 134, 701–704; doi:10.1038/sj.bjp.0704312
Methylamine and benzylamine induced hypophagia in mice: Modulation by semicarbazide‐sensitive benzylamine oxidase inhibitors and aODN towards Kv1.1 channels
Authors: Pirisino R , Ghelardini C , Banchelli G , Galeotti N , Raimondi L 
Published: January 2005

In starved mice, the anorectic activity of methylamine (MET) and benzylamine (BZ), both substrates of semicarbazide‐sensitive benzylamine oxidases (Bz‐SSAO), was compared with that of the potassium channel blocking agents charybdotoxin (ChTX), tetraethylammonium (TEA), gliquidone (GLI), ammonium chloride (NH4+) and of the anoressants amphetamine (AMPH) and nicotine (NIC). After i.c.v. administration, an approximate ranking order of potency was: ChTXAMPH>NIC=TEAGLIMET>BZ>NH4+.
Clorgyline (2.5 mg kg−1 i.p.) or deprenyl (10 mg kg−1 i.p.) potentiated the anorectic effect of i.c.v.‐administered BZ, NIC and AMPH. The effect of TEA was increased only by deprenyl, while MET, NH4+, ChTX and GLI were not affected by either of the inhibitors.
The Bz‐SSAO inhibitors α‐aminoguanidine (50 mg kg−1 i.p.), B24 (100 mg kg−1 i.p.) and MDL 72274 (2.5 mg kg−1 i.p.) potentiated the effect of i.p., but not of i.c.v.‐administered MET.
Antisense oligodeoxyribonucleotides (aODN) to Kv1.1 potassium channels abolished the effect of BZ and TEA, but was ineffective in reducing the activity of MET and other compounds.
These results suggest that MET is endowed with peculiar hypophagic effects at dosage levels that are not able to affect gross behaviour in mice. The effect of MET, differently from BZ, seems unrelated to an increase in the central release of monoaminergic mediators, as well as to a Kv1.1 blocking activity. Through a reduction of the endogenous breakdown of MET, Bz‐SSAO inhibitors enhance the central pharmacological activity of this amine.

British Journal of Pharmacology (2001) 134, 880–886; doi:10.1038/sj.bjp.0704316
Intracellular distribution of psychotropic drugs in the grey and white matter of the brain: the role of lysosomal trapping
Authors: Daniel Władysława A , Wójcikowski Jacek , Pałucha Agnieszka 
Published: January 2005

Since the brain is not a homogenous organ (i.e. the phospholipid pattern and density of lysosomes may vary in its different regions), in the present study we examined the uptake of psychotropic drugs by vertically cut slices of whole brain, grey (cerebral cortex) and white (corpus callosum, internal capsule) matter of the brain and by neuronal and astroglial cell cultures.Moreover, we assessed the contribution of lysosomal trapping to total drug uptake (total uptake=lysosomal trapping+phospholipid binding) by tissue slices or cells conducting experiments in the presence and absence of ‘lysosomal inhibitors’, i.e., the lysosomotropic compound ammonium chloride (20 mM) or the Na+/H+‐ionophore monensin (10 μM), which elevated the internal pH of lysosomes. The initial concentration of psychotropic drug in the incubation medium was 5 μM.Both total uptake and lysosomal trapping of the antidepressants investigated (imipramine, amitriptyline, fluoxetine, sertraline) and neuroleptics (promazine, perazine, thioridazine) were higher in the grey matter and neurones than in the white matter and astrocytes, respectively. Lysosomal trapping of the psychotropics occurred mainly in neurones where thioridazine sertraline and perazine showed the highest degree of lysosomotropism.Distribution interactions between antidepressants and neuroleptics took place in neuronesviamutual inhibition of lysosomal trapping of drugs.A differential number of neuronal and glial cells in the brain may mask the lysosomal trapping and the distribution interactions of less potent lysosomotropic drugs in vertically cut brain slices.A reduction (viaa distribution interaction) in the concentration of psychotropics in lysosomes (depot), which leads to an increase in their level in membranes and tissue fluids, may intensify the pharmacological action of the combined drugs.British Journal of Pharmacology(2001)134, 807–814; doi:10.1038/sj.bjp.0704319
Effect of long‐term treatment with trandolapril on Hsp72 and Hsp73 induction of the failing heart following myocardial infarction
Authors: Tanonaka Kouichi , Toga Wakako , Yoshida Hiroyuki , Furuhama Ken‐ichi , Takeo Satoshi 
Published: January 2005

The effect of long‐term treatment of rats with chronic heart failure (CHF) following acute myocardial infarction with trandolapril, an angiotensin I‐converting enzyme (ACE) inhibitor, on heat shock‐induced Hsp72 and Hsp73 production was examined.
Acute myocardial infarction was induced by coronary artery ligation (CAL). The animals with CAL showed symptoms of CHF at the 8th week after the operation. The hearts isolated from animals with CAL at the 2nd and 8th week after surgery were subjected to hyperthermia at 42°C for 15 min followed by 6‐h perfusion (hyperthermia/6‐h perfusion).
In the hearts isolated from the animals at the 2nd week, an approximate 20% decline in the rate pressure product (RPP) was seen after hyperthermia/6‐h perfusion, which was similar to that in non‐operated controls. In contrast, a significant reduction in the RPP after hyperthermia/6‐h perfusion was seen in the hearts of rats with CHF. These hearts did not increase Hsp72 and Hsp73 production after hyperthermia. The decline in RPP was associated with failure in the production of myocardial Hsp72 and Hsp73.
When rats with CAL were treated with 3 mg kg−1 day−1 trandolapril from the 2nd to 8th week after the operation, the decline in RPP of the failing heart after hyperthermia was similar to that of the sham‐operated rats. The induction of myocardial Hsp72 and Hsp73 production of the coronary artery‐ligated rats after hyperthermia was reversed by treatment with trandolapril.
These findings suggest that the preserved ability to induce Hsp72 and Hsp73 production in the heart with CAL by trandolapril treatment may be attributed to the increased tolerance against heat stress‐induced deterioration of myocardial contractile function.

British Journal of Pharmacology (2001) 134, 969–976; doi:10.1038/sj.bjp.0704323
GABA receptors modulate trigeminovascular nociceptive neurotransmission in the trigeminocervical complex
Authors: Storer R James , Akerman Simon , Goadsby Peter J 
Published: January 2005

GABA (γ‐aminobutyric acid) receptors involved in craniovascular nociceptive pathways were characterised by in vivo microiontophoresis of GABA receptor agonists and antagonists onto neurones in the trigeminocervical complex of the cat.
Extracellular recordings were made from neurones in the trigeminocervical complex activated by supramaximal electrical stimulation of superior sagittal sinus, which were subsequently stimulated with L‐glutamate.
Cell firing evoked by microiontophoretic application of L‐glutamate (n=30) was reversibly inhibited by GABA in every cell tested (n=19), the GABAA agonist muscimol (n=10) in all cells tested, or both where tested, but not by iontophoresis of either sodium or chloride ions at comparable ejection currents. Inhibited cells received wide dynamic range (WDR) or nociceptive specific input from cutaneous receptive fields on the face or forepaws.
The inhibition of trigeminal neurones by GABA or muscimol could be antagonized by the GABAA antagonist N‐methylbicuculline, 1(S),9(R) in all but two cells tested (n=16), but not by the GABAB antagonist 2‐hydroxysaclofen (n=11).
R(−)‐baclofen, a GABAB agonist, inhibited the firing of three out of seven cells activated by L‐glutamate. Where tested, this inhibition could be antagonized by 2‐hydroxysaclofen. These baclofen‐inhibited cells were characterized as having low threshold mechanoreceptor/WDR input.
GABA thus appears to modulate nociceptive input to the trigeminocervical complex mainly through GABAA receptors. GABAA receptors may therefore provide a target for the development of new therapeutic agents for primary headache disorders.

British Journal of Pharmacology (2001) 134, 896–904; doi:10.1038/sj.bjp.0704325