bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential modulation of AMPA receptor mediated currents by Evans Blue in postnatal rat hippocampal neurones
Authors: Schürmann Britta , Wu Xueqing , Dietzel Irmgard D , Leßmann Volkmar 
Published: August 2006

The modulation of non‐N‐methyl‐D‐aspartate (NMDA) receptor‐mediated whole cell currents and of glutamatergic synaptic transmission by purified Evans Blue (EB) was investigated in rat cultured postnatal hippocampal neurones by use of patch clamp recordings and a fast drug application system.
Three different groups of neurones could be distinguished with respect to the type of modulation obtained with 10 μM EB: EB was either a predominant inhibitor of desensitization (13% of the neurones), a predominant inhibitor of current amplitudes (42%) or a mixed inhibitor of both properties (45%). Both effects were not use‐dependent and reached maximal levels after 30 s of pre‐equilibration with the diazo dye.
Dose‐response curves obtained from glutamate activated whole cell currents yielded an IC50 value for EB of 13.3 μM (Hill coefficient: 1.3) for the inhibition of desensitization, and an IC50 value of 10.7 μM (Hill coefficient: 1.2) for the inhibition of current amplitudes.
Chicago acid SS (100 μM) which is one of the synthesis precursors of EB had no effect on current amplitudes of glutamate activated whole cell currents but was a weak inhibitor of desensitization in all hippocampal neurones investigated, irrespective of the type of modulation obtained with EB in the same neurone.
Oxidatively modified EB (the so‐called VIMP (10 μM)) had no effect on the kinetics but was a partial inhibitor of glutamate‐activated whole cell currents in all hippocampal neurones investigated.
EB (10 μM) inhibited the amplitudes of non‐NMDA receptor mediated autaptic currents to the same extent (to 39±19% of control) as observed for glutamate activated whole cell currents (to 41±17% and 56±20%). However, the decay of the autaptic responses remained uninfluenced upon EB application, indicating that either receptor desensitization does not dominate the time course of the synaptic response or that the non‐NMDA receptors sensitive to modulation of desensitization by EB are not present in the postsynaptic membrane.
In conclusion, EB differentially modulates α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) receptor gating in different subsets of neurones. Upon identification of the cellular determinants for the differential modulation (e.g. AMPA receptor subunit composition) EB could become a useful tool to investigate receptor subtypes during electrophysiological recordings.

British Journal of Pharmacology (1997) 121, 237–247; doi:10.1038/sj.bjp.0701125
Inhibition by nociceptin of the light‐evoked release of ACh from retinal cholinergic neurones
Authors: Neal M. J. , Cunningham J. R. , Paterson S. J. , Mcknight A. T. 
Published: August 2006

The retina possesses cholinergic amacrine cells which release acetylcholine (ACh) in response to flickering light. Using an eye‐cup preparation in anaesthetized rabbits we found that when the retina was exposed to nociceptin, the light‐evoked release of ACh was reduced in a concentration‐dependent manner (IC50 = 100 nm), the maximum effect being 60% inhibition. Opioid receptors were not involved in the inhibitory effect of nociceptin because its action was not blocked by naloxone (1 μm) and furthermore μ‐opioids enhanced the light‐evoked release of ACh. Using rabbit retina homogenates we found that the retina possessed a substantial number of high‐affinity binding sites for [3H]‐nociceptin indicating the presence of ORLI‐receptors. Since [des‐Phe1]‐nociceptin, which has no affinity for the ORLI‐receptor, had no effect on the light‐evoked release of ACh it is unlikely that the action of nociceptin was simply non‐specific. We conclude that the inhibitory effect of nociceptin on retinal ACh release involves activation of the ORLI receptors.British Journal of Pharmacology (1997) 120, 1399–1400; doi:10.1038/sj.bjp.0701135
Endothelin receptors and their cellular signal transduction mechanism in human cultured prostatic smooth muscle cells
Authors: Saita Yuji , Koizumi Tomonobu , Yazawa Hidenori , Morita Takashi , Takenaka Toichi , Honda Kazuo 
Published: August 2006

Endothelin (ET) receptors, and their cellular signal transduction mechanism, were characterized in a primary culture of human prostatic smooth muscle cells (HP cell).
[125I]‐ET‐1 and [125I]‐ET‐3 binding studies revealed that both ETA and ETB receptors were present in the HP cells, and the ratio of ETA to ETB receptors was 1.4:1.
Analysis of ET receptor mRNA by reverse transcription‐polymerase chain reaction also demonstrated that HP cells express both ETA and ETB receptors.
ET‐1 and ET‐3 increased intracellular free Ca2+ concentration ([Ca2+]i) in the HP cells in a concentration‐dependent manner. Use of subtype selective antagonists BQ‐123 and BQ‐788, indicated that both ETA and ETB receptors were coupled to an increase in [Ca2+]i.
Pretreatment of the cells with pertussis toxin resulted in a significant but partial attenuation of the [Ca2+]i increase mediated through the ETA and ETB receptors. However, sensitivity to pertussis toxin (PTX) was significantly different between them.
In conclusion, HP cells possess ETA and ETB receptors. Further, these two endothelin receptor subtypes evoke an increase in [Ca2+]i possibly via the action of different GTP‐binding proteins.

British Journal of Pharmacology (1997) 121, 687–694; doi:10.1038/sj.bjp.0701179
Effect of a novel selective and potent phosphinic peptide inhibitor of endopeptidase 3.4.24.16 on neurotensin‐induced analgesia and neuronal inactivation
Authors: Vincent Bruno , Jiracek Jirì , Noble Florence , Loog Mart , Roques Bernard , Dive Vincent , Vincent Jean‐Pierre , Checler Frédéric 
Published: August 2006

We have examined a series of novel phosphinic peptides as putative potent and selective inhibitors of endopeptidase 3.4.24.16.
The most selective inhibitor, Pro‐Phe‐Ψ(PO2CH2)‐Leu‐Pro‐NH2 displayed a Ki value of 12 nM towards endopeptidase 3.4.24.16 and was 5540 fold less potent on its related peptidase endopeptidase 3.4.24.15. Furthermore, this inhibitor was 12.5 less potent on angiotensin‐converting enzyme and was unable to block endopeptidase 3.4.24.11, aminopeptidases B and M, dipeptidylaminopeptidase IV and proline endopeptidase.
The effect of Pro‐Phe‐Ψ(PO2CH2)‐Leu‐Pro‐NH2, in vitro and in vivo, on neurotensin metabolism in the central nervous system was examined.
Pro‐Phe‐Ψ(PO2CHH2)‐Leu‐Pro‐NH2 dose‐dependently inhibited the formation of neurotensin 1‐10 and concomittantly protected neurotensin from degradation by primary cultured neurones from mouse embryos.
Intracerebroventricular administration of Pro‐Phe‐Ψ(PO2CH2)‐Leu‐Pro‐NH2 significantly potentiated the neurotensin‐induced antinociception of mice in the hot plate test.
Altogether, our study has established Pro‐Phe‐Ψ(PO2CH2)‐Leu‐Pro‐NH2 as a fully selective and highly potent inhibitor of endopeptidase 3.4.24.16 and demonstrates, for the first time, the contribution of this enzyme in the central metabolism of neurotensin.

British Journal of Pharmacology (1997) 121, 705–710; doi:10.1038/sj.bjp.0701182
Role of Ca2+‐activated K+ channel in epithelium‐dependent relaxation of human bronchial smooth muscle
Authors: Tamaoki J. , Tagaya E. , Isono K. , Kondo M. , Konno K. 
Published: August 2006

To elucidate whether K+ channels play a role in the action of epithelium‐dependent bronchodilatation, we studied responses in human bronchial strips in the presence of indomethacin and NG‐nitro‐L‐arginine methylester under isometric conditions, in vitro.
Mechanical removal of the epithelium increased the contractile responses to acetylcholine; the pD2 values increased from 5.0±0.2 to 5.9±0.3 (P<0.001). This potentiation was abolished by iberiotoxin but not by apamin or glibenclamide.
In cascade bioassay, application of the bathing medium from dispersed, bronchial epithelial cells to epithelium‐denuded bronchial strips decreased acetylcholine‐induced contraction by 44±6%. This effect was reduced to 10±3% (P<0.01) when the epithelial cells were pretreated with iberiotoxin, and to 4±1% (P<0.001) when the epithelial cells were incubated with Ca2+‐free medium containing [1,2‐bis (2) aminophenoxy] ethane N,N,N′,N′‐tetraacetic acid‐acetomethoxy ester.
In contrast, the bronchodilator effect of the medium bathing epithelial cells was not altered by the direct addition of iberiotoxin to epithelium‐denuded tissues.
These results suggest that the Ca2+‐activated K+ channel may play a role in the synthesis and/or release of smooth muscle relaxing factor, which is neither nitric oxide nor a cyclo‐oxygenase product, from airway epithelial cells.

British Journal of Pharmacology (1997) 121, 794–798; doi:10.1038/sj.bjp.0701183
Effects of calcium dobesilate on the synthesis of endothelium‐dependent relaxing factors in rabbit isolated aorta
Authors: Ruiz E. , Lorente R. , Tejerina T. 
Published: August 2006

Some cardiovascular disturbances which occur in diabetics are a consequence of alterations in vascular contractility as well as in endothelium‐dependent relaxation.
Calcium dobesilate (DOBE) is a drug used in diabetic retinopathy and its mechanism of action is not yet understood.
The aim of this study was to investigate the effects of DOBE on synthesis and release of endothelium‐dependent relaxing factor (EDRF) and endothelium‐dependent hyperpolarizing factor (EDHF) in rabbit isolated aorta.
Endothelium‐dependent relaxation induced by acetylcholine (ACh) (10−8–10−5 M) increased in the presence of DOBE 10−5 M only when vascular endothelium was kept intact.
NG‐nitro‐L‐arginine methyl ester (L‐NAME; 10−8–10−4 M progressively decreased the enhancing effect of DOBE on endothelium‐dependent relaxation whereas it was progressively increased by L‐Arg.
DOBE 10−5 M increased in a non‐significant manner endothelium‐dependent relaxation induced by ACh when the arteries were incubated with both L‐NAME 10−4 M and indomethacin 10−6 M.
DOBE (10−6 M and 10−5 M) was able to scavenge superoxide anion radicals generated by the hypoxanthine/xanthine oxidase reaction.
These results provide evidence that DOBE is able to affect the vascular disorders associated with diabetes mellitus since it enhances the synthesis of endothelium‐dependent relaxing factors.

British Journal of Pharmacology (1997) 121, 711–716; doi:10.1038/sj.bjp.0701184
A study of the neurotoxic effect of MDMA (‘ecstasy’) on 5‐HT neurones in the brains of mothers and neonates following administration of the drug during pregnancy
Authors: Colado M. I. , O'Shea E. , Granados R. , Misra A. , Murray T. K. , Green A. R. 
Published: August 2006

It is well established that 3,4‐methylenedioxymethamphetamine (MDMA or ‘ecstasy’) is neurotoxic and produces long term degeneration of cerebral 5‐hydroxytryptamine (5‐HT) nerve terminals in many species. Since MDMA is used extensively as a recreational drug by young people, it is being ingested by many women of child bearing age. We have therefore examined the effect of administering high doses of MDMA to rats during pregnancy on the cerebral content of both the dams and the neonates.
MDMA (20 mg kg−1, s.c.) was injected twice daily on days 14–17 of the gestation period. The initial dose produced a marked hyperthermic response in the dam which was progressively attenuated in both peak height and area under the curve following further doses of the drug. The body weight of the dams decreased during the period of treatment.
There was a modest decrease in litter size (−20%) of the MDMA‐treated dams.
The concentration of 5‐HT and its metabolite 5‐HIAA was decreased by over 65% in the hippocampus and striatum and 40% in the cortex of the dams 1 week after parturition. In contrast, the content of 5‐HT and 5‐HIAA in the dorsal telencephalon of the pups of the MDMA‐treated dams was the same as that seen in tissue from pups born to control animals.
Administration of MDMA (40 mg kg−1, s.c.) to adult rats increased thiobarbituric acid reacting substances (TBARS) in cortical tissue 3 h and 6 h later, indicating increased lipid peroxidation. No increase in TBARS was seen in the cortical tissue of 7–10 day neonates injected with this dose of MDMA 3 h or 6 h earlier.
The data suggest that exposure to MDMA in utero during the maturation phase does not produce damage to 5‐HT nerve terminals in the foetal rat brain, in contrast to the damage seen in the brains of the mothers. This may be due to MDMA being metabolized to free radical producing entities in the adult brain but not in the immature brain or, alternatively, to more effective or more active free radical scavenging mechanisms being present in the immature brain.

British Journal of Pharmacology (1997) 121, 827–833; doi:10.1038/sj.bjp.0701201
Hydrogen peroxide induced responses of cat tracheal smooth muscle cells
Authors: Bauer V , Oike M , Tanaka H , Inoue R , Ito Y 
Published: August 2006

The effects of hydrogen peroxide H2O2 (10−6 and 10−3 M) on membrane potential, membrane currents, intracellular calcium concentration, resting muscle tone and contractions elicited by electrical field stimulation (EFS) and carbachol were examined in cat tracheal strips and isolated smooth muscle cells.
H2O2 (10−4 and 10−5 M) enhanced the amplitude of contractions and excitatory junction potentials (e.j.p.) evoked by EFS without changing muscle tone and resting membrane potential of the tracheal smooth muscle, and enhanced the contraction induced by carbachol (10−8 M). At an increased concentration (10−3 M), H2O2 elevated resting muscle tone and marginally hyperpolarized the membrane in the majority of the cells.
In 51 out of 56 cells examined, H2O2 (10−6–10−3 M) elicited an outward current at a holding potential of −40 mV and enhanced the frequency of the spontaneous transient outward current (STOC). In 20 cells the outward current was preceded by a small inward current. In the other cells, H2O2 elicited only an inward current or did not affect the background current.
In Ca2+ free solution the action of H2O2 on the resting muscle tone, STOCs, background current and on the current induced by ramp depolarization was significantly reduced.
H2O2 (10−4 M) increased the intracellular ionized calcium concentration both in the absence and presence of external Ca2+. However, the effect developed faster and was of a higher amplitude in the presence of external Ca2+.
These results suggest that H2O2 increases intracellular Ca2+, with a subsequent augmentation of stimulation‐evoked contractions, and enhances Ca2+ and voltage‐sensitive potassium conductance.
Pharmacological pleiotropism of the human recombinant α1A‐adrenoceptor: implications for α1‐adrenoceptor classification
Authors: Ford Anthony P D W , Daniels Donald V , Chang David J , Gever Joel R , Jasper Jeffrey R , Lesnick John D , Clarke David E 
Published: August 2006

Three fully‐defined α1‐adrenoceptors (α1A, α1B and α1D) have been established in pharmacological and molecular studies. A fourth α1‐adrenoceptor, the putative α1L‐adrenoceptor, has been defined in functional but not molecular studies, and has been proposed to mediate contraction of human lower urinary tract tissues; its relationship to the three fully characterized α1‐adrenoceptors is not known.
In the present study, binding affinities were estimated by displacement of [3H]‐prazosin in membrane homogenates of Chinese hamster ovary (CHO‐K1) cells stably expressing the human α1A‐, α1B‐ and α1D‐adrenoceptors and were compared with affinity estimates obtained functionally in identical cells by measuring inhibition of noradrenaline (NA)‐stimulated accumulation of [3H]‐inositol phosphates.
For the α1A‐adrenoceptor, binding studies revealed a pharmacological profile typical for the classically defined α1A‐adrenoceptor, such that prazosin, RS‐17053, WB4101, 5‐methylurapidil, Rec15/2739 and S‐niguldipine all displayed subnanomolar affinity. A different profile of affinity estimates was obtained in inositol phosphates accumulation studies: prazosin, WB4101, 5‐methylurapidil, RS‐17053 and S‐niguldipine showed 10 to 40 fold lower affinity than in membrane binding. However, affinity estimates were not ‘frameshifted’, as tamsulosin, indoramin and Rec15/2739 yielded similar, high affinity estimates in binding and functional assays.
In contrast, results from human α1B‐ and α1D‐adrenoceptors expressed in CHO‐K1 cells gave antagonist affinity profiles in binding and functional assays that were essentially identical.
A concordance of affinity estimates from the functional (inositol phosphates accumulation) studies of the α1A‐adrenoceptor in CHO‐K1 cells was found with estimates published recently from contractile studies in human lower urinary tract tissues (putative α1L‐adrenoceptor). These data show that upon functional pharmacological analysis, the cloned α1A‐adrenoceptor displays pharmacological recognition properties consistent with those of the putative α1L‐adrenoceptor. Why this profile differs from that obtained in membrane binding, and whether it explains the α1L‐adrenoceptor pharmacology observed in many native tissues, requires further investigation.
The selectivity and structural determinants of peptide antagonists at the CGRP receptor of rat, L6 myocytes
Authors: Howitt Stephen G , Poyner David R 
Published: August 2006

Potency orders were determined for a series of agonists and antagonists on the calcitonin gene‐related peptide (CGRP) receptor of rat L6 myocytes. The agents tested were all shown to have been active against CGRP, amylin or adrenomedullin receptors.
AC187 had a pIC50 of 6.8±0.10, making it 14 fold less potent as an antagonist than CGRP8–37 (pIC50, 7.95±0.14). Amyline8–37 was equipotent to AC187 (pIC50, 6.6±0.16) and CGRP19–37 was 3 fold less potent than either (pIC50, 6.1±0.24).
[Ala11]‐CGRP8–37 was 6 fold less potent than CGRP8–37, (pIC50, 7.13±0.14), whereas [Ala18]‐CGRP8–37 was approximately equipotent to CGRP8–37 (pIC50, 7.52±0.15). However, [Ala11,Ala18]‐CGRP8–37 was over 300 fold less potent than CGRP8–37 (pIC50, 5.30±0.04).
[Tyr0]‐CGRP28–37, amylin19–37 and adrenomedullin22–52 were inactive as antagonists at concentrations of up to 1 μM.
Biotinyl‐human α‐CGRP was 150 fold less potent than human α‐CGRP itself (EC50 values of 48±17 nM and 0.31±0.13 nM, respectively). At 1 μM, [Cys(acetomethoxy)2,7]‐CGRP was inactive as an agonist.
These results confirm a role for Arg11 in maintaining the high affinity binding of CGRP8–37. Arg18 is of less direct significance for high affinity binding, but it may be important in maintaining the amphipathic nature of CGRP and its analogues.
Lack of involvement of glutamate‐induced excitotoxicity in MPP+ toxicity in striatal dopaminergic terminals: possible involvement of ascorbate
Authors: Matarredona Esperanza R , Santiago Marti , Machado Alberto , Cano Josefina 
Published: August 2006

The present study concerns the possible relationship between glutamate excitotoxicity and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine/1‐methyl‐4‐phenylpyridinium (MPTP/MPP+) neurotoxicity on striatal dopaminergic terminals.
MPP+ neurotoxicity has been studied by means of two MPP+ perfusions separated by 24 h. After the second MPP+ 1 mM perfusion, dopamine extracellular output, measured by microdialysis, was considered to be an index of the dopaminergic neurone damage produced by the first MPP+ 1 mM perfusion.
High concentration (10 mM) of glutamate uptake inhibitor L‐trans‐pyrrolidine‐2,4‐dicarboxylic acid (PDC) stimulated basal release of dopamine and protected against the neurotoxic effect of MPP+.
PDC 10 mM perfusion produced an increase in the extracellular output of glutamate and aspartate, and a decrease in that of ascorbate.
The protective effect against MPP+ toxicity observed with PDC 10 mM was completely abolished when this glutamate uptake inhibitor was co‐perfused with ascorbate 0.5 mM.
These results suggest that glutamate‐induced neurotoxicity is not involved in MPP+ toxicity. The protective effect found with the glutamate uptake inhibitor could be due to a decrease in extracellular ascorbate levels.
Neurochemical actions of the desglycinyl metabolite of remacemide hydrochloride (ARL 12495AA) in mouse brain
Authors: Paul Leach John , Sills Graeme J , Butler Elaine , Forrest Gerard , Thompson George G , Brodie Martin J 
Published: August 2006

Remacemide hydrochloride, a recently developed antiepileptic drug, is believed to exert its effects, at least in part, via its desglycinyl metabolite, ARL 12495AA.
We have investigated the effects of ARL 12495AA on several neurochemical parameters in mouse brain. Adult male ICR mice were randomized into two groups and administered ARL 12495AA (0–75 mg kg−1) intraperitoneally, either as a single dose or once daily for 5 days.
Six hours after the final dose, animals were killed and their brains removed. Brain tissues were analysed for concentrations of γ‐aminobutyric acid (GABA), glutamine and glutamate and for the activities of GABA‐transaminase (GABA‐T) and glutamic acid decarboxylase (GAD).
Single dose ARL 12495AA was without effect on any of the parameters investigated.
Repeated ARL 12495AA treatment did not alter brain concentrations of GABA and glutamine, but at a high dose there was a trend toward reduced brain glutamate concentrations (P=0.10).
Repeated administration of ARL 12495AA at a high dose significantly increased GABA‐T activity (P<0.05) and decreased that of GAD (P<0.05). 7 These findings may have relevance to the clinical use of remacemide hydrochloride in human epilepsy.
Characterization of lamotrigine inhibition of Na+ channels in rat hippocampal neurones
Authors: Kuo Chung‐Chin , Lu Lu 
Published: August 2006

Lamotrigine (LTG), a new antiepileptic drug, requires long depolarizations to inhibit Na+ currents. This suggests either slow binding of LTG to the fast inactivated state or selective binding of LTG to the slow inactivated state of Na+ channels. To differentiate between these possibilities and to characterize further the action of LTG, we studied the affinity and kinetics of LTG binding to the Na+ channels in acutely dissociated hippocampal neurones of the rat.
LTG inhibited more Na+ currents at more depolarized holding potentials. The inhibitory effect at various holding potentials could be described by one‐to‐one binding curves, which yielded an apparent dissociation constant of ∼7μm for LTG binding to the inactivated channels (KI), and a dissociation constant more than 200 times larger for LTG binding to the resting channels. A similar value of KI (∼9μm) was also derived from the LTG concentration‐dependent shift of the inactivation curve.
The recovery of LTG‐bound inactivated Na+ channels was faster than the recovery of normal (drug‐free) slow inactivated channels. Moreover, the binding kinetics of LTG onto the inactivated channels were faster than the development of the slow inactivated state, and were linearly correlated with LTG concentrations, with a binding rate constant of ∼10,000M−1s−1. These findings suggest that LTG chiefly binds to the fast inactivated state rather than the slow inactivated state.
We conclude that LTG, in therapeutic concentrations and at relatively depolarized membrane potentials, may potently inhibit Na+ currents by slow binding to the fast inactivated state of Na+ channels. Like phenytoin, the slow binding rates may explain why LTG effectively inhibits seizure discharges, yet spares most normal neuronal activities.