bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein kinase C co‐expression and the effects of halothane on rat skeletal muscle sodium channels
Authors: Mounsey J Paul , Patel Manoj K , Mistry Dilaawar , John J Edward , Moorman J Randall 
Published: January 2005

Voltage‐gated Na channels, which are potential targets for general anaesthetics, are substrates for PKC, which phosphorylates a conserved site in the channel inactivation gate. We investigated the idea that PKC modulates the effect of volatile anaesthetics on Na channels via phosphorylation of this inactivation gate site.
Na currents through rat skeletal muscle Na channel α‐subunits expressed in Xenopus oocytes were measured by two‐microelectrode voltage clamp in the presence of the volatile anaesthetic agent halothane (2‐bromo‐2‐chloro‐1,1,1‐trifluroethane). PKC activity was modulated by co‐expression of a constitutively active PKC α‐isozyme.
Halothane (0.4 mM) had no effect on Na currents. With co‐expression of PKC, however, halothane dose‐dependently enhanced the rate of Na current decay and caused a small, but statistically significant reduction in Na current amplitude.
The enhancement of Na current decay was absent in a Na channel mutant in which the inactivation gate phosphorylation site was disabled. Effects of halothane on amplitude were independent of this mutation.
Co‐expression of a PKC α‐isozyme permits an effect of halothane to hasten current decay and reduce current amplitude, at least in part through interaction with the inactivation gate phosphorylation site. We speculate that the interaction between halothane and Na channels is direct, and facilitated by PKC activity and by phosphorylation of a site in the channel inactivation gate.

British Journal of Pharmacology (1999) 128, 989–998; doi:10.1038/sj.bjp.0702877
The anticonvulsant BW534U87 depresses epileptiform activity in rat hippocampal slices by an adenosine‐dependent mechanism and through inhibition of voltage‐gated Na+ channels
Authors: Dupere Joe R B , Dale Tim J , Starkey Sarah J , Xie Xinmin 
Published: January 2005

The cellular and molecular actions of BW534U87 were studied using intracellular and extracellular recordings from the CA1 region of rat hippocampal slices and whole‐cell voltage‐clamp recordings of recombinant human brain type IIA Na+ channels expressed in Chinese hamster ovary (CHO) cells.
Normal excitatory and inhibitory postsynaptic potentials evoked in hippocampal slices were unaffected by BW534U87 or the adenosine deaminase inhibitor EHNA. However, epileptiform activity was depressed by BW534U87 (50 μM) and this inhibition was reversed by the adenosine receptor antagonist 8‐phenyl theophylline (8‐PT, 30 μM). EHNA (10 μM) mimicked the effects of BW534U87. Furthermore, BW534U87 enhanced the inhibitory effects of exogenous adenosine on evoked synaptic potentials. BW534U87 (50 μM) also voltage‐ and use‐dependently inhibited action potentials elicited by current injection, independent of the adenosine system, since it was not affected by 8‐PT.
In CHO cells expressing the recombinant human brain Na+ channel, BW534U87 produced a concentration‐ and voltage‐dependent inhibition of Na+ currents with a half‐maximal inhibitory concentration of 10 μM at a Vh of −60 mV. Use‐dependent inhibition was evident at high‐frequencies (20×20 ms pulse train at 10 Hz).
In conclusion, BW534U87 blocks hippocampal epileptiform activity by a dual mechanism. The first action is similar to that produced by EHNA and is dependent on endogenous adenosine probably by inhibition of adenosine deaminase. Secondly, BW534U87 directly inhibits voltage‐gated Na+ channels in a voltage‐ and frequency‐dependent manner. Both actions of BW534U87 are activity‐dependent and may synergistically contribute to its overall anticonvulsant effects in animal models of epilepsy.

British Journal of Pharmacology (1999) 128, 1011–1020; doi:10.1038/sj.bjp.0702881
Chronic and acute effects of thiazolidinediones BM13.1258 and BM15.2054 on rat skeletal muscle glucose metabolism
Authors: Fürnsinn C , Brunmair B , Meyer M , Neschen S , Furtmüller R , Roden M , Kühnle H F , Nowotny P , Schneider B , Waldhäusl W 
Published: January 2005

New thiazolidinediones BM13.1258 and BM15.2054 were studied with regard to their PPARγ‐agonistic activities and to their acute and chronic effects on glucose metabolism in soleus muscle strips from lean and genetically obese rats.
Both BM13.1258 and BM15.2054 revealed to be potent PPARγ‐activators in transient transfection assays in vitro.
In insulin‐resistant obese rats, but not in lean rats, 10 days of oral treatment with either compound increased the stimulatory effect of insulin on muscle glycogen synthesis to a similar extent (insulin‐induced increment in μmol glucose incorporated into glycogen g−1 h−1: control, +1.19±0.28; BM13.1258, +2.50±0.20; BM15.2054, +2.55±0.46; P<0.05 vs control each).
In parallel to insulin sensitization, mean glucose oxidation increased insulin‐independently in response to BM13.1258 (to 191 and 183% of control in the absence and presence of insulin, respectively; P<0.01 each), which was hardly seen in response to BM15.2054 (to 137 and 124% of control, respectively; ns).
Comparable effects on PPARγ activation and on amelioration of insulin resistance by BM13.1258 and BM15.2054 were therefore opposed by different effects on glucose oxidation.
In contrast to chronic oral treatment, acute exposure of muscles to BM13.1258 or BM15.2054 in vitro elicited a distinct catabolic response of glucose metabolism in specimens from both lean and obese rats.
The results provide evidence that BM13.1258 and BM15.2054 can affect muscle glucose metabolism via more than one mechanism of action.
Further efforts are required to clarify, to what extent other mechanisms besides insulin sensitization via the activation of PPARγ are involved in the antidiabetic actions of thiazolidinediones.

British Journal of Pharmacology (1999) 128, 1141–1148; doi:10.1038/sj.bjp.0702886
Effects of rupatadine, a new dual antagonist of histamine and platelet‐activating factor receptors, on human cardiac Kv1.5 channels
Authors: Caballero Ricardo , Valenzuela Carmen , Longobardo Mónica , Tamargo Juan , Delpón Eva 
Published: January 2005

The effects of rupatadine, a new dual antagonist of both histamine H1 and platelet‐activating factor receptors, were studied on human cloned hKv1.5 channels expressed in Ltk− cells using the whole‐cell patch‐clamp technique.
Rupatadine produced a use‐ and concentration‐dependent block of hKv1.5 channels (KD=2.4±0.7 μM) and slowed the deactivation of the tail currents, thus inducing the ‘crossover’ phenomenon.
Rupatadine‐induced block was voltage‐dependent increasing in the voltage range for channel opening suggesting an open channel interaction. At potentials positive to +10 mV the blockade decreased with a shallow voltage‐dependence. Moreover, rupatadine also modified the voltage‐dependence of hKv1.5 channel activation, which exhibited two components, the midpoint of the steeper component averaging −25.2±2.7 mV.
When the intracellular K+ concentration ([K+]i) was lowered to 25% the voltage‐dependent unblock observed at positive potentials was suppressed and the activation curve in the presence of rupatadine did not exhibit two components even when the midpoint of the activation curve was shifted to more negative potentials (−30.3±1.3 mV).
On channels mutated on the residue R485 (R485Y) which is located on the external entryway of the pore the rupatadine‐induced block did not decrease at potentials positive to +10 mV. In contrast, on V512M channels rupatadine reproduced all the features of the blockade observed on wild type channels.
All these results suggest that rupatadine blocks hKv1.5 channels binding to an external and to an internal binding site but only at concentrations much higher than therapeutic plasma levels in man. Efflux of K+ promotes the unbinding from the external site. Furthermore, rupatadine binds to an internal site and dramatically modifies the voltage‐dependence of channel opening.

British Journal of Pharmacology (1999) 128, 1071–1081; doi:10.1038/sj.bjp.0702890
Changes in EEG spectral power in the prefrontal cortex of conscious rats elicited by drugs interacting with dopaminergic and noradrenergic transmission
Authors: Sebban C , Zhang X Q , Tesolin‐Decros B , Millan M J , Spedding M 
Published: January 2005

The electroencephalographic (EEG) effects of drugs interacting with dopaminergic and noradrenergic systems were studied in conscious rats. Power spectra (0–30 Hz) were recorded from electrodes implanted bilaterally in the prefrontal cortex. Drug effects on EEG power were calculated as the spectral power following drug administration divided by the spectral power after vehicle administration.
Dopaminergic agonists at low doses, (apomorphine 0.01 mg kg−1 s.c., quinpirole 0.01 mg kg−1 i.p.) and dopaminergic antagonists (haloperidol 1 mg kg−1 i.p., raclopride 2.5 mg kg−1 s.c.), which decrease dopaminergic transmission, induced an increase of EEG power. Conversely, dopaminergic agonists at higher doses (apomorphine 0.5 mg kg−1 s.c., quinpirole 0.5 mg kg−1 i.p.) which increase activation of postsynaptic D2 and D3 receptors, induced a decrease of EEG power.
The α1‐adrenoceptor antagonists (phenoxybenzamine 0.64 mg kg−1 s.c., prazosin 0.32 mg kg−1 s.c.) and the α2‐adrenoceptor agonists (UK 14304 0.05 mg kg−1 s.c., clonidine 0.025 mg kg−1 i.p.), which decrease noradrenergic transmission, induced an increase of EEG power. Conversely, the α1‐adrenoceptor agonist, cirazoline (0.05 mg kg−1 s.c.), the adrenergic agent modafinil (250, 350 mg kg−1 i.p.) and α2‐adrenoceptor antagonists (RX 821002 0.01 mg kg−1 s.c., yohimbine 0.5 mg kg−1 i.p.), which increase noradrenergic transmission, induced a decrease of EEG power. The effects of prazosin (0.64 mg kg−1 s.c.) were dose‐dependently antagonized by co‐administration with modafinil and cirazoline, but not by apomorphine.
In conclusion, pharmacological modulation of dopaminergic and noradrenergic transmission may result in consistent EEG changes: decreased dopaminergic or noradrenergic activity induces an increase of EEG spectral power; while increased dopaminergic or noradrenergic activity decreases EEG spectral power.

British Journal of Pharmacology (1999) 128, 1045–1054; doi:10.1038/sj.bjp.0702894
Effects of glibenclamide on glycylsarcosine transport by the rat peptide transporters PEPT1 and PEPT2
Authors: Sawada Kyoko , Terada Tomohiro , Saito Hideyuki , Hashimoto Yukiya , Inui Ken‐ichi 
Published: January 2005

Glibenclamide is a widely used sulphonylurea for the treatment of non‐insulin‐dependant diabetes mellitus (NIDDM). This agent has been reported to inhibit the activities of various ion channels and transporters. In the present study, we examined the effects of glibenclamide on the function of the H+/peptide cotransporters PEPT1 and PEPT2 by using stable transfectants.
Uptake of [14C]‐glycylsarcosine, a typical substrate for peptide transporters, by PEPT1‐ or PEPT2‐expressing transfectant was inhibited by glibenclamide as well as other sulphonylureas including tolbutamide. 3 Kinetic analysis revealed that the inhibition by glibenclamide was noncompetitive. Dixon plot analyses showed that the Ki values of this agent were 25 and 7.8 μM for PEPT1 and PEPT2, respectively.
Glibenclamide did not inhibit Na+‐coupled alanine and α‐methyl‐D‐glucoside transport, suggesting that the inhibitory effects of glibenclamide on peptide transporters were not due to nonspecific interactions.
There was little uptake of [3H]‐glibenclamide by PEPT‐expressing transfectants as compared to mock‐transfected cells, suggesting that glibenclamide was not a substrate for these peptide transporters.
In summary, glibenclamide inhibited the [14C]‐glycylsarcosine transport by PEPT1 and PEPT2 in a noncompetitive fashion, although glibenclamide per se was not transported through these transporters. These findings would provide important information for clinical, physiological and biochemical aspects of peptide transporters.

British Journal of Pharmacology (1999) 128, 1159–1164; doi:10.1038/sj.bjp.0702895
Early increases in renal kallikrein secretion on administration of potassium or ATP‐sensitive potassium channel blockers in rats
Authors: Fujita Tomoe , Hayashi Izumi , Kumagai Yuji , Inamura Naoya , Majima Masataka 
Published: January 2005

This study aimed to examine whether administration of potassium or ATP‐sensitive potassium channel (KATP channel) blockers caused early increases in renal kallikrein (KK) secretion. To clarify this mechanism, the effect on renal KK secretion of a KATP channel blocker was compared with the effect resulting from use of an osmotic diuretic or volume load. Furthermore, the effect on potassium‐induced increases in renal KK secretion by an additional treatment using a KATP channel blocker was examined. Lastly, the effect of a KATP channel blocker on renal KK secretion was also examined in superfused slices of kidney cortex.
Intravenous infusion of potassium augmented renal KK secretion within 30 min while urine volume increased gradually in both the potassium loading and control groups.
Administration of the KATP channel blocker, 4‐morpholinecarboximidine‐N‐1‐adamantyl‐N′‐cyclohexylhydrochloride (PNU‐37883A) or glibenclamide, caused a dose‐dependent increase in renal KK secretion.
The concentration of KK in urine was higher in the PNU‐37883A group as compared to the osmotic‐diuretic or volume‐load group.
PNU‐37883A had no additive effect on the potassium‐induced increase in renal KK secretion.
Renal KK secretion increased in slices of kidney cortex incubated with PNU‐37883A within 10 min of superfusion.
In conclusion, administration of both potassium and KATP channel blockers induced early increases in renal KK secretion in the absence of the washout phenomenon. Potassium loading may have increased renal KK secretion through the same mechanism as the KATP channel blocker.

British Journal of Pharmacology (1999) 128, 1275–1283; doi:10.1038/sj.bjp.0702899
Increased hindrance on the chiral carbon atom of mexiletine enhances the block of rat skeletal muscle Na+ channels in a model of myotonia induced by ATX
Authors: Desaphy Jean‐François , Camerino Diana Conte , Franchini Carlo , Lentini Giovanni , Tortorella Vincenzo , De Luca Annamaria 
Published: January 2005

The antiarrhythmic drug mexiletine (Mex) is also used against myotonia. Searching for a more efficient drug, a new compound (Me5) was synthesized substituting the methyl group on the chiral carbon atom of Mex by an isopropyl group. Effects of Me5 on Na+ channels were compared to those of Mex in rat skeletal muscle fibres using the cell‐attached patch clamp method.
Me5 (10 μM) reduced the maximal sodium current (INa) by 29.7±4.4 % (n=6) at a frequency of stimulation of 0.3 Hz and 65.7±4.4 % (n=6) at 1 Hz. At same concentration (10 μM), Mex was incapable of producing any effect (n=3). Me5 also shifted the steady‐state inactivation curves by −7.9±0.9 mV (n=6) at 0.3 Hz and −12.2±1.0 mV (n=6) at 1 Hz.
In the presence of sea anemone toxin II (ATX; 5 μM), INa decayed more slowly and no longer to zero, providing a model of sodium channel myotonia. The effects of Me5 on peak INa were similar whatever ATX was present or not. Interestingly, Me5 did not modify the INa decay time constant nor the steady‐state INa to peak INa ratio.
Analysis of ATX‐induced late Na+ channel activity shows that Me5 did not affect mean open times and single‐channel conductance, thus excluding open channel block property.
These results indicate that increasing hindrance on the chiral atom of Mex increases drug potency on wild‐type and ATX‐induced noninactivating INa and that Me5 might improve the prophylaxis of myotonia.

British Journal of Pharmacology (1999) 128, 1165–1174; doi:10.1038/sj.bjp.0702901
The sulphonylurea glibenclamide inhibits voltage dependent potassium currents in human atrial and ventricular myocytes
Authors: Schaffer Peter , Pelzmann Brigitte , Bernhart Eva , Lang Petra , Mächler Heinrich , Rigler Bruno , Koidl Bernd 
Published: January 2005

It was the aim of our study to investigate the effects of the sulphonylurea glibenclamide on voltage dependent potassium currents in human atrial myocytes.
The drug blocked a fraction of the quasi steady state current (ramp response) which was activated positive to −20 mV, was sensitive to 4‐aminopyridine (500 μM) and was different from the ATP dependent potassium current IK(ATP).
Glibenclamide dose dependently inhibited both, the peak as well as the late current elicited by step depolarization positive to −20 mV. The IC50 for reduction in charge area of total outward current was 76 μM.
The double‐exponential inactivation time‐course of the total outward current was accelerated in the presence of glibenclamide with a τfast of 12.7±1.5 ms and a τslow of 213±25 ms in control and 5.8±1.9 ms (P<0.001) and 101±20 ms (P<0.05) under glibenclamide (100 μM).
Our data suggest, that both repolarizing currents in human atrial myocytes, the transient outward current (Ito1) and the ultrarapid delayed rectifier current (IKur) were inhibited by glibenclamide.
In human ventricular myocytes glibenclamide inhibited Ito1 without affecting the late current.
Our data suggest that glibenclamide inhibits human voltage dependent cardiac potassium currents at concentrations above 10 μM.

British Journal of Pharmacology (1999) 128, 1175–1180; doi:10.1038/sj.bjp.0702904
Pharmacological characterization of the human P2Y11 receptor
Authors: Communi Didier , Robaye Bernard , Boeynaems Jean‐Marie 
Published: January 2005

The human P2Y11 receptor is coupled to both the phosphoinositide and the cyclic AMP pathways. A pharmacological characterization of the recombinant human P2Y11 receptor has been conducted following stable expression in two different cell lines: the 1321N1 astrocytoma cells for inositol trisphosphate measurements and the CHO‐K1 cells for cyclic AMP assays. The rank order of potency of a series of nucleotides was almost identical for the two pathways: ATPγS∼BzATP>dATP>ATP>ADPβS>2MeSATP.
ADPβS, AMPαS and A3P5PS behaved as partial agonists of the human P2Y11 receptor. At high concentrations, these three nucleotides were able to partially inhibit the ATP response.
Suramin was a more potent antagonist than reactive blue 2, whereas pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulphonic acid was completely inactive. The P2Y11 receptor proved to be sensitive to suramin in a competitive way with an apparent Ki value of 0.82±0.07 μM.
The ATP derivative AR‐C67085 (2‐propylthio‐β, γ‐dichloromethylene‐D‐ATP), a potent inhibitor of ADP‐induced platelet aggregation, was the most potent agonist of the P2Y11 receptor, among the various nucleotides tested.
The pharmacological profile of the recombinant human P2Y11 receptor is closely similar to that of the cyclic AMP‐coupled P2 receptor recently described in HL‐60 cells, suggesting that it is the same receptor.

British Journal of Pharmacology (1999) 128, 1199–1206; doi:10.1038/sj.bjp.0702909
Suppression of human inflammatory cell function by subtype‐selective PDE4 inhibitors correlates with inhibition of PDE4A and PDE4B
Authors: Manning Carol D , Burman Miriam , Christensen Siegfried B , Cieslinski Lenora B , Essayan David M , Grous Marilyn , Torphy Theodore J , Barnette Mary S 
Published: January 2005

Of the four major phosphodiesterase 4 (PDE4) subtypes, PDE4A, PDE4B and PDE4D are widely expressed in human inflammatory cells, including monocytes and T lymphocytes. We explored the functional role of these subtypes using ten subtype‐selective PDE4 inhibitors, each belonging to one of two classes: (i) dual PDE4A/PDE4B inhibitors or (ii) PDE4D inhibitors.
These compounds were evaluated for their ability to inhibit antigen‐stimulated T‐cell proliferation and bacterial lipopolysaccharide (LPS)‐stimulated tumour necrosis factor α (TNFα) release from peripheral blood monocytes.
All compounds inhibited T‐cell proliferation in a concentration‐dependent manner; with IC50 values distributed over an approximately 50 fold range. These compounds also inhibited TNFα release concentration‐dependently, with a wider (∼1000 fold) range of IC50 values.
In both sets of experiments, mean IC50 values were significantly correlated with compound potency against the catalytic activity of recombinant human PDE4A or PDE4B when analysed by either linear regression of log IC50 values or by Spearman's rank‐order correlation. The correlation between inhibition of inflammatory cell function and inhibition of recombinant PDE4D catalytic activity was not significant in either analysis.
These results suggest that PDE4A and/or PDE4B may play the major role in regulating these two inflammatory cell functions but do not rule out PDE4D as an important mediator of other activities in mononuclear leukocytes and other immune and inflammatory cells. Much more work is needed to establish the functional roles of the PDE4 subtypes across a broader range of cellular functions and cell types.

British Journal of Pharmacology (1999) 128, 1393–1398; doi:10.1038/sj.bjp.0702911
Leukotrienes are involved in leukocyte recruitment induced by live Histoplasma capsulatum or by the β‐glucan present in their cell wall
Authors: Medeiros Alexandra I , Silva Célio L , Malheiro Adriana , Maffei Cláudia M L , Faccioli Lúcia H 
Published: January 2005

The inflammatory cell influx towards the peritoneal cavity in mice inoculated i.p. with live or dead Histoplasma capsulatum or with its subcellular preparations was studied. We also evaluated the effects of dexamethasone (Dexa) or MK886, an inhibitor of leukotriene (LT) biosynthesis, on the recruitment of leukocytes.
Live yeast form of fungus (LYH) induced an increase in neutrophils (NE) which was highest 4 to 24 h after inoculation. Mononuclear cell (MN) migration beginning at 24 h with a gradual increase over 48 and 168 h, and an eosinophil (EO) recruitment occurs between 24 and 48 h.
NE and EO recruitment induced by dead mycelial form of fungus (DMH) was greater than that observed for dead yeast form of fungus (DYH). A similar leukocyte migration pattern was seen after i.p. injection of the alkali‐insoluble fraction (F1) from DYH (F1Y) and F1 from DMH (F1M) this being more active than former. The difference in concentration of β‐glucan in DYH and DMH could explain the different inflammatory capacity exhibited by the two forms of H. capsulatum.
LT seems to be the principal mediator of leukocyte migration in response to LYH, DYH or DMH or to β‐glucan. However, other mediators appear to contribute to NE and EO migration since the treatment with Dexa was more effective in inhibiting cell migration than MK886. Complement dependent leukocyte migration may participate in this recruitment. Treatment with MK886 completely abolished MN cell migration, indicating its dependence on the presence of LT.

British Journal of Pharmacology (1999) 128, 1529–1537; doi:10.1038/sj.bjp.0702912