bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced isoflurane suppression of excitatory synaptic transmission in the aged rat hippocampus
Authors: Ouanounou Aviv , Carlen Peter L. , El‐Beheiry Hossam 
Published: January 2005

The effects of the volatile anaesthetic, isoflurane, were investigated on evoked dendritic field excitatory postsynaptic potentials (f.e.p.s.p.) and antidromic and orthodromic population spikes recorded extracellularly in the CA1 cell layer region in the in vitro hippocampal slice taken from young mature (2–3 months) and old (24–27 months) Fisher 344 rats.
Isoflurane depressed the f.e.p.s.ps and the orthodromically‐evoked population spikes in both old and young hippocampi. However, the magnitude of the anaesthetic‐induced depression was greater in slices taken from old rats compared to those taken from young rats during the application of different isoflurane concentrations (0.5–5%).
In the presence of the GABAA antagonist, bicuculline methiodide (15 μm), isoflurane suppressed the f.e.p.s.ps to the same extent as was observed in the absence of the GABAA antagonist.
Orthodromically evoked population spikes were suppressed by isoflurane in a manner quantitatively similar to the suppression of the f.e.p.s.ps. However, antidromic population spikes and presynaptic volleys evoked in young and old slices were resistant to anaesthetic action. In addition, paired pulse facilitation ratio of the evoked dendritic f.e.p.s.ps was not affected in both young and old slices during the application of isoflurane.
When slices were exposed to low Ca2+/high Mg2+ solution, isoflurane (1 and 3%) depressed the f.e.p.s.ps in aged slices to the same extent as in young slices.
The augmented anaesthetic depression of f.e.p.s.ps in old compared to young hippocampi in the absence and presence of bicuculline, and the lack of anaesthetic effects on antidromic population spikes and presynaptic volleys in old and young slices, suggest that the increased sensitivity of anaesthetic actions in old hippocampi is due to age‐induced attenuation of synaptic excitation rather than potentiation of synaptic inhibition. Furthermore, elimination of the increased sensitivity of old slices to anaesthetic actions when the slices were perfused with low Ca2+/high Mg2+ medium, which presumably would decrease intracellular [Ca2+], suggests that the enhanced anaesthetic effects in aged neurones might be related to increased intraneuronal [Ca2+] in the synaptic terminal.

British Journal of Pharmacology (1998) 124, 1075–1082; doi:10.1038/sj.bjp.0701911
Induction of an ATPase inhibitor protein by propylthiouracil and protection against paracetamol (acetaminophen) hepatotoxicity in the rat
Authors: Banerjee Atreyee , Linscheer Willem G. , Chiji Hideyuki , Murthy Uma K. , Cho Chaidong , Nandi Jyotirmoy , Chan Samuel H. P. 
Published: January 2005

The purpose of the present study was to test the following hypothesis: propylthiouracil (PTU) treatments of rats induces an increase in the concentration and activity of the mitochondrial ATPase (m‐ATPase) inhibitor protein (IF1). The PTU‐induced elevated baseline levels of this inhibitor protein inactivated m‐ATPase, and prevented hepatotoxicity by a toxic dose of acetaminophen (AAP) (paracetamol), by maintaining hepatic adenosine 5′‐triphosphate (ATP) levels.
Male Wistar rats were either gavaged with a toxic dose of AAP alone, or after pretreatment with PTU for periods of 3 and 12 days.
Twenty four hours after acetaminophen treatment alone, toxicity was manifested by: an approximately 10 fold increase in serum transaminase levels (serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase); depletion of hepatic reduced glutathione (GSH) and ATP levels; loss of inhibitor protein activity, and extensive pericentral necrosis of the hepatocytes. Propylthiouracil pretreatment for 12 days enhanced the concentration of the following metabolites in the liver: ATP (1.5 fold), ATPase inhibitor protein (IF1) (4.5 fold), and reduced glutathione (1.3 fold), while the activity of the inhibitor protein increased 2 fold. When the PTU treated rats were challenged with AAP, transaminases were not elevated, and only sporadic areas of necrosis were detected by histological examination of the liver tissue. In contrast to the 12 day treatment with PTU the 3 day treatment had no protection against AAP. No histological evidence of protection was manifested and the transaminases were not different from AAP treated controls. Most of the protective metabolites were depleted.
Our findings suggest that PTU‐induced increased concentration of inhibitor protein and GSH, are contributing factors in the prevention of hepatotoxicity by maintaining hepatic m‐ATP levels and reducing the harmful effect of the toxic metabolite of AAP.

British Journal of Pharmacology (1998) 124, 1041–1047; doi:10.1038/sj.bjp.0701917
Voltage‐ and use‐dependent inhibition of Na+ channels in rat sensory neurones by 4030W92, a new antihyperalgesic agent
Authors: Trezise D J. , John V H. , Xie X M. 
Published: January 2005

Whole cell patch clamp techniques were used to study the effects of 4030W92 (2,4‐diamino‐5‐(2,3‐dichlorophenyl)‐6‐fluoromethylpyrimidine), a new antihyperalgesic agent, on rat dorsal root ganglion (DRG) neurones.
In small diameter, presumably nociceptive DRG neurones under voltage‐clamp, 4030W92 (1–100 μM) produced a concentration‐related inhibition of slow tetrodotoxin‐resistant Na+ currents (TTXR). From a holding potential (Vh) of −90 mV, currents evoked by test pulses to 0 mV were inhibited by 4030W92 with a mean IC50 value of approximately 103 μM.
The inhibitory effect of 4030W92 on TTXR was both voltage‐ and use‐dependent. Currents evoked from a Vh of −60 mV were inhibited by 4030W92 with a mean IC50 value of 22 μM, which was 5 fold less than the value obtained at −90 mV. Repeated activation of TTXR by a train of depolarizing pulses (5 Hz, 20 ms duration) enhanced the inhibitory effects of 4030W92. These data could be explained by a preferential interaction of the drug with inactivation states of the channel. In support of this hypothesis 4030W92 (30 μM) produced a significant hyperpolarizing shift of 10 mV in the slow inactivation curve for TTXR and markedly slowed the recovery from channel inactivation.
Fast TTX‐sensitive Na+ currents (TTXS) were also inhibited by 4030W92 in a voltage‐dependent manner. The IC50 values obtained from Vhs of −90 mV and −70 mV were 37 μM and 5 μM, respectively. 4030W92 (30 μM) produced a 13 mV hyperpolarizing shift in the steady‐state inactivation curve of TTXS.
High threshold voltage‐gated Ca2+ currents were only weakly inhibited by 4030W92. The reduction in peak Ca2+ current amplitude produced by 100 μM 4030W92 was 20±6% (n=6). Low threshold T‐type Ca2+ currents were inhibited by 17±8% and 43±3% by concentrations of 4030W92 of 30 μM and 100 μM, respectively (n=6).
Under current clamp, some cells exhibited broad TTX‐resistant action potentials whilst others showed fast TTX‐sensitive action potentials in response to a depolarizing current injection. In most cells a long duration (800 ms) supramaximal current injection evoked a train of action potentials. 4030W92 (10–30 μM) had little effect on the first spike in the train but produced a concentration‐related inhibition of the later spikes. The number of spikes per train was significantly reduced from 9.7±1.5 to 4.2±1.0 and 2.6±1.1 in the presence of 10 μM and 30 μM 4030W92, respectively (n=5).
Thus, 4030W92 is a potent voltage‐ and use‐dependent inhibitor of Na+ channels in sensory neurones. This profile can be explained by a preferential action of the drug on a slow inactivation state of the channel that results in a delayed recovery to the resting state. This state‐dependent modulation by 4030W92 of Na+ channels that are important in sensory neurone function may underlie or contribute to the antihyperalgesic profile of this compound observed in vivo.
The agonist activities of the putative antipsychotic agents, L‐745,870 and U‐101958 in HEK293 cells expressing the human dopamine D4.4 receptor
Authors: Gazi L , Bobirnac I , Danzeisen M , Schüpbach E , Bruinvels A T. , Geisse S , Sommer B , Hoyer D , Tricklebank M , Schoeffter P 
Published: January 2005

Dopamine D4 receptor antagonists are being developed by several pharmaceutical companies as putative novel antipsychotics, possibly with low propensity to side‐effects. Two such compounds, L‐745,870 and U‐101958 have been recently introduced.
The radioligand binding and functional activities of L‐745,870 and U‐101958 were investigated in human embryonic kidney (HEK)293 cells expressing the human recombinant dopamine D4.4 receptor (HEK293/D4 cells). [3H]‐spiperone binding experiments were performed and inhibition of forskolin‐stimulated cyclic AMP accumulation was used as the functional response.
[3H]‐spiperone was found to label a homogeneous and saturable population of specific binding sites in HEK293/D4 cell homogenates (Bmax 505±90 fmol mg−1 protein, pKD 9.5±0.1, n=3). Inhibition of specific [3H]‐spiperone binding was observed with spiperone (pKi 9.6±0.1, n=3), clozapine (pKi 7.4±0.1, n=4), L‐745,870 (pKi 8.5±0.1, n=3) and U‐101958 (pKi 8.9±0.1, n=3). By contrast, raclopride was very weak (pKi<5, n=3).
Dopamine inhibited forskolin‐stimulated cyclic AMP accumulation in HEK293/D4 cells in a concentration‐dependent fashion (Emax 71±2% inhibition of forskolin‐stimulated levels, pEC50 8.7±0.1, n=10). This effect was mimicked by the dopamine D2‐like receptor agonists, quinpirole and 7‐hydroxy‐2‐dipropylaminotetralin (7‐OH‐DPAT).
L‐745,870 and U‐101958 also inhibited forskolin‐stimulated cyclic AMP accumulation in HEK293/D4 cells in a concentration‐dependent way. L‐745,870 was less efficacious than dopamine (71% the efficacy of dopamine), whereas U‐101958 behaved as a full agonist compared to dopamine. Potencies (pEC50) values of L‐745,870 and U‐101958 were 9.0±0.2 (n=4) and 8.7±0.3 (n=3), consistent with pKi values determined in radioligand binding studies.
Dopamine, L‐745,870 and U‐101958 (up to 1 μM) were devoid of effect on forskolin‐stimulated cyclic AMP accumulation in control, non‐transfected HEK293 cells.
The agonist effects of dopamine, L‐745,870 and U‐101958 in HEK293/D4 cells could be antagonized by spiperone (pKB 8.2–8.8) and clozapine (pKB 7.1), but not by raclopride (pKB<5). None of these antagonists had any significant agonist activity at concentrations up to 10 μM.
These results show that the putative dopamine D4 receptor antagonists, L‐745,870 and U‐101958 are not devoid of intrinsic activity at human recombinant dopamine D4.4 receptors. Therefore, they may not represent the most appropriate drugs for testing the benefit of D4 receptor antagonism in schizophrenic patients, if agonism should translate in vivo.
Comparison of antioxidant activities of aminoguanidine, methylguanidine and guanidine by luminol‐enhanced chemiluminescence
Authors: Yildiz Gülüzar , Demiryürek A Tuncay , Sahin‐Erdemli Inci , Kanzik Ilker 
Published: January 2005

The objective of this study was to investigate the ability of aminoguanidine, methylguanidine and guanidine to inhibit free radicals or metabolites generated by either stimulated human leucocytes or cell‐free systems using luminol‐enhanced chemiluminescence (CL).
Aminoguanidine (0.1 μM–10 mM), methylguanidine (10 μM–10 mM) and guanidine (10 μM–10 mM) produced concentration‐dependent inhibition (96±0.1%, n=7, 59±1.3%, n=6, and 62±3%, n=6, P<0.05 at 10 mM, respectively) in FMLP‐stimulated leucocytes CL.
In cell‐free experiments, hydrogen peroxide (H2O2), hypochlorous acid (HOCl), hydroxyl radical and peroxynitrite‐induced CL responses were initiated by hydrogen peroxide (3.5 mM), NaOCl (50 μM), FeSO4 (40 nM) and peroxynitrite (20 nM), respectively. Aminoguanidine, methylguanidine and guanidine produced concentration‐dependent inhibition in H2O2‐(69±0.7%, n=7, 26±1%, n=6, and 15±0.5%, n=6, at 1 mM, respectively) and HOCl‐(84±0.3%, n=6, 50±1%, n=6, and 29±1%, n=7, at 1 mM, respectively) induced luminol CL. Peroxynitrite‐induced CL was markedly attenuated in a concentration‐dependent manner by aminoguanidine (99±0.1%, n=6, at 10 mM), methylguanidine (5±0.2%, n=6, at 10 mM) and guanidine (27±0.4%, n=7, at 10 mM). However, inhibition with aminoguanidine was found to be more marked than with methylguanidine and guanidine. Aminoguanidine (95±0.5%, n=6, at 1 mM) and methylguanidine (25±1%, n=6, at 1 mM), but not guanidine (2±1%, n=6, at 1 mM), significantly decreased ferrous iron‐induced CL.
Collectively, these data suggest that aminoguanidine and a high concentration (0.1 mM) of methylguanidine have direct scavenging activities against H2O2, HOCl, hydroxyl radical and peroxynitrite. Guanidine, at a high concentration (0.1 mM), scavenges H2O2, HOCl and peroxynitrite, but not the hydroxyl radical. These direct scavenging properties may contribute to inhibitory effects of these compounds on human leucocyte CL.
Comparison of rSP‐C surfactant with natural and synthetic surfactants after late treatment in a rat model of the acute respiratory distress syndrome
Authors: Häfner Dietrich , Germann Paul‐Georg , Hauschke Dieter 
Published: January 2005

In a previous paper we showed that an SP‐C containing surfactant preparation has similar activity as bovine‐derived surfactants in a rat lung lavage model of the adult respiratory distress syndrome. In this study surfactant was given ten minutes after the last lavage (early treatment). In the present investigation we were interested how different surfactant preparations behave when they are administered 1 h after the last lavage (late treatment).
Four protein containing surfactants (rSP‐C surfactant, bLES, Infasurf and Survanta) were compared with three protein‐free surfactants (ALEC, Exosurf and the phospholipid (PL) mixture of the rSP‐C surfactant termed PL surfactant) with respect to their ability to improve gas exchange in this more stringent model when surfactant is given one hour after the last lavage. For better comparison of the surfactants the doses were related to phospholipids. The surfactants were given at doses of 25, 50 and 100 mg kg−1 body weight. The surfactants were compared to an untreated control group that was only ventilated for the whole experimental period.
Tracheotomized rats (8–12 per dose and surfactant) were pressure‐controlled ventilated (Siemens Servo Ventilator 900C) with 100% oxygen at a respiratory rate of 30 breaths min−1, inspiration expiration ratio of 1: 2, peak inspiratory pressure of 28 cmH2O at positive endexpiratory pressure (PEEP) of 8 cmH2O. Animals were ventilated for one hour after the last lavage and thereafter the surfactants were intratracheally instilled. During the whole experimental period the ventilation was not changed.
Partial arterial oxygen pressures (Pao2, mmHg) at 30 min and 120 min after treatment were used for statistical comparison. All protein containing surfactants caused a dose‐dependent increase of the reduced Pao2 values at 30 min after treatment. The protein‐free surfactants showed only weak dose‐dependent increase in Pao2 values at this time. This difference between the protein‐containing and the protein‐free surfactants was even more pronounced when comparing the Pao2 values at 120 min after treatment. Only rSP‐C surfactant, bLES and Infasurf showed a dose‐dependent increase in Pao2 at this time.
With this animal model of late treatment it is possible even to differentiate between bovine derived surfactants. The differences between protein‐containing and protein‐free surfactants become even more pronounced. From the comparison of rSP‐C surfactant with bovine‐derived surfactants and the PL surfactant without rSP‐C, it can be concluded that addition of rSP‐C is sufficient to achieve the same activity as that of natural surfactants.

British Journal of Pharmacology (1998) 124, 1083–1090; doi:10.1038/sj.bjp.0701931
Modulation by dantrolene of endotoxin‐induced interleukin‐10, tumour necrosis factor‐α and nitric oxide production in vivo and in vitro
Authors: Haskó György , Szabó Csaba , Németh Zoltán H. , Lendvai Balázs , Vizi E. Sylvester 
Published: January 2005

Intracellular calcium has been suggested to be an important mediator of the cellular response in endotoxaemia and shock. Dantrolene is an agent that interferes with intracellular calcium fluxes resulting in a decreased availability of calcium in the cytoplasm. Here we have investigated the effect of dantrolene on lipopolysaccharide (LPS)‐induced production of interleukin‐10 (IL‐10), tumour necrosis factor‐α (TNF‐α), and nitric oxide (NO) in mice and in cultured RAW 264.7 macrophages in vitro.
In BALB/c mice, LPS‐induced plasma IL‐10 levels were significantly enhanced by pretreatment with dantrolene (20 mg kg−1, i.p.) (P<0.005 at the 90 min time‐point). On the other hand, dantrolene pretreatment suppressed circulating TNF‐α and nitrite/nitrate (breakdown products of NO) concentrations. However, dantrolene had no effect on LPS‐induced plasma interleukin‐6 (IL‐6) levels (67.22±5.51 ng ml−1 in vehicle‐pretreated mice and 62.22±3.66 ng ml−1 in dantrolene‐pretreated mice, n = 9).
Dantrolene inhibited TNF‐α and NO production in C57BL/6 IL‐10+/+ mice, as well as in their IL‐10 deficient counterparts (C57BL/6 IL‐100/0).
In RAW 264.7 macrophages, dantrolene (10–300 μm) reduced IL‐10, TNF‐α, and nitrite (breakdown product of NO) production elicited by LPS (10 μg ml−1). Dantrolene (300 μm) did not affect the LPS‐induced nuclear translocation of transcription factor nuclear factor κB in these cells.
Although LPS failed to alter the intracellullar concentration of calcium in single macrophages loaded with Fura‐2, dantrolene caused a significant decrease of the basal calcium level as determined 30 min after dantrolene treatment (P<0.005). ATP (1 mm) caused a rapid rise in intracellular calcium levels in both dantrolene‐pretreated and vehicle‐pretreated cells.
These results indicate that unlike the secretion of TNF‐α and NO, IL‐10 production is differentially regulated in vitro and in vivo. The decrease of plasma levels of the pro‐inflammatory mediators TNF‐α and NO, and increase in circulating IL‐10 concentrations by dantrolene suggest that this drug might offer a new therapeutic approach in inflammatory diseases and septic shock.

British Journal of Pharmacology (1998) 124, 1099–1106; doi:10.1038/sj.bjp.0701934
Nitric oxide (NO)‐induced activation of large conductance Ca2+‐dependent K+ channels (BKCa) in smooth muscle cells isolated from the rat mesenteric artery
Authors: Mistry D. K. , Garland C. J. 
Published: January 2005

To assess the action of nitric oxide (NO) and NO‐donors on K+ current evoked either by voltage ramps or steps, patch clamp recordings were made from smooth muscle cells freshly isolated from secondary and tertiary branches of the rat mesenteric artery.
Inside‐out patches contained channels, the open probability of which increased with [Ca2+]i. The channels had a linear slope conductance of 212±5 pS (n = 12) in symmetrical (140 mm) K+ solutions which reversed in direction at 4.4 mV. In addition, the channels showed K+ selectivity, in that the reversal potential shifted in a manner similar to that predicted by the Nernst potential for K+. Barium (1 mm) applied to the intracellular face of the channel produced a voltage‐dependent block and external tetraethylammonium (TEA; at 1 mm) caused a large reduction in the unitary current amplitude. Taken together, these observations indicate that the channel most closely resembled BKCa.
In five out of six inside‐out patches, NO (45 or 67 μm) produced an increase in BKCa activity. In inside‐out patches, BKCa activity was also enhanced in some patches with 100 or 200 μm 3‐morpholino‐sydnonimine (SIN‐1) (4/11) and 100 μm sodium nitroprusside (SNP) (3/8). The variability in channel opening with the NO donors may reflect variability in the release of NO from these compounds.
In inside‐out patches, 100 μm SIN‐1 failed to increase BKCa activity (in all 4 patches tested), while at a higher (500 μm) concentration SIN‐1 had a direct blocking effect on the channels (n = 3). NO applied directly to inside‐out patches increased (P<0.05) BKCa activity in two patches.
In the majority of cells (6 out of 7), application of NO (45 or 67 μm) evoked an increase in the amplitude of whole‐cell currents in perforated patches. This action was not affected by the soluble guanylyl cyclase inhibitor, 1H‐[1,2,4] oxadiazolo [4,3‐a]quinoxalin‐1‐one (ODQ). An increase in whole‐cell current was also evoked with either of the NO donors, SIN‐1 or SNP (each at 100 μm). With SIN‐1, the increase in current was blocked with the BKCa channel blocker, iberiotoxin (50 nm).
With conventional whole‐cell voltage clamp, the increase in the outward K+ current evoked with SIN‐1 (50–300 μm) showed considerable variability. Either no effect was obtained (11 out of 18 cells), or in the remaining cells, an average increase in current amplitude of 38.7±10.2% was recorded at 40 mV.
In cell‐attached patches, large conductance voltage‐dependent K+ channels were stimulated by SIN‐1 (100 μm) applied to the cell (n = 5 patches).
These data indicate that NO and its donors can directly stimulate BKCa activity in cells isolated from the rat mesenteric artery. The ability of NO directly to open BKCa channels could play an important functional role in NO‐induced relaxation of the vascular smooth muscle cells in this small resistance artery.

British Journal of Pharmacology (1998) 124, 1131–1140; doi:10.1038/sj.bjp.0701940
Interaction between Ca2+, K+, carbamazepine and zonisamide on hippocampal extracellular glutamate monitored with a microdialysis electrode
Authors: Okada Motohiro , Kawata Yuko , Mizuno Kazuhisa , Wada Kazumaru , Kondo Tuyoshi , Kaneko Sunao 
Published: January 2005

Multiple components of hippocampal glutamate release were examined by study of Ca2+‐ and K+‐evoked hippocampal extracellular glutamate release using an in vivo microdialysis glutamate biosensor in urethane‐anaesthetized rats. In addition, the effects of the antiepileptic drugs, carbamazepine (CBZ) and zonisamide (ZNS) perfused through the probe on glutamate release were assessed.
Basal glutamate levels were below detection limits (∼0.1 μm). An increase in extracellular KCl (from 2.7 to 50 and 100 mm) increased extracellular hippocampal glutamate levels to 9.2±1.4 and 20.0±2.6 μm, respectively, calculated from the area under curve (AUC) for 60 min.
This KCl‐evoked glutamate release consisted of three components: an initial transient rise, a late gentle rise, and late multiple phasic transient rises.
An increase in or removal of extracellular CaCl2 levels respectively enhanced and reduced the 50 mm KCl‐evoked hippocampal glutamate release (AUC for 60 min) from 9.2±1.4 to 12.4±2.1 and 5.8±0.9 μm.
Perfusion with 100 μm CBZ or 1 mm ZNS inhibited both the 50 mm KCl‐evoked hippocampal glutamate release (AUC for 60 min) from 9.2±1.4 to 5.5±1.1 and to 5.8±1.3 μm, respectively, as well as the stimulatory effects of Ca2+ on KCl‐evoked hippocampal glutamate release.
These results suggest that both CBZ and ZNS may reduce epileptiform events by inhibiting excitatory glutamatergic transmission.

British Journal of Pharmacology (1998) 124, 1277–1285; doi:10.1038/sj.bjp.0701941