bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic index for rosiglitazone in dietary obese rats: separation of efficacy and haemodilution
Authors: Pickavance L C , Tadayyon M , Widdowson P S , Buckingham R E , Wilding J P H 
Published: January 2005

The blood glucose‐lowering efficacy of rosiglitazone (RSG) and the mechanisms of associated weight gain were determined in dietary obese rats (DIOs). DIO and chow‐fed rats received RSG 0.3–30 mg kg−1 daily for 21 days.
In DIOs, plasma glucose and insulin concentrations were reduced by RSG at dosages of 3 and 10 mg kg−1, respectively. Homeostasis model assessment (HOMA) indicated the threshold for a reduction of insulin resistance was 1 mg kg−1. Neither glucose nor insulin levels were affected by treatment in chow‐fed rats.
RSG 0.3 mg kg−1 lowered free fatty acids (FFAs) in DIOs, whereas for plasma triglycerides (TGs), the threshold was 3 mg kg−1. By contrast, the threshold for reducing packed red cell volume (PCV) and increasing cardiac mass was 10 mg kg−1. Thus, the therapeutic index for RSG in DIOs was >3 and 10.
Energy intake and weight gain increased in treated DIOs (by 20% and 50 g, at 30 mg kg−1) and chow‐fed rats (by 25% and 35 g, at 30 mg kg−1). In DIOs, these increases coincided with falls in plasma leptin (40% lower at 30 mg kg−1) and insulin (43% lower at 30 mg kg−1). By contrast, in chow‐fed rats, weight gain and hyperphagia occurred without changes in either leptin or insulin. However, reductions in FFAs below 0.4–0.3 mM were associated with hyperphagia and weight gain in DIO and chow‐fed rats.
We conclude that increased energy intake and body weight did not attenuate the improved metabolism evoked by RSG in DIO rats, and that insulin action was enhanced at a dose >3 fold below the threshold for causing haemodilution and cardiac hypertrophy in DIO rats.

British Journal of Pharmacology (1999) 128, 1570–1576; doi:10.1038/sj.bjp.0702932
Effect of Gd3+ on bradykinin‐induced catecholamine secretion from bovine adrenal chromaffin cells
Authors: Bales Peter J R , Zerbes Mariann , Powis David A , Marley Philip D 
Published: January 2005

The effects of Gd3+ on bradykinin‐ (BK‐) induced catecholamine secretion, 45Ca2+ efflux and cytosolic [Ca2+] were studied using bovine adrenal chromaffin cells.
BK increased secretion in a Ca2+‐dependent manner. From 1–100 μM, Gd3+ progressively inhibited secretion induced by 30 nM BK to near‐basal levels, however from 0.3–3 mM Gd3+ dramatically enhanced BK‐induced secretion to above control levels. Gd3+ also increased basal catecholamine secretion by 2–3 fold at 1 mM. These effects were mimicked by Eu3+ and La3+.
Gd3+ enhanced secretion induced by other agonists that mobilize intracellular Ca2+ stores, but simply blocked the response to K+.
Gd3+ still enhanced basal and BK‐induced secretion in Ca2+‐free solution or in the presence of 30 μM SKF96365, however both effects of Gd3+ were abolished after depleting intracellular Ca2+ stores.
Gd3+ (1 mM) reduced the rate of basal 45Ca2+ efflux by 57%. In Ca2+‐free buffer, BK transiently increased cytosolic [Ca2+] measured with Fura‐2. The [Ca2+] response to BK was substantially prolonged in the presence of Gd3+ (1 mM).
The results suggest that Gd3+ greatly enhances the efficacy of Ca2+ released from intracellular stores in evoking catecholamine secretion, by inhibiting Ca2+ extrusion from the cytosol. This suggests that intracellular Ca2+ stores are fully competent to support secretion in chromaffin cells to levels comparable to those evoked by extracellular Ca2+ entry. Drugs that modify Ca2+ extrusion from the cell, such as lanthanide ions, will be useful in investigating the mechanisms by which intracellular Ca2+‐store mobilization couples to Ca2+‐dependent exocytosis.

British Journal of Pharmacology (1999) 128, 1435–1444; doi:10.1038/sj.bjp.0702933
Pharmacological activation of the ryanodine receptor in Jurkat T‐lymphocytes
Authors: Hohenegger Martin , Berg Ingeborg , Weigl Lukas , Mayr Georg W , Potter Barry V L , Guse Andreas H 
Published: January 2005

Recently, we provided evidence for cyclic adenosine 5′‐diphosphate‐ribose, cADP‐ribose, as a second messenger in Jurkat T‐lymphocytes upon stimulation of the T‐cell receptor/CD3‐ complex (Guse et al., 1999). cADP‐ribose mobilizes Ca2+ from an intracellular Ca2+ store which is sensitive to caffeine and gated by the ryanodine receptor/Ca2+ release channel. In the present study we investigated the ability of the trypanocidal drug, suramin, to activate the ryanodine receptor of T‐cells. Since suramin cannot permeate the plasma membrane, it was necessary to microinject the drug into Fura‐2 loaded T‐lymphocytes.
In a dose dependent manner suramin increased the intracellular Ca2+ concentration. The dose‐response curve is very steep and calculates for an EC50 of 7.6±2.9 mM suramin in the injection pipette.
Co‐injection of the selective ryanodine receptor inhibitor ruthenium red completely abolished the suramin induced Ca2+ transient. This finding allows for the conclusion that the IP3‐receptor sensitive Ca2+ pool is not the primary target of the suramin induced Ca2+ transient.
Furthermore, Ins(1,4,6)PS3, an antagonist of the InsP3‐receptor could not suppress the suramin‐induced Ca2+ signal. The suramin induced Ca2+ transients declined very slowly; however, in the presence of Ins(1,4,6)PS3 this decay was accelerated. In addition, suramin did not interact with the cADP‐ribose binding site of the ryanodine receptor of T‐cells.
In conclusion, suramin is found to be an agonist for the T‐cell ryanodine receptor as previously found for the cardiac and skeletal muscle isoform. Therefore, suramin can be designated a universal ryanodine receptor agonist.

British Journal of Pharmacology (1999) 128, 1235–1240; doi:10.1038/sj.bjp.0702935
Putative β4‐adrenoceptors in rat ventricle mediate increases in contractile force and cell Ca2+: comparison with atrial receptors and relationship to (−)‐[3H]‐CGP 12177 binding
Authors: Sarsero Doreen , Molenaar Peter , Kaumann Alberto J , Freestone Nicholas S 
Published: January 2005

We identified putative β4‐adrenoceptors by radioligand binding, measured increases in ventricular contractile force by (−)‐CGP 12177 and (±)‐cyanopindolol and demonstrated increased Ca2+ transients by (−)‐CGP 12177 in rat cardiomyocytes.
(−)‐[3H]‐CGP 12177 labelled 13–22 fmol mg−1 protein ventricular β1, β2‐adrenoceptors (pKD ∼9.0) and 50–90 fmol mg−1 protein putative β4‐adrenoceptors (pKD ∼7.3). The affinity values (pKi) for (β1,β2‐) and putative β4‐adrenoceptors, estimated from binding inhibition, were (−)‐propranolol 8.4, 5.7; (−)‐bupranolol 9.7, 5.8; (±)‐cyanopindolol 10.0,7.4.
In left ventricular papillary muscle, in the presence of 30 μM 3‐isobutyl‐1‐methylxanthine, (−)‐CGP 12177 and (±)‐cyanopindolol caused positive inotropic effects, (pEC50, (−)‐CGP 12177, 7.6; (±)‐cyanopindolol, 7.0) which were antagonized by (−)‐bupranolol (pKB 6.7–7.0) and (−)‐CGP 20712A (pKB 6.3–6.6). The cardiostimulant effects of (−)‐CGP 12177 in papillary muscle, left and right atrium were antagonized by (±)‐cyanopindolol (pKP 7.0–7.4).
(−)‐CGP 12177 (1 μM) in the presence of 200 nM (−)‐propranolol increased Ca2+ transient amplitude by 56% in atrial myocytes, but only caused a marginal increase in ventricular myocytes. In the presence of 1 μM 3‐isobutyl‐1‐methylxanthine and 200 nM (−)‐propranolol, 1 μM (−)‐CGP 12177 caused a 73% increase in Ca2+ transient amplitude in ventricular myocytes. (−)‐CGP 12177 elicited arrhythmic transients in some atrial and ventricular myocytes.
Probably by preventing cyclic AMP hydrolysis, 3‐isobutyl‐1‐methylxanthine facilitates the inotropic function of ventricular putative β4‐adrenoceptors, suggesting coupling to Gs protein‐adenylyl cyclase. The receptor‐mediated increases in contractile force are related to increases of Ca2+ in atrial and ventricular myocytes. The agreement of binding affinities of agonists with cardiostimulant potencies is consistent with mediation through putative β4‐adrenoceptors labelled with (−)‐[3H]‐CGP 12177.

British Journal of Pharmacology (1999) 128, 1445–1460; doi:10.1038/sj.bjp.0702936
Inhibition of nuclear factor kappa B and induction of apoptosis in T‐lymphocytes by sulfasalazine
Authors: Liptay Susanne , Bachem Max , Häcker Georg , Adler Guido , Debatin Klaus M , Schmid Roland M 
Published: January 2005

Chronic inflammatory diseases have been shown to be associated with NF‐κB activation and impaired apoptosis of immune cells. The aim of the present study was to investigate if sulfasalazine and its colonic metabolites 5‐aminosalicylic acid (5ASA) and sulfapyridine affect NF‐κB/Rel activation and viability of T‐lymphocytes.
Sulfasalazine inhibits NF‐κB/Rel activation in the murine T‐lymphocyte cell line RBL5 using electrophoretic mobility shift assays. In transfection assays sulfasalazine treatment for 4 h inhibits κB‐dependent transcription with an IC50 value of ∼0.625 mM.
Higher doses or prolonged treatment result in cell death of T‐lymphocytes in a dose‐ and time‐dependent manner. Cell death is caused by apoptosis as judged by DNA fragmentation, annexin V and Apo 2.7 staining. Induction of apoptosis is a fast event with 50% apoptotic cells after a 4 h incubation with 2.5 mM sulfasalazine. The ED50 value for apoptosis induction after 24 h treatment was ∼0.625 mM.
In contrast, 5ASA and sulfapyridine neither inhibit NF‐κB/Rel activation nor induce apoptosis in T‐lymphocytes at doses up to 5.0 mM.
These results demonstrate that sulfasalazine, but not 5ASA or sulfapyridine, strongly inhibits NF‐κB activation and potently induces apoptosis in T‐lymphocytes. Inhibition of NF‐κB/Rel activation and subsequent clearance of activated T‐lymphocytes by apoptosis might thus explain the beneficial effects of sulfasalazine in the treatment of chronic inflammatory disorders.

British Journal of Pharmacology (1999) 128, 1361–1369; doi:10.1038/sj.bjp.0702937
Activation of muscle nicotinic acetylcholine receptor channels by nicotinic and muscarinic agonists
Authors: Akk Gustav , Auerbach Anthony 
Published: January 2005

The dose‐response parameters of recombinant mouse adult neuromuscular acetylcholine receptor channels (nAChR) activated by carbamylcholine, nicotine, muscarine and oxotremorine were measured. Rate constants for agonist association and dissociation, and channel opening and closing, were estimated from single‐channel kinetic analysis.
The dissociation equilibrium constants were (mM): ACh (0.16)<oxotremorine M (0.6)<carbamylcholine (0.8)<nicotine (2.6).
The gating equilibrium constants (opening/closing) were: ACh (45)>carbamylcholine (5.1)>oxotremorine M (0.6)>nicotine (0.5)>muscarine (0.15).
Rat neuronal α4β2 nAChR can be activated by all of the agonists. However, detailed kinetic analysis was impossible because the recordings lacked clusters representing the activity of a single receptor complex. Thus, the number of channels in the patch was unknown and the activation rate constants could not be determined.
Considering both receptor affinity and agonist efficacy, muscarine and oxotremorine are significant agonists of muscle‐type nAChR. The results are discussed in terms of structure‐function relationships at the nAChR transmitter binding site.

British Journal of Pharmacology (1999) 128, 1467–1476; doi:10.1038/sj.bjp.0702941
Novel cardiac protective effects of urea: from shark to rat
Authors: Wang Xintao , Wu Lingyun , Aouffen M'hamed , Mateescu Mircea‐Alexandru , Nadeau Réginald , Wang Rui 
Published: January 2005

This study was carried out to investigate novel cardioprotective effects of urea and the underlying mechanisms. The cardiac functions under oxidative stress were evaluated using Langendorff perfused isolated heart.
Isolated dogfish shark hearts tolerated the oxidative stress generated by electrolysis (10 mA, 1 min) of the perfusion solution (n=4), and also showed normal cardiac functions during post‐ischaemia reperfusion (n=4). The high concentration of urea (350 mM) in the heart perfusate was indispensable for maintaining the normal cardiac functions of the shark heart.
Urea at 3–300 mM (n=4 for each group) protected the isolated rat heart against both electrolysis‐induced heart damage and post‐ischaemia reperfusion‐induced cardiac injury.
A concentration‐dependent scavenging effect of urea (3–300 mM, n=4 for each group) against electrolysis‐induced reactive oxygen species was also demonstrated in vitro.
Urea derivatives as hydroxyurea, dimethylurea, and thiourea had antioxidant cardioprotective effect against the electrolysis‐induced cardiac dysfunction of rat heart, but were not as effective as urea in suppressing the post‐ischaemia reperfusion injury.
Our results suggest that urea and its derivatives are potential antioxidant cardioprotective agents against oxidative stress‐induced myocardium damage including the post‐ischaemia reperfusion‐induced injury.

British Journal of Pharmacology (1999) 128, 1477–1484; doi:10.1038/sj.bjp.0702944
Inducible expression and pharmacology of the human excitatory amino acid transporter 2 subtype of L‐glutamate transporter
Authors: Dunlop J , Lou Z , Zhang Y , McIlvain H B 
Published: January 2005

In this study we have examined the use of the ecdysone‐inducible mammalian expression system (Invitrogen) for the regulation of expression of the predominant L‐glutamate transporter EAAT2 (Excitatory Amino Acid Transporter) in HEK 293 cells.
HEK 293 cells which were stably transformed with the regulatory vector pVgRXR (EcR 293 cells) were used for transfection of the human EAAT2 cDNA using the inducible vector pIND and a clone designated HEK/EAAT2 was selected for further characterization.
Na+‐dependent L‐glutamate uptake activity (3.2 pmol min−1 mg−1) was observed in EcR 293 cells and this was increased approximately 2 fold in the uninduced HEK/EAAT2 cells, indicating a low level of basal EAAT2 activity in the absence of exogenous inducing agent. Exposure of HEK/EAAT2 cells to the ecdysone analogue Ponasterone A (10 μM for 24 h) resulted in a 10 fold increase in the Na+‐dependent activity.
L‐glutamate uptake into induced HEK/EAAT2 cells followed first‐order Michaelis‐Menten kinetics and Eadie‐Hofstee transformation of the saturable uptake data produced estimates of kinetic parameters as follows; Km 52.7±7.5 μM, Vmax 3.8±0.9 nmol min−1 mg−1 protein.
The pharmacological profile of the EAAT2 subtype was characterized using a series of L‐glutamate transport inhibitors and the rank order of inhibitory potency was similar to that described previously for the rat homologue GLT‐1 and in synaptosomal preparations from rat cortex.
Addition of the EAAT2 modulator arachidonic acid resulted in an enhancement (155±5% control in the presence of 30 μM) of the L‐glutamate transport capacity in the induced HEK/EAAT2 cells.
This study demonstrates that the expression of EAAT2 can be regulated in a mammalian cell line using the ecdysone‐inducible mammalian expression system.

British Journal of Pharmacology (1999) 128, 1485–1490; doi:10.1038/sj.bjp.0702945
Anaesthetic/amnesic agents disrupt beta frequency oscillations associated with potentiation of excitatory synaptic potentials in the rat hippocampal slice
Authors: Faulkner H J , Traub R D , Whittington M A 
Published: January 2005

Anaesthetic agents produce disruption in cognitive function typified by reductions in sensory perception and memory formation. Oscillations within the EEG gamma and beta bands have been linked to sensory perception and memory and have been shown to be modified by anaesthetic agents.
Synchronous gamma oscillations generated by brief tetanic stimulation in two regions of hippocampal area CA1 in slices in vitro were seen to potentiate excitatory synaptic communication between the areas. This synaptic potentiation, was seen to contribute to a transition from gamma frequency (30–70 Hz) to beta frequency (12–30 Hz) oscillations.
Four drugs having anaesthetic/hypnotic and amnesic properties were tested on this synchronous gamma‐induced beta oscillation. Thiopental 10–200 μM, Diazepam 0.05–1.0 μM, Morphine 10–200 μM, and Ketamine 10–200 μM were all added to the bathing medium. Each drug markedly disrupted the formation of beta oscillations in a manner consistent with their primary modes of action. Thiopental and morphine disrupted synchrony of gamma oscillations and prevented potentiation of recurrent excitatory potentials measured in stratum oriens (fEPSPs). Neither diazepam, nor ketamine produced such marked changes in synchrony at gamma frequencies or reduction in potentiation of fEPSPs. However, each disrupted expression of subsequent beta oscillation via changes in the magnitude of inhibitory network gamma oscillations and the duration and magnitude of tetanus‐induced depolarization respectively.
The degree of disruption of fEPSP potentiation correlated quantitatively with the degree of disruption in synchrony between sites during gamma oscillations. The data indicate that synchronous gamma‐induced beta oscillations represent a mode of expression of excitatory synaptic potentiation in the hippocampus, and that anaesthetic/amnesic agents can disrupt this process markedly.

British Journal of Pharmacology (1999) 128, 1813–1825; doi:10.1038/sj.bjp.0702948
Inhibition of neuronal KV potassium currents by the antidepressant drug, fluoxetine
Authors: Yeung Shuk Yin , Millar Julie A , Mathie Alistair 
Published: January 2005

The effect of the antidepressant drug, fluoxetine on neuronal delayed rectifier (KV) potassium (K) currents was investigated using perforated‐patch whole‐cell electrophysiological recording methods.
Fluoxetine was an effective inhibitor of KV currents in cerebellar granule neurons (CGNs) and also inhibited recombinant KV1.1 channels expressed in Chinese hamster ovary (CHO) cells.
Fluoxetine had an IC50 of 11 μM in CGNs but was slightly less potent on KV1.1 channels (IC50=55 μM). Interestingly, fluoxetine was a much more potent inhibitor of KV1.1 expressed in mammalian cells than has been found previously for the same homomeric channel expressed in Xenopus oocytes.
At concentrations that produced around 50% block, the shape of the KV currents in the presence of fluoxetine was simply scaled down when compared to control currents.
The effect of fluoxetine on KV currents in CGNs was neither voltage‐dependent nor dependent on the channels being in their open state. Both of these observations suggest that fluoxetine does not act as a simple open channel blocking agent.
It is concluded that block of KV currents in mammalian neurons can occur at therapeutic levels of fluoxetine. This could lead to an increase in neuronal excitability and this effect may contribute to the therapeutic antidepressant action of fluoxetine.

British Journal of Pharmacology (1999) 128, 1609–1615; doi:10.1038/sj.bjp.0702955
Tetrandrine ameliorates ischaemia‐reperfusion injury of rat myocardium through inhibition of neutrophil priming and activation
Authors: Shen Yuh‐Chiang , Chen Chieh‐Fu , Sung Yen‐Jen 
Published: January 2005

We have previously shown that tetrandrine (TTD), a bisbenzyltetrahydroiosquinoline isolated from the Chinese herb Stephania tetrandra, inhibits neutrophil adhesion, Mac‐1 expression, and reactive oxygen species (ROS) production. To examine whether inhibition of neutrophil function may confer upon TTD the ability to prevent myocardial ischaemia‐reperfusion (MI/R) injury, experiments were performed on rats subjected to coronary ligation followed by reperfusion for induction of MI/R injury.
Intravenous administration of TTD (0.1 and 1.0 mg kg−1) 15 min prior to coronary ligation completely prevented MI/R‐associated mortality. TTD pretreatment also significantly reduced MI/R‐induced ventricular tachyarrhythmia, myocardial infarct size, and neutrophil infiltration.
However, TTD pretreatment did not influence mean arterial blood pressure, heart rate, or product of pressure‐rate, indicating that TTD extenuated MI/R through mechanisms independent of modulating haemodynamics or myocardial oxygen demand.
Peripheral blood neutrophils were isolated for ex vivo examination of shape change and Mac‐1 upregulation of neutrophils, two sensitive indicators of proinflammatory priming, as well as N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLP)‐induced adhesion and ROS production, parameters commonly used for the assessment of neutrophil activation.
Neutrophils from MI/R animals showed significant shape change and Mac‐1 upregulation, both of which were prevented by TTD‐pretreatments. On the other hand, fMLP‐induced adhesion and ROS production of neutrophils were markedly enhanced by MI/R but diminished in TTD‐pretreated animals.
These data suggest that the protective effect of TTD against MI/R injury can be accounted for by inhibition of neutrophil priming and activation, thereby abolishing subsequent infiltration and ROS production that cause MI/R injury.

British Journal of Pharmacology (1999) 128, 1593–1601; doi:10.1038/sj.bjp.0702958
Bepridil differentially inhibits two delayed rectifier K+ currents, IKr and IKs, in guinea‐pig ventricular myocytes
Authors: Wang Jin‐Cheng , Kiyosue Tatsuto , Kiriyama Kuninori , Arita Makoto 
Published: January 2005

We investigated the effects of bepridil on the two components of the delayed rectifier K+ current, i.e., the rapidly activating (IKr) and the slowly activating (IKs) currents using tight‐seal whole‐cell patch‐clamp techniques in guinea‐pig ventricular myocytes, under blockade of L‐type Ca2+ current with nitrendipine (5 μM) or D600 (1 μM).
Bepridil decreased IKs under blockade of IKr with E4031 (5 μM), in a concentration‐dependent manner. The concentration‐dependent inhibition of IKs by bepridil was fitted by a curve, assuming one‐to‐one interactions between the channel and the drug molecule. The concentration of half‐maximal inhibition (IC50) was found to be 6.2 μM.
The effect of bepridil on IKr was assessed using an envelope‐of‐tails test. In the control condition, a ratio of the tail current to the time‐dependent current measured during depolarization was large (>1) at shorter pulses (<200 ms), and it decreased to a steady state value of ∼0.4 with increases in the pulse duration. Bepridil at a concentration of 2 μM did not decrease this ratio at shorter pulses.
In a short‐pulse (duration=50 ms) experiment that largely activates IKr, the drug was found to block IKr in a cooperative manner (Hill coefficient=3.03) and the IC50 was 13.2 μM.
These results suggest that bepridil at a clinical therapeutic concentration (∼2 μM) selectively blocks IKs but does not inhibit IKr. This may relate to the characteristic frequency‐dependent effects of bepridil on the action potential duration (APD), e.g., the non‐reverse use‐dependent prolongation of APD.

British Journal of Pharmacology (1999) 128, 1733–1738; doi:10.1038/sj.bjp.0702959
Functional studies in atrium overexpressing A1‐adenosine receptors
Authors: Neumann Joachim , Vahlensieck Ute , Boknik Peter , Linck Bettina , Lüss Hartmut , Müller Frank U , Matherne G Paul , Schmitz Wilhelm 
Published: January 2005

Adenosine and the A1‐adenosine receptor agonist R‐PIA, exerted a negative inotropic effect in isolated, electrically driven left atria of wild‐type mice.
In left atria of mice overexpressing the A1‐adenosine receptor, adenosine and R‐PIA exerted a positive inotropic effect.
The positive inotropic effect of adenosine and R‐PIA in transgenic atria could be blocked by the A1‐adenosine receptor antagonist DPCPX.
In the presence of isoprenaline, adenosine exerted a negative inotropic effect in wild‐type atria but a positive inotropic effect in atria from A1‐adenosine receptor overexpressing mice.
The rate of beating in right atria was lower in mice overexpressing A1‐adenosine receptors compared with wild‐type.
Adenosine exerted comparable negative chronotropic effects in right atria from both A1‐adenosine receptor overexpressing and wild‐type mice.
A1‐adenosine receptor overexpression in the mouse heart can reverse the inotropic but not the chronotropic effects of adenosine, implying different receptor‐effector coupling mechanisms.

British Journal of Pharmacology (1999) 128, 1623–1629; doi:10.1038/sj.bjp.0702963