bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thyrotropin regulates adenosine A1 receptor expression in rat thyroid FRTL‐5 cells
Authors: Vainio Minna , Fredholm Bertil B , Törnquist Kid 
Published: January 2005

The effect of thyrotropin (TSH), on adenosine A1 receptor expression in thyroid FRTL‐5 cells was examined by [3H]‐1,3‐dipropyl‐,8‐cyclopentyl xanthine ([3H]‐DPCPX) binding on cells in suspension and on membrane preparation, and by in situ mRNA labelling.
The estimated KD for intact cells was 0.19 nM and about 47,000 binding sites per cell were found in cells constantly grown in the presence of TSH.
Three days deprivation of TSH decreased the number of [3H]‐DPCPX binding sites without any significant effect of KD. Reintroduction of TSH to the cells returned the higher level of A1 receptors both in suspension binding studies on whole cells and on membrane preparations.
In situ hybridization revealed that TSH evoked an increase in the number of cells densely labelled with a probe against A1 receptor mRNA.
The potency of the A1 receptor agonist N6‐cyclohexyladenosine (CHA) as an inhibitor of cyclic AMP formation induced by forskolin was increased in TSH‐treated cells, with a shift in the IC50 from 2.05 nM in TSH‐deprived cells to 0.14 nM in TSH‐treated cells.
Since the activation of A1 receptors inhibits TSH‐mediated cyclic AMP signalling, our results suggest a regulatory feedback mechanism between signalling via adenosine A1 receptors and TSH receptors.

British Journal of Pharmacology (2000) 130, 471–477; doi:10.1038/sj.bjp.0703325
The mechanism of cryoinjury: In vitro studies on human internal mammary arteries
Authors: Müller‐Schweinitzer Else , Brett Wolfgang , Zerkowski Hans‐Reinhard , Haefeli Walter E 
Published: January 2005

The mechanism of cryoinjury was investigated in human internal mammary arteries (IMA) by monitoring contractile responses to ET‐1 and KCl.
For cryopreservation segments of IMA were equilibrated for 20 min with the cryomedium (RPMI 1640 culture medium containing 1.8 M DMSO and 0.1 M sucrose), frozen at a mean cooling rate of 1.3°C min−1 to −70°C and stored in liquid nitrogen. Before use, samples were thawed slowly and the cryomedium removed by dilution.
Compared to unfrozen controls, ET‐1 stimulated frozen/thawed IMA with similar efficacy but at 3 fold lower concentrations (P<0.001). Addition of ET‐1 (100 nM) induced maximal contraction of unfrozen IMA within 10 min, declining thereafter to 25% after 90 min. In frozen/thawed IMA the ET‐1‐induced contraction was sustained but could be reversed if protein kinase C was blocked by staurosporine (100 nM). Responses to ET‐1 of cryostored IMA were 5 fold more susceptible to blockade by nifedipine than those of controls.
After cryostorage the efficacy of KCl was diminished to 40% (P<0.05) and the KCl curve was shifted to the left (2 fold, P<0.001). In both unfrozen and cryostored IMA the KCl (60 mM) effect was sustained and equally susceptible to nifedipine.
It is suggested that the smooth muscle cell of IMA is receptive to physical forces which occur during cryopreservation. These forces modify transmembrane signal transduction and intracellular pathways, that are common to pharmacological agonists thereby changing vascular responses to several contractile agonists after thawing.

British Journal of Pharmacology (2000) 130, 636–640; doi:10.1038/sj.bjp.0703326
Effects of peroxisome proliferator‐activated receptor‐α and ‐γ agonist, JTT‐501, on diabetic complications in Zucker diabetic fatty rats
Authors: Shibata Tsutomu , Takeuchi Satomi , Yokota Seiko , Kakimoto Kochi , Yonemori Fumihiko , Wakitani Korekiyo 
Published: January 2005

This study has investigated the effects of JTT‐501, a peroxisome proliferator‐activated receptor (PPAR)‐α and PPAR‐γ agonist, on the pathogenesis of diabetic complications in the Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. Comparison is made with troglitazone, a PPAR‐γ agonist.
The ZDF rats exhibited hyperglycaemia and hyperlipidaemia, and developed diabetic complications such as cataract, nephropathy, and neuropathy. Treatment with JTT‐501 from the prediabetic stage controlled glycaemia and lipidaemia, and prevented the development of diabetic complications. Troglitazone was less effective in controlling serum cholesterol and neuropathy.
ZDF rats developed diabetic osteopenia with reduced bone turnover, and this was prevented by JTT‐501 and troglitazone, possibly mediated by increased bone turnover and bone formation.
Since JTT‐501 controlled glycaemia and lipidaemia in ZDF rats and prevented several diabetic complications, it is suggested that treatment with JTT‐501, which activates both PPAR‐α and PPAR‐γ, could provide a valuable therapeutic approach against diabetic complications in type 2 diabetes.

British Journal of Pharmacology (2000) 130, 495–504; doi:10.1038/sj.bjp.0703328
Effects of halothane on the membrane potential in skeletal muscle of the frog
Authors: Sauviat Martin‐Pierre , Frizelle Henry P , Descorps‐Declère Adrien , Mazoit Jean‐Xavier 
Published: January 2005

Halothane has many effects on the resting membrane potential (Vm) of excitable cells and exerts numerous effects on skeletal muscle one of which is the enhancement of Ca2+ release by the sarcoplasmic reticulum (SR) resulting in a sustained contracture. The aim of this study was to analyse the effects of clinical doses of halothane on Vm, recorded using intracellular microelectrodes on cleaned and non stimulated sartorius muscle which was freshly isolated from the leg of the frog Rana esculenta.
We assessed the mechanism of effects of superfused halothane on Vm by the administration of selective antagonists of membrane bound Na+, K+ and Cl− channels and by inhibition of SR Ca2+ release.
Halothane (3%) induced an early and transient depolarization (4.5 mV within 7 min) and a delayed and sustained hyperpolarization (about 11 mV within 15 min) of Vm.
The halothane‐induced transient depolarization was sensitive to ryanodine (10 μM) and to 4‐acetamido‐4′‐isothiocyanatostilbene 2,2′ disulphonic acid (SITS, 1 mM).
The hyperpolarization of Vm induced by halothane (0.1–3%) was dose‐dependent and reversible. It was insensitive to SITS (1 mM), tetrodotoxin (0.6 μM), and tetraethylammonium (10 mM) but was blocked and/or prevented by ryanodine (10 μM), charybdotoxin (CTX, 1 μM), and glibenclamide (10 nM).
Our observations revealed that the effects of halothane on Vm may be related to the increase in intracellular Ca2+ concentration produced by the ryanodine‐sensitive Ca2+ release from the SR induced by the anaesthetic. The depolarization may be attributed to the activation of Ca2+‐dependent Cl− (blocked by SITS) channels and the hyperpolarization to the activation of large conductance Ca2+‐dependent K+ channels, blocked by CTX, and to the opening of ATP‐sensitive K+ channels, inhibited by glibenclamide.

British Journal of Pharmacology (2000) 130, 619–624; doi:10.1038/sj.bjp.0703330
EDHF, NO and a prostanoid: hyperpolarization‐dependent and ‐independent relaxation in guinea‐pig arteries
Authors: Tare Marianne , Parkington Helena C , Coleman H A 
Published: January 2005

The contribution of endothelium‐derived hyperpolarizing factor (EDHF), nitric oxide (NO) and a prostanoid (PG) to endothelium‐dependent hyperpolarization and relaxation were assessed in coronary and mammary arteries of guinea‐pigs by integration of the responses evoked during discrete applications of acetylcholine (ACh). The results of this integration approach were compared with those using traditional peak analysis methods.
Nω‐nitro‐L‐arginine methyl ester (L‐NAME, 100 μM) and indomethacin (1 μM), alone or in combination, were without effect on peak hyperpolarizations or relaxations while they markedly reduced the integrated responses in both arteries.
Integrated responses attributed to NO and PG were larger than those attributed to EDHF in the coronary artery (at 2 μM ACh, hyperpolarization (mV s): NO, 4200±91; PG, 5046±157; EDHF, 1532±94; relaxation (mN s mm−1): NO, 2488±122; PG, 2234±96; EDHF, 802±54). Integrated responses attributed to NO, PG and EDHF were similar in the mammary artery (at 2 μM ACh, hyperpolarization: NO, 347±69; PG, 217±49; EDHF, 310±63; relaxation: NO, 462±94; PG, 456±144; EDHF, 458±40).
Gilbenclamide (1 μM) all but abolished the hyperpolarization attributable to NO and PG but not EDHF in both arteries allowing assessment of the role of the hyperpolarization in relaxation. Gilbenclamide was without effect on the integrated relaxation due to NO but significantly reduced the relaxation associated with PG in the two arteries.
In conclusion, integration of the responses enabled a more complete assessment of the contribution of EDHF, NO and PG to endothelium‐dependent responses, which were strikingly different in the two arteries. There is commonality in the role of hyperpolarization in relaxation in both arteries: EDHF‐dependent relaxation is strongly dependent on hyperpolarization; hyperpolarization plays an important role in PG relaxation, whereas it has a small facilitatory role in NO‐dependent relaxation.

British Journal of Pharmacology (2000) 130, 605–618; doi:10.1038/sj.bjp.0703332
Properties and pharmacological modification of ATP‐sensitive K+ channels in cat tracheal myocytes
Authors: Teramoto Noriyoshi , Nakashima Tadasu , Ito Yushi 
Published: January 2005

The effects of levcromakalim and nucleoside diphosphates (NDPs) on both membrane currents and unitary currents in cat trachea myocytes were investigated by use of patch‐clamp techniques.
In conventional whole‐cell configuration, levcromakalim produced a concentration‐dependent K+ current which was suppressed by additional application of 5 μM glibenclamide at −70 mV. When 3 mM ATP was added in the pipette solution, the peak amplitude of the levcromakalim‐induced current was much smaller than that in the absence of ATP.
When 3 mM uridine 5′‐diphosphate (UDP) was included in the pipette solution, much higher concentrations of glibenclamide (50 μM) were required to suppress the 100 μM levcromakalim‐induced membrane current in comparison with those in the absence of UDP.
In the cell‐attached patches, levcromakalim activated a 40 pS K+ channel which was inhibited by additional application of glibenclamide in symmetrical 140 mM K+ conditions.
UDP (0.1 mM) was capable of reactivating the channel in inside‐out patches in which the glibenclamide‐sensitive K+ channel had run down, in the presence of levcromakalim. The K+ channel reactivated by UDP was suppressed by additional application of either intracellular 3 mM ATP or 100 μM glibenclamide.
These results demonstrate that smooth muscle cells in the cat trachea possess ATP‐sensitive 40 pS K+ channels which are blocked by glibenclamide (i.e. KATP) and can be activated by levcromakalim and that intracellular UDP causes a significant shift of the glibenclamide‐sensitivity of these channels.

British Journal of Pharmacology (2000) 130, 625–635; doi:10.1038/sj.bjp.0703333
Effects of a quaternary bupivacaine derivative on delayed rectifier K+ currents
Authors: Longobardo M , González T , Navarro‐Polanco R , Caballero R , Delpón E , Tamargo J , Snyders D J , Tamkun M M , Valenzuela C 
Published: January 2005

Block of hKv1.5 channels by R‐bupivacaine has been attributed to the interaction of the charged form of the drug with an intracellular receptor. However, bupivacaine is present as a mixture of neutral and charged forms both extra‐ and intracellularly.
We have studied the effects produced by the R(+) enantiomer of a quaternary bupivacaine derivative, N‐methyl‐bupivacaine, (RB+1C) on hKv1.5 channels stably expressed in Ltk− cells using the whole‐cell configuration of the patch‐clamp technique.
When applied from the intracellular side of the membrane, RB+1C induced a time‐ and voltage‐dependent block similar to that induced by R‐bupivacaine. External application of 50 μM RB+1C reduced the current at +60 mV by 24±2% (n=10), but this block displayed neither time‐ nor voltage‐dependence.
External RB+1C partially relieved block induced by R‐bupivacaine (61±2% vs 56±3%, n=4, P<0.05), but it did not relieve block induced by internal RB+1C. In addition, it did not induce use‐dependent block, but when applied in combination with internal RB+1C a use‐dependent block that increased with pulse duration was observed.
These results indicate that RB+1C induces different effects on hKv1.5 channels when applied from the intra or the extracellular side of the membrane, suggesting that the actions of bupivacaine are the resulting of those induced on the external and the internal side of hKv1.5 channels.

British Journal of Pharmacology (2000) 130, 391–401; doi:10.1038/sj.bjp.0703334
Activation and block of recombinant GABAA receptors by pentobarbitone: a single‐channel study
Authors: Akk Gustav , Steinbach Joe Henry 
Published: January 2005

Recombinant GABAA receptors (α1β2γ2L) were transiently expressed in HEK 293 cells. We have investigated activation and block of these receptors by pentobarbitone (PB) using cell‐attached single‐channel patch clamp.
Clusters of single‐channel activity elicited by 500 μM PB were analysed to estimate rate constants for agonist binding and channel gating. The minimal model able to describe the kinetic data involved two sequential binding steps, followed by channel opening. The estimated channel opening rate constant is ∼1500 s−1, and the estimated equilibrium dissociation constants for the binding steps involved in activation are ∼2 mM.
Our results show a dose‐dependent block of receptors at millimolar concentrations of PB that results in reduced open interval durations. The reduction in mean open time is linearly proportional to PB concentration, indicating that block can be produced by binding of a single PB molecule.
Addition of millimolar concentrations of PB in the presence of GABA also produces a reduction of open channel lifetime in addition to a progressive increase in the closed interval durations within a cluster. The data suggest that the receptor contains two or more blocking sites while occupancy of only one of the sites is sufficient for channel block.
Neither the blocking rate constant nor return rate from the blocked state(s) is affected by pH (ionization status of the PB molecule) demonstrating that both neutral and anionic forms of PB cause channel block.

British Journal of Pharmacology (2000) 130, 249–258; doi:10.1038/sj.bjp.0703335
Octopamine receptors in the honey bee and locust nervous system: pharmacological similarities between homologous receptors of distantly related species
Authors: Degen Joern , Gewecke Michael , Roeder Thomas 
Published: January 2005

Honey bees are perhaps the most versatile models to study the cellular and pharmacological basis underlying behaviours ranging from learning and memory to sociobiology. For both aspects octopamine (OA) is known to play a vital role.
The neuronal octopamine receptor of the honey bee shares pharmacological similarities with the neuronal octopamine receptor of the locust. Both, agonists and antagonists known to have high affinities for the locust neuronal octopamine receptor have also high affinities for the bee neuronal octopamine receptor.
The distribution of receptors is more or less congruent between locusts and bees. Optic lobes and especially the mushroom bodies are areas of greatest octopamine receptor expression in both species, which mirrors the physiological significance of octopamine in the insect nervous system.
The neuronal octopamine receptor of insects served as a model to study the pharmacological similarity of homologous receptors from distantly related species, because bees and locusts are separated by at least 330 million years of evolution.

British Journal of Pharmacology (2000) 130, 587–594; doi:10.1038/sj.bjp.0703338
Long‐lasting cholecystokinin2 receptor blockade after a single subcutaneous injection of YF476 or YM022
Authors: Kitano Masayuki , Norlén Per , Ding Xi‐Qin , Nakamura Sanae , Håkanson Rolf 
Published: January 2005

Histamine‐forming ECL cells in the rat stomach operate under the control of gastrin. They represent a convenient target for studying cholecystokinin‐B/gastrin (CCK2) receptor antagonists in vivo.
We examined the effectiveness and duration of action of two CCK2 antagonists, YM022 and YF476, with respect to their effect on ECL‐cell histidine decarboxylase (HDC) activity in the rat.
Oral administration of subcutaneous deposition of YF476 or YM022 reduced the HDC activity. The maximum/near‐maximum dose for both drugs and for both modes of administration was 300 μmol kg−1 (effects measured 24 h after dose). At this dose and time the serum concentration of YF476 was 20–40 nmol l−1. The dose 300 μmol kg−1 was used in all subsequent studies.
A single subcutaneous injection of YF476 inhibited the HDC activity for 8 weeks. The circulating concentration of YF476 remained high for the same period of time (15 nmol l−1). Subcutaneous YM022 suppressed the HDC activity for 4 weeks. A single oral dose of YF476 or YM022 inhibited the HDC activity for 2–3 days.
Chronic gastric fistula rats were used to study the effect of subcutaneous YF476 on gastrin‐stimulated acid secretion. A single injection of YF476 prevented gastrin from causing an acid response for at least 4 weeks (the longest time studied).
We conclude that a single subcutaneous injection of 300 μmol kg−1 YF476 causes blockade of CCK2 receptors in the stomach of the rat for 8 weeks thus providing a convenient method for studies of the consequences of long‐term CCK2 receptor inhibition.

British Journal of Pharmacology (2000) 130, 699–705; doi:10.1038/sj.bjp.0703342
Substance P mediates inflammatory oedema in acute pancreatitis via activation of the neurokinin‐1 receptor in rats and mice
Authors: Grady Eileen F , Yoshimi Shandra K , Maa John , Valeroso Dahlia , Vartanian Robert K , Rahim Shamila , Kim Edward H , Gerard Craig , Gerard Norma , Bunnett Nigel W , Kirkwood Kimberly S 
Published: January 2005

Pancreatic oedema occurs early in the development of acute pancreatitis, and the overall extent of fluid loss correlates with disease severity. The tachykinin substance P (SP) is released from sensory nerves, binds to the neurokinin‐1 receptor (NK1‐R) on endothelial cells and induces plasma extravasation, oedema, and neutrophil infiltration, a process termed neurogenic inflammation. We sought to determine the importance of neurogenic mechanisms in acute pancreatitis.
Pancreatic plasma extravasation was measured using the intravascular tracers Evans blue and Monastral blue after administration of specific NK1‐R agonists/antagonists in rats and NK1‐R(+/+)/(−/−) mice. The effects of NK1‐R genetic deletion/antagonism on pancreatic plasma extravasation, amylase, myeloperoxidase (MPO), and histology in cerulein‐induced pancreatitis were characterized.
In rats, both SP and the NK1‐R selective agonist [Sar9 Met(O2)11]SP stimulated pancreatic plasma extravasation, and this response was blocked by the NK1‐R antagonist CP 96,345. Selective agonists of the NK‐2 or NK‐3 receptors had no effect.
In rats, cerulein stimulated pancreatic plasma extravasation and serum amylase. These responses were blocked by the NK1‐R antagonist CP 96,345.
In wildtype mice, SP induced plasma extravasation while SP had no effect in NK1‐R knockout mice.
In NK1‐R knockout mice, the effects of cerulein on pancreatic plasma extravasation and hyperamylasemia were reduced by 60%, and pancreatic MPO by 75%, as compared to wildtype animals.
Neurogenic mechanisms of inflammation are important in the development of inflammatory oedema in acute interstitial pancreatitis.

British Journal of Pharmacology (2000) 130, 505–512; doi:10.1038/sj.bjp.0703343
Accelerated resequestration of cytosolic calcium and suppression of the pro‐inflammatory activities of human neutrophils by CGS 21680 in vitro
Authors: Anderson R , Visser S S , Ramafi G , Theron A J 
Published: January 2005

We have investigated the effects of the adenosine A2A receptor agonist CGS 21680 (0.01–1 μM) on reactive oxidant production by, and elastase release from FMLP‐activated human neutrophils, as well as on cytosolic Ca2+ fluxes and intracellular concentrations of cyclic AMP.
Oxidant production, elastase release and cyclic AMP were assayed using lucigenin‐enhanced chemiluminescence, colourimetric and radioimmunoassay procedures respectively, while cytosolic Ca2+ fluxes were measured by fura‐2 spectrofluorimetry in combination with radiometric procedures which distinguish between net efflux and influx of the cation.
Treatment of neutrophils with CGS 21680 did not affect the FMLP‐activated release of Ca2+ from intracellular stores, but resulted in dose‐related acceleration of the rate of decline in fura‐2 fluorescence, as well as decreases in both efflux and store‐operated influx of Ca2+, compatible with enhancement of resequestration of the cation by the endo‐membrane Ca2+‐ATPase. These effects on neutrophil Ca2+ handling were associated with increased intracellular cyclic AMP and with inhibition of oxidant production and release of elastase.
In contrast, treatment of neutrophils with the selective A2A receptor antagonist, ZM 241385 (2.5 μM), prevented the transient increase in cyclic AMP in FMLP‐activated neutrophils which was associated with delayed sequestration of incoming Ca2+ during store‐operated influx.
The CGS 21680‐mediated reduction of Ca2+ efflux from FMLP‐activated neutrophils was also antagonized by pretreatment of the cells with ZM 241385 (2.5 μM), as well as by thapsigargin (1 μM), an inhibitor of the endo‐membrane Ca2+‐ATPase. ZM 241385 also neutralized the cyclic AMP‐elevating and anti‐inflammatory interactions of CGS 21680 with neutrophils.
We conclude that A2A receptors regulate the pro‐inflammatory activities of human neutrophils by promoting cyclic AMP‐dependent sequestration of cytosolic Ca2+.

British Journal of Pharmacology (2000) 130, 717–724; doi:10.1038/sj.bjp.0703344
Retinoid‐mediated inhibition of interleukin‐12 production in mouse macrophages suppresses Th1 cytokine profile in CD4+ T cells
Authors: Kang B Y , Chung S W , Kim S H , Kang S N , Choe Y K , Kim T S 
Published: January 2005

Interleukin‐12 (IL‐12) plays a central role in the immune system by driving the immune response towards T helper 1 (Th1) type responses characterized by high IFN‐γ and low IL‐4 production. In this study we investigated whether retinoid‐mediated inhibition of interleukin‐12 production in mouse macrophages could regulate cytokine profile of antigen (Ag)‐primed CD4+ Th cells.
Pretreatment with retinoids (9‐cis‐RA, all‐trans‐RA, TTNPB) significantly inhibited IL‐12 production by mouse macrophages stimulated with lipopolysaccharide (LPS) or heated‐killed Listeria monocytogenes (HKL). Retinoid‐pretreated macrophages reduced their ability to induce IFN‐γ and increased the ability to induce IL‐4 in Ag‐primed CD4+ T cells.
Addition of recombinant IL‐12 to cultures of retinoid‐pretreated macrophages and CD4+ T cells restored IFN‐γ production in CD4+ T cells.
The in vivo administration of 9‐cis‐RA resulted in the inhibition of IL‐12 production by macrophages stimulated in vitro with either LPS or HKL, leading to the inhibition of Th1 cytokine profile (decreased IFN‐γ and increased IL‐4 production) in CD4+ T cells.
These findings may explain some known effects of retinoids including the inhibition of encephalitogenicity, and point to a possible therapeutic use of retinoids in the Th1‐mediated immune diseases such as autoimmune diseases.

British Journal of Pharmacology (2000) 130, 581–586; doi:10.1038/sj.bjp.0703345