bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional role of angiotensin II AT2 receptor in modulation of AT1 receptor‐mediated contraction in rat uterine artery: involvement of bradykinin and nitric oxide
Authors: Hannan Ruth E , Davis Elizabeth A , Widdop Robert E 
Published: October 2003

The aim of the present study was to explore the mechanisms underlying angiotensin II AT2 receptor modulation of AT1 receptor‐mediated vasoconstriction in the rat isolated uterine artery, since previous studies have suggested that AT2 receptors may oppose AT1 receptor‐mediated effects.
Segments of uterine artery were obtained from Sprague–Dawley rats and mounted in small vessel myographs. Concentration–response (CR) curves to angiotensin II (0.1 nM–0.1 μM) were constructed in the absence and presence of PD 123319 (AT2 antagonist; 1 μM), HOE 140 (bradykinin B2 antagonist; 0.1 μM), Nω‐nitro‐L‐arginine (NOLA) (NOS inhibitor; 30 μM), as well as combinations of these inhibitors. Contractile responses to angiotensin II were expressed as a percent of the response to a K+ depolarizing solution.
PD 123319 (1 μM) potentiated angiotensin II‐induced contractions; reflected by a significant four‐fold leftward shift of the angiotensin II CR curve.
HOE 140 (0.1 μM) significantly increased the pEC50 of the angiotensin II CR curve. The combination of HOE 140 plus PD 123319 did not produce additive potentiation.
NOLA (30 μM) significantly enhanced sensitivity to angiotensin II, seen as a five‐fold leftward shift of the curve, and an augmented maximum contractile response. Combinations of PD 123319 (1 μM) plus NOLA, and of HOE 140 (0.1 μM) plus NOLA, both induced a similar magnitude of potentiation.
Cyclic GMP measurements confirmed angiotensin II‐induced activation of the nitric oxide (NO) pathway.
In conclusion, AT2 receptor‐mediated inhibition of angiotensin II‐induced contraction of the rat uterine artery involves NO production; a component of which occurs through a bradykinin B2 receptor pathway.

British Journal of Pharmacology (2003) 140, 987–995. doi:10.1038/sj.bjp.0705484
Rho‐kinase inhibitor inhibits both myosin phosphorylation‐dependent and ‐independent enhancement of myofilament Ca2+ sensitivity in the bovine middle cerebral artery
Authors: Maeda Yoshihisa , Hirano Katsuya , Nishimura Junji , Sasaki Tomio , Kanaide Hideo 
Published: October 2003

The role of Rho kinase in Ca2+ sensitization of the contractile apparatus in smooth muscle was investigated in the bovine middle cerebral artery.
U46619, a thromboxane A2 analog, induced a greater sustained contraction with a smaller [Ca2+]i elevation than that seen with 118 mM K+. The level of myosin light chain (MLC) phosphorylation obtained in the initial phase of the contraction was higher than that seen with 118 mM K+; thereafter, it gradually declined to a comparable level in the late phase.
During the steady state of the U46619‐induced contraction, Y27632 (10 μM), a Rho‐kinase inhibitor, partially inhibited [Ca2+]i, although it substantially inhibited tension and MLC phosphorylation. Wortmannin (10 μM), an MLC kinase inhibitor, had no significant effect on [Ca2+]i, but it completely inhibited MLC phosphorylation and partially inhibited tension. The wortmannin‐resistant tension development was thus not associated with MLC phosphorylation, and this component was completely inhibited by Y27632.
In conclusion, U46619 enhanced Ca2+ sensitivity in a manner both dependent and independent of MLC phosphorylation in the bovine middle cerebral artery. Both mechanisms of Ca2+ sensitization can be inhibited by the Rho‐kinase inhibitor.

British Journal of Pharmacology (2003) 140, 871–880. doi:10.1038/sj.bjp.0705487
Riluzole inhibits spontaneous Ca2+ signaling in neuroendocrine cells by activation of K+ channels and inhibition of Na+ channels
Authors: Beltran‐Parrazal Luis , Charles Andrew 
Published: October 2003

The neuroprotective drug riluzole has multiple effects on cellular signaling. We found that riluzole rapidly and reversibly inhibited spontaneous Ca2+ oscillations in both immortalized GnRH‐secreting hypothalamic neurons (GT1 cells) and in the prolactin and growth‐hormone‐secreting GH3 cell line. At lower concentrations (100 nM–5 μM), riluzole reduced the amplitude and frequency of spontaneous Ca2+ oscillations, whereas at higher concentrations it abolished spontaneous Ca2+ signaling.
Whole‐cell current clamp recordings in GH3 cells revealed that riluzole decreased the action potential frequency, amplitude, and duration.
Riluzole inhibited voltage‐gated Na+ currents, increased iberiotoxin‐sensitive voltage‐gated K+ currents, and had no effect on voltage‐gated Ca2+ currents in GH3 cells. Riluzole also inhibited voltage‐gated Na+ currents and increased voltage‐gated K+ channels in GT1 cells.
The inhibitory effects of riluzole on Ca2+ signaling were blocked by pretreatment with iberiotoxin in GH3 cells, but only partially reduced by iberiotoxin in GT1 cells.
These results indicate that riluzole inhibits Ca2+ signaling primarily by activation of K+ channels in GH3 cells, and also by inhibition of Na+ channels in GT1 cells. Riluzole's inhibition of spontaneous excitability and Ca2+ signaling may be involved in its multiple effects on cellular function in the nervous system.

British Journal of Pharmacology (2003) 140, 881–888. doi:10.1038/sj.bjp.0705491
Effects of TRA‐418, a novel TP‐receptor antagonist, and IP‐receptor agonist, on human platelet activation and aggregation
Authors: Miyamoto Mitsuko , Yamada Naohiro , Ikezawa Shiho , Ohno Michihiro , Otake Atsushi , Umemura Kazuo , Matsushita Teruo 
Published: October 2003

{4‐[2‐(1,1‐Diphenylethylsulfanyl)‐ethyl]‐3,4‐dihydro‐2H‐benzo[1,4]oxazin‐8‐yloxy}‐acetic acid N‐Methyl‐D‐glucamine salt (TRA‐418) has both thromboxane A2 (TP)‐receptor antagonist and prostacyclin (IP)‐receptor agonist properties. The present study examined the advantageous effects of TRA‐418 based on the dual activities, over an agent having either activity alone and also the difference in the effects of TRA‐418 and a glycoprotein αIIb/β3 integrin (GPIIb/IIIa) inhibitor.
TRA‐418 inhibited platelet GPIIb/IIIa activation as well as P‐selectin expression induced by adenosine 5′‐diphosphate, thrombin receptor agonist peptide 1–6 (Ser‐Phe‐Leu‐Leu‐Arg‐Asn‐NH2), and U‐46619 in the presence of epinephrine (U‐46619+ epinephrine). TRA‐418 also inhibited platelet aggregation induced by those platelet‐stimulants in Ca2+ chelating anticoagulant, citrate and in nonchelating anticoagulant, D‐phenylalanyl‐L‐prolyl‐L‐arginyl‐chloromethyl ketone (PPACK).
The TP‐receptor antagonist SQ‐29548 inhibited only U‐46619+epinephrine‐induced GPIIb/IIIa activation, P‐selectin expression, and platelet aggregation.
The IP‐receptor agonist beraprost sodium inhibited platelet activation. Beraprost also inhibited platelet aggregation induced by platelet stimulants we tested in citrate and in PPACK.
The GPIIb/IIIa inhibitor abciximab blocked GPIIb/IIIa activation and platelet aggregation. However, abciximab showed slight inhibitory effects on P‐selectin expression.
TRA‐418 is more advantageous as an antiplatelet agent than TP‐receptor antagonists or IP‐receptor agonists separately used. TRA‐418 showed a different inhibitory profile from abciximab in the effects on P‐selectin expression.

British Journal of Pharmacology (2003) 140, 889–894. doi:10.1038/sj.bjp.0705499
Activation and proliferation signals in primary human T lymphocytes inhibited by ergosterol peroxide isolated from Cordyceps cicadae
Authors: Kuo Y C , Weng S C , Chou C J , Chang T T , Tsai W J 
Published: October 2003

Effects of ergosterol peroxide (C28H44O3; Cpd 6A) from Cordyceps cicadae on phytohemagglutinin (PHA)‐stimulated cell proliferation were studied in primary human T cells.
The results showed that Cpd 6A suppressed T‐cell proliferation for about 24 h after stimulation with PHA. Cell cycle analysis indicated that Cpd 6A arrested the cell cycle progression of activated T cells from the G1 transition to the S phase.
To localize the point in the cell cycle where arrest occurred, a set of key regulatory events leading to the G1/S boundary, including the expression of cyclins D2, E, A1, and B1, interleukin (IL)‐2, IL‐4, interferon‐γ (IFN‐γ), and activating protein‐1 (AP‐1), was examined.
Cpd 6A suppressed, in activated T lymphocytes, the production and mRNA expression of cyclin E, IL‐2, IL‐4, IL‐10, and IFN‐γ in a dose‐dependent manner.
Expression of AP‐1 proteins, consisting of c‐Fos and c‐Jun, in activated T lymphocytes was decreased by Cpd 6A. The kinetic study indicated that the inhibitory effects of Cpd 6A on IL‐2 mRNA expressed in T cells might be related to blocking c‐Fos protein synthesis. T‐cell proliferation after Cpd 6A treatment was partially restored by addition of IL‐2, IL‐4, and IFN‐γ.
These suppressant effects of Cpd 6A on T‐cell proliferation, activated by PHA, appeared to be mediated, at least in part, through the inhibition of early gene transcripts, especially those of cyclin E, IFN‐γ, IL‐2, and IL‐4, and by arresting cell cycle progression in the cells.

British Journal of Pharmacology (2003) 140, 895–906. doi:10.1038/sj.bjp.0705500
Acute effects of dronedarone on both components of the cardiac delayed rectifier K+ current, HERG and KvLQT1/minK potassium channels
Authors: Thomas Dierk , Kathöfer Sven , Zhang Wei , Wu Kezhong , Wimmer Anna‐Britt , Zitron Edgar , Kreye Volker A W , Katus Hugo A , Schoels Wolfgang , Karle Christoph A , Kiehn Johann 
Published: October 2003

Dronedarone is a noniodinated benzofuran derivative that has been synthesized to overcome the limiting iodine‐associated adverse effects of the potent antiarrhythmic drug amiodarone. In this study, the acute electrophysiological effects of dronedarone on repolarizing potassium channels were investigated to determine the class III antiarrhythmic action of this compound. HERG and KvLQT1/minK potassium channels conduct the delayed rectifier potassium current IK in human heart, being a primary target for class III antiarrhythmic therapy.
HERG and KvLQT1/minK were expressed heterologously in Xenopus laevis oocytes, and the respective potassium currents were recorded using the two‐microelectrode voltage‐clamp technique.
Dronedarone blocked HERG channels with an IC50 value of 9.2 μM and a maximum tail current reduction of 85.2%.
HERG channels were blocked in the closed, open, and inactivated states. The half‐maximal activation voltage was shifted by −6.1 mV, and HERG current block by dronedarone was voltage‐dependent, but not use‐dependent.
Dronedarone exhibited a weaker block of KvLQT1/minK currents (33.2% at 100 μM drug concentration), without causing significant changes in the corresponding current–voltage relationships.
In conclusion, these data demonstrate that dronedarone is an antagonist of cloned HERG potassium channels, with additional inhibitory effects on KvLQT1/minK currents at higher drug concentrations, providing a molecular mechanism for the class III antiarrhythmic action of the drug.

British Journal of Pharmacology (2003) 140, 996–1002. doi:10.1038/sj.bjp.0705502
Rivastigmine blocks voltage‐activated K+ currents in dissociated rat hippocampal neurons
Authors: Pan Yaping , Xu Xianghua , Wang Xiaoliang 
Published: October 2003

Rivastigmine is an acetylcholinesterase inhibitor used in Alzheimer's disease therapy. In the present study, we investigated the effects of rivastigmine on the transient outward K+ current (IK(A)) and the delayed rectifier K+ current (IK(DR)) in acutely dissociated rat hippocampal pyramidal neurons using the whole‐cell patch‐clamp technique.
Rivastigmine inhibited the amplitudes of IK(A) and IK(DR) in a reversible and concentration‐dependent manner. At a concentration of 100 μM, rivastigmine inhibited IK(A) and IK(DR), recorded when the cells were depolarized from −50 to +40 mV, by 65.9 (P<0.01) and 67.3% (P<0.01), respectively. The IC50 values for IK(A) and IK(DR) were 3.8 and 1.7 μM, respectively.
The decay time constant of IK(A), recorded following a test pulse to +40 mV, was prolonged reversibly by rivastigmine at concentrations of 10 and 100 μM (both P<0.05).
Rivastigmine affected the voltage dependence of IK(A) and IK(DR). At a concentration of 10 μM, it shifted the steady‐state inactivation curve of IK(A) towards more negative potentials by −11 mV (P<0.05), but had no effect on the steady‐state activation curve or the recovery from inactivation. Regarding the kinetic properties of IK(DR), 10 μM rivastigmine shifted the steady‐state activation and inactivation curves towards more negative potentials by −10 (P<0.05) and −27 mV (P<0.01), respectively.
Our findings that rivastigmine inhibits IK(A) and IK(DR) in rat hippocampal pyramidal neurons suggest that this agent has other pharmacological actions besides its antiacetylcholinesterase activity.

British Journal of Pharmacology (2003) 140, 907–912. doi:10.1038/sj.bjp.0705503
Importance of ERK activation in behavioral and biochemical effects induced by MDMA in mice
Authors: Salzmann Julie , Marie‐claire Cynthia , Guen Stéphanie Le , Roques Bernard P , Noble Florence 
Published: October 2003

Little is known about the cellular effects induced by 3,4‐methylenedioxymethamphetamine (MDMA, ecstasy), although changes in gene expression have been observed following treatments with other psychostimulants. Thus, the aim of this study was to investigate in mice, the relationships between the ras‐dependent protein kinase ERK and MDMA‐induced reinforcement using the conditioned place preference (CPP) and locomotor activity measurements. This was completed using real‐time quantitative PCR method by a study of immediate early‐genes (IEGs) transcription known to be involved in neuronal plasticity.
A significant CPP was observed after repeated MDMA treatment in CD‐1 mice at a dose of 9 mg kg−1 i.p. but not at 3 and 6 mg kg−1. This rewarding effect was abolished by the selective inhibitor of ERK activation, SL327 (50 mg kg−1; i.p.). Similar results were obtained on MDMA‐induced locomotor activity, clearly suggesting a role of ERK pathway in these behavioral responses.
Following acute i.p. injection, MDMA induced a strong c‐fos transcription in brain structures, such as caudate putamen, nucleus accumbens and hippocampus, whereas egr‐1 and egr‐3 transcripts were only increased in the caudate putamen. MDMA‐induced IEGs transcription was selectively suppressed by SL327 in the caudate putamen, suggesting a role for other signaling pathways in regulation of IEGs transcription in the other brain structures. In agreement with these results, MDMA‐induced c‐fos protein expression was blocked by SL327 in the caudate putamen.
This study confirms and extends to mice the reported role of ERK pathway in the development of addiction‐like properties of MDMA. This could facilitate studies about the molecular mechanism of this process by using mutant mice.

British Journal of Pharmacology (2003) 140, 831–838. doi:10.1038/sj.bjp.0705506
In vivo characterization of 5‐HT1A receptor‐mediated gastric relaxation in conscious dogs
Authors: Janssen P , Prins N H , Moreaux B , Meulemans A L , Lefebvre R A 
Published: October 2003

Accumulating data have been published emphasizing the important role of 5‐hydroxytryptamine (5‐HT) receptors in proximal stomach relaxation. However, a proper in vivo characterization of 5‐HT receptors mediating gastric relaxation is still missing. In the current study, we focus on the in vivo characterization of 5‐HT1A receptors mediating relaxation of the proximal stomach in conscious dogs.
Beagle dogs were equipped with a gastric fistula. In the conscious state, volume changes within an intragastric bag were measured at constant pressure by means of a barostat. Results are presented as the maximum volume increase after treatment (mean±s.e.m.). All drugs were injected intravenously.
The 5‐HT1A receptor agonist flesinoxan (10, 50, 100 and 150 μg kg−1) induced a dose‐dependent relaxation of the canine proximal stomach (50±10, 230±51, 290±38 and 275±33 ml, respectively; n=9–11). The selective 5‐HT1A receptor antagonist WAY‐100635 dose‐dependently inhibited the flesinoxan‐induced relaxation. NG‐nitro‐L‐arginine methyl ester did not affect this relaxation, suggesting that nitrergic nerves are not involved.
After supradiaphragmatic vagotomy, the baseline of the intragastric volume was larger compared to that before vagotomy (317±50 vs 142±28 ml, respectively; n=5). Compensation for this by either reduction of the intraballoon pressure or infusion of a contractile dose of bethanechol did not establish a condition in which flesinoxan was able to relax the stomach. In contrast, nitroprusside induced a significant gastric relaxation when tone was increased by bethanechol.
It is concluded that flesinoxan induces proximal gastric relaxation in conscious dogs via 5‐HT1A receptors. The response is mediated through a vagal pathway without involvement of nitrergic nerves.

British Journal of Pharmacology (2003) 140, 913–920. doi:10.1038/sj.bjp.0705507
Theophylline attenuates Ca2+ sensitivity and modulates BK channels in porcine tracheal smooth muscle
Authors: Ise Shinji , Nishimura Junji , Hirano Katsuya , Hara Nobuyuki , Kanaide Hideo 
Published: October 2003

Theophylline, a nonselective phosphodiesterase inhibitor, has long been regarded as a major bronchodilator in the treatment of human asthma. Using front‐surface fluorometry with fura‐2 and α‐toxin permeabilization, the effects of theophylline on intracellular Ca2+ concentration ([Ca2+]i), tension development and Ca2+ sensitivity of the contractile apparatus were investigated in porcine tracheal smooth muscle strips.
Application of theophylline induced a relaxation without a significant decrease in [Ca2+]i when strips were precontracted by 40 mM K+ depolarization, while theophylline significantly decreased both [Ca2+]i and tension induced by carbachol.
The effects of theophylline on the increases in [Ca2+]i and tension induced by carbachol were significantly inhibited by iberiotoxin, an inhibitor of large‐conductance Ca2+‐activated K+ channels.
In the absence of extracellular Ca2+, theophylline significantly attenuated carbachol‐induced transient increases in tension development, while it did not affect carbachol‐induced transient increase in [Ca2+]i.
The [Ca2+]i–force relationship, which was determined by cumulative applications of extracellular Ca2+ (0–5 mM) during 40 mM K+ depolarization, was significantly shifted to the right by theophylline.
In α‐toxin permeabilized strips, theophylline significantly increased the EC50 value of [Ca2+]i for contraction and enhanced the effect of cAMP, but not of cGMP.
These results indicate that theophylline induces relaxation of the porcine tracheal smooth muscle through an activation of BK channels, and a resultant decrease in [Ca2+]i and an attenuation of Ca2+ sensitivity, presumably through the action of cAMP.

British Journal of Pharmacology (2003) 140, 939–947. doi:10.1038/sj.bjp.0705508
Inhibition by ethanol of NMDA‐induced responses and acute tolerance to the inhibition in rat sympathetic preganglionic neurons in vitro and in vivo
Authors: Lin Hsun Hsun , Hsieh Wei‐Kung , Shiu Jing‐Yi , Chiu Ted H , Lai Chih‐Chia 
Published: October 2003

N‐methyl‐D‐aspartate (NMDA) receptors have been demonstrated to be a pivotal target for ethanol action. The present study examined the actions of acute ethanol exposure on NMDA‐induced responses and the acute tolerance to ethanol actions in rat sympathetic preganglionic neurons (SPNs) in vitro and in vivo.
NMDA (50 μM) applied every 5 min induced reproducible membrane depolarizations of SPNs in neonatal spinal cord slice preparations. Ethanol (50 – 100 mM) applied by superfusion for 15 min caused a sustained decrease in NMDA‐induced depolarizations in a dose‐dependent and reversible manner. When the superfusion time of ethanol (100 mM) was increased to 50 min, NMDA‐induced depolarizations were attenuated initially but a gradual recovery was seen in ∼40% of SPNs tested.
Repeated injections of NMDA (2 nmol) intrathecally at 30 min interval caused reproducible increases in mean arterial pressure (MAP) in urethane‐anesthetized rats. Intravenous injections of ethanol (0.16 or 0.32 g, 1 ml) inhibited NMDA‐induced pressor effects in a blood concentration‐dependent manner. The inhibition by ethanol of NMDA‐induced pressor effects was reduced over time during continuous infusion of ethanol or on the second injection 3.5 h after prior injection of a higher dose of ethanol.
Ethanol, at concentrations significantly inhibited NMDA‐induced responses, had no significant effects on α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid‐induced responses. The study demonstrated the selective inhibition by ethanol of NMDA‐induced responses and the development of acute tolerance to the inhibitory effects in SPNs both in vitro and in vivo. These effects may play important roles in the ethanol regulation of cardiovascular function.

British Journal of Pharmacology (2003) 140, 955–963. doi:10.1038/sj.bjp.0705512
Inhibition of interleukin‐12 expression by α‐thrombin in human peripheral blood mononuclear cells: a potential mechanism for modulating Th1/Th2 responses
Authors: Naldini A , Aarden L , Pucci A , Bernini C , Carraro F 
Published: October 2003

In addition to its central role in blood coagulation and hemostasis, human α‐thrombin is a powerful regulator of inflammatory responses and is known to affect cell‐mediated immunity. Interleukin (IL)‐12 is a strong promoter of the development of Th1‐type lymphocytes and its downregulation implies a positive feedback mechanism for development of Th2 responses. We have previously shown that thrombin enhances the release of IL‐6, a Th2‐related cytokine, in human peripheral blood mononuclear cells (PBMC).
Here we show that thrombin downregulates IL‐12 production at both protein and mRNA levels in human PBMC. The inhibition of IL‐12 production was accompanied by an enhanced release of IL‐10, which inhibits Th1‐related processes and promotes Th2‐type responses.
The use of proteolytically inactive thrombin and of the specific thrombin receptor agonist peptide, SFLLRN, reveals that this downregulation is thrombin‐specific and requires thrombin proteolytic activity.
In addition, activation of coagulation inhibits IL‐12 production in whole blood cultures, confirming the tight relationship between the coagulation pathway, where thrombin is a key enzyme, and inflammation.
Decreased IL‐12 production appears to be related also to IL‐10 production, since the addition of an anti‐IL‐10 monoclonal antibody to thrombin‐treated PBMC resulted in a partial restoration of IL‐12 production.
In conclusion, the observation that thrombin significantly affects the production of IL‐12, as well as of IL‐10, implies a concerted role orchestrated by thrombin in PBMC that could be crucial to effective immunity and inflammation.

British Journal of Pharmacology (2003) 140, 980–986. doi:10.1038/sj.bjp.0705514