bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vascular effects of ovariectomy and chronic oestrogen treatment in rats: controversy or experimental protocol diversity?
Authors: Chataigneau Thierry , Schini‐Kerth Valérie B 
Published: January 2005

Several clinical studies have indicated that oestrogens have protective properties on the cardiovascular system. Although the beneficial effect has been attributable, at least in part, to their ability to stimulate the endothelial fomation of nitric oxide (NO) and endothelium‐derived hyperpolarizing factor (EDHF), the underlying mechanism still remains unclear. In a study from this issue of British Journal of Pharmacology, Nawate et al. have examined the effects of rat ovariectomy and chronic treatment with 17β‐oestradiol on the endothelial function as assessed ex vivo. The data indicate that acetylcholine‐induced endothelium‐dependent relaxations of the isolated mesenteric artery are affected by neither ovariectomy nor chronic hormonal treatment. Despite the maintained endothelium‐dependent relaxation, the contribution of the two major endothelial factors NO and EDHF was changed. Indeed, ovariectomy increased the NO‐mediated component of the relaxation, most likely as a consequence of the downregulation of the physiological allosteric inhibitor of endothelial NO synthase, caveolin‐1. In addition, ovariectomy decreased the EDHF‐mediated component of the relaxation and membrane hyperpolarization of the smooth muscle cells, an effect which might be explained by a concomitant decrease of the expression of the gap junction connexin‐40 and connexin‐43. Furthermore, chronic administration of 17β‐estradiol to ovariectomized rats normalized all these effects. This study provides further experimental evidence indicating that the hormonal status plays a determinant role in the control of the endothelial formation of both NO and EDHF.British Journal of Pharmacology (2005) 144, 161–163. doi:10.1038/sj.bjp.0706092
Somatostatin‐receptor 2 (sst2)‐mediated effects of endogenous somatostatin on exocrine and endocrine secretion of the rat stomach
Authors: Fykse Vidar , Coy David H , Waldum Helge Lyder , Sandvik Arne Kristian 
Published: January 2005

Somatostatin is a potent inhibitor of gastric acid secretion. Its effects are mediated through five specific receptor subtypes (sst1–5), of which sst2 is dominant on the enterochromaffin‐like (ECL) cell and the parietal cell. To study the paracrine mechanisms of somatostatin, the sst2‐specific antagonist PRL‐2903 was used.
Effects of PRL‐2903 on acid secretion and release of histamine were studied in the totally isolated, vascularly perfused rat stomach. Further, the release of histamine and gastrin after bombesin, alone and in combination with PRL‐2903, were studied. Results are presented as mean±standard error of the mean (s.e.m.).
PRL‐2903 concentration‐dependently increased the venous histamine concentration from basal 55.6±7.5 to 367±114 nM at 50 μM PRL‐2903. With 10 μM PRL‐2903, venous histamine output increased from baseline 6.2±0.5 to 20.9±4.9 nmol h−1; P=0.008. The combination of 520 pM gastrin and 10 μM PRL‐2903 increased venous histamine output from 41.7±7.3 nmol h−1 with gastrin alone to 95.2±9.8 nmol h−1; P=0.016. Further, 10 μM PRL‐2903 increased acid output from baseline 8.5±1.8 to 37.4±11 μmol h−1; P=0.017. When combined with 10 μM ranitidine, PRL‐2903 did not significantly stimulate acid secretion. Bombesin/PRL‐2903 increased venous histamine concentration from 50.4±14.8 to 292±64.2 nM; P=0.008, and gastrin concentration from 38.6±13.1 to 95.8±20.3 pM; P=0.037.
Endogenous somatostatin exerts a continuous restraint on histamine and gastrin release from the gastric mucosa and significantly reduces baseline acid secretion.

British Journal of Pharmacology (2005) 144, 416–421. doi:10.1038/sj.bjp.0706094
Blockade of HERG cardiac K+ current by antifungal drug miconazole
Authors: Kikuchi Kan , Nagatomo Toshihisa , Abe Haruhiko , Kawakami Kazunobu , Duff Henry J , Makielski Jonathan C , January Craig T , Nakashima Yasuhide 
Published: January 2005

Miconazole, an imidazole antifungal agent, is associated with acquired long QT syndrome and ventricular arrhythmias. Miconazole increases the plasma concentration of QT‐prolonging drugs by inhibiting the hepatic cytochrome P450 metabolic pathway, but whether it has direct effects on cardiac ion channels has not been elucidated.
To determine the mechanism underlying these clinical findings, we investigated the effect of miconazole on human ether‐a‐go‐go‐related gene (HERG) K+ channels.
HERG channels were heterologously expressed in human embryonic kidney 293 (HEK293) cells and whole‐cell currents were recorded using a patch‐clamp technique (23°C).
Miconazole inhibited HERG peak tail current in a concentration‐dependent manner (0.4–40 μM) with an IC50 of 2.1 μM (n=3–5 cells at each concentration, Hill coefficient 1.2). HERG block was not frequency‐dependent. It required channel activation, occurred rapidly, and had very slow dissociation properties.
The activation curve was shifted in a negative direction (V1/2: −9.5±2.3 mV in controls and −15.3±2.4 mV after 4 μM miconazole, P<0.05, n=6). Miconazole did not change other channel kinetics (activation, deactivation, onset of inactivation, recovery from inactivation, steady‐state inactivation).
The S6 domain mutation, F656C, abolished the inhibitory action of miconazole on HERG current indicating that miconazole preferentially binds to an aromatic amino‐acid residue within the pore‐S6 region.
Our findings indicate that miconazole causes HERG channel block by binding to a common drug receptor, and this involves preferential binding to activated channels. Thus, miconazole prolongs the QT interval by direct inhibition of HERG channels.

British Journal of Pharmacology (2005) 144, 840–848. doi:10.1038/sj.bjp.0706095
Positive interaction of the β2‐agonist CHF 4226.01 with budesonide in the control of bronchoconstriction induced by acetaldehyde in the guinea‐pigs
Authors: Rossoni Giuseppe , Manfredi Barbara , Razzetti Roberta , Civelli Maurizio , Bongrani Stefano , Berti Ferruccio 
Published: January 2005

Pretreatment of anaesthetized guinea‐pigs with either CHF 4226.01 (8‐hydroxy‐5‐[(1R)‐1‐hydroxy‐2‐[N‐[(1R)‐2‐(p‐methoxyphenyl)‐1‐methylethyl]amino]ethyl] carbostyril hydrochloride), formoterol or budesonide reduced acetaldehyde (AcCHO)‐evoked responses in the lungs with a rank order of potency CHF 4226.01 (ED50 values, from 1.88 to 3.31 pmol) > formoterol (ED50 values, from 3.03 to 5.51 pmol) ≫ budesonide (ED50 values, from 335 to 458 nmol). The duration of action of CHF 4226.01 in antagonizing the airway obstruction elicited by AcCHO was also substantially longer than formoterol (area under the curve) at 10 pmol, 763±58 and 480±34, respectively; P<0.01).
Continuous infusion of a subthreshold dose of AcCHO enhanced the intratracheal pressure (ITP) increases caused by subsequent challenges with substance P (from 9.7±0.8 to 27.5±1.6 cm H2O as a peak, P<0.001). Pretreatment with either CHF 4226.01 or formoterol prevented the sensitizing effect of AcCHO on substance P responses (ED50 values, 2.85 and 6.11 pmol, respectively; P<0.01).
The ED50 value of budesonide (396 nmol) in preventing AcCHO‐evoked ITP increase was reduced when this glucocorticoid was combined with 0.1 pmol CHF 4226.01 (ED50 76 nmol; P<0.001). CHF 4226.01/budesonide was two‐fold more effective (P<0.01) than the formoterol/budesonide combination.
These results suggest that CHF 4226.01/budesonide, by optimizing each other's beneficial potential in the control of pulmonary changes caused by AcCHO in the guinea‐pigs, may represent a new fixed combination in asthma.

British Journal of Pharmacology (2005) 144, 422–429. doi:10.1038/sj.bjp.0706096
Differential action of a protein tyrosine kinase inhibitor, genistein, on the positive inotropic effect of endothelin‐1 and norepinephrine in canine ventricular myocardium
Authors: Chu Li , Zhang Jian‐Xin , Norota Ikuo , Endoh Masao 
Published: January 2005

Experiments were carried out in isolated canine ventricular trabeculae and acetoxymethylester of indo‐1‐loaded single myocytes to elucidate the role of protein tyrosine kinase (PTK) in the inotropic effect of endothelin‐1 (ET‐1) induced by crosstalk with norepinephrine (NE). The PTK inhibitor genistein was used as a pharmacological tool.
Genistein but not daidzein inhibited the positive inotropic effect and the increase in Ca2+ transients induced by ET‐1 by crosstalk with NE at low concentrations.
Genistein and daidzein antagonized the negative inotropic effect and the decrease in Ca2+ transients induced by ET‐1 by crosstalk with NE at high concentrations, but genistein did not affect the antiadrenergic effect of carbachol.
Genistein but not daidzein enhanced the positive inotropic effect and the increase in Ca2+ transients induced by NE via β‐adrenoceptors, while the enhancing effect of genistein was abolished by the protein tyrosine phosphatase inhibitor vanadate.
These findings indicate that genistein (1) induces a positive inotropic effect in association with an increase in Ca2+ transients, (2) inhibits the positive inotropic effect of ET‐1 induced by crosstalk with NE, and (3) enhances the positive inotropic effect of NE induced via β‐adrenoceptors by inhibition of PTK. In addition, genistein inhibits the negative inotropic effect of ET‐1 induced by crosstalk with NE through a PTK‐unrelated mechanism. PTK may play a crucial role in the receptor‐mediated regulation of cardiac contractile function in canine ventricular myocardium.

British Journal of Pharmacology (2005) 144, 430–442. doi:10.1038/sj.bjp.0706097
Aldosterone does not mediate angiotensin II‐induced atherosclerosis and abdominal aortic aneurysms
Authors: Cassis Lisa A , Helton Marc J , Howatt Deborah A , King Victoria L , Daugherty Alan 
Published: January 2005

We have demonstrated previously that infusion of angiotensin II (AngII) into hyperlipidemic mice augments atherosclerosis and results in the formation of abdominal aortic aneurysms (AAA). The purpose of this study was to determine the role of aldosterone in these AngII‐induced vascular pathologies.
Male apolipoprotein E−/− (apoE) mice were infused with either vehicle or aldosterone (50 or 200 ng kg−1 min−1). Arterial blood pressure was determined throughout the study and serum lipid concentrations and vascular pathology were quantified after 28 days of infusion.
Infusion of aldosterone did not influence body weight or serum cholesterol concentrations. Kidney weight was increased dose‐dependently by aldosterone infusion. Systolic blood pressure was not significantly altered by aldosterone. Plasma aldosterone concentrations were increased dose‐dependently by infusion of aldosterone. However, there was no effect of aldosterone on the extent of atherosclerosis and AAAs were not formed.
Implantation of pellets containing spironolactone (16 mg kg−1 day−1) in AngII‐infused apoE−/− mice (1000 ng kg−1 min−1) had no effect on AngII‐induced elevations in blood pressure. Plasma aldosterone concentration was not influenced by coadministration of spironolactone with AngII. Spironolactone administration did not influence the extent of atherosclerosis. Moreover, spironolactone had no significant effect on AngII‐induced AAA (incidence of AAA formation: 80 versus 70% for vehicle versus spironolactone, respectively; not significant).
These studies demonstrate that the AngII‐induced vascular pathologies of atherosclerosis and AAA formation are not mediated through aldosterone.

British Journal of Pharmacology (2005) 144, 443–448. doi:10.1038/sj.bjp.0706098
Mediators of coronary reactive hyperaemia in isolated mouse heart
Authors: Zatta Amanda J , Headrick John P 
Published: January 2005

Mechanisms regulating coronary tone under basal conditions and during reactive hyperaemia following transient ischaemia were assessed in isolated mouse hearts.
Blockade of NO‐synthase (50 μM L‐NAME), KATP channels (5 μM glibenclamide), A2A adenosine receptors (A2AARs; 100 nM SCH58261), prostanoid synthesis (100 μM indomethacin), and EDHF (100 nM apamin+100 nM charybdotoxin) all reduced basal flow ∼40%. Effects of L‐NAME, glibenclamide, and apamin+charybdotoxin were additive, whereas coadministration of SCH58261 and indomethacin with these inhibitors failed to further limit flow.
Substantial hyperaemia was observed after 5–40 s occlusions, with flow increasing to a peak of 48±1 ml min−1 g−1. Glibenclamide most effectively inhibited peak flows (up to 50%) while L‐NAME was ineffective.
With longer occlusions (20–40 s), glibenclamide alone was increasingly ineffective, reducing peak flows by ∼15% after 20 s occlusion, and not altering peak flow after 40 s occlusion. However, cotreatment with L‐NAME+glibenclamide inhibited peak hyperaemia by 70 and 25% following 20 and 40 s occlusions, respectively.
In contrast to peak flow changes, sustained dilation and flow repayment over 60 s was almost entirely KATP channel and NO dependent (each contributing equally) with all occlusion durations.
Antagonism of A2AARs with SCH58261 reduced hyperaemia 20–30% whereas inhibition of prostanoid synthesis was ineffective. Effects of A2AAR antagonism were absent in hearts treated with L‐NAME and glibenclamide, supporting NO and KATP‐channel‐dependent effects of A2AARs.
EDHF inhibition alone exerted minor effects on hyperaemia and only with longer occlusions. However, residual hyperaemia after 40 s occlusion in hearts treated with L‐NAME+glibenclamide+SCH58261+indomethacin was abrogated by cotreatment with apamin+charybdotoxin.
Data support a primary role for KATP channels and NO in mediating sustained dilation after coronary occlusion. While KATP channels (and not NO) are also important in mediating initial peak flow adjustments after brief 5–10 s occlusions, their contribution declines with longer 20–40 s occlusions. Intrinsic activation of A2AARs is important in triggering KATP channel/NO‐dependent hyperaemia. Synergistic effects of combined inhibitors implicate interplay between mediators, with compensatory changes occurring in KATP channel, NO, and/or EDHF responses when one is individually blocked.

British Journal of Pharmacology (2005) 144, 576–587. doi:10.1038/sj.bjp.0706099
Nitric oxide relaxes circular smooth muscle of rat distal colon through RhoA/Rho‐kinase independent Ca2+ desensitisation
Authors: Colpaert Erwin E , Levent Adnan , Lefebvre Romain A 
Published: January 2005

The aim of this study in circular smooth muscle of rat distal colon was to determine whether Ca2+ desensitisation, in addition to mechanisms lowering cytosolic free Ca2+ concentration ([Ca2+]cyt), was involved in the relaxation elicited by nitric oxide (NO). Changes in isometric tension and [Ca2+]cyt were recorded simultaneously in fura‐2‐loaded strips.
In methacholine (10−5 M)‐precontracted preparations, exogenous NO (10−4 M), adenosine 5′‐triphosphate (ATP; 10−3 M) and electrical field stimulation (EFS; 1 ms, 40 V, 4 Hz, 1 min) induced a decrease in smooth muscle tension, which was accompanied by a fall in [Ca2+]cyt.
The sarcoplasmic/endoplasmic reticulum Ca2+ ATP‐ase (SERCA) inhibitor thapsigargin (10−6 M) did not exert an influence on the decrease in tension produced by exogenous NO, but significantly attenuated the fall in [Ca2+]cyt. Both the relaxation and the fall in [Ca2+]cyt to ATP and EFS were unaffected by thapsigargin.
Calyculin‐A (10−6 M), a myosin light chain phosphatase (MLCP) inhibitor, significantly reduced the decrease in tension elicited by exogenous NO, but did not alter the fall in [Ca2+]cyt to exogenous NO. Inactivating RhoA by exoenzyme C3 (2 μg ml−1) or inhibiting Rho‐kinase with (+)‐(R)‐trans‐4‐(1‐aminoethyl)‐N‐(4‐pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate (Y‐27632; 10−5 M) had no effect on the decrease of both tension and [Ca2+]cyt generated by exogenous NO.
This paper demonstrates that a RhoA/Rho‐kinase independent Ca2+ desensitisation pathway contributes to the relaxation by NO in circular smooth muscle strips of rat distal colon.

British Journal of Pharmacology (2005) 144, 588–594. doi:10.1038/sj.bjp.0706111
The role of membranes and membrane trafficking in RNA localization
Authors: Cohen Robert S. 
Published: January 2005

AbstractEukaryotic cells possess highly sophisticated membrane trafficking pathways that define specific membrane domains and provide a means for moving vesicles between them (Mostov, Su, and ter Beest, 2003, Nat. Cell Biol. 5, 287–293). Here, I review recent data that indicate a role for membrane trafficking in mRNA localization. Specifically, I review evidence that some localized mRNAs are anchored to specific membrane domains and/or transported on membranous organelles or vesicles to specific subcellular sites. This review is not intended as a discussion on indirect influences of membrane trafficking on mRNA localization. I will not, for example, discuss the role of membrane trafficking in the regulation of extracellular signalling events that could indirectly influence mRNA localization through polarization of the actin or microtubule cytoskeleton (for examples, see reviews by Drubin and Nelson, 1996, Cell 84, 335–344; Shulman and St Johnston, 1999, Trends Cell Biol. 9, M60–M64).
How and why does β‐actin mRNA target?
Authors: Condeelis John , Singer Robert H. 
Published: January 2005

Abstractβ‐Actin mRNA is localized near the leading edge in several cell types where actin polymerization is actively promoting forward protrusion. The localization of the β‐actin mRNA near the leading edge is facilitated by a short sequence in the 3′UTR (untranslated region), the ‘zipcode’. Localization of the mRNA at this region is important physiologically. Treatment of chicken embryo fibroblasts with antisense oligonucleotides complementary to the localization sequence (zipcode) in the 3′UTR leads to delocalization of β‐actin mRNA, alteration of cell phenotype and a decrease in cell motility. The dynamic image analysis system (DIAS) used to quantify movement of cells in the presence of sense and antisense oligonucleotides to the zipcode showed that net pathlength and average speed of antisense‐treated cells were significantly lower than in sense‐treated cells. This suggests that a decrease in persistence of direction of movement and not in velocity results from treatment of cells with zipcode‐directed antisense oligonucleotides. We postulate that delocalization of β‐actin mRNA results in delocalization of nucleation sites and β‐actin protein from the leading edge followed by loss of cell polarity and directional movement. Hence the physiological consequences of β‐actin mRNA delocalization affect the stability of the cell phenotype.
Drosophila neural progenitor polarity and asymmetric division
Authors: Wang Hongyan , Chia William 
Published: January 2005

AbstractIn the Drosophila embryonic central nervous system, the neural precursor cells called neuroblasts undergo a number of asymmetric divisions along the apical—basal axis to give rise to different daughter cells of distinct fates. This review summarizes recent progress in understanding the mechanisms of these asymmetric cell divisions. We discuss proteins that are localized at distinct domains of cortex in the neuroblasts and their role in generating asymmetry. We also review uniformly cortical localized factors and actin cytoskeleton‐associated motor proteins with regard to their potential role to serve as a link between distinct cortical domains in the neuroblasts. In this review, asymmetric divisions of sensory organ precursor and larval neuroblasts are also briefly discussed.
RNA localization in yeast: moving towards a mechanism
Authors: Gonsalvez Graydon B. , Urbinati Carl R. , Long Roy M. 
Published: January 2005

AbstractRNA localization is a widely utilized strategy employed by cells to spatially restrict protein function. In Saccharomyces cerevisiae asymmetric sorting of mRNA to the bud has been reported for at least 24 mRNAs. The mechanism by which the mRNAs are trafficked to the bud, illustrated by ASH1 mRNA, involves recognition of cis‐acting localization elements present in the mRNA by the RNA‐binding protein, She2p. The She2p/mRNA complex subsequently associates with the myosin motor protein, Myo4p, through an adapter, She3p. This ribonucleoprotein complex is transported to the distal tip of the bud along polarized actin cables. While the mechanism by which ASH1 mRNA is anchored at the bud tip is unknown, current data point to a role for translation in this process, and the rate of translation of Ash1p during the transport phase is regulated by the cis‐acting localization elements. Subcellular sorting of mRNA in yeast is not limited to the bud; certain mRNAs corresponding to nuclear‐encoded mitochondrial proteins are specifically sorted to the proximity of mitochondria. Analogous to ASH1 mRNA localization, mitochondrial sorting requires cis‐acting elements present in the mRNA, though trans‐acting factors involved with this process remain to be identified. This review aims to discuss mechanistic details of mRNA localization in S. cerevisiae.
Putting RNAs in the right place at the right time: RNA localization in the frog oocyte
Authors: King Mary Lou , Messitt Timothy J. , Mowry Kimberly L. 
Published: January 2005

AbstractLocalization of maternal mRNAs in many developing organisms provides the basis for both initial polarity during oogenesis and patterning during embryogenesis. Prominent examples of this phenomenon are found in Xenopus laevis, where localized maternal mRNAs generate developmental polarity along the animal/vegetal axis. Targeting of mRNA molecules to specific subcellular regions is a fundamental mechanism for spatial regulation of gene expression, and considerable progress has been made in defining the underlying molecular pathways.
Maternal determinants and mRNAs in the cortex of ascidian oocytes, zygotes and embryos
Authors: Sardet Christian , Dru Philippe , Prodon François 
Published: January 2005

AbstractThe peripheral region of ascidian oocytes and zygotes contains five determinants for morphogenesis and differentiation of the embryo. The determinant for the 24 primary muscle cells of the tadpole, macho1, is one of several cortical mRNAs localized in a gradient along the animal—vegetal axis in the oocyte. After fertilization these mRNAs, together with cortical endoplasmic reticulum (cER) and a subcortical mitochondria‐rich domain (myoplasm), relocate in two major reorganization phases forming the posterior plasm (postplasm) of the zygote. At the 8‐cell stage cortical mRNAs concentrate in a macroscopic cortical structure called the centrosome‐attracting body (CAB), forming a characteristic posterior end mark (PEM) in the two posterior vegetal blastomeres. We propose to call the numerous mRNAs showing this particular cortical localization in the posterior region of the embryo postplasmic/PEM RNAs and suggest a nomemclature. We do not know how postplasmic/PEM RNAs reach their polarized distribution in the oocyte cortex but at least PEM1 and macho1 (and probably others) bind to the network of cER retained in isolated cortical fragments. We propose that after fertilization, these postplasmic/PEM mRNAs move in the zygote cortex together with the cER network (cER/mRNA domain) via microfilament‐ and microtubule‐driven translocations. The cER/mRNA domain is localized posteriorly at the time of first cleavage and distributed equally between the first two blastomeres. After the third cleavage, the cER/mRNA domain and dense particles compact to form the CAB in posterior vegetal blastomeres of the 8‐cell stage. We discuss the identity of postplasmic/PEM RNAs, how they localize, anchor, relocate and may be translated. We also examine their roles in unequal cleavage and as a source of posterior morphogenetic and differentiation factors.