British Journal of Pharmacology Impact Factor & Information

Publisher: British Pharmacological Society, Wiley

Journal description

All aspects of experimental pharmacology including: Cellular and molecular pharmacology Biochemical pharmacology Neuroscience All aspects of general pharmacology Special Reports for rapid publication of important new results of special pharmacological significance The British Journal of Pharmacology is the leading 'original papers' publication in the field of general pharmacology.

Current impact factor: 4.99

Impact Factor Rankings

2015 Impact Factor Available summer 2015
2013 / 2014 Impact Factor 4.99
2012 Impact Factor 5.067
2011 Impact Factor 4.409
2010 Impact Factor 4.925
2009 Impact Factor 5.204
2008 Impact Factor 4.902
2007 Impact Factor 3.767
2006 Impact Factor 3.825
2005 Impact Factor 3.41
2004 Impact Factor 3.325
2003 Impact Factor 3.611
2002 Impact Factor 3.45
2001 Impact Factor 3.502
2000 Impact Factor 3.689
1999 Impact Factor 3.722
1998 Impact Factor 3.704
1997 Impact Factor 3.619
1996 Impact Factor 4.075
1995 Impact Factor 4.739
1994 Impact Factor 4.695
1993 Impact Factor 5.27
1992 Impact Factor 5.094

Impact factor over time

Impact factor

Additional details

5-year impact 4.90
Cited half-life 7.70
Immediacy index 1.29
Eigenfactor 0.05
Article influence 1.37
Website British Journal of Pharmacology website
Other titles British journal of pharmacology (Online), BJP
ISSN 1476-5381
OCLC 39502220
Material type Document, Periodical, Internet resource
Document type Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details


  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • 12 months embargo
  • Conditions
    • Some journals have separate policies, please check with each journal directly
    • On author's personal website, institutional repositories, arXiv, AgEcon, PhilPapers, PubMed Central, RePEc or Social Science Research Network
    • Author's pre-print may not be updated with Publisher's Version/PDF
    • Author's pre-print must acknowledge acceptance for publication
    • On a non-profit server
    • Publisher's version/PDF cannot be used
    • Publisher source must be acknowledged with citation
    • Must link to publisher version with set statement (see policy)
    • If OnlineOpen is available, BBSRC, EPSRC, MRC, NERC and STFC authors, may self-archive after 12 months
    • If OnlineOpen is available, AHRC and ESRC authors, may self-archive after 24 months
    • Publisher last contacted on 07/08/2014
    • This policy is an exception to the default policies of 'Wiley'
  • Classification
    ​ yellow

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: The intermediate-conductance calcium/calmodulin-regulated K(+) -channel, KCa3.1 produces hyperpolarizing K(+) currents that counteract depolarizing currents carried by transient receptor potential (TRP) channels, and provide the electrochemical driving force for Cl(-) and fluid movements. We investigated whether KCa3.1 deficiency (KCa3.1(-/-) ) protects against fatal pulmonary circulatory collapse in mice after pharmacological activation of the calcium-permeable TRP subfamily vanilloid type 4 (TRPV4) channels. An opener of TRPV4 channels, GSK1016790A was infused in wild-type (wt) and KCa3.1(-/-) mice, hemodynamic parameters, histology, and pulmonary vascular reactivity were measured, and patch clamp was performed on pulmonary arterial endothelial cells (PAEC). In wt mice, GSK1016790A induced a drop in right ventricular and systemic pressure leading to fatal circulatory collapse that was accompanied by increased protein permeability, lung hemorrhage, and fluid extravasation. In contrast, KCa3.1(-/-) mice exhibited a significant smaller drop in pressure to GSK1016790A infusion, no hemorrhage, and fluid water extravasation, and the mice survived. Moreover, compared to wt, KCa3.1(-/-) mice showed significantly less relaxation of pulmonary arteries to GSK1016790A. GSK1016790A induced TRPV4-currents in PAEC from wt and KCa3.1(-/-) mice, that co-activated KCa3.1 and produced breakdown of membrane resistance in wt PAEC, but not in KCa3.1(-/-) PAEC. Our findings show that genetic deficiency of KCa3.1 channels prevented fatal pulmonary circulatory collapse and reduced lung damage caused by pharmacological activation of calcium-permeable TRPV4-channels. Therefore, inhibition of KCa3.1 channels may have therapeutic utility in conditions characterized by abnormal high endothelial calcium signaling, barrier disruption, lung edema, and pulmonary circulatory collapse. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; DOI:10.1111/bph.13234
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    ABSTRACT: Inflammasomes are multimeric complexes that facilitate caspase-1-mediated processing of the pro-inflammatory cytokines interleukin(IL)-1β and IL-18. Clinical hypertension is associated with renal inflammation, and elevated circulating levels of IL-1β and IL-18. Therefore, we investigated whether hypertension in mice is associated with increased expression and/or activation of the inflammasome in the kidney, and if inhibition of inflammasome activity reduces blood pressure (BP), markers of renal inflammation and fibrosis. Wild-type and inflammasome-deficient ASC(-/-) mice were uninephrectomised and received deoxycorticosterone acetate and saline to drink (1K/DOCA/salt). Control mice were uninephrectomised and received placebo and water. BP was measured by tail cuff; renal expression of inflammasome subunits and inflammatory markers was measured by real-time PCR and immunoblotting; macrophage and collagen accumulation was assessed by immunohistochemistry. 1K/DOCA/salt-induced hypertension in mice was associated with increased renal mRNA expression (fold-change vs control; P<0.05) of inflammasome subunits NLRP3 (2.3±0.2), ASC (2.8±0.6) and pro-caspase-1 (2.6±0.5), and the cytokine, pro-IL-1β (4.0±0.8), as well as protein levels of active caspase-1 (1.6±0.2) and mature IL-1β (2.1±0.3). Following treatment with 1K/DOCA/salt, ASC(-/-) mice displayed blunted pressor responses (140±3 vs 155±8 mmHg in wild-types; P<0.05), and were also protected from increases in renal expression of IL-6, IL-17A, CCL2, ICAM-1 and VCAM-1, and accumulation of macrophages and collagen. Finally, treatment with a novel inflammasome inhibitor, MCC950, reversed hypertension in 1K/DOCA/salt-treated mice. Renal inflammation, fibrosis and elevated BP induced by 1K/DOCA/salt-treatment are dependent on inflammasome activity, highlighting the inflammasome/IL-1β pathway as a potential therapeutic target in hypertension. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; DOI:10.1111/bph.13230
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    ABSTRACT: The N-K-Cl cotransporters (NKCCs) mediate the coupled, electroneutral movement of Na(+) , K(+) and Cl(-) ions across cell membranes. There are two isoforms of this cation cotransporter, NKCC1 and NKCC2. NKCC2 is expressed primarily in the kidney and is the target of diuretics such as bumetanide. Bumetanide was discovered as a result of screening of ∼5000 3-amino-5-sulfamoylbenzoic acid derivatives long before NKCC2 was identified in the kidney. Therefore structure-activity studies on effects of bumetanide derivatives on NKCC2 are not available. In this study, the effect of a series of diuretically active bumetanide derivatives was investigated on human NKCC2 variant A (hNKCC2A) expressed in Xenopus laevis oocytes. hNKCC2A displayed an IC50 towards bumetanide of 4 μM. A good correlation between the diuretic potency of bumetanide and its derivatives in dogs and their inhibition of hNKCC2A was found (r(2) = 0.817; P<0.01). Replacement of the carboxylic group of bumetanide by a nonionic residue, e.g., an anilinomethyl group, resulted in a loss of inhibition of hNKCC2A, indicating that an acidic group is required for transporter inhibition. Exchange of the phenoxy group of bumetanide by a 4-chloroanilino group or the sulfamoyl group by a methylsulfonyl group resulted in compounds with higher potency to inhibit hNKCC2A than bumetanide. The Xenopus laevis oocyte expression system as used in these experiments allows studying the structural requirements that determine relative potency of loop diuretics on human NKCC2 splice variants, and may lead to the discovery of novel high-ceiling diuretics. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; DOI:10.1111/bph.13231
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    ABSTRACT: Dynamic polymerization of microtubules are essential for cancer cell growth and metastasis. As such, microtubule disrupting agents have became the most successful anti-cancer agent in clinical use. Numerous studies have indicated that, besides anti-oxidant properties, flavonoids also demonstrate strong microtubule-disrupting activity against tumor growth and are the focus of intense studies aimed at developing novel compounds with multiple pharmacological applications. Accordingly, a series of oxime/amide-containing flavone derivatives were designed, synthesized and evaluated for their anti-proliferative efficacy by our team. Among all the compounds tested, one oxime-containing flavone, WTC-01, showed highly specific anti-proliferative activity against human nasopharyngeal carcinoma (NPC) cell lines with an IC50 of around 0.45 μM, however, the detailed mechanisms still need to be elucidated. In the present study, our results showed that WTC-01 could induce NPC cell G2 /M accumulation and early apoptosis in a temporal and concentration dependent manner. The colchicine-competition binding experiments and computer modeling results suggested that WTC-01 causes microtubule disruption via binding to the colchicine-binding site of tubulin resulting in mitochondrial membrane damage and cell apoptosis via activation of caspase-9/-3 without noticeable activation of the caspase-8. Notably, our in vivo studies demonstrated that at doses of 25 and 50 mg·kg(-1) , WTC-01 exhibited good pharmacokinetic properties and completely inhibited the growth of NPC-TW01 in a xenograft nude mouse model. Our findings indicated that WTC-01, a novel synthetic oxime-containing flavone, exhibits potent anti-tumor activity against NPC growth and is worthy of further investigation. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; DOI:10.1111/bph.13227
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    ABSTRACT: Increasing evidence suggests that an overactive endocannabinoid system (ECS) may contribute to the development of diabetes by promoting energy intake and storage, impairing both glucose and lipid metabolism, and by exerting pro-apoptotic effects in pancreatic β cells, and by facilitating inflammation in pancreatic islets. Furthermore, hyperglycemia associated with diabetes has also been implicated in triggering perturbations of the ECS amplifying the above mentioned pathological processes, eventually culminating in a vicious circle. Compelling evidence from preclinical studies indicates that the ECS also influences diabetes-induced oxidative stress, inflammation, fibrosis, and subsequent tissue injury in target organs for diabetic complications. In this review, we provide an update on the contribution of the ECS to the pathogenesis of diabetes and diabetic microvascular (retinopathy, nephropathy, and neuropathy) and cardiovascular complications. The therapeutic potential of targeting the ECS is also discussed. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; DOI:10.1111/bph.13226
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    ABSTRACT: Myeloid differentiation 2 (MD-2) recognizes LPS, which is required for TLR4 activation, and represents an attractive therapeutic target for severe inflammatory disorders. We previously found that a chalcone derivative, L6H21, could inhibit LPS-induced overexpression of TNF-α and IL-6 in macrophages. Here, a series of biochemical experiments demonstrate L6H21 specifically targets MD-2 and inhibits the interaction and signaling transduction of LPS-TLR4/MD-2. The binding affinity of L6H21 to MD-2 protein was analyzed using computer docking, surface plasmon resonance analysis, ELISA, fluorescence measurements, and flow cytometric analysis. The effects of L6H21 on MAPK and NF-κB signaling were determined using EMSA, fluorescence staining, western blotting, and immunoprecipitation. The anti-inflammatory effects of L6H21 were confirmed using ELISA and RT-qPCR in vitro. Finally, the anti-inflammatory effects of L6H21 in septic C57BL/6 mice were evaluated. Compound L6H21 was inserted into the hydrophobic region of MD-2 pocket, forming hydrogen bonds with Arg(90) and Tyr(102) in the MD-2 pocket. In vitro, L6H21 subsequently suppressed MAPK phosphorylation, NF-κB activation, and cytokine expression in macrophages stimulated by LPS. In vivo, L6H21 pretreatment improved survival, protected lung injury, decreased serum and hepatic cytokine level in mice subjected to LPS. In addition, the MD-2 gene knockout led to universal protection from LPS-induced septic shock in mice. Overall, this work identified a new chalcone derivative, L6H21, as a potential candidate in the treatment of sepsis; more importantly, the data confirmed that MD-2 is an important therapeutic target against inflammatory disorders. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; DOI:10.1111/bph.13221
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    ABSTRACT: The Munich Wistar Frömter(MWF) rat strain represents an experimental model to study cardiovascular alterations under conditions of progressive albuminuria. The aim of this study was to evaluate the association between genetic predisposition to albuminuria and the development of arterial stiffness and/or vascular remodeling. Experiments were performed in mesenteric arteries from 12-week-old MWF, Wistar Kyoto(WKY) and consomic MWF-6(SHR) and MWF-8(SHR) rats, in which chromosomes 6 or 8 associated with albuminuria from MWF were replaced by the respective chromosome from SHR rats. Incremental distensibility, wall stress and strain were reduced and arterial stiffness was significantly increased in albuminuric MWF(6.0±0.3) compared to WKY(4.5±0.5, p<0.05). Albuminuria suppression in both consomic strains was associated with lower β-values in MWF-8(SHR) (3.8±0.1) and MWF-6(SHR) (4.3±0.1) compared to MWF(p<0.05). Moreover, elastin content was significantly lower in MWF external elastic lamina compared to WKY and both consomic strains(p<0.05, respectively). In addition, a reduction in arterial external and internal diameter and cross sectional area was detected in MWF compared to WKY, thus exhibiting an inward hypotrophic remodeling. These alterations remained however unchanged in both consomic strains. These data demonstrate that albuminuria in MWF is associated with increased arterial stiffness due to a reduction of elastin content in the external elastic lamina. Moreover, inward hypotrophic remodeling in MWF is not directly associated with albuminuria. In contrast, we demonstrate that two major genetic loci affect both the development of albuminuria and arterial stiffness, thus linking albuminuria and impairment of mechanical properties of resistance arteries. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; DOI:10.1111/bph.13223
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    ABSTRACT: Pharmacological models used to describe drug agonism and antagonism have evolved over the past 20 years from a parsimonious model describing single active and inactive receptor states, to models of multi-conformational receptor systems modified by ligand conformational selection. These latter models describe the observed, presently under-exploited, pharmacological mechanism of ligand-directed biased signaling. Biased signals can be quantified with transduction coefficients (ΔΔLog(τ/KA ) values) a scale grounded in the Black/Leff operational model; this enables the optimization of biased profiles through medicinal chemistry. The past decades also have brought the availability of new technologies to measure multiple functional effects mediated by seven transmembrane receptors. These have confirmed that drugs can have many efficacies which may be collaterally linked, i.e. there is no linear sequence of activities required. In addition, new functional screening assays have introduced increasing numbers of allosteric ligands into drug discovery. These molecules are permissive (they do not necessarily preclude endogenous signaling in vivo) therefore they may allow better fine tuning of pathological physiology. The permissive quality of allosteric ligands also can change the quality of endogenous signaling efficacy ('induced bias') as well as the quantity of signal; in this regard, indices related to ΔΔLog(τ/KA ) values (namely ΔLog(αβ) values) can be used to quantify these effects for optimization in the drug discovery process. All of these added scales of drug activity hopefully will allow better targeting of candidate molecules toward therapies. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; DOI:10.1111/bph.13217
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    ABSTRACT: In pigs, ivabradine reduced infarct size even when given only at reperfusion and in the absence of heart rate reduction. The mechanism of such non-heart rate-related cardioprotection is unknown. Anesthetized mice were pretreated ±ivabradine (1.7 mg/kg i.v.) before a cycle of coronary occlusion/reperfusion (30/120 min ±left atrial pacing). Infarct size was determined. Isolated ventricular cardiomyocytes were exposed to simulated ischaemia/reperfusion (60/5 min) ±ivabradine, viability was quantified, and intra- and extracellular reactive oxygen species formation (ROS) was detected. Mitochondria were isolated from mouse hearts and exposed to simulated ischaemia/reperfusion (6/3 min) in glutamate/malate- and adenosine diphosphate-containing buffer ±ivabradine, respectively. Mitochondrial respiration, extramitochondrial ROS, mitochondrial adenosine triphosphate production (ATP) and calcium retention capacity (CRC) were assessed. Ivabradine decreased infarct size from 39±5% to 17±4% of the area at risk (P<0.05), even with atrial pacing (20±5%; P<0.05). Cardiomyocyte viability after simulated ischaemia/reperfusion was better preserved with ivabradine (10±1 vs. 25±2%; P<0.01), along with a decrease in the accumulation of intra- (8.2±0.4 vs. 6.4±0.6 a.u.; P<0.05) and extracellular (29±4 vs. 17±4 nmol H2 O2 /100 μg; P<0.001) ROS. Mitochondrial complex I respiration was not different without/with ivabradine, but ivabradine significantly inhibited the accumulation of extramitochondrial ROS (160±26 vs. 104±19 nmol H2 O2 /100 μg; P<0.001), increased mitochondrial ATP production (148±20 vs. 181±21 μmol/100 μg; P=0.01) and increased CRC (1163±86 vs. 1625±98 nmol/100 μg; P<0.05). Ivabradine reduces infarct size independently of heart rate reduction and improves ventricular cardiomyocyte viability, possibly by reduced mitochondrial ROS formation, increased ATP production and CRC. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; DOI:10.1111/bph.13220
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    ABSTRACT: Monoglyceride lipase (MGL) degrades 2-arachidonoyl glycerol (2-AG), an endogenous agonist of cannabinoid receptors (CB1/2 ). Since CB1 receptor is involved in the control of gut function, we investigated the effects of pharmacological inhibition and genetic deletion of MGL on intestinal motility. Furthermore, we were interested whether defective 2-AG degradation affects μ-opioid receptor (μ-receptor) signaling, a parallel pathway regulating gut motility. Gut motility was investigated by monitoring Evan's blue transit and colonic bead propulsion in response to MGL inhibition and CB1 receptor or μ-receptor stimulation. Ileal contractility was investigated by electrical field stimulation. CB1 receptor expression in ileum and colon was studied by immunohistochemical analyses. Pharmacological inhibition of MGL slows down whole gut transit in a CB1 receptor-dependent manner. Conversely, genetic deletion of MGL does not affect gut transit despite increased 2-AG levels. Notably, MGL-deficiency causes complete insensitivity to CB1 receptor agonist-mediated inhibition of whole gut transit and ileal contractility suggesting local desensitization of CB1 receptors. Accordingly, immunohistochemical analyses of myenteric ganglia of MGL-deficient mice revealed that CB1 receptors are trapped in endocytic vesicles. Finally, MGL-deficient mice display accelerated colonic propulsion and respond hypersensitive to μ-opioid receptor agonist-mediated inhibition of colonic motility. This phenotype can be reproduced by chronic pharmalogical inhibition of MGL. Constantly elevated 2-AG levels induce severe desensitization of intestinal CB1 receptors and increased sensitivity to μ-receptor-mediated inhibition of colonic motility. These changes should be considered for the use of cannabinoid-based drugs in the therapy of gastrointestinal diseases. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; DOI:10.1111/bph.13224
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    ABSTRACT: Preclinical cardiovascular safety studies (CVS) have been compared between facilities with respect to their sensitivity to detect drug-induced QTc prolongation (ΔQTc). Less is known about the consistency of quantitative ΔQTc predictions that are relevant for translation to human. We derived typical ΔQTc-predictions at therapeutic exposure (ΔQTcTHER ) with 95% confidence intervals (95%CI) for 3 hERG-channel-blockers (moxifloxacin, dofetilide and sotalol) from a total of 14 CVS of varying designs in the conscious dog. Population pharmacokinetic-pharmacodynamic (PKPD) analysis of each study was followed by a meta-analysis (pooling 2-6 studies including 10-32 dogs/compound) to derive meta-predictions of typical ΔQTcTHER . Meta-predictions were used as reference to evaluate the consistency of study predictions and to relate results with clinical literature. 95%CIs of study-predicted ΔQTcTHER comprised in 13 out of 14 cases the meta-prediction. Overall inter-study variability (mean deviation from meta-prediction at upper level of therapeutic exposure) was 30% (range: 1-69%). Meta-ΔQTcTHER predictions were 4-12 ms for moxifloxacin (2.9-5.6 μM free), 4-18 ms for dofetilide (0.4-2 nM free), and 14-19 ms for sotalol (3.7-11 μM free), and overlapping with reported clinical QTc prolongation when expressed as %-prolongation from baseline. Consistent exposure-ΔQTc predictions can be obtained from single preclinical dog studies of highly varying designs by systematic PKPD analysis, i.e. suitable for translational purpose. Considering additionally the good preclinical-clinical pharmacodynamic correlations this suggests that such analysis should be more routinely applied to increase the informative and predictive value of conducted animal experiments. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; DOI:10.1111/bph.13218
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    ABSTRACT: The history of ketamine and phencyclidine from their development as potential clinical anaesthetics, through drugs of abuse and animal models of schizophrenia to potential rapidly acting antidepressants is reviewed. The discovery in 1983 of the NMDA receptor antagonist property of ketamine and phencyclidine was a key step to understanding their pharmacology, including their psychotomimetic effects in man. This review describes the historical context and the course of that discovery and its expansion into other hallucinatory drugs. The relevance of these findings to modern hypotheses of schizophrenia and the implications for drug discovery are reviewed. The finding of the rapidly acting antidepressant effects of ketamine in man are discussed in relation to other glutamatergic mechanisms. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; DOI:10.1111/bph.13222
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    ABSTRACT: The aim of this study was to investigate the effects of short term (2 weeks) Angiotensin-(1-7) [Ang-(1-7)] treatment on cardiovascular and renal function in a mouse model of type 2 diabetes (db/db). Diabetic patients are at an increased risk of cardiovascular disease, in part due to inflammation and oxidative stress. These two pathological mechanisms also affect other organs and cells including the kidneys and progenitor cells. Ang-(1-7) has been previously shown to counter balance pathological effects of angiotensin II, including inflammation and oxidative stress. 8-9 week old db/db mice were administered either vehicle, Ang-(1-7) alone, or Ang-(1-7) combined with an inhibitor (losartan, PD123319, A-779, L-NAME or icatibant) daily for 14 days. An improvement in physiological heart function was observed in Ang-(1-7)-treated mice. Ang-(1-7) also reduced cardiomyocyte hypertrophy, fibrosis and inflammatory cell infiltration of the heart tissue and increased blood vessel number. These changes were blocked by antagonists of the MAS1 receptor, angiotensin II receptor type 2, bradykinin receptor, and inhibition of nitric oxide formation. Treatment with Ang-(1-7) reduced glomerular damage and oxidative stress in kidney tissue. Bone marrow and circulating endothelial progenitors, as well as bone marrow mesenchymal stem cells were increased in mice treated with Ang-(1-7). Short term Ang-(1-7) treatment of young db/db mice improved heart function and reduced kidney damage. Treatment also improved bone marrow and circulating levels of endothelial and mesenchymal stem cells. All of this may contribute to improved cardiovascular and renal function. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; DOI:10.1111/bph.13225
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    ABSTRACT: The bioactive monoamine 5-hydroxytryptamine (5-HT), implicated in the pathogenesis of functional gastrointestinal disorders, is abundantly synthesized and stored in rat proximal colonic mucosa and released to the gut lumen and to the subepithelial space. Despite much data regarding its expression and function, the effects of luminal 5-HT on colonic anion secretion have not been fully investigated. We measured short-circuit current (Isc ) as an indicator of ion transport in mucosa-submucosa or mucosa-only preparations of rat proximal colon. Luminal 5-HT gradually increased the amplitude and sustained the elevation of Isc . Luminal 5-HT-evoked ΔIsc was acetazolamide-sensitive and HCO3 (-) -dependent, consistent with cytosolic carbonic anhydrase-dependent electrogenic HCO3 (-) secretion, while not affected by tetrodotoxin (TTX), atropine or indomethacin. Pretreatment with the selective 5-HT4 antagonist GR113808, but not antagonists for 5-HT3 , 5-HT6 , or 5-HT7 , inhibited luminal 5-HT-evoked ΔIsc . Furthermore, luminal cisapride and tegaserod increased Isc to the same extent as did 5-HT in the presence of indomethacin and TTX. Removal of the submucosa or pretreatment with nitric oxide synthase (NOS) inhibitors enhanced luminal 5-HT-evoked ΔIsc , suggesting that NO synthesized in the submucosa suppresses mucosal anion secretion. NOS1 and NOS2 were immunostained in the submucosal neurons and glial cells, respectively. Luminal 5-HT-evoked HCO3 (-) secretion was confirmed in vivo, inhibited by co-perfusion of GR113808, but not by ondansetron. We conclude that a novel apical 5-HT4 -mediated HCO3 (-) secretory pathway and an NO-dependent inhibitory mechanism are present in the proximal colon. Luminal 5-HT-evoked HCO3 (-) secretion may be important for the maintenance of mucosal integrity by regulating luminal pH. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; DOI:10.1111/bph.13216
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    ABSTRACT: Matrine is a small molecule drug used in humans for the treatment of chronic viral infections and tumors in the liver with little adverse effects. The present study investigated its therapeutic efficacy for insulin resistance and hepatic steatosis in high fat-fed mice. C57BL/J6 mice were fed a chow or high-fat diet for 10 weeks and then treated with matrine or metformin for four weeks. The effects on lipid metabolism and glucose tolerance were evaluated. Our results first showed that matrine reduced glucose intolerance and plasma insulin level, hepatic triglyceride content and adiposity in high fat-fed mice without affecting caloric intake. The effect to reduce hepatosteatosis was attributed to suppressed lipid synthesis and increased fatty acid oxidation. In contrast to metformin, matrine neither suppressed mitochondrial respiration nor activated AMPK in the liver. A computational docking simulation revealed HSP90, a negative regulator of HSP72, as a potential binding target of matrine. Consistent with the simulation results, matrine, but not metformin, increased the hepatic protein level of HSP72 in an inverse correlation with both liver triglyceride level and glucose intolerance. These results together indicate that matrine may be used for the treatment of type 2 diabetes and hepatic steatosis, and the molecular action of this hepatoprotective drug involves an activation of HSP72 in the liver. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; DOI:10.1111/bph.13209
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    ABSTRACT: BJP is changing its procedures for the submission of articles so that authors can optimize transparency and experimental design. This relates to current moves to strengthen the robustness of the basic research that underpins drug discovery and therapeutics. To this end we are publishing new Instructions to Authors (ITA). Some are already in place and take immediate effect while others will be introduced over the next few months. Emphasis is placed on gathering essential information that authors often forget to include; this will also facilitate peer-review by hard-pressed reviewers. We have been in discussion with the Editors of other Pharmacology journals and plan that similar changes will be taking place across the sector. This will ensure that the various generic guidelines are more clearly specified for pharmacology. The major changes will be supported by three editorials: In order to link published work to the growing network of databases we are introducing hyperlinks to drug targets and key drugs in the authoritative Guide to PHARMACOLOGY database of the International Union of Basic and Clinical Pharmacology, which is now produced with the support of BPS. This is then further linked to other biological and chemical databases, placing the work first in a pharmacological then in a broader scientific context. (McGrath et al., 2015a). We have assessed the implementation of the 2010 ARRIVE guidelines for reporting experiments involving animals and respond by significantly strengthening our requirements, especially relating to disclosure of information, rather than urging compliance with respect to every conceivable issue (McGrath & Lilley, 2015). As an international journal we believe that this must be done on a worldwide basis, taking account of differing practices but adhering to one ethical standard (McGrath et al., 2015b). Inadequacy of experimental design and statistical validity of analysis of drug-related research that underpins the discovery of new medicines has attracted recent criticism. We will publish new guidance for reporting statistical analysis and experimental design (Curtis et al., 2015). This Editorial is part of a series. To view the other Editorials in this series, visit: and © 2015 The British Pharmacological Society.
    British Journal of Pharmacology 06/2015; 172(11):2671-2674. DOI:10.1111/bph.12954
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    ABSTRACT: Breast cancer (BC) is the second most common cause of cancer deaths. Triple negative breast cancer (TNBC) does not show immunohistochemical expression of the estrogen receptors, progesterone receptors and human epidermal growth factor receptor-2. Hitherto, no promising treatment option is available for patients of TNBC. The dearth of effective conventional therapies for the treatment of advanced stage breast cancer has inspired awareness in the development of novel strategies for the management of patients with TNBC. This review presents recent information associated with different therapeutic targets for the treatment of TNBC focusing on promising targets such as Notch signalling, Wnt/β-catenin and Hedge-hog pathways; EGFR, PARP1, mTOR, TGF-β and angiogenesis inhibitors. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2015; DOI:10.1111/bph.13211