British Journal of Pharmacology (Br J Pharmacol )

Publisher: British Pharmacological Society, Blackwell Publishing

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.

  • Impact factor
    5.07
  • 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

Blackwell Publishing

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • Some journals impose embargoes typically of 6 or 12 months, occasionally of 24 months
    • no listing of affected journals available as yet
  • Conditions
    • See Wiley-Blackwell entry for articles after February 2007
    • Publisher's version/PDF cannot be used
    • On author's server, institutional server or subject-based server
    • Server must be non-commercial
    • Publisher copyright and source must be acknowledged with set statement ("The definitive version is available at www.blackwell-synergy.com")
    • Articles in some journals can be made Open Access on payment of additional charge
    • 'Blackwell Publishing' is an imprint of 'Wiley'
  • Classification
    ​ yellow

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Linked ArticlesThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
    British Journal of Pharmacology 01/2015; 172(2).
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    ABSTRACT: Background and Purpose The function of the endocannabinoid system (ECS) in the renal tissue is not completely understood. Kidney function is closely related to ion reabsorption in the proximal tubule, the nephron segment responsible for the reabsorption of 70- 80% of the filtrate. We studied the effect of compounds modulating the activity of cannabinoid CB receptors on the active reabsorption of Na+ in LLC-PK1 cells. Experimental Approach Changes in (Na++K+)-ATPase activity were assessed after treatment with WIN55,212-2 (WIN), a non-selective lipid agonist, and hemopressin (HP), a peptide inverse agonist at CB1 receptors. The signaling pathways involved in the modulation of Na+ transport were investigated with pharmacological tool. Key Results The mRNAs encoding for enzymes of the ECS are expressed in LLC-PK1 as well as the CB1 and CB2 receptors and TRPV1 channels. WIN (10-7 M) and HP (10-6 M) altered Na+ reabsorption in LLC-PK1 in a dual manner. They both acutely (after 1 min) increased (Na++K+)-ATPase activity in a way attenuated by a TRPV1 antagonist. WIN stimulatory effect persisted until 30 min, when it was attenuated by a CB1 antagonist and by a PKC inhibitor. HP instead inhibited (Na++K+)-ATPase after 30 min incubation, and this effect was attenuated by a CB1 antagonist and a PKA inhibitor Conclusion and Implications ECS is expressed in LLC-PK1 cells. Both TRPV1 and CB1 regulate (Na++K+)-ATPase activity in these cells, and are modulated by lipid and peptide CB1 ligands, which act via different signaling pathways
    British Journal of Pharmacology 12/2014;
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    ABSTRACT: Hydroxamate derivatives have been attracted considerable attention, due to their broad pharmacological properties. Recent studies reported their potential use in the treatment of cardiovascular diseases, arthritis or infectious diseases. However, the inhibitory mechanisms of hydroxamate derivatives in inflammation remain to be elucidated. In an effort to develop a novel pharmacological agent that could suppress abnormally activated macrophages, we investigated a novel aliphatic hydroxamate derivative, WMJ-S-001, and explored its anti-inflammatory mechanisms. RAW264.7 macrophages were exposed to lipopolysaccharide (LPS) in the absence or presence of WMJ-S-001. COX-2 expression and signaling molecules activated by LPS were assessed. The LPS-induced COX-2 expression was suppressed by WMJ-S-001. WMJ-S-001 inhibited p38MAPK, NF-κB subunit p65 and C/EBPβ phosphorylation in cells exposed to LPS. Treatment of cells with a p38MAPK inhibitor (p38MAPK inhibitor III) markedly inhibited LPS-induced p65 and C/EBPβ phosphorylation and COX-2 expression. LPS-increased p65 and C/EBPβ binding to the COX-2 promoter region was suppressed in the presence of WMJ-S-001. In addition, WMJ-S-001 suppression of p38MAPK, p65 and C/EBPβ phosphorylation, and subsequent COX-2 expression were restored in cells transfected with mitogen-activated protein kinase phosphatase-1 (MKP-1) dominant negative (DN) mutant. WMJ-S-001 also caused an increase in MKP-1 phosphatase activity in RAW264.7 macrophages. WMJ-S-001 may cause MKP-1 activation to dephosphorylate p38MAPK, resulting in the decrease in p65 and C/EBPβ binding to the COX-2 promoter region and COX-2 down-regulation in LPS-stimulated RAW264.7 macrophages. The present study suggests that WMJ-S-001 may be a potential drug candidate in alleviating LPS-associated inflammatory diseases. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 12/2014;
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    ABSTRACT: Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the Chinese medicinal herb Stephaniae tetrandrae, has a long history in Chinese clinical applications to treat diverse diseases. We previously demonstrated that at the proper concentration, tetrandrine has potential as a cancer chemotherapeutic agent able to induce cell apoptosis or autophagy of human hepatocellular carcinoma cells. We found that the 4-aminoquinoline drug chloroquine (CQ), which is widely used to prevent or treat malaria and other diseases, showed a synergistic antitumor effect in combination with tetrandrine. Combination treatment with tetrandrine and CQ induced caspase-dependent apoptotic cell death in various cancer cell lines. Although combined treatment significantly inhibited Akt activity, ectopic Akt overexpression did not rescue cell viability after combination treatment. The potential molecular mechanisms involved stimulating intracellular reactive oxygen species (ROS) production because tetrandrine plus CQ dramatically increased ROS levels, and treatment with ROS scavengers significantly abrogated the combined treatment-induced apoptosis. Additionally, p21(CIP1/WAF1) expression plays a critical role in tetrandrine and chloroquine-induced cancer cell apoptosis. Consistent with in vitro studies, similar results were observed in vivo, where combined treatment induced ROS accumulation and induced cell apoptosis in a tumor xenograft model. Combination of tetrandrine and chloroquineinduced induce cell apoptosis CONCLUSIONS & IMPLICATIONS: Our findings suggest that the combination of tetrandrine and chloroquine has synergistic antitumor activity, which provides a novel promising therapeutic strategy for tumor treatment. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 12/2014;
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    ABSTRACT: Pulmonary hypertension (PH) is a devastating disease characterized by increased pulmonary arterial pressure, which progressively leads to right heart failure and death. A dysregulated renin angiotensin system (RAS) has been implicated in the development and progression of PH. However, the role of the angiotensin type II receptor (AT2 receptor) in PH has not been fully elucidated. We have taken advantage of a recently identified non-peptide AT2 receptor agonist, Compound 21 (C21), to investigate its effects on the well-established monocrotaline (MCT) rat model of PH. A single subcutaneous injection of MCT (50 mg/kg) was used to induce PH in 8-week-old male Sprague Dawley rats. After 2-weeks of MCT administration, a subset of animals began receiving, either 0.03mg/kg C21, 3mg/kg PD-123319, 0.5mg/kg A779 for an additional 2-weeks, after which right-ventricular hemodynamic parameters were measured and tissues collected for gene expression and histological analyses. Initiation of C21 treatment significantly attenuated much of the pathophysiology associated with MCT-induced PH. Most notably, C21 reversed pulmonary fibrosis and prevented right ventricular fibrosis. These beneficial effects were associated with improvement in right heart function, decreased pulmonary vessel wall thickness, reduced pro-inflammatory cytokines, and favorable modulation of the lung RAS. Conversely, co-administration of the AT2 receptor antagonist, PD-123319, or the Mas antagonist, A779, completely abolished the protective actions of C21. Collectively, our results suggest that the AT2 receptor agonist, C21, may hold promise for patients with PH. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 12/2014;
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    ABSTRACT: Background and purpose: Fibrates are a class of drugs widely used to treat dyslipidemias. They regulate lipid metabolism and act as peroxisome proliferator (PPAR) α receptor agonists. Clinical trials demonstrate that besides changes in lipid profiles fibrates decrease the incidence of cardiovascular events, with gemfibrozil exhibiting the most pronounced benefit. This study aims to characterize the effect of gemfibrozil on activity and function of soluble guanylyl cyclase (sGC), the key mediator of NO signaling. Experimental approach. High-throughput screening of a drug library identified gemfibrozil as a direct sGC activator. Activation of sGC is unique to gemfibrozil and is not shared by other fibrates. Results: Gemfibrozil activates purified sGC, induces endothelium-independent relaxation of aortic rings and inhibits platelet aggregation. Gemfibrozil-dependent activation is absent when sGC heme domain is deleted, but is significantly enhanced when sGC heme is lacking or oxidized. Oxidation of sGC heme enhances the vasoactive and anti-platelet effects of gemfibrozil. Gemfibrozil competes with heme-independent sGC activators ataciguat and cinaciguat. Computational modeling predicts that gemfibrozil occupies the space of the heme group and interacts with residues crucial for heme stabilization. This is consistent with structure-activity data which reveal an absolute requirement for gemfibrozil’s carboxyl group. Conclusions and implications: These data suggest that cardiovascular preventive benefits of gemfibrozil may derive not only from altered lipid and lipoprotein state, but also from direct activation and protection of sGC function in circulation. sGC-directed action may explain the more pronounced cardiovascular benefit of gemfibrozil observed over other fibrates and some of the described side-effects of gemfibrozil.
    British Journal of Pharmacology 12/2014;
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    ABSTRACT: Background and purposeThe catalytic topoisomerase II inhibitor dexrazoxane (DRZ) has been associated not only with improved cancer patient survival, but also with secondary malignancies and reduced tumor response.Experimental approachWe investigated the DNA damage response and the role of the activating transcription factor 3 (ATF3) accumulation in tumor cells exposed to DRZ.Key resultsDRZ exposure resulted in topoisomerase IIα (TOP2A)-dependent cell death, γ-H2AX accumulation, and increased tail moment in neutral comet assays. DRZ induced DNA damage response, as evidenced by enhanced levels of γ-H2AX/53BP1 foci, ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related), Chk1 and Chk2 phosphorylation, and by p53 accumulation. DRZ-induced γ-H2AX accumulation was dependent on ATM. ATF3 protein was induced by DRZ in a concentration- and time-dependent manner, which was abolished in TOP2A-depleted cells and in cells pre-incubated with ATM inhibitor. Knock-down of ATF3 gene expression by siRNA triggered apoptosis in control cells and diminished the p53 protein level in both control and DRZ-treated cells. This was accompanied by an increase in γ-H2AX accumulation. ATF3 knock-down also delayed the repair of DRZ-induced DNA double-strand breaks.Conclusions and ImplicationsSimilar to TOP2A poisons, DRZ induces DNA double-strand breaks followed by activation of DNA damage response. The DNA damage-triggered ATF3 controls the level of p53 accumulation as well as double-strand breaks generation and is proposed to serve as a switch between DNA damage and cell death following DRZ treatment. These findings suggest a mechanistic explanation for the diverse clinical observations associated with DRZ.
    British Journal of Pharmacology 12/2014;
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    ABSTRACT: Background and PurposeMethcathinone (MCAT) is a potent monoamine releaser and parent compound to emerging drugs of abuse including mephedrone (4-CH3 MCAT), the para-methyl analog of MCAT. This study examined quantitative structure-activity relationships (QSAR) for MCAT and six para-substituted MCAT analogs on (a) in vitro potency to promote monoamine release via dopamine and serotonin transporters (DAT and SERT), and (b) in vivo modulation of intracranial self-stimulation (ICSS), a behavioral procedure used to evaluate abuse potential. Correlations were evaluated for neurochemical and behavioral effects relative to steric (Es), electronic (σp) and lipophilic (πp) parameters of the para substituents.Experimental ApproachFor neurochemical studies, drug effects on monoamine release through DAT and SERT were evaluated in rat-brain synaptosomes. For behavioral studies, drug effects were tested in male Sprague-Dawley rats implanted with electrodes targeting the medial forebrain bundle and trained to respond on a lever for electrical brain stimulation (2.2–1.75 log Hz).Key ResultsMCAT and all six para-substituted analogs promoted monoamine release via DAT and SERT and produced dose- and time-dependent modulation of ICSS. In vitro DAT-vs.-SERT selectivity correlated with in vivo efficacy to produce abuse-related ICSS facilitation (R=0.92, P=0.003). In addition, the Es values of the para substituents correlated with both DAT-vs.-SERT selectivity (R=0.78, P=0.04) and magnitude of ICSS facilitation (R=0.81, P=0.03).Conclusions and ImplicationsThese results suggest that in vitro DAT-vs.-SERT selectivity is a key determinant of abuse-related ICSS facilitation by these MCAT analogs, and steric aspects of para substituents of the MCAT scaffold (indicated by Es) are key determinants of DAT-vs.-SERT selectivity.
    British Journal of Pharmacology 12/2014;
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    ABSTRACT: Reorganization of the actin cytoskeleton is essential for cell motility and chemotaxis. Actin-binding proteins (ABPs) and membrane lipids, especially phosphoinositides PI(4,5)P2 and PI(3,4,5)P3 are involved in the regulation of this reorganization. At least 15 ABPs have been reported to interact with, or regulated by phosphoinositides (PIPs) whose synthesis is regulated by extracellular signals. Recent studies have uncovered several parallel intracellular signalling pathways that crosstalk in chemotaxing cells. Here, we review the roles of ABPs and phosphoinositides in chemotaxis and cell migration.
    British Journal of Pharmacology 12/2014;
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    ABSTRACT: Background and purposeItch associates with increased sensitization to nociceptive stimuli. We investigated whether 3 iodothyroacetic acid (TA1), by releasing histamine, induced itch and increased sensitization to noxious and painful heat stimuli.Experimental ApproachItch was evaluated after sub-cutaneous (s.c.) administration of TA1 (0.4, 1.32 and 4 μgkg-1). Mice threshold to noxious (NHT) and to painful heat stimuli were evaluated by the increasing temperature hot plate (from 45.5° to 49.5°C) or by the hot plate (51.5°C) test respectively, 15 min after intraperitoneal (i.p.) injection of TA1 (0.4, 1.32 and 4 μgkg-1). Itch, NHT and pain threshold evaluation were repeated in mice pre-treated with pyrilamine (10 mgkg-1).Itch and NHT were also measured in HDC+/+ and HDC-/- following injection of saline or TA1 (1.32, 4 and 11 μgkg-1) (s.c. and i.p.).pERK1/2 levels were determined by Western-blot in dorsal root ganglia (DRG) isolated from CD1 mice 15 min after they received (i.p.): saline , saline and noxious heat stimulus (46.5°C), TA1 (0.1, 0.4,1.32,4 μgkg-1) or TA1 1.32 μgkg-1 and noxious heat stimulus.Key Results0.4 and 1.32 μgkg-1 TA1 induced itch and reduced NHT. Both effects were prevented by pyrilamine pre-treatment. TA1 4 μgkg-1 (i.p.) reduced pain threshold without inducing itch or modifying NHT. In HDC-/-, TA1 failed to induce itch and to reduce NHT.In DRG pERK1/2 levels were significantly increased by noxious heat stimuli and by TA1 0.1, 0.4 and 1.32 μgkg-1; i.p..Conclusions and ImplicationsIncreased TA1 levels induce itch and an enhanced sensitivity to noxius heat stimuli suggesting that TA1 might represent a potential cause of itch in thyroid diseases.
    British Journal of Pharmacology 12/2014;
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    ABSTRACT: Background and purposeSelective agonists of sigma-1 (σ1) protein are generally reported to protect against neuronal damage and modulate oligodendrocyte differentiation. Human and rodent lymphocytes possess saturable, high-affinity binding sites for σ ligands and potential immunomodulatory properties have been described for σ1 compounds. Experimental auto-immune encephalomyelitis (EAE) has unequivocal value as a model of the inflammatory aspects of multiple sclerosis (MS). Here, we have assessed the role of σ1 agonist containing the tetrahydroisoquinoleine-hydantoin structure in EAE.Experimental approachEAE was induced in SJL/J female mice by active immunization with myelin proteolipid protein (PLP)139-151 peptide. The σ1 agonist was injected i.p. at immunization time (D0). Disease severity was assessed clinically and by histopathological evaluation of the central nervous system (CNS). Phenotyping of B-cell subsets and Tregs were performed by flow cytometry in spleen and cervical lymph nodes.Key resultsProphylactic treatment of EAE mice with σ1 agonist prevented mononuclear cell accumulation and demyelination in brain and spinal cord and increased T2 B cells and Tregs, resulting in an overall reduction in the clinical progression of EAE.Conclusions and implicationsσ1 agonist containing the tetrahydroisoquinoleine-hydantoin structure dampened the magnitude of inflammation in EAE. This was associated with the increase in the proportion of B-cell subsets and Tregs with potential immunoregulatory functions. Targeting σ1 might thus provide new therapeutic opportunities for MS.
    British Journal of Pharmacology 12/2014;
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    ABSTRACT: Background And PurposeMitochondria-derived oxidative stress is believed to be centrally involved in cardiac ischemia-reperfusion (I/R) injury, although currently no therapies exist that specifically target mitochondrial reactive oxygen species (ROS) production. The present study was designed to evaluate the potential effects of the structural analogues of apelin-12, an adipocyte-derived peptide, on mitochondrial ROS generation, cardiomyocyte apoptosis, metabolic and functional recovery to myocardial I/R injury.Experimental ApproachIn cultured H9C2 cardiomyoblasts and adult cardiomyocytes oxidative stress was induced by hypoxia-reoxygenation. Isolated rat hearts were subjected to 35 minutes of global ischemia and 30 minutes of reperfusion. Apelin-12, apelin-13, structural apelin-12 analogues, AI and AII, were infused during 5 min prior to ischemia.Key ResultsIn cardiac cells, we demonstrated inhibition of mitochondrial ROS production by the structural analogues of apelin, AI and AII, in comparison with natural peptides, apelin-12 and apelin-13. Treatment of cardiomyocytes with AI and AII significantly decreased cell apoptosis in a dose-dependent manner. In a rat model of I/R injury, preischemic infusion of AI and AII markedly reduced ROS formation in the myocardial effluent and attenuated cell membrane damage. Prevention of oxidative damage by AI and AII was associated with the improvement of functional and metabolic recovery to I/R in the heart.Conclusions And ImplicationsThese data provide the evidence for the potential of the structural apelin analogues in selective reduction of mitochondrial ROS generation and myocardial apoptosis and form the basis for a promising therapeutic strategy in the treatment of oxidative stress-related heart diseases.
    British Journal of Pharmacology 12/2014;
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    ABSTRACT: Background and PurposeSphingosine-1-phosphate (S1P) has been shown to be involved in the asthmatic disease as well in preclinical mouse experimental models. The aim of this study was to understand the mechanism(s) underlying S1P effects on the lung.Experimental ApproachBALB/c, mast cell-deficient and Nude mice were injected with S1P subcutaneously on day 0 and 7. Functional, molecular and cellular studies were performed.Key ResultsS1P administration to BALB/c mice increased airway smooth muscle reactivity , mucus production, PGD2, IgE, IL-4 and IL-13 release. These features were associated to a higher recruitment of mast cells to the lung. Mast cell-deficient Kit W-sh/W-shmice injected with S1P did not display airway smooth muscle hyper-reactivity. However, lung inflammation and IgE production were still present. Treatment in vivo with the anti- CD23 antibody B3B4, that blocks IgE production, inhibited both S1P-induced airway smooth muscle reactivity in vitro and lung inflammation. S1P administration to Nude mice did not elicit airway smooth muscle hyper-reactivity and lung inflammation. Naïve (non-treated) mice subjected to the adoptive transfer of CD4+ T cells harvested from S1P-treated mice presented all the features elicited by S1P in the lung.Conclusions and ImplicationsS1P triggers a cascade of events that sequentially involves T cells, IgE and mast cells reproducing several asthma-like features. This model may represent a useful tool to define the role of S1P in the mechanism of action of drugs currently used as well as in order to define new therapeutic approaches in asthma like diseases.
    British Journal of Pharmacology 12/2014;
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    ABSTRACT: Background and PurposePolymorphisms of the μ-opioid receptor (MOPr) may contribute to the variation in responses to opioid drugs in clinical and unregulated situations. The A6V variant of MOPr (MOPr-A6V) is present in up to 20% of individuals in some populations, and may be associated with heightened susceptibility to drug abuse. There are no functional studies examining the acute signalling of MOPr-A6V in vitro, so we investigated potential functional differences between MOPr and MOPr-A6V at several signalling pathways using structurally distinct opioid ligands.Experimental ApproachCHO and AtT-20 cells stably expressing MOPr and MOPr-A6V used. Adenylyl cyclase (AC) inhibition and ERK1/2 phosphorylation assays were conducted in CHO cells, assays of K channel activation in AtT-20 cells.Key ResultsBuprenorphine did not inhibit AC or stimulate ERK1/2 phosphorylation in CHO cells expressing MOPr-A6V, but buprenorphine activation of K channels in AtT-20 cells was preserved. DAMGO, morphine and β-endorphin inhibition of AC was significantly reduced via MOPr-A6V, as was signalling of all opioids to ERK1/2. However, there was little effect of the A6V variant on K channel activation.Conclusions and ImplicationsThis study shows that signalling to AC and ERK via MOPr-A6V is reduced for many opioids, including the clinically significant drugs morphine, buprenorphine and fentanyl, as well endogenous opioids. The MOPr-A6V variant can be common and this compromised signalling may affect individual responses to opioid therapy, while the possible disruption of the endogenous opioid system may contribute to susceptibility to substance abuse.
    British Journal of Pharmacology 12/2014;
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    ABSTRACT: Ischaemic heart disease (IHD) remains a lead cause of morbidity/mortality globally, firmly established in Westernised or ‘developed′ countries and rising in prevalence in developing nations. Cardioprotective therapies to limit myocardial damage with associated ischaemia-reperfusion (I-R), during infarction or surgical ischaemia, are thus a very important though still elusive clinical goal. The opioid receptor (OPR) system, encompassing the δ (vas deferens), κ (ketocyclazocine) and μ (morphine) OPRs and their endogenous opioid ligands (endorphins, dynorphins, enkephalins), appears a logical candidate for such exploitation. This regulatory system may orchestrate organism and organ responses to stress, induces mammalian hibernation and associated metabolic protection, triggers powerful adaptive stress-resistance in response to ischaemia/hypoxia (preconditioning), and mediates cardiac benefit stemming from physical activity. In addition to direct myocardial actions, central OPR signalling may also enhance the ability of the heart to withstand I-R injury. The δ- and κ-OPR sub-types are strongly implicated in cardioprotection across models and species (including anti-infarct and anti-arrhythmic actions), with mixed evidence for μ-OPR dependent protection in animal and human tissues. A small number of clinical trials evidence cardiac benefit via morphine or remifentanil in cardiopulmonary by-pass or coronary angioplasty patients, though further trials of sub-type specific OPR agonists are needed. The precise roles and utility of this G-protein coupled receptor (GPCR) family in healthy and diseased human myocardium, and in mediating central and peripheral survival responses, warrant further investigation, as do the putative negative influences of ageing, IHD co-morbidities, and relevant drugs on OPR signalling and protective responses.
    British Journal of Pharmacology 12/2014;
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    ABSTRACT: Background and purposeWe have demonstrated previously that oxycodone had potent antinociceptive effects at supraspinal sites. In this study, we investigated changes in neuronal function and antinociceptive mechanisms of oxycodone at ventrolateral periaqueductal grey (VLPAG) neurons, which are a major site of opioid action, in a femur bone cancer (FBC) model with bone cancer-related pain.Experimental approachWe characterised the supraspinal antinociceptive profiles of oxycodone and morphine on mechanical hypersensitivity in the FBC model. Based on the disinhibition mechanism underlying supraspinal opioid antinociception, the effects of oxycodone and morphine on GABAA receptor-mediated inhibitory post-synaptic currents (IPSCs) in VLPAG neurons were evaluated in slices from the FBC model.Key resultsSupraspinal antinociceptive effects of oxycodone, but not morphine, were abolished by blocking G protein-gated inwardly rectifying potassium1 (KIR3.1) channels. In slices from the FBC model, GABAergic synaptic transmission at VLPAG neurons was enhanced, as indicated by a leftward shift of the input-output relationship curve of evoked IPSCs, the increased paired pulse facilitation and the enhancement of miniature IPSC frequency. Following treatment with oxycodone and morphine, IPSCs were reduced in the FBC model, and the inhibition of pre-synaptic GABA release by oxycodone but not morphine was enhanced and dependent on KIR3.1 channels.Conclusion and ImplicationsOur results demonstrate that KIR3.1 channels are important for supraspinal antinociception and pre-synaptic GABA release inhibition by oxycodone in the FBC model. Enhanced GABAergic synaptic transmission at VLPAG neurons in the FBC model is an important site of supraspinal antinociception by oxycodone via KIR3.1 channel activation.
    British Journal of Pharmacology 12/2014;
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    ABSTRACT: Peroxisome proliferator-activated receptors, PPARα, PPARβ/δ and PPARγ, are ligand-activated transcriptional factors of nuclear receptors superfamily that play important roles in glucose and lipid metabolism. Experimental studies in animal models of metabolic diseases reveal that activation of PPARs protects against diabetic vascular complications, hypertension, atherosclerosis, myocardial infarction, and stroke, through exerting their anti-inflammatory, anti-atherogenic, and antioxidant effects. In clinical trials and post-market surveillance, agonists of PPARs have been shown to effectively prevent cardiovascular events. However, adverse effects, particularly for PPARγ agonists, are also observed with the use of investigational PPAR agonists and even some approved agents. Further exploration of underlying mechanisms is needed to develop novel ways of PPAR activation without causing serious side effects. This article reviews the cardiovascular effects of PPARs, with emphasis on the therapeutic potential of PPAR agonists in combating metabolic vascular diseases.
    British Journal of Pharmacology 12/2014;
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    ABSTRACT: Background and purposeAt the early stage of Alzheimer’ Disease (AD), the accumulation of beta-amyloid (Aβ) oligomers disturbs intracellular Ca2+ homeostasis and disrupts synaptic plasticity of brain neurons. How to prevent Aβ-induced synaptic failure remains an unsolved obstacle for the therapeutics of AD. In this study, the effects of 2-aminoethoxydiphenyl borate (2-APB), a nonspecific but moderately potent Ca2+ channel inhibitor, on Aβ-induced deficit of synaptic long-term potentiation (LTP) and the underlying molecular mechanisms were explored.Experimental approachElectrophysiological recording, membrane protein extraction, hippocampal neuron culture, Western blot assay, and Ca2+ imaging were applied in our study.Key results2-APB at the concentration of 10 μM effectively reversed oligomeric Aβ1-42 (500 nM) suppression of LTP in hippocampal slices from C57BL/6 wild-type mice. 2-APB also restored AMPA receptor subunit GluR1 phosphorylation and trafficking in Aβ-treated hippocampal slices, supporting its protective action on synaptic function. Aβ-mediated abnormal neuronal [Ca2+]i elevation and hyperactivation of BAX, caspase-3, and GSK-3, which are known as mitochondrial apoptotic proteins, were significantly blocked by 2-APB pretreatment. Moreover, hippocampal LTP deficit in APPswe/PS1ΔE9 gene mutant mice was rescued by 2-APB at 10 μM.Conclusions and ImplicationsThese data demonstrate that 2-APB is a potentially useful chemical to protect synaptic plasticity against Aβ neurotoxicity in AD.
    British Journal of Pharmacology 12/2014;