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 version cannot be used
    • On author or institutional 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-Blackwell'
  • Classification
    ​ yellow

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Protein kinases transfer a phosphate from ATP to the side-chain hydroxyl group of a Serine, Threonine or Tyrosine residue of a substrate protein. This in turn can alter that protein's function; modulating fundamental cellular processes including, metabolism, transcription, growth, division, differentiation, motility and survival. Protein kinases are subdivided into families based on homology. One such group are the stress-activated kinases, which as the name suggests are activated in response to cellular stresses such as toxins, cytokines, mechanical deformation and osmotic stress. Members include the p38 MAPK family which is composed of alpha, beta, gamma and delta isoforms which are encoded by separate genes. These kinases transduce extracellular signals and coordinate the cellular responses needed for adaptation and survival. However, in cardiovascular and other disease states, these same systems can trigger maladaptive responses that aggravate, rather than alleviate, the disease. This situation is analogous to adrenergic, angiotensin and aldosterone signalling in heart failure, where inhibition is beneficial despite the importance of these hormones to homeostasis. The question is whether similar benefits could accrue from p38 inhibition? In this review, we will discuss the structure and function of p38, the history of p38 inhibitors and their use in preclinical studies. Finally we will summarise the results of recent cardiovascular clinical trials with p38 inhibitors.
    British Journal of Pharmacology 09/2014;
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    ABSTRACT: Linked ArticlesThis article is part of a themed section on Nanomedicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-17
    British Journal of Pharmacology 09/2014; 171(17).
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    ABSTRACT: Hydrogen sulfide (H2S) has traditionally been viewed as a highly toxic gas; however, recent studies have implicated H2S as a third member of the gasotransmitter family, exhibiting properties similar to nitric oxide (NO) and carbon monoxide (CO). Accumulating evidence has suggested that H2S influenced a wide range of physiological and pathological processes, among which blood vessel relaxation, cardioprotection and atherosclerosis have been particularly studied. In the cardiovascular system, H2S production is predominantly catalyzed by cystathionine γ-lyase (CSE). Decreased endogenous H2S levels have been found in hypertensive patients and animals, and CSE-/- mice develop hypertension with age, suggesting that deficiency of H2S contributes importantly to blood pressure regulation. H2S supplementation attenuates hypertension in different hypertensive animal models. The mechanism by which H2S was originally proposed to attenuate hypertension was by virtue of its action on vascular tone, which may be related to effects on different ion channels. Both H2S and NO cause vasodilation and there is cross talk between these two molecules to regulate blood pressure. Suppression of oxidative stress may also contribute to anti-hypertensive effects of H2S. This review also summarizes the state of research on H2S and hypertension in China. A better understanding of the role of H2S in hypertension and related cardiovascular diseases will allow novel strategies to be devised for their treatment.
    British Journal of Pharmacology 09/2014;
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    ABSTRACT: Neglected tropical diseases are a group of some 17 diseases that afflict poor and predominantly rural people in developing nations. One significant disease that contributes to substantial morbidity in endemic areas is schistosomiasis, caused by infection with one of 5 species of blood fluke belonging to the trematode genus Schistosoma. Although there is one drug available for treatment of affected individuals in clinics, or for mass administration in endemic regions, there is a need for new therapies. A prominent target organ of schistosomes, either for drug or vaccine development, is the peculiar epithelial syncytium that forms the body wall (tegument) of this parasite. This dynamic layer is maintained and organized by concerted activity of a range of proteins, among which are the abundant tegumentary annexins. In this review, we will outline advances in structure-function analyses of these annexins, as a means to understanding tegument cell biology in host- parasite interaction and their potential exploitation as targets for anti-schistosomiasis therapies.
    British Journal of Pharmacology 09/2014;
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    ABSTRACT: Background And PurposePalmitoylethanolamide is both an endogenous lipid mediator chemically related to the endocannabinoid anandamide and a food component contained in over-the-counter preparations promoted for inflammatory bowel disease. Additionally, palmitoylethanolamide acts via targets, i.e. cannabinoid (CB1 and CB2) receptors, transient receptor potential vanilloid type-1 (TRPV1), peroxisomal proliferator activated receptor α (PPARα) and orphan G protein-coupled receptor 55 (GPR55) involved in the control of intestinal inflammation. Here, we investigated the effect of PEA in a murine model of colitis.Experimental ApproachColitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS). Inflammation was assessed by evaluating inflammatory markers/parameters and by histology; intestinal permeability by a fluorescent method; colonic cell proliferation by immunohistochemistry; palmitoylethanolamide and endocannabinoid levels by chromatography-mass spectrometry; receptor and enzyme mRNA expression by quantitative reverse transcription-PCR.Key ResultsDNBS administration caused inflammatory damage, increased colonic levels of palmitoylethanolamide and endocannabinoids, down-regulation of TRPV1 and GPR55 mRNA expression (with no changes in CB1, CB2, and PPARα). Exogenous palmitoylethanolamide (intraperitoneally and/or orally, 1 mg kg-1) attenuated inflammation and intestinal permeability, stimulated colonic cell proliferation and increased colonic TRPV1 and CB1 receptor expression. The anti-inflammatory effect of PEA was attenuated or abrogated by CB2 receptor, GPR55 or PPARα antagonists and further increased by the TRPV1 antagonist capsazepine.Conclusion And ImplicationsPalmitoylethanolamide improves murine colitis, the effect being mediated by CB2 receptors, GPR55 and PPARα, and modulated by TRPV1 channels.
    British Journal of Pharmacology 09/2014;
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    ABSTRACT: In patients with acute myocardial infarction, timely reperfusion is mandatory to limit infarct size. However, reperfusion also adds to myocardial injury. Brief episodes of ischaemia/reperfusion in the myocardium or on organ remote from the heart, prior to or shortly after sustained myocardial ischaemia effectively reduce infarct size, provided there is eventual reperfusion. Such conditioning phenomena have been established in many experimental studies and also translated to humans. The underlying signal transduction, i.e. the molecular identity of triggers, mediators and effectors, is not clear yet in detail, but several extracellular signalling molecules such as adenosine, bradykinin, and opioids have been identified to contribute to cardioprotection by conditioning manoeuvres. Several trials have attempted the translation of cardioprotection by such autacoids into a clinical scenario of myocardial ischaemia and reperfusion. Adenosine and its selective agonists reduced infarct size in a few studies, but this benefit was not translated into improved clinical outcome. All studies with bradykinin or drugs which increase bradykinin′s bioavailability reported reduced infarct size and some of them also improved clinical outcome. Synthetic opioid agonists did not result in a robust infarct size reduction, but this failure of translation may relate to the cardioprotective properties of the underlying anaesthesia per se or of the comparator drugs. The translation of findings in healthy and young animals with acute coronary occlusion/reperfusion to patients of older age and with a variety of co-morbidities and co-medications suffering from different scenarios of myocardial ischaemia/reperfusion remains a challenge.
    British Journal of Pharmacology 09/2014;
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    ABSTRACT: Background And PurposeAdenylyl cyclase (AC) is a key signalling enzyme for many GPCRs which catalyses the conversion of ATP to cAMP which is involved in a range of biological responses. β agonists are prescribed as bronchodilators for asthma and COPD and dogma suggests that they elicit their actions via AC-dependent production of cAMP, however empirical evidence in support of this is lacking and the exact mechanism by which this class of drug acts remains elusive. This is partly due to the fact that there are at least 10 different isoforms of AC known to exist and there are currently no truly selective pharmacological inhibitors.Experimental ApproachThe aim of this study was to utilize genetically modified mice and model systems to establish the role of AC isoforms in β agonist responses in the airway. The receptor responsible for β agonist responses in airway smooth muscle (ASM) and sensory nerve responses was established in isolated tissue systems. mRNA expression of AC isoforms in the ASM and neurones was determined and functional responses assessed in AC isoform KO mice and wild type controls.Key ResultsqPCR indicated the cells expressed mRNA for various isoforms of AC, with the most prominent one being AC6. b agonist responses in tissue from mice missing functional AC6 were virtually abolished.Conclusions And ImplicationsIn summary, AC6 plays a key role in β1 agonist relaxation of ASM and β1-3 agonist modulation of sensory nerves. These data represent a step in unravelling the signalling pathway of this extensively prescribed class of medicine.
    British Journal of Pharmacology 09/2014;
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    ABSTRACT: Mitochondrial permeability transition pore (mPTP) opening plays a critical role in cardiac reperfusion injury and its prevention is cardioprotective. Tumour cell mitochondria usually have high levels of hexokinase isoform 2 (HK2) bound to their outer mitochondrial membranes (OMM) and HK2 binding to heart mitochondria has also been implicated in resistance to reperfusion injury. HK2 dissociates from heart mitochondria during ischaemia and the extent of this correlates with the infarct size on reperfusion. Here we review the mechanisms and regulation of HK2 binding to mitochondria and how this inhibits mPTP opening and consequent reperfusion injury. Major determinants of HK2 dissociation are the elevated glucose-6-phosphate (G-6-P) concentrations and decreased pH in ischaemia. These are modulated by the myriad of signalling pathways implicated in preconditioning protocols as a result of a decrease in pre-ischaemic glycogen content. Loss of mitochondrial HK2 during ischaemia is associated with permeabilisation of the OMM to cytochrome c which leads to greater ROS production and mPTP opening during reperfusion. Potential interactions between HK2 and OMM proteins associated with mitochondrial fission (e.g. Drp1) and apoptosis (Bcl-2 family members) in these processes are examined. Also considered is the role of HK2 binding in stabilising contact sites between the OMM and the inner membrane. Breakage of these during ischaemia is proposed to facilitate cytochrome c loss during ischaemia while increasing mPTP opening and compromising cellular bioenergetics during reperfusion. We end by highlighting the many unanswered questions and discussing the potential of modulating mitochondrial HK2 binding as a pharmacological target.
    British Journal of Pharmacology 09/2014;
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    ABSTRACT: Background and PurposeWe recently reported that the glucagon-like peptide-1 receptor (GLP-1R) peptidic agonists exenatide and GLP-1 produced anti-hypersensitive effects in neuropathic, cancer and diabetic pain. In this study, we investigated the anti-allodynic and anti-hyperalgesic effects of the nonpeptidic agonist WB4-24 in inflammatory nociception and possible involvements of microglial β-endorphin and pro-inflammatory cytokines.Experimental ApproachRat formalin-, carrageenan- and complete Freund's adjuvant (CFA)-induced inflammatory nociceptive models were employed and mechanical allodynia and thermal hyperalgesia were tested. The expression of β-endorphin and pro-inflammatory cytokines was measured using the real-time quantitative PCR and fluorescent immunoassay.Key ResultsWB4-24 displaced the specific binding of exendin(9-39) in microglia. Single intrathecal injection of WB4-24 (0.3, 1, 3, 10, 30 and 100 μg) exerted, in a dose-dependent manner, specific anti-hypersensitive effects in acute and chronic inflammatory nociception induced by formalin, carrageenan and CFA, with a maximal inhibition of 60-80%. Spinal WB4-24 was not effective in altering nociceptive pain. Subcutaneous injection of WB4-24 also led to antinociception in CFA-treated rats. WB4-24 evoked β-endorphin release but did not inhibit the expression of pro-inflammatory cytokines in either the spinal cords of CFA-treated rats or cultured microglia stimulated by lipopolysaccharide. WB4-24 anti-allodynia was prevented by the microglial inhibitor, β-endorphin antiserum and μ-opioid receptor antagonist.Conclusions and ImplicationsOur results suggest that WB4-24 inhibits inflammatory nociception by releasing analgesic β-endorphin rather than inhibiting the expression of proalgesic pro-inflammatory cytokines in spinal microglia, and that the spinal GLP-1R is a potential target molecule for the treatment of pain hypersensitivity including inflammatory nociception.
    British Journal of Pharmacology 09/2014;
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    ABSTRACT: Background and PurposeTreatment of Parkinson's disease (PD) with L-DOPA eventually causes abnormal involuntary movements known as dyskinesias in most patients. Dyskinesia can be reduced using compounds that act as direct or indirect agonists of the serotonin (5-HT)1A receptor, but these drugs have been reported to worsen PD features and are known to produce “5-HT syndrome”, symptoms of which include tremor, myoclonus, rigidity and hyperreflexia.Experimental ApproachSprague-Dawley rats were given unilateral nigrostriatal dopamine lesions with 6-hydroxydopamine. Each of the following three purportedly anti-dyskinetic 5-HT compounds were administered 15 min prior to L-DOPA (0 or 6 mg/kg): the full 5-HT1A agonist ±8-OH-DPAT (0, 0.3 or 1 mg/kg), the partial 5-HT1A agonist buspirone (0, 1 or 3 mg/kg) or the 5-HT transporter inhibitor citalopram (0, 2 or 5 mg/kg). After injections, animals were monitored for dyskinesia, 5-HT syndrome, motor activity and PD akinesia.Key ResultsEach 5-HT drug dose-dependently reduced dyskinesia by relatively equal amounts (±8-OH-DPAT ≥ citalopram ≥ buspirone), but 5-HT syndrome was higher with ±8-OH-DPAT, lower with buspirone and not present with citalopram. Importantly, with or without L-DOPA, all three compounds provided an additional improvement of PD akinesia. All drugs tempered the locomotor response to L-DOPA suggesting dyskinesia reduction, but vertical rearing was reduced with 5-HT drugs, potentially reflecting features of 5-HT syndrome.Conclusions and ImplicationsResults suggest that compounds that indirectly facilitate 5-HT1A activation, such as citalopram, may be more effective therapeutics than direct 5-HT1A receptor agonists because they exhibit similar anti-dyskinesia efficacy, while possessing a lesser side-effect profile.
    British Journal of Pharmacology 09/2014;
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    ABSTRACT: Background and purposeNeovascularization occurring in atherosclerotic lesions may promote plaque expansion, intraplaque haemorrhage and rupture. Oxidized LDL (oxLDL) are atherogenic, but their angiogenic effect is controversial because both angiogenic and anti-angiogenic effects were reported. The angiogenic mechanism of oxLDL is partly understood, but the role of the angiogenic sphingolipid mediator sphingosine-1-phosphate (S1P) in this proces is not known. Thus, we aimed to investigate whether S1P is implicated in the oxLDL-induced angiogenesis and whether an anti-S1P monoclonal antibody could prevent this effect.Experimental approachAngiogenesis was assessed by capillary tube formation by Human Microvascular Endothelial Cells (HMEC-1) cultured on Matrigel and in vivo by the Matrigel plug assay in C57BL/6 mice.Key resultsHuman oxLDL exhibited a biphasic angiogenic effect on HMEC-1, low concentration being angiogenic, higher concentration being cytotoxic. The angiogenic response to oxLDL was blocked by the sphingosine kinase (SPHK) inhibitor, dimethylsphingosine, by SPHK1-siRNA and by an anti-S1P monoclonal antibody. Moreover, inhibition of oxLDL uptake and subsequent redox signaling by anti-CD36 and anti-LOX-1 receptor antibodies and by N-acetylcysteine, respectively, blocked SPHK1 activation and tube formation. In vivo, in the Matrigel plug assay, low concentration of human oxLDL or murine oxVLDL also triggered angiogenesis, which was prevented by intraperitoneal injection of the anti-S1P antibody.Conclusion and ImplicationsThese data emphasize the role of S1P in angiogenesis induced by oxLDL both in HMEC-1 cultured on Matrigel and in vivo in the Matrigel plug model in mice, and the efficacy of the anti-S1P antibody in blocking the angiogenic effect of oxLDL.
    British Journal of Pharmacology 09/2014;
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    ABSTRACT: Ischemic pre- and postconditioning are potent cardioprotective interventions that spare ischemic myocardium and decrease infarct size after periods of myocardial ischemia/reperfusion. They are dependent on complex signaling pathways involving ligands released from ischemic myocardium, G-protein-linked receptors, membrane growth factor receptors, phospholipids, signaling kinases, nitric oxide, protein kinase C and G, mitochondrial ATP-sensitive potassium channels, reactive oxygen species, tissue necrosis factor-alpha, and sphingosine-1-phosphate. The final effector is likely the mitochondrial permeability transition pore, and the signaling produces protection by preventing pore formation. Many investigators have worked to produce a roadmap of this signaling with the hope that it would reveal where one could intervene to therapeutically protect patients with acute myocardial infarction whose hearts are being reperfused. However, attempts to date to show efficacy of such an intervention in large clinical trials have been unsuccessful. Reasons for this inability to translate successes in the experimental laboratory to the clinical arena are evaluated in this review. It is suggested that all patients with acute coronary syndromes currently presenting to the hospital and being treated with platelet P2Y12 antagonists, the current standard of care, are indeed already benefiting from protection from the conditioning pathways outlined above. If that proves to be the case, then future attempts to further decrease infarction will have to rely on interventions which protect by a different mechanism.
    British Journal of Pharmacology 09/2014;
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    ABSTRACT: Background and purposeA ligand is believed to produce either positive or negative efficacies, or to block both of them. However, an indole compound was found to promote both positive and negative efficacies at the 5-HT3AB receptor that displays low level of spontaneous activity. The present study attempted to delineate mechanisms underlying this phenomenon.Experimental approachThe spontaneously active V291S 5-HT3A receptor was used to explore behaviors of 5-hydroxyindole (5-HoI) and 5-methoxyindole (5-MoI), structural analogs of 5-HT, either alone or in combination with orthosteric probes.Key resultsTwo types of efficacy switching were initiated by altering ligand structure and concentration. At lower concentrations, a subtle structure change at position 5 of the indole molecule resulted in opposite efficacies. 5-HoI apparently elicited partial allosteric inverse agonism, whereas 5-MoI engendered allosteric agonism. Interestingly, these indoles at a higher concentration produced distinct auto-inhibition, manifested as a switch from positive to negative efficacies. 5-HoI induced a transition from orthosteric agonism to allosteric inverse agonism, whereas 5-MoI produced a shift from allosteric agonism to orthosteric inverse agonism. The auto-inhibition appears to involve communication between orthosteric and allosteric sites of the active receptor conformation and/or between inactive and active conformations. Additionally, an additive effect of orthosteric and allosteric inverse agonism and insensitivity of allosteric agonism to orthosteric antagonism were also demonstrated.Conclusions and ImplicationsTogether, the present study suggests that the moiety at position 5 of the indole structure is a critical determinant of ligand property at the 5-HT3A receptor, providing new insights into understanding ligand-receptor interactions.
    British Journal of Pharmacology 09/2014;
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    ABSTRACT: Despite high sequence similarity between NOP (nociceptin/orphaninFQ opioid peptide) and opioid receptors, marked differences in endogenous ligand selectivity, signal transduction, phosphorylation, desensitization, internalization and trafficking have been identified; underscoring the evolutionary difference between NOP and opioid receptors. Activation of NOP receptors affects nociceptive transmission in a site-specific manner, with antinociceptive effects prevailing after peripheral and spinal activation, and pronociceptive effects after supraspinal activation in rodents. The net effect of systemically administered NOP receptor agonists on nociception is proposed to depend on the relative contribution of peripheral, spinal and supraspinal activation and this may depend on experimental conditions. Functional expression and regulation of NOP receptors at peripheral and central sites of the nociceptive pathway exhibits a high degree of plasticity under conditions of neuropathic and inflammatory pain. In rodents, systemically administered NOP receptor agonists exerted antihypersensitive effects in models of neuropathic and inflammatory pain. However they were largely ineffective in acute pain while concomitantly evoking severe motor side effects. In contrast, systemic administration of NOP receptor agonists to non-human primates (NHPs) exerted potent and efficacious antinociception in the absence of motor and sedative side effects. The reason for this species difference with respect to antinociceptive efficacy and tolerability is not clear. Moreover, co-activation of NOP and μ-opioid peptide (MOP) receptors synergistically produced antinociception in NHPs. Hence, both selective NOP receptor as well as NOP/MOP receptor agonists may hold potential for clinical use as analgesics effective in conditions of acute and chronic pain.
    British Journal of Pharmacology 08/2014; 171(16):3777-3800.
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    ABSTRACT: Multidrug resistance protein 1 (MRP1, ABCC1) plays a critical role in the development of multidrug resistance (MDR). Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK). Here we investigated the reversal effect of ibrutinib on MRP1-mediated MDR.
    British Journal of Pharmacology 08/2014;
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    ABSTRACT: the hematopoietic activity of erythropoietin (EPO) is mediated by the classic EPO receptor (EpoR) homodimer, whereas the tissue-protective effects by a hetero-complex between EpoR and the β-common receptor (βcR). Here, we investigated the effects of a novel, selective ligand of the hetero-complex EpoR/βcR (pyroglutamate helix B surface peptide [pHBSP]) in mice chronically exposed to a diet enriched in sugars and saturated fats.
    British Journal of Pharmacology 08/2014;
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    ABSTRACT: Since the discovery of endothelin-1 in 1988, the main components of the signalling pathway have become established comprising three structurally similar endogenous twenty-one amino acids peptides, ET-1, ET-2 and ET-3, that activate two G-protein coupled receptors, ETA and ETB. . Our aim in this review is to highlight the recent progress in endothelin research. The endothelin-like domain peptide, corresponding to prepro-ET-193-166 , has been proposed to be co-synthesised and released with ET-1, to modulate the actions of the peptide. ET-1 remains the most potent vasoconstrictor in the human cardiovascular system with a particularly long lasting action. To date, the major therapeutic strategy to block the unwanted actions of ET in disease, principally in pulmonary arterial hypertension, has been to use antagonists that are selective for the ETA receptor (ambrisentan) or that block both receptor subtypes (bosentan). Macitentan represents the next generation of antagonists, being more potent than bosentan, with longer receptor occupancy and it is converted to an active metabolite; properties contributing to greater pharmacodynamic and pharmacokinetic efficacy. A second strategy is now being more widely tested in clinical trials and uses combined inhibitors of endothelin converting enzyme and neutral endopeptidase such as SLV306 (daglutril). A third strategy based on activating the ETB receptor, has led to the renaissance of the modified peptide agonist IRL1620 as a clinical candidate in delivering anti-tumour drugs and as a pharmacological tool to investigate experimental pathophysiological conditions. Finally we discuss biased signalling, epigenetic regulation and targeting with monoclonal antibodies as prospective new areas for endothelin research.
    British Journal of Pharmacology 08/2014;
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    ABSTRACT: One of the hallmarks of cancer is aberrant DNA methylation which is associated with abnormal gene expression. Both hypermethylation and silencing of tumor suppressor genes as well as hypomethylation and activation of prometastatic genes are characteristic of cancer cells. Since DNA methylation is reversible, DNA methylation inhibitors were tested as anticancer drugs with the idea that such agents would demethylate and reactivate tumor suppressor genes. Two cytosine analogs, 5-azacytidine (5-azaC) (Vidaza) and 5-aza-2'-deoxycytidine (5-azadC), have been approved by FDA as antitumor agents in 2004 and 2006 respectively. However these agents might cause activation of a panel of prometastatic genes in addition to activating tumor suppressor genes which might lead to increased metastasis. This poses the challenge of how to target tumor suppressor genes and block cancer growth with DNA demethylating drugs while avoiding the activation of prometastatic genes and precluding the morbidity of cancer metastasis. This paper reviews current progress in using DNA methylation inhibitors in cancer therapy and the potential promise and challenges ahead.
    British Journal of Pharmacology 08/2014;
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    ABSTRACT: The universal second messenger cyclic AMP (cAMP) is generated upon stimulation of Gs protein-coupled receptors, such as the β2 -adrenergic receptor (β2 -AR), and leads to the activation of protein kinase A (PKA), the major cAMP effector protein. PKA oscillates between an on and off state and thereby regulates a plethora of distinct biological responses. The broad activation pattern of PKA and its contribution to several distinct cellular functions lead to the introduction of the concept of compartmentalization of cAMP. A-kinase anchoring proteins (AKAPs) are of central importance due to their unique ability to directly and/or indirectly interact with proteins that either determine the cellular content of cAMP, such as β2 -AR, adenylyl cyclases and phosphodiesterases, or are regulated by cAMP such as the exchange protein directly activated by cAMP (Epac). We report on lessons learned from neurons indicating that maintenance of cAMP compartmentalization by AKAP5 is linked to neurotransmission, learning and memory. Disturbance of cAMP compartments seem to be linked to neurodegenerative disease including Alzheimer's disease. We translate this knowledge to compartmentalized cAMP signalling in the lung. Next to AKAP5, we focus here on AKAP12 and Ezrin (AKAP78). These topics will be highlighted in the context of the development of novel pharmacological interventions to tackle AKAP-dependent compartmentalization.
    British Journal of Pharmacology 08/2014;
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    ABSTRACT: Background and PurposeFluoxetine, a so-called selective serotonin reuptake inhibitor, elevates brain concentrations of the neuroactive progesterone metabolite allopregnanolone, an effect suggested to underlie its use in the treatment of premenstrual dysphoria. One report showed fluoxetine to activate the aldo-keto reductase component of 3α-hydroxysteroid dehydrogenase, which catalyses the production of allopregnanolone from 5α-dihydroprogesterone. However, this action was not observed by others. The present study sought to clarify the site of action for fluoxetine in elevating brain allopregnanolone.Experimental ApproachAdult male rats and female rats in dioestrus were treated with fluoxetine and their brains assayed for allopregnanolone and its precursors progesterone and 5α-dihydroprogesterone. Subcellular fractions of rat brain were also used to investigate the actions of fluoxetine on 3α-hydroxysteroid dehydrogenase activity in both the reductive direction, producing allopregnanolone from 5α-dihydroprogesterone, and the reverse oxidative direction. Finally, actions of fluoxetine were tested on the above recombinant enzyme activities expressed in HEK cells.Key ResultsShort-term treatment of female rats with fluoxetine caused a significant increase in brain allopregnanolone concentration, an effect not seen in male rats. Enzyme assays on native rat brain fractions and on activities expressed in HEK cells showed fluoxetine to have no effect on the aldo-keto reductase producing allopregnanolone from 5α-dihydroprogesterone but to inhibit the microsomal dehydrogenase oxidising allopregnanolone to 5α-dihydroprogesterone.Conclusions and ImplicationsFluoxetine elevates allopregnanolone in female rat brain by inhibiting its oxidation to 5α-dihydroprogesterone by a microsomal dehydrogenase. A novel site of action has been identified for fluoxetine, with implications for the development of new agents and/or dosing regimens to raise brain allopregnanolone.
    British Journal of Pharmacology 08/2014;

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