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
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    • Some journals impose embargoes typically of 6 or 12 months, occasionally of 24 months
    • no listing of affected journals available as yet
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    • 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
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    • 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: Abstract Background & Purpose GoSlo-SR compounds are efficacious BK channel openers, but little is known about their mechanism of action or effect on bladder contractility. We examined the effects of two closely related compounds on BK currents and bladder contractions. Experimental approach A combination of electrophysiology, molecular biology and synthetic chemistry was used to examine the effects of two novel channel agonists on BK channels from bladder smooth muscle cells and in HEK cells expressing BKα alone or in combination with either β1 or β4 subunits. Key Results GoSlo-SR-5-6 shifted the voltage required for half maximal activation (V1/2) of BK channels ∼-100 mV, irrespective of the presence of regulatory β subunits. The deaminated derivative, GoSlo-SR-5-130, also shifted the activation V1/2 in smooth muscle cells by ∼-100 mV, however this was reduced by ∼80% in HEK cells expressing only BKα subunits. When β1 or β4 subunits were co-expressed with BKα, efficacy was restored. GoSlo-SR-5-130 caused a concentration dependent reduction in spontaneous bladder contraction amplitude and this was abolished by iberiotoxin, consistent with an effect on BK channels. Conclusions & implications GoSlo-SR-5-130 required β1 or β4 subunits to mediate its full effects, whereas GoSlo-SR-5-6 worked equally well in the absence or presence of β subunits. GoSlo-SR-5-130 inhibited spontaneous bladder contractions by activating BK channels. Significance The novel BK channel opener, GoSlo-SR-5-130, is ∼5 fold more efficacious on BK channels with regulatory β subunits and may be a useful scaffold in the development of drugs to treat diseases such as overactive bladder.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Inhaled glucocorticoid (ICS)/long-acting β2 -adrenoceptor agonist (LABA) combination therapy is a recommended treatment option for patients with moderate/severe asthma in whom adequate control cannot be achieved by an ICS alone. Previously, we discovered that LABAs can augment dexamethasone-inducible gene expression and proposed that this effect may explain how these two drugs interact to deliver superior clinical benefit. Herein, we have extended that observation by analysing, pharmacodynamically, the effect of the LABA, indacaterol, on glucocorticoid receptor (GR)-mediated gene transcription induced by seven ligands with intrinsic activity values that span the spectrum of full agonism to antagonism. BEAS-2B human airway epithelial cells stably transfected with a 2×glucocorticoid response element luciferase reporter were used to model gene transcription together with an analysis of several glucocorticoid-inducible genes. Indacaterol augmented glucocorticoid-induced reporter activation in a manner that was positively related to the intrinsic activity of the GR agonist. This effect was described by an increase in response maxima without a change in GR agonist affinity or efficacy. Indacaterol also enhanced glucocorticoid-inducible gene expression. However, the magnitude of this effect was dependent on both the GR agonist and the gene of interest. These data suggest that indacaterol activates a molecular rheostat, which increases the transcriptional competency of GR in an agonist- and gene-dependent manner without apparently changing the relationship between fractional GR occupancy and response. These findings provide a platform to rationally design ICS/LABA combination therapy that is based on the generation of agonist-dependent gene expression profiles in target and off-target tissues. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 01/2015;
  • C Devader, A Khayachi, J Veyssière, H Moha Ou Maati, M Roulot, S Moreno, M Borsotto, S Martin, C Heurteaux, J Mazella
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    ABSTRACT: We previously discovered a novel antidepressant called spadin. Spadin is a peptide which displays its properties by blocking the potassium channel TREK-1. The present study examines the spadin mechanisms of action at both molecular and cellular levels. To characterize the cellular and molecular functions of spadin, we combined several approaches using in vitro primary culture of neurons and in vivo injections of the antidepressant in mice. In vitro, we demonstrated that spadin increases the neuronal membrane potential and activates both the MAP and PI3 kinase pathways in a time and concentration-dependent manner, the latter pathway being involved in the protective effect of the peptide against staurosporine-induced apoptosis. We also showed that spadin enhances both the mRNA expression and the protein content of two markers of synaptogenesis PSD-95 and synapsin. We confirmed these synaptogenesis effects by the observation that a spadin treatment significantly increases the proportion of mature spines in cortical neurons. Finally, in vivo injections of spadin led to a rapid increase in both mRNA expression and protein level of the brain-derived neurotrophic factor (BDNF) in the hippocampus confirming the effective antidepressive action of the peptide. We argue for a new role of spadin in synaptogenesis as both PSD-95 and synapsin mRNA expression and protein levels are further enhanced in the hippocampus. These findings provide new mechanisms of action for the rapid-acting antidepressant spadin through BDNF and synaptic proteins both in vitro and in vivo. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Asthma exacerbations contribute to corticosteroid insensitivity. Lipopolysaccharide (LPS) is ubiquitous in the environment. It causes bronchoconstriction and airways inflammation and may therefore exacerbate allergen responses. This study examined whether LPS and ovalbumin co-administration could exacerbate the airways inflammatory and functional responses to ovalbumin in conscious guinea-pigs and whether these exacerbated responses were insensitive to inhaled corticosteroid treatment with fluticasone propionate. Guinea-pigs were sensitized and challenged with ovalbumin and airways function recorded as specific airways conductance (sGaw) by whole body plethysmography. Airways inflammation was measured from lung histology and bronchoalveolar lavage. Airways hyperreactivity (AHR) to inhaled histamine was examined 24h after ovalbumin. LPS was inhaled alone or 24 or 48 hours before ovalbumin and combined with ovalbumin. Fluticasone propionate (0.05, 0.1, 0.5 or 1mg/ml) or vehicle (ethanol:DMSO:saline 30:30:40) was nebulised for 15 minutes twice daily for 6 days before ovalbumin or LPS exposure. Ovalbumin inhalation caused early (EAR) and late asthmatic responses (LAR), airways hypereactivity to histamine and influx of inflammatory cells into the lungs. LPS 48 hours before and co-administered with ovalbumin exacerbated the response with increased length of the EAR, prolonged response to histamine and elevated inflammatory cells. FP 0.5 and 1mg/ml reduced the LAR, AHR and cell influx with ovalbumin alone, but was ineffective when guinea-pigs were exposed to LPS before and with ovalbumin. LPS exposure exacerbates airways inflammatory and functional responses to allergen inhalation and decreases corticosteroid sensitivity. Its widespread presence in the environment could contribute to asthma exacerbations and corticosteroid insensitivity in humans. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Background and PurposeCancer cells develop resistance to stress induced by chemotherapy. In tumours, a considerable glucose-gradient exists, resulting in stress. Notably, hypoxia-inducible factor-1 (HIF-1) is a redox-sensitive transcription factor that regulates P-glycoprotein (Pgp), a crucial drug-efflux transporter involved in multidrug-resistance (MDR). Here, we investigate how glucose-levels regulate Pgp-mediated drug-transport and resistance.Experimental ApproachHuman tumour cells (KB31, KBV1, A549 and DMS-53) were incubated under glucose-starvation to hyperglycaemic conditions. Flow cytometry assessed reactive oxygen species (ROS)-generation and Pgp-activity. HIF-1α, NF-κB and Pgp-expression were assessed by RT-PCR and western blotting. Fluorescence microscopy examined p65 distribution and a luciferase-reporter assay assessed HIF-1 promoter-binding activity. The effect of glucose-induced stress on Pgp-mediated drug-resistance was examined after incubating cells with the chemotherapeutic agent and Pgp-substrate, doxorubicin (DOX), and performing MTT assays validated by viable cell counts.Key ResultsChanges in glucose-levels markedly enhanced cellular ROS and conferred Pgp-mediated drug-resistance. Low and high glucose-levels significantly induced: (1) ROS-generation via NADPH oxidase 4 and mitochondrial-membrane destabilization; (2) HIF-1 activity; (3) nuclear translocation of the NF-κB p65-subunit; and (4) increased HIF-1α mRNA and protein-levels. Increased HIF-1α could also be due to the significantly decreased prolyl hydroxylase protein under these conditions. The HIF-1α target, Pgp, was significantly up-regulated at low and high glucose-levels. These increased Pgp-levels led to significantly lower cellular accumulation of the Pgp-substrate, Rhodamine-123, and significantly greater resistance to DOX.Conclusions and ImplicationsAs tumour cells become glucose-deprived or exposed to high glucose-levels, this increases stress, leading to a more aggressive MDR-phenotype via up-regulation of Pgp.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Background and PurposeRecently, we demonstrated that the nucleus accumbens is required for the acquisition and expression of relief memory. Purpose of this study was to investigate the role of NMDA receptors within the nucleus accumbens in relief learning.Experimental ApproachThe NMDA receptor antagonist AP-5 (2-amino-5-phosphonopentanoic acid) was injected into the nucleus accumbens. The effects of these injections on the acquisition and expression of relief memory, as well as on the reactivity to aversive electric stimuli were tested.Key ResultsIntra-accumbal AP-5 injections blocked acquisition but not expression of relief memory. Furthermore, reactivity to aversive electric stimuli was not affected by the AP-5 injections.Conclusion and ImplicationThe present data indicates that NMDA-dependent plasticity within the nucleus accumbens is crucial for the acquisition of relief memory.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Background and PurposeCryptotanshinone (CTS) is a major bioactive diterpenoid isolated from Danshen, an eminent medicinal herb that treats cardiovascular disorders in Asian medicine. However, it remains unknown whether CTS can prevent experimental atherosclerosis. The present study was designed to investigate the protective effects and whereby the molecular mechanisms of CTS on atherosclerosis.Experimental ApproachApolipoprotein E deficient (ApoE-/-) mice fed an atherogenic diet were dosed daily with CTS (15, 45 mg/kg/d) by oral gavage. In vitro studies were carried out in oxidized LDL (oxLDL)-stimulated human umbilical vein endothelial cells (HUVECs) treated with or without CTS.Key ResultsCTS significantly attenuated atherosclerotic plaque formation and enhanced plaque stability in ApoE-/- mice by inhibiting lectin-like oxLDL receptor-1 (LOX-1) and matrix metalloproteinase-9 (MMP-9) expression, as well as inhibiting reactive oxygen species (ROS) generation and nuclear factor- kappa B (NF-κB) activation. CTS treatment led to a significant decrease in serum pro-inflammatory mediators, without altering serum lipid profile. In vitro, CTS decreased oxLDL-induced LOX-1 mRNA and protein expression, and thereby, inhibited LOX-1-mediated monocytes adhesion to HUVECs through reducing the expression of adhesion molecules (ICAM-1 and VCAM-1). Furthermore, we observed that, CTS inhibited NADPH oxidase subunit 4 (NOX4)-mediated ROS generation and consequent activation of NF-κB in HUVECs.Conclusions and ImplicationsThe present findings unveil the novel anti-atherosclerotic activity of CTS through the inhibition of LOX-1 mediated signaling pathway and suggest that CTS is a vasculoprotective drug that has potential therapeutic value in clinical treatment of atherosclerotic cardiovascular diseases.
    British Journal of Pharmacology 01/2015;
  • K J Coote, D Paisley, S Czarnecki, M Tweed, H Watson, A Young, R Sugar, M Vyas, N J Smith, U Baettig, [......], B Ethell, G Williams, A Schumacher, J Harris, W M Abraham, J Sabater, C T Poll, T Faller, S P Collingwood, H Danahay
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    ABSTRACT: Background and purposeInhaled amiloride, a blocker of the epithelial sodium channel (ENaC), enhances mucociliary clearance (MCC) in cystic fibrosis (CF) patients. However the dose of amiloride is limited by the mechanism based side effect of hyperkalaemia resulting from renal ENaC blockade. Inhaled ENaC blockers with a reduced potential to induce hyperkalaemia represent a therapeutic strategy to improve mucosal hydration and MCC in the lungs of CF patients. The present study describes the preclinical profile of a novel ENaC blocker, NVP-QBE170, designed for inhaled delivery, with a reduced potential to induce hyperkalaemia.Experimental approachThe in vitro potency and duration of action of NVP-QBE170 were compared with amiloride and 552-02 in primary human bronchial epithelial cells (HBEC) by short circuit current. In vivo efficacy and safety were assessed in guinea pig (tracheal potential difference / hyperkalaemia), rat (hyperkalaemia) and sheep (MCC).Key resultsIn vitro, NVP-QBE170 potently inhibited ENaC function in HBEC and showed a superior duration of action to comparator molecules. In vivo, intra-tracheal instillation of NVP-QBE170 attenuated ENaC activity in the guinea pig airways with superior potency and duration of action to that of amiloride without inducing hyperkalaemia in either guinea pig or rat. Dry powder inhalation of NVP-QBE170 by conscious sheep increased MCC and showed superiority over inhaled hypertonic saline in terms of efficacy and duration of action.Conclusions and implicationsNVP-QBE170 highlights the potential for inhaled ENaC blockers to exhibit efficacy in the airways with a reduced risk of hyperkalaemia relative to existing compounds.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Background and PurposeCannabinoid ligands have been demonstrated to have utility as novel therapeutic agents for the treatment of pain, metabolic conditions and gastrointestinal (GI) disorders. However, many of these ligands are centrally active, which limits their usefulness. Here we examine a unique novel covalent cannabinoid receptor ligand, AM841, to assess its potential for use in physiological and pathophysiological in vivo studies.Experimental ApproachThe covalent nature of AM841 was determined in vitro using electrophysiological and receptor internalization studies on isolated cultured hippocampal neurons. Mouse models were used for behavioural analysis of analgesia, hypothermia and hypolocomotion. Motility of the small and large intestine was assessed in vivo under normal conditions and after acute stress. Brain penetration of AM841 was also determined.Key ResultsAM841 behaves as an irreversible cannabinoid (CB)1 receptor agonist in vitro. AM841 potently reduces GI motility through an action on CB1 receptors in the small (EC50 0.004 mg/kg) and large (EC50 0.03 mg/kg) intestine under physiological conditions. AM841 is even more potent under conditions of acute stress, and was shown to normalize accelerated GI motility under these conditions. This compound behaves as a peripherally-restricted ligand, showing very little brain penetration and no characteristic centrally-mediated CB1 receptor-mediated effects (analgesia, hypothermia or hypolocomotion).Conclusions and ImplicationsAM841, a novel peripherally-restricted covalent CB1 receptor ligand that possess remarkable potency represents a new class of potential therapeutic agents for the treatment of functional GI disorders.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Background and PurposeTransient Receptor Potential Vanilloid-4 (TRPV4) is a calcium-permeant ion channel that is known to affect vascular function. The ability of TRPV4 to cause a vasoconstriction in blood vessels has not yet been mechanistically examined. Further in neuronal cells, TRPV4 signaling can be potentiated by GPCR activation. Thus we studied the mechanisms underlying the vascular contractile action of TRPV4 and the GPCR mediated potentiation of such vasoconstriction, both of which are as yet unappreciated aspects of TRPV4 function.Experimental ApproachThe mechanisms of TRPV4 dependent regulation of vascular tone in isolated mouse aortae were studied using wire myography. TRPV4 dependent calcium signaling and prostanoid production was studied in cultured human umbilical vein endothelial cells.Key ResultsIn addition to the well-documented vasorelaxation response triggered by TRPV4 activation, we report here a TRPV4 triggered vasoconstriction in the mouse aorta that involves a cyclo-oxygenase generated thromboxane receptor (TP) agonist that acts in a MAP kinase and Src Kinase signaling dependent manner. This constriction is potentiated by activation of the GPCRs for angiotensin (AT1R) or proteinases (PAR1 and PAR2) via transactivation of the Epidermal Growth Factor (EGF) receptor and a process involving protein kinase C (PKC). TRPV4 dependent vascular contraction can be blocked by cyclooxygenase inhibitors or with TP antagonists. Further, TRPV4 activation in HUVECs stimulated thromboxane release as detected by an ELISA.Conclusion and implicationsWe conclude that the GPCR potentiation of TRPV4 action and TRPV4 dependent thromboxane receptor activation are important regulators of vascular function and could be therapeutically targeted in vascular diseases.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Background and purposeThe activation of the metabotropic glutamate receptor 2 (mGlu2) reduces glutamatergic transmission in brain regions where excess excitatory signalling is implicated in disorders such as anxiety and schizophrenia. Positive allosteric modulators (PAMs) can provide a fine-tuned potentiation of these receptors’ function and are being pursued as a novel therapeutic approach. An extensive set of mutant human mGlu2 receptors were used to investigate the molecular determinants that are important for positive allosteric modulation at this receptor.Experimental approachSite-directed mutagenesis, binding and functional assays were employed to identify amino acids important for the activity of 9 PAMs. The data from the radioligand binding and mutagenesis studies were used with computational docking to predict a binding mode at an mGlu2 receptor model based on the recent mGlu1 structure.Key resultsNew amino acids in TM3 (R635, L639, F643), TM5 (L732) and TM6 (W773, F776) were identified for the first time as playing an important role in the activity of mGlu2 positive allosteric modulators.Conclusions and implicationsThis extensive study furthers our understanding of positive allosteric modulation of the mGlu2 receptor and can contribute to improved future design of mGlu2 PAMs.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Background and PurposeCognitive deficits in patients with Alzheimer's Disease, Parkinson's Disease, traumatic brain injury and stroke often involve alterations in cholinergic signaling. Currently available therapeutic drugs provide only symptomatic relief. Therefore, novel therapeutic strategies are needed to retard and/or arrest the progressive loss of memory.Experimental ApproachScopolamine-induced memory impairment provides a rapid and reversible phenotypic screening paradigm for cognition enhancement drug discovery. Male C57BL/6J mice administered scopolamine (1mg/kg) were used to evaluate the ability of LS-1-137, a novel sigma-1 receptor selective agonist, to improve the cognitive deficits associated with muscarinic antagonist administration.Key ResultsLS-1-137 is a high affinity (Ki = 3.2 nM) sigma-1 receptor agonist that is 80-fold selective for sigma-1 compared to sigma-2 receptor. LS-1-137 binds with low affinity at D2-like (D2, D3 and D4) dopamine and muscarinic receptors. LS-1-137 was found to partially reverse the learning deficits associated with scopolamine administration using a water maze test and an active avoidance task. LS-1-137 treatment was also found to trigger the release of BDNF from rat astrocytes.Conclusions and ImplicationsThe sigma-1 receptor selective compound such as LS-1-137 may represent a novel candidate cognitive enhancer for the treatment of cholinergic muscarinic-dependent cognitive deficits.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Background and PurposeThe locus coeruleus (LC) is the principal nucleus containing the noradrenergic neurons and is a major endogenous source of pain modulation in the brain. Glial cell line-derived neurotrophic factor (GDNF), a well-established neurotrophic factor for noradrenergic neurons, is a major pain modulator in the spinal cord and primary sensory neurons. However, it is unknown whether GDNF is involved in pain modulation in the LC.Experimental ApproachRats with chronic constriction injury (CCI) of the left sciatic nerve were used as a model of neuropathic pain. GDNF was injected into the left LC of rats with CCI for 3 consecutive days, and changes in mechanical allodynia and thermal hyperalgesia were assessed. The α2-adrenoceptor antagonist yohimbine was intrathecally administered to examine the involvement of descending inhibition in GDNF-mediated analgesia. The MEK inhibitor U0126 was used to investigate whether the ERK signaling pathway plays a role in the analgesic effects of GDNF.Key ResultsBoth mechanical allodynia and thermal hyperalgesia were attenuated 24 h after the first GDNF injection. GDNF increased the noradrenaline content in the dorsal spinal cord. The analgesic effects continued for at least 3 days after the last injection. Yohimbine abolished these effects of GDNF. The analgesic effects of GDNF were partially, but significantly, inhibited by prior injection of U0126 into the LC.Conclusions and ImplicationsGDNF injection into the LC exerts prolonged analgesic effects on neuropathic pain in rats by enhancing descending noradrenergic inhibition.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Background and Purposeμ-Opioid receptors (μORs), pro-opiomelanocortin, and pro-enkephalin are highly expressed in the nucleus tractus solitarii (NTSs). μ-Opioid agonists in the NTS cause dose-dependent increases in blood pressure (BP). However, the molecular mechanisms of this process remain unclear. Previous studies have revealed that the μORs heterodimerise with the α2A-adrenergic receptors (α2A-ARs) in vitro. We hypothesised that α2A-ARs lose their depressor effect when components of μOR/α2A-AR heterodimers in the NTS.Experimental ApproachWe microinjected μ-opioid agonists and antagonists into the NTSs of the rats and evaluated the resultant changes in BP and μOR/α2A-AR heterodimers.Key ResultsImmunofluorescence staining revealed the colocalisation of α2A-ARs and μORs in NTS neurons. A coimmunoprecipitation study also revealed an interaction between α2A-ARs and μORs. An in situ proximity ligation assay confirmed that μOR/α2A-AR heterodimers were present in the NTS. More endogenous endomorphin-1 and μOR/α2A-AR heterodimers were found in the NTSs of hypertensive rats than in those of normotensive rats. Microinjection of the μOR agonist [D-Ala2, MePhe4, Gly5-ol]-enkephalin (DAMGO) into the NTSs of normotensive rats promoted μOR/α2A-AR heterodimer-formations and BP elevation; however, the α2A-AR agonist guanfacine did not have the same effect. The nitric oxide (NO)-dependent BP-lowering effect of α2A-ARs was blunted as a result of greater μOR/α2A-AR heterodimer-formations in the NTSs of hypertensive rats and DAMGO-treated normotensive rats.Conclusions and ImplicationsOur results suggest that inappropriate increases in endogenous μ-opioids in the NTS induce μOR/α2A-AR heterodimer-formations and reduce the NO-dependent depressor effect of α2A-ARs. Therefore, this process contributes to the pathogenesis of hypertension.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Traditional pharmacology is defined as the science that deals with drugs and their actions. While small molecule drugs have clear advantages, there are many cases where they have proved to be ineffective, prone to unacceptable side effects, or where due to particular disease etiology small molecules cannot possibly be effective. A dominant feature of the small molecule drugs is their single-mindedness: they provide either continuous inhibition or continuous activation of the target. Because of that, these drugs tend to engage compensatory mechanisms leading to drug tolerance, drug resistance, or, in some cases, sensitization, and consequent loss of therapeutic efficacy over time and/or unwanted side effects. Here we discuss new and emerging therapeutic tools and approaches that have potential for treating the majority of disorders for which small molecules are either failing or cannot be developed. These new tools include biologics, such as recombinant hormones and antibodies, as well as approaches involving gene transfer (gene therapy and genome editing) and introduction of specially designed self-replicating cells. It is clear that no single method is going to be a “silver bullet”, but collectively these novel approaches hold promise for curing practically every disorder.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Background and PurposeSchizandrin (SCH) has been reported to prevent or reduce learning and memory defects. However, it remains unknown whether SCH ameliorates cognitive impairments induced by estrogen deficiency. In the present study, we investigated the effect of SCH on memory activity in ovariectomized (OVX) and non-OVX rats.Experimental ApproachA passive avoidance test was used to evaluate the effect of SCH on memory activity. Field excitatory postsynaptic potentials (fEPSPs) were recorded by using an electrophysiological method. In OVX rats, bilateral hippocampus was tested biochemical parameters including superoxide dismutase (SOD), malondialdehyde (MDA) and acetylcholinesterase (AChE). The number of nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) positive neurons was counted by NADPH-d histochemistry staining technique.Key ResultsOral SCH improves the memory activity and facilitates the induction of long-term potentiation in non-OVX and OVX rats, and more obvious effect was obtained from OVX rats. Similarly, SCH perfusion enhances synaptic transmission in the hippocampal slice both from non-OVX and OVX rats. However, SCH perfusion reduces the ratio of paired-pulse facilitation only in OVX but not non-OVX rats. In addition, SCH decreases AChE activity and MDA level, and increases SOD activity and the number of NADPH-d positive neurons in OVX rats.Conclusions and ImplicationsSCH improves memory activity and the potential mechanisms in OVX rats may include reducing the loss of hippocampal NADPH-d positive neurons, increasing antioxidation, and improving synaptic transmission that is possible involving from enhancing cholinergic function. Overall, our findings demonstrate that SCH could provide a potential therapeutic role for menopause cognitive dysfunction.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Background and PurposeIn arterial smooth muscle cells (myocytes) intravascular pressure stimulates membrane depolarization and vasoconstriction (the myogenic response). Ion channels proposed to mediate pressure-induced depolarization include several transient receptor potential (TRP) channels, including TRPM4, and transmembrane protein 16A (TMEM16A), a Ca2+-activated Cl- channel. 9-phenanthrol, a putative selective TRPM4 channel inhibitor, abolishes myogenic tone in cerebral arteries, suggesting that either TRPM4 is essential for pressure-induced depolarization, upstream of activation of other ion channels or that 9-phenanthrol is non-selective. Here, we tested the hypothesis that 9-phenanthrol is also a TMEM16A channel blocker, an ion channel for which few inhibitors have been identified.Experimental ApproachPatch-clamp electrophysiology was used to measure rat cerebral artery myocyte and human recombinant TMEM16A (rTMEM16A) currents or currents generated by recombinant bestrophin-1, another Ca2+-activated Cl- channel, expressed in HEK293 cells.Key Results9-phenanthrol blocked myocyte TMEM16A currents activated by either intracellular Ca2+ or Eact, a TMEM16A channel activator. In contrast, 9-phenanthrol did not alter recombinant bestrophin-1 currents. 9-phenanthrol reduced arterial myocyte TMEM16A currents with an IC50 of ∼12 μM. Cell-attached patch recordings indicated that 9-phenanthrol reduced single rTMEM16A channel open probability and mean open time, and increased mean closed time without affecting amplitude.Conclusions and ImplicationsThese data identify 9-phenanthrol as a novel TMEM16A channel blocker and provide and explanation for the previous observation that 9-phenanthrol abolishes myogenic tone when both TRPM4 and TMEM16A channels contribute to this response. 9-phenanthrol may be a promising candidate from which to develop TMEM16A channel-specific inhibitors.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Background and PurposeSodium butyrate (NaB), an epigenetic modifier, is effective in promoting insulin sensitivity. The specific genomic loci and mechanisms underlying epigenetically-induced obesity and insulin resistance (IR) and the targets of NaB are not fully understood.Experimental ApproachWe determined the effectiveness of NaB treatment as an anti-diabetic and anti-obesogenic agent by comparing phenotypes and physiologies of C57BL/6J mice fed a low fat diet (LF), high fat diet (HF) or high fat diet plus NaB (HF+NaB) for 10wks. We determined a possible mechanism of NaB action through induction of beneficial skeletal muscle mitochondrial adaptations and applied the method of MNase-seq to assess whole genome differences in nucleosome occupancy or positioning and identify associated epigenetic targets of NaB.Key ResultsNaB prevented HFD-induced increases in body weight and adiposity without altering food intake or energy expenditure, improved insulin sensitivity as measured by glucose and insulin tolerance tests and decreased respiratory exchange ratio. In skeletal muscle, NaB increased the percentage of type 1 fibers, improved acylcarnitine profiles as measured by metabolomics and produced a chromatin structure, determined by MNase-seq, similar to that seen in LF. Targeted analysis of representative nuclear-encoded mitochondrial genes showed specific repositioning of the -1 nucleosome in association with altered gene expression.Conclusions and ImplicationsNaB treatment may be an effective pharmacological approach for type 2 diabetes and obesity by inducing -1 nucleosome repositioning within nuclear-encoded mitochondrial genes, causing skeletal muscle mitochondrial adaptations that result in more complete beta oxidation and a lean, insulin sensitive phenotype.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Background and purposeThe Ca2+ sensitizer pimobendan is a unique inotropic agent that improves cardiac contractility with less of an increase in oxygen consumption and potentially fewer adverse effects on myocardial remodelling and arrhythmia, compared with traditional inotropes. However, clinical trials report contradictory effects of pimobendan in heart failure (HF) patients. We provide mechanistic experimental evidence of the efficacy of pimobendan using a novel mouse model of progressive HF.Experimental approachA knock-in mouse model of human genetic dilated cardiomyopathy, which shows a clear transition from compensatory to end-stage HF at a fixed time during growth, was used to evaluate the efficacy of pimobendan and explore the underlying molecular and cellular mechanisms.Key resultsPimobendan prevented myocardial remodelling in compensated HF and significantly extended the life span in both compensated and end-stage HF, but dose-dependently increased the sudden death in end-stage HF. In cardiomyocytes isolated from end-stage HF mice, pimobendan induced triggered activity probably due to early or delayed afterdepolarizations. The L-type Ca2+ channel blocker verapamil decreased the incidence of triggered activity, suggesting that this was from overly elevated cytoplasmic Ca2+ through increased Ca2+ entry by phosphodiesterase 3 inhibition under diminished sarcoplasmic reticulum Ca2+ reuptake and increased Ca2+ leakage from sarcoplasmic reticulum in end-stage HF.Conclusions and implicationsPimobendan is beneficial irrespective of HF stage, but increases sudden cardiac death in end-stage HF with extensive remodelling of Ca2+ handling. Reduction of cytoplasmic Ca2+ elevated by phosphodiesterase 3 inhibition might be able to decrease the risk of sudden cardiac death.
    British Journal of Pharmacology 01/2015;