J.C. McGrath

Guidelines for reporting experiments involving animals: the ARRIVE guidelines

British Journal of Pharmacology (BJP) is pleased to publish a new set of guidelines for reporting research involving animals, simultaneously with several other journals; the ‘ARRIVE’ guidelines (Animals in Research: Reporting In Vivo Experiments). This editorial summarizes the background to the guidelines, gives our view of their significance, considers aspects of specific relevance to pharmacology, re‐states BJPs guidelines for authors on animal experiments and indicates our commitment to carrying on discussion of this important topic. We also invite feedback via the British Pharmacological Society website.

The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands

The IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb, http://www.guidetopharmacology.org) provides expert-curated molecular interactions between successful and potential drugs and their targets in the human genome. Developed by the International Union of Basic and Clinical Pharmacology (IUPHAR) and the British Pharmacological Society (BPS), this resource, and its earlier incarnation as IUPHAR-DB, is described in our 2014 publication. This update incorporates changes over the intervening seven database releases. The unique model of content capture is based on established and new target class subcommittees collaborating with in-house curators. Most information comes from journal articles, but we now also index kinase cross-screening panels. Targets are specified by UniProtKB IDs. Small molecules are defined by PubChem Compound Identifiers (CIDs); ligand capture also includes peptides and clinical antibodies. We have extended the capture of ligands and targets linked via published quantitative binding data (e.g. Ki, IC50 or Kd). The resulting pharmacological relationship network now defines a data-supported druggable genome encompassing 7% of human proteins. The database also provides an expanded substrate for the biennially published compendium, the Concise Guide to PHARMACOLOGY. This article covers content increase, entity analysis, revised curation strategies, new website features and expanded download options.

The IUPHAR/BPS Guide to PHARMACOLOGY: an expert-driven knowledgebase of drug targets and their ligands

The International Union of Basic and Clinical Pharmacology/British Pharmacological Society (IUPHAR/BPS) Guide to PHARMACOLOGY (http://www.guidetopharmacology.org) is a new open access resource providing pharmacological, chemical, genetic, functional and pathophysiological data on the targets of approved and experimental drugs. Created under the auspices of the IUPHAR and the BPS, the portal provides concise, peer-reviewed overviews of the key properties of a wide range of established and potential drug targets, with in-depth information for a subset of important targets. The resource is the result of curation and integration of data from the IUPHAR Database (IUPHAR-DB) and the published BPS ‘Guide to Receptors and Channels’ (GRAC) compendium. The data are derived from a global network of expert contributors, and the information is extensively linked to relevant databases, including ChEMBL, DrugBank, Ensembl, PubChem, UniProt and PubMed. Each of the ∼6000 small molecule and peptide ligands is annotated with manually curated 2D chemical structures or amino acid sequences, nomenclature and database links. Future expansion of the resource will complete the coverage of all the targets of currently approved drugs and future candidate targets, alongside educational resources to guide scientists and students in pharmacological principles and techniques.

Experimental design and analysis and their reporting: new guidance for publication in BJP

This Editorial is part of a series. To view the other Editorials in this series, visit: http://onlinelibrary.wiley.com/doi/10.1111/bph.12956/abstract; http://onlinelibrary.wiley.com/doi/10.1111/bph.12954/abstract; http://onlinelibrary.wiley.com/doi/10.1111/bph.12955/abstract and http://onlinelibrary.wiley.com/doi/10.1111/bph.13112/abstract

Implementing guidelines on reporting research using animals (ARRIVE etc.): new requirements for publication in BJP

The ARRIVE guidelines have been implemented in BJP for 4 years with the aim of increasing transparency in reporting experiments involving animals. BJP has assessed our success in implementing them and concluded that we could do better. This editorial discusses the issues and explains how we are changing our requirements for authors to report their findings in experiments involving animals. This is one of a series of editorials discussing updates to the BJP Instructions to Authors

The Concise Guide to PHARMACOLOGY 2015/16: Overview

The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands ( www.guidetopharmacology.org ), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13347/full . This compilation of the major pharmacological targets is divided into eight areas of focus: G protein‐coupled receptors, ligand‐gated ion channels, voltage‐gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org , superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC‐IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR‐DB and GRAC and provides a permanent, citable, point‐in‐time record that will survive database updates.

The Concise Guide to PHARMACOLOGY 2013/14 : overview.

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties from the IUPHAR database. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full.

Separation of adrenergic and non-adrenergic contractions to field stimulation in the rat vas deferens.

1 Adrenergic and ‘non‐adrenergic’ nerve‐induced contractions in rat vas deferens were separated pharmacologically. 2 Responses to single stimuli comprised two components, an α‐noradrenergic component (IIs), dominant in the epididymal portion, and a ‘non‐adrenergic’ component (Is), dominant in the prostatic portion. Is but not IIs was blocked by nifedipine. A combination of adrenergic blockade and nifedipine virtually abolished all components. After cocaine, a third component (IIIs) emerged which was abolished by either adrenergic blockade or nifedipine. 3 The response to trains of stimuli consisted of ‘twitch’ and ‘secondary’ components. This biphasic time course was modified by adrenergic blockade or nifedipine to reveal the time course of the ‘non‐adrenergic’ and adrenergic components, respectively: these did not correspond to the ‘twitch’ and ‘secondary’ components. A combination of adrenergic blockade and nifedipine virtually abolished the whole response. 4 Prejunctional α2‐adrenoceptor‐mediated inhibition of the contractile responses could be blocked by selective α2‐adrenoceptor antagonists. The adrenergic contractile response demonstrated this ‘feed‐back’ even on the second pulse at 0.5 Hz. Endogenous inhibition of the ‘non‐adrenergic’ contraction required higher frequencies or enhancement of the extracellular concentration of noradrenaline by blockade of its neuronal uptake. 5 Contractile responses to exogenous noradrenaline were abolished by nifedipine, at a concentration that did not affect the adrenergic (IIs) neurotransmission. 6 These results reinforce the view that part of the motor transmission in rat vas deferens is non‐adrenergic and allow the disentanglement of the various postjunctional and prejunctional elements contributing to the complex response to a train of stimuli.

α2‐Adrenoceptor subtypes and imidazoline‐like binding sites in the rat brain

1 The binding of [3H]‐yohimbine and [3H]‐idazoxan to rat cortex and hippocampus is rapid, reversible and of high affinity. Saturation data indicate that a single population of binding sites exist for [3H]‐yohimbine in the cortex (Bmax 121 ± 10 fmol mg−1, protein; Kd 5.2 ± 0.9 nm) and hippocampus (Bmax 72 ± 6 fmol mg−1 protein; Kd 5.8 ± 0.7 nm). [3H]‐idazoxan labels one site in the cortex (Bmax 87 ± 8 fmol mg−1 protein; Kd 4.1± 0.9 nm) and hippocampus (Bmax 30 ± 6 fmol mg−1 protein; Kd 3.5 + 0.5 nm), when 3 μm phentolamine is used to define non‐specific binding. A second distinct [3H]‐idazoxan binding site (Bmax 110 ± 21fmolmg_1 protein; Kd 3.6 ± 0.07 nm) is identified in rat cortex if 0.3 μm cirazoline is used to define non‐specific binding and 3 μm yohimbine is included to prevent binding to α2‐adrenoceptors. 2 Displacement studies indicate that the α1‐adrenoceptor antagonist prazosin and the 5‐HT1 ligands 8‐OH‐DPAT, RU 24969 and methysergide differentiate [3H]‐yohimbine binding into two components; a high and low affinity site. In contrast the displacement of [3H]‐idazoxan by each ligand was monophasic. 3 The affinities of 8‐OH‐DPAT, RU 24969 and methysergide determined against [3H]‐idazoxan binding to the cortex and hippocampus correlate significantly with the binding site displaying low affinity for prazosin and previously designated α2A. In contrast, a poor correlation exists for the high affinity site for prazosin designated α2B. 4 [3H]‐idazoxan, in the presence of 3 μm yohimbine, labels a site that displays high affinity towards cirazoline, naphazoline and guanabenz, but low affinity towards clonidine, p‐aminoclonidine, adrenaline, noradrenaline and the α2‐adrenoceptor antagonists yohimbine, rauwolscine, WY 26703 and BDF 6143. 5 The results of this study indicate that [3H]‐yohimbine labels two sites; the α2A‐ and α2B‐adrenoceptors whereas [3H]‐idazoxan labels an α2‐adrenoceptor with a profile consistent with the α2A‐adrenoceptor subtype. In addition, [3H]‐idazoxan labels an imidazoline binding site in the rat cortex that is pharmacologically distinct from α2‐adrenoceptors. The low affinity of clonidine and p‐aminoclonidine indicates that the imidazoline‐like binding site in rat cortex is different from the site labelled by [3H]‐clonidine and [3H]‐p‐aminoclonidine in human, rat and bovine brain stem, providing evidence of potential heterogeneity within this class of binding sites.

Role of Elastin in Spontaneously Hypertensive Rat Small Mesenteric Artery Remodelling

Chronic hypertension is associated with resistance artery remodelling and mechanical alterations. However, the contribution of elastin has not been thoroughly studied. Our objective was to evaluate the role of elastin in vascular remodelling of mesenteric resistance arteries (MRA) from spontaneously hypertensive rats (SHR). MRA segments from Wistar Kyoto rats (WKY) and SHR were pressurised under passive conditions at a range of physiological pressures with pressure myography. Confocal microscopy was used to determine differences in the quantity and organisation of elastin in intact pressure‐fixed arteries. To assess the contribution of elastin to MRA structure and mechanics, myograph‐mounted vessels were studied before and after elastase incubation. When compared with WKY, MRA from SHR showed: (1) a smaller lumen, (2) decreased distensibility at low pressures, (3) a leftward shift of the stress‐strain relationship, (4) redistribution of elastin within the internal elastic lamina (IEL) leading to smaller fenestrae but no change in fenestrae number or elastin amount. Elastase incubation (1) fragmented the structure of IEL in a concentration‐dependent fashion, (2) abolished all the structural and mechanical differences between strains, and (3) decreased distensibility at low pressures. The study shows the overriding role of elastin in determining vascular dimensions and mechanical properties in a resistance artery. In addition, it informs hypertensive remodelling. MRA remodelling and increased stiffness are accompanied by elastin restructuring within the IEL and elastin degradation reverses structural and mechanical alterations of SHR MRA. Differences in elastin organisation are, therefore, a central element in small artery remodelling in hypertension.