Abstract：
:We investigated the action of the phenylalkylamines verapamil and N-methyl-verapamil on the Kv1.3 potassium channel using the whole-cell configuration of the patch-clamp technique. Our goal was to identify their binding as a prerequisite for using the phenylalkylamines as small, well-defined molecular probes, not only to expand the structural findings made with peptide toxins or by crystallization, but also to use them as lead compounds for the generation of more potent and therefore more specific K+ channel modulators. Competition experiments with charybdotoxin, known to interact with external residues of Kv1.3, showed no interaction with verapamil. The internal application of quarternary N-methyl-verapamil in combination with verapamil suggested competition for the same internal binding site. Verapamil affinity was decreased 6 fold by a mutation (M395V) in a region of the internal pore which forms part of the internal tetraethylammonium (TEA+) binding site, although mutations at neighbouring residues (T396 and T397) were without effect. Modification of C-type inactivation by mutations in the internal pore suggest that this region participates in the inactivation process. The action of phenylalkylamines and local anaesthetics on L-type Ca2+ channels and Na channels, respectively, and verapamil on Kv1.3 indicate very similar blocking mechanisms. This might allow the use of these compounds as molecular probes to map the internal vestibule of all three channel types.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Rauer H,Grissmer Sdoi
10.1038/sj.bjp.0702599subject
Has Abstractpub_date
1999-07-01 00:00:00pages
1065-74issue
5eissn
0007-1188issn
1476-5381journal_volume
127pub_type
杂志文章abstract：:1. In guinea-pigs previously sensitized with ovalbumin, the intra-plantar administration of the antigen induced dose-dependent and sustained oedema. An intense infiltrate of neutrophils and eosinophils was observed at the peak of the oedema (4 h). 2. Oedema induced by ovalbumin at the doses of 50 or 200 micrograms/paw...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1994.tb13038.x
更新日期：1994-05-01 00:00:00
abstract：:We have performed a systematic mutagenesis of three hydrophobic rings (17', 13' and 9') within transmembrane region (TM) 2 of the alpha9alpha10 nicotinic cholinergic receptor (nAChR) to a hydrophilic (threonine) residue and compared the properties of mutant receptors reconstituted in Xenopus laevis oocytes. Phenotypic...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0706224
更新日期：2005-08-01 00:00:00
abstract：:A study has been made of the pharmacology of the 5-hydroxytryptamine (5-HT)-induced depolarization responses that can be recorded extracellularly from the rat isolated cervical vagus nerve. Phenylbiguanide (PBG) and 2-methyl-5-hydroxytryptamine (2-methyl-5-HT) were found to mimic the effects of 5-HT on the vagus nerve...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1987.tb16844.x
更新日期：1987-01-01 00:00:00
abstract：:The role of putative neurotransmitters of the central nervous system in the central gastric antisecretory effect of prostaglandin E2 (PGE2) was investigated in pylorus-ligated rats. Pretreatment of the rats with an intracerebroventricular (i.c.v.) injection of 6-hydroxydopamine (6-OHDA) prevented the antisecretory eff...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1985.tb08849.x
更新日期：1985-05-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Botulinum toxin type A (BoNT/A) injections into hyperactive muscles provide effective treatment for spasticity and dystonias, presumably due to its local effects on extrafusal and intrafusal motor fibres. A recent discovery of toxin's retrograde axonal transport to CNS might suggest additional ac...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/bph.14846
更新日期：2020-01-01 00:00:00
abstract：:1. Taxanes are antineoplastic drugs which have cardiovascular side effects of unknown mechanism. We investigated their influence on blood viscosity and erythrocyte morphology. 2. Whole blood was incubated in vitro with increasing concentrations of Taxol, Taxotere, paclitaxel (0-100 microM) and the vehicles Cremophor-E...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0704387
更新日期：2001-11-01 00:00:00
abstract：:1. The present study was undertaken to investigate the effect of Delta9-tetrahydrocannabinol (Delta9-THC) and possible serotoninergic involvement on the extracellular level of dopamine (DA) in the striatum using microdialysis in conscious, freely-moving rats. 2. A dose-dependent increase in striatal DA release occurre...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0702753
更新日期：1999-09-01 00:00:00
abstract：:To establish that bradykinin is formed in the heart we measured bradykinin in the venous effluent from rat isolated hearts perfused with Krebs-Henseleit buffer. In addition, we examined the effect on bradykinin outflow of the angiotensin converting enzyme (ACE) inhibitor, ramiprilat. From rat isolated normoxic hearts ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1993.tb12797.x
更新日期：1993-02-01 00:00:00
abstract：:The consumption of green tea (Camellia sinensis) has been shown to have many physiological and pharmacological health benefits. In the past two decades several studies have reported that epigallocatechin-3-gallate (EGCG), the main constituent of green tea, has anti-infective properties. Antiviral activities of EGCG wi...
journal_title：British journal of pharmacology
pub_type： 杂志文章,评审
doi：10.1111/bph.12009
更新日期：2013-03-01 00:00:00
abstract：:Muscularis mucosa of the distal oesophagus of the opossum contains nerves which release acetylcholine and substance P(SP)-like material on field stimulation. The release of SP-like material appeared to be inhibited by the presence of exogenous muscarinic agonists and potentiated by muscarinic antagonists. Analysis of ...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1986.tb10254.x
更新日期：1986-07-01 00:00:00
abstract：:Dopamine, noradrenaline (NA) and adrenaline (Ad) depletion by 6-hydroxydopamine (6-OHDA) and pargyline plus 6-OHDA was investigated in the cat left ventricle, mesenteric and renal arteries, renal cortex, renal medulla and adrenal medulla. Catecholamine concentrations in plasma were also analyzed in these two experimen...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1985.tb08903.x
更新日期：1985-10-01 00:00:00
abstract：:The gastrointestinal (GI) tract is exposed to a large array of proteases, under both physiological and pathophysiological conditions. The discovery of G protein-coupled receptors activated by proteases, the protease-activated receptors (PARs), has highlighted new signaling functions for proteases in the GI tract, part...
journal_title：British journal of pharmacology
pub_type： 杂志文章,评审
doi：10.1038/sj.bjp.0705750
更新日期：2004-04-01 00:00:00
abstract：:1. In the present study we tested the hypothesis that insulin-like growth factor-1 (IGF-1) modulates resting chloride conductance (G(Cl)) of rat skeletal muscle by activating a phosphatase and that the chloride channel, based on the activity of phosphorylating-dephosphorylating pathways, has different sensitivity to s...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0702107
更新日期：1998-10-01 00:00:00
abstract：:There are proposals for the implementation of beta(2)-adrenoceptor agonists for the management of muscle wasting diseases. The idea has been initiated by studies in animal models which show that beta(2)-adrenoceptor agonists cause hypertrophy of skeletal muscle. Their use in clinical practice will also need an underst...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0706670
更新日期：2006-03-01 00:00:00
abstract：:A new C5a receptor antagonist, the cyclic peptide Phe-[Orn-Pro-D-cyclohexylalanine-Trp-Arg], (F-[OPdChaWR]), was tested for its ability to antagonize the neutropenic effects of both C5a and endotoxin in rats. Human recombinant C5a (2 microg kg(-1) i.v.) caused rapid neutropenia, characterized by an 83% decrease in cir...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0702338
更新日期：1999-02-01 00:00:00
abstract：:1. The aim of this study was to investigate the cardiovascular effects of a novel, potent and specific phosphodiesterase 5 (PDE 5) inhibitor, 1,3 dimethyl-6-(2-propoxy-5-methane sulphonylamidophenyl)-pyrazolo[3,4-d]pyrimidin-4-(5H)-one (DMPPO) in phenylephrine-precontracted rat aortic rings and different in vivo rat p...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1996.tb15548.x
更新日期：1996-07-01 00:00:00
abstract：:The Wnt/β-catenin signalling pathway is pivotal for stem cell function and the control of cellular differentiation, both during embryonic development and tissue homeostasis in adults. Its activity is carefully controlled through the concerted interactions of concentration-limited pathway components and a wide range of...
journal_title：British journal of pharmacology
pub_type： 杂志文章,评审
doi：10.1111/bph.14038
更新日期：2017-12-01 00:00:00
abstract：:1. The effects of the muscarinic agonist carbachol on phosphoinositide metabolism and its relationship to alteration of intracellular calcium were examined in SK-N-SH human neuroblastoma cells. Muscarinic receptors on these cells are coupled to phospholipase C and the myo [2-3H]-inositol phosphates resulting from rece...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1989.tb12681.x
更新日期：1989-12-01 00:00:00
abstract：:1. We have compared the effects of ouabain on the maintenance of gap junctional communication in rat aortic A7r5 smooth muscle cells, monkey COS-1 fibroblasts and human HeLa epithelial cells. 2. Ouabain (1 mM) interrupted dye coupling between confluent A7r5 cells within approximately 1 h, and high concentrations of ou...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0705556
更新日期：2003-12-01 00:00:00
abstract：:1 The effects of alpha- and beta-adrenoceptor stimulants on the histamine-forming capacity (HFC) of human isolated leucocytes have been studied, in vitro.2 It was confirmed that antigen significantly stimulates the HFC of human leucocytes.3 beta-Adrenoceptor stimulants, such as isoprenaline and salbutamol (10(-6)-10(-...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1974.tb09702.x
更新日期：1974-10-01 00:00:00
abstract：:In the last 20 years, the global regulatory frameworks for drug assessment have been managing the challenges posed by using cellular products as new therapeutic tools. Currently, they are defined as "Advanced Therapy Medicinal Products", comprising a large group of cellular types that either alone or in combination wi...
journal_title：British journal of pharmacology
pub_type： 杂志文章,评审
doi：10.1111/bph.15305
更新日期：2020-11-03 00:00:00
abstract：:1 The effects of opioids on synaptic transmission in cat sacral parasympathetic colonic ganglia were studied in vitro, using intracellular electrophysiological techniques. Electrical stimulation of the pelvic nerve evoked fast excitatory postsynaptic potentials (e.p.s.ps), which were blocked by hexamethonium and tetro...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1987.tb11340.x
更新日期：1987-10-01 00:00:00
abstract：:(1) We have investigated the properties of native and haemagglutinin (HA)-tagged neuropeptide Y (NPY) Y(1) receptors after mutation of the palmitoylation site Cys(337) to Ser or Ala. (2) In Chinese hamster ovary cells expressing similar receptor levels, the C337A mutation abolished incorporation of [(3)H]palmitic acid...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0705276
更新日期：2003-06-01 00:00:00
abstract：:1. The effects of inhibiting endogenous Cu/Zn superoxide dismutase (SOD) with diethyldithiocarbamate (DETCA) were examined on the ability of hydroquinone, hydroxocobalamin and carboxy-PTIO to block nitrergic relaxation in the bovine retractor penis (BRP) muscle. 2. Incubation of strips of BRP with DETCA (3 mM) for 2 h...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1996.tb15333.x
更新日期：1996-04-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Marijuana smoking is widespread in many countries, and the use of smoked synthetic cannabinoids is increasing. Smoking a marijuana joint leads to bronchodilation in both healthy subjects and asthmatics. The effects of Δ(9) -tetrahydrocannabinol and synthetic cannabinoids on human bronchus reactiv...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/bph.12597
更新日期：2014-06-01 00:00:00
abstract：:1 Noradrenaline (0.2 to 20 micrograms) and carbachol (0.1 to 1 microgram) injected into the preoptic/anterior hypothalamic area, evoked dose-dependent falls in core temperature at all sites tested, followed in most experiments by delayed increases that were not dose-related. Muscarine (0.1 to 10 microgram) produced ef...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1979.tb17332.x
更新日期：1979-01-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Some neurosteroids, notably 3alpha-hydroxysteroids, positively modulate GABA(A) receptors, but sulphated steroids negatively modulate these receptors. Recently, other lipophilic amphiphiles have been suggested to positively modulate GABA receptors. We examined whether there was similarity among t...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.2010.00679.x
更新日期：2010-05-01 00:00:00
abstract：:The Secretin family of GPCRs are endocrine peptide hormone receptors that share a common genomic organization and are the subject of a wide variety of alternative splicing. All GPCRs contain a central seven transmembrane domain responsible for transducing signals from the outside of the cell as well as extracellular a...
journal_title：British journal of pharmacology
pub_type： 杂志文章,评审
doi：10.1111/j.1476-5381.2011.01571.x
更新日期：2012-05-01 00:00:00
abstract：:1 Contractions of the cat nictitating membrane were elicited on stimulation of the internal carotid nerve, and the effects were studied of desipramine and two inhibitors of catechol-O-methyltransferase, U-0521 and pyrogallol, on the subsequent relaxation of the muscle. 2 The relaxation of the nictitating membrane occu...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1111/j.1476-5381.1978.tb07762.x
更新日期：1978-04-01 00:00:00
abstract：:1. The role of alpha2-adrenoceptor (AR) subtypes in the modulation of acute nociception, motor behaviour and body temperature, has been investigated by determining the activity of the alpha2AR selective agonist dexmedetomidine (Dex) in mice devoid of individual alpha2AR subtypes through either a point (alpha2A) or nul...
journal_title：British journal of pharmacology
pub_type： 杂志文章
doi：10.1038/sj.bjp.0701520
更新日期：1997-12-01 00:00:00
