Abstract:
BACKGROUND AND PURPOSE:Ca(2+)-dependent Cl(-) secretion (CaCC) in airways and other tissues is due to activation of the Cl(-) channel TMEM16A (anoctamin 1). Earlier studies suggested that Ca(2+) -activated Cl(-) channels are regulated by membrane lipid inositol phosphates, and that 1-O-octyl-2-O-butyryl-myo-inositol 3,4,5,6-tetrakisphosphate octakis(propionoxymethyl) ester (INO-4995) augments CaCC. Here we examined whether TMEM16A is the target for INO-4995 and if the channel is regulated by inositol phosphates. EXPERIMENTAL APPROACH:The effects of INO-4995 on CaCC were examined in overexpressing HEK293, colonic and primary airway epithelial cells as well as Xenopus oocytes. We used patch clamping, double electrode voltage clamp and Ussing chamber techniques. KEY RESULTS:We found that INO-4995 directly activates a TMEM16A whole cell conductance of 6.1 ± 0.9 nS pF(-1) in overexpressing cells. The tetrakisphosphates Ins(3,4,5,6)P(4) or Ins(1,3,4,5)P(4) and enzymes controlling levels of InsP(4) or PIP(2) and PIP(3) had no effects on the magnitude or kinetics of TMEM16A currents. In contrast in Xenopus oocytes, human airways and colonic cells, which all express TMEM16A endogenously, Cl(-) currents were not acutely activated by INO-4995. However incubation with INO-4995 augmented 1.6- to 4-fold TMEM16A-dependent Cl(-) currents activated by ionomycin or ATP, while intracellular Ca(2+) signals were not affected. The potentiating effect of INO-4995 on transient ATP-activated TMEM16A-currents in cystic fibrosis (CF) airways was twice of that observed in non-CF airways. CONCLUSIONS AND IMPLICATIONS:These data indicate that TMEM16A is the target for INO-4995, although the mode of action appears different for overexpressed and endogenous channels. INO-4995 may be useful for the treatment of CF lung disease.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Tian Y,Schreiber R,Wanitchakool P,Kongsuphol P,Sousa M,Uliyakina I,Palma M,Faria D,Traynor-Kaplan AE,Fragata JI,Amaral MD,Kunzelmann Kdoi
10.1111/j.1476-5381.2012.02193.xsubject
Has Abstractpub_date
2013-01-01 00:00:00pages
253-65issue
1eissn
0007-1188issn
1476-5381journal_volume
168pub_type
杂志文章abstract::1. The relaxant effects of Zeneca ZD7114, BRL37344 (putative beta 3-adrenoceptor agonists) and various phenylethylamine-based agonists were studied in isolated ileum of the rat where tone was increased with carbachol (0.5 microM). Agonist-induced relaxation.was measured under equilibrium conditions with alpha-, beta 1...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1993.tb13972.x
更新日期:1993-12-01 00:00:00
abstract:BACKGROUND AND PURPOSE:The increased proliferation and migration of vascular smooth muscle cells (VSMCs) after arterial injury contributes greatly to the pathogenesis of neointimal hyperplasia. As a major component of epigenetics, histone methylation plays an important role in several cardiovascular diseases. However, ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.14754
更新日期:2019-09-01 00:00:00
abstract::1. Changes in membrane potential (measured with an intracellular microelectrode) and in cyclic nucleotide (adenosine 3':5'-cyclic monophosphate, cyclic AMP and guanosine 3':5'-cyclic monophosphate, cyclic GMP) levels (measured by radioimmunoassay) in response to inhibitory non-adrenergic non-cholinergic (NANC) field s...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1990.tb15804.x
更新日期:1990-06-01 00:00:00
abstract::(1) We determined the effects of long-term treatment with aminoguanidine (AG), an inhibitor of advanced glycation end products, on the mechanical properties of the arterial system in aged Fisher 344 rats, using the aortic impedance analysis. (2) Normotensive rats were treated from 18 to 24 months with AG (1 g/l-1 in d...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705410
更新日期:2003-09-01 00:00:00
abstract:BACKGROUND AND PURPOSE:The thiourea derivative KB-R7943, originally developed as inhibitor of the plasma membrane Na(+)/Ca(2+) exchanger, has been shown to protect against myocardial ischemia-reperfusion injury. We have studied here its effects on mitochondrial Ca(2+) fluxes. EXPERIMENTAL APPROACH:[Ca(2+)] in cytosol,...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0707260
更新日期:2007-07-01 00:00:00
abstract::1. Endothelin-1 (ET-1) binding site densities and constrictor activities were compared in airway smooth muscle preparations of human, guinea-pig, rat and mouse. 2. The mean contractile response to 0.3 microM ET-1 (measured as the % maximum response to 10 microM carbachol, % Cmax +/- s.e.mean) and the mean concentratio...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1990.tb14093.x
更新日期:1990-08-01 00:00:00
abstract::1. Carrageenin or 5-hydroxytryptamine-induced oedema of the mouse hind paw was antagonized by catecholamines acting on both alpha- and beta-adrenoceptors.2. Increased permeability of the mouse peritoneum induced by the local injection of acetic acid or pro-inflammatory mediators was antagonized by catecholamines actin...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1972.tb08086.x
更新日期:1972-06-01 00:00:00
abstract::1. The pharmacokinetics of cyclophosphamide were investigated in cancer patients. The data can be characterized by a two-compartment open model. The half life of the elimination phase of the drug ranged between 3 and 11 hours.2. Extensive tubular reabsorption of the drug resulted in the excretion of only a small perce...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1971.tb07199.x
更新日期:1971-11-01 00:00:00
abstract::1. Prostaglandin E2 (PGE2) relaxes circular smooth muscle of the rabbit isolated jugular vein at very low concentrations (mean pIC50 against histamine-induced contraction = 9.34). This effect is not blocked by the EP1-receptor antagonist, AH 6809 (2 microM). 2. From a group of prostaglandin E analogues examined, 16,16...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1992.tb09063.x
更新日期:1992-04-01 00:00:00
abstract::1. Salmeterol is a potent, selective and long acting beta 2-adrenoceptor agonist. In vitro, salmeterol exerts 'reassertion' relaxation of airways smooth muscle. Reassertion relaxation refers to the capacity of salmeterol to cause repeated functional antagonism of induced contraction when airway smooth muscle is interm...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb16690.x
更新日期:1996-03-01 00:00:00
abstract::Adrenomedullin (ADM) 2/intermedin (IMD) is a short peptide that belongs to the CGRP superfamily. Although it shares receptors with CGRP, ADM and amylin, ADM2 has significant and unique functions in the cardiovascular system. In the past decade, the cardiovascular effect of ADM2 has been carefully analysed. In this rev...
journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1111/bph.13814
更新日期:2018-04-01 00:00:00
abstract::Ginsenoside Rg1, an active ingredient in ginseng, was previously shown to be a novel class of potent phytoestrogen. The present study aims at investigating the molecular mechanisms involved in mediating its actions in human breast cancer (MCF-7) cells. Rg1 (1 pM) stimulates cell proliferation (P<0.01) and estrogen-res...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0706640
更新日期:2006-03-01 00:00:00
abstract::1. By use of the whole-cell configuration of the patch-clamp technique, membrane currents induced by cyclopiazonic acid (CPA; an inhibitor of the sarcoplasmic reticulum (SR) calcium-ATPase) were investigated in single smooth muscle cells freshly dispersed from the mouse anococcygeus. Voltage-dependent calcium currents...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb15228.x
更新日期:1996-02-01 00:00:00
abstract::1. The action of the non-steroidal anti-inflammatory drugs (NSAID), sodium salicylate, aspirin, phenylbutazone and indomethacin was investigated on the migration of human polymorphonuclear cells (PMNs) and lymphocytes, using the system of migration of leucocytes from glass capillary tubes. 2. All NSAID produced a dose...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:
更新日期:1978-11-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Rho kinase (ROCK) activation is involved in neuroinflammatory processes leading to progression of neurodegenerative diseases such as Parkinson's disease. Furthermore, ROCK plays a major role in angiogenesis. Neuroinflammation and angiogenesis are mechanisms involved in developing l-DOPA-induced d...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.15275
更新日期:2020-12-01 00:00:00
abstract::In moderate-to-severe asthma, adding an inhaled long-acting β2 -adenoceptor agonist (LABA) to an inhaled corticosteroid (ICS) provides better disease control than simply increasing the dose of ICS. Acting on the glucocorticoid receptor (GR, gene NR3C1), ICSs promote anti-inflammatory/anti-asthma gene expression. In vi...
journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1111/bph.13628
更新日期:2016-12-01 00:00:00
abstract::1 The effects of pretreatment with aspirin, and of prostacyclin (PGI(2)) infusions, on responses to myocardial ischaemia and infarction produced by ligation of a coronary artery were investigated in conscious rats.2 Surgical preparation, under halothane anaesthesia, consisted of implanting exteriorized aortic and jugu...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1983.tb09359.x
更新日期:1983-01-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Tanshinol borneol ester (DBZ) is a novel synthetic compound derived from Dantonic® , a botanical drug approved in 26 countries outside the United States for angina pectoris and currently undergoing FDA Phase III clinical trial. Here, we investigated the angiogenic effects of (S)-DBZ and (R)-DBZ i...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.14714
更新日期:2019-09-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Hydrogen sulphide (H2 S) is an endogenous gaseous signalling molecule with putative functions in gastrointestinal motility regulation. Characterization of H2 S effects on colonic motility is crucial to establish its potential use as therapeutic agent in the treatment of colonic disorders. EXPERI...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.12100
更新日期:2013-05-01 00:00:00
abstract::Despite progression in anticancer drug development and improvements in the clinical utilization of therapies, current treatment regimes are still dependent upon the use of systemic antiproliferative cytotoxic agents. Although these agents are unquestionably potent, their efficacy is limited by toxicity towards 'normal...
journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1038/sj.bjp.0707657
更新日期:2008-04-01 00:00:00
abstract::The antioestrogen, tamoxifen, blocks volume-regulated chloride channels and reduces transparency in bovine lenses maintained in vitro. In contrast to tamoxifen, the steroidal antioestrogen, ICI 182780, did not block volume-regulated chloride currents in three cultured cell lines and required 10 fold higher concentrati...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1995.tb16622.x
更新日期:1995-08-01 00:00:00
abstract::1 Burimamide injected intravenously in the anaesthetized or conscious cat produced significant increases in gastric acid secretion: in the anaesthetized cat it produced increased gastric mucosal blood flow. 2 Metiamide, in doses which inhibited pentagastrin-stimulated acid secretion, produced no increase in gastric ac...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1975.tb07361.x
更新日期:1975-02-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Kyotorphin (KTP; L-Tyr-L-Arg), an endogenous neuropeptide, is potently analgesic when delivered directly to the central nervous system. Its weak analgesic effects after systemic administration have been explained by inability to cross the blood-brain barrier (BBB) and detract from the possible cl...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2011.01290.x
更新日期:2011-07-01 00:00:00
abstract::(1) Here, we introduce a beta-casomorphin-5-derived cyclic pentapeptide, cCD-2 (Tyr-cyclo[d-Orn-Tyr(Bzl)-Pro-Gly]), which inhibits the cell growth of a variety of human cancer cell lines. (2) This opioid-derived peptide possesses only low affinity for mu-receptors, but enhances the agonist binding to mu-receptors in v...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705416
更新日期:2003-09-01 00:00:00
abstract::1. A pentobarbitone-anaesthetized canine model of myocardial conduction was developed to evaluate drug effects on intra-atrial (I-A), intra-ventricular (I-V) and atrioventricular (A-V) conduction parameters, both at rest and during electrical pacing of the right atrium or ventricle. Drug effects on the ability of the ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1988.tb11444.x
更新日期:1988-02-01 00:00:00
abstract::1. The pharmacological characteristics of RP 67580, a non-peptide tachykinin NK1 receptor antagonist, and its effects on a reflex response evoked by stimulation of primary afferent fibres, were examined in isolated neonatal spinal cord preparations of the rat. Potentials were recorded extracellularly from a lumbar ven...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb17116.x
更新日期:1994-12-01 00:00:00
abstract::1. This study investigated whether a single administration of a range of doses (1, 4 and 8 mg kg-1, i.p.) of paroxetine, citalopram or venlafaxine may simultaneously increase extracellular levels of 5-HT ([5-HT]ext) and noradrenaline ([NA]ext) by using in vivo microdialysis in the frontal cortex (FCx) of awake, freely...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705538
更新日期:2003-11-01 00:00:00
abstract::1. Behavioural activity (delayed differentiation and spatial delayed alternation) and pharmacokinetics of diazepam and its metabolites, N-desmethyldiazepam (nordiazepam), 3-hydroxydiazepam (temazepam) and 3-hydroxy-N-desmethyldiazepam (oxazepam), and of dipotassium clorazepate (clorazepate), were studied in the monkey...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1977.tb08423.x
更新日期:1977-11-01 00:00:00
abstract::1. Neurally-evoked output of newly synthesized [3H]-acetylcholine from the rat phrenic nerve was measured in the absence of cholinesterase inhibitors. 2. Noradrenaline and isoprenaline enhanced neurally-evoked transmitter output markedly. Moreover, immediately after the application of noradrenaline the basal tritium e...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1988.tb11574.x
更新日期:1988-07-01 00:00:00
abstract::1. Endotoxaemia causes an enhanced formation of reactive oxygen species (ROS) which contribute to the multiple organ dysfunction syndrome (MODS) in septic shock. Here we investigate (i) the effects of endotoxin on the expression of two isoforms of superoxide dismutase (SOD), namely Cu/Zn-SOD (cytosol) and Mn-SOD (mito...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702123
更新日期:1998-10-01 00:00:00