Abstract:
:1. The role of endogenous ADP in platelet aggregation in vivo remains unclear due to the lack of suitable P2T-antagonist probes. This paper describes the potency, selectivity and specificity of the novel P 2T-purinoceptor antagonist, FPL 67085 (2-propylthio-D-beta,gamma-dichloromethylene ATP) both in vitro and in the anaesthetized rat in vivo. 2. FPL 67085 (3-30 nM) produced concentration-dependent rightward displacement of the concentration-effect (E/[A]) curve for ADP-induced aggregation of human washed platelets with no effect on ADP-independent aggregation at < or = 10 microM. 3. Logistic fitting of ADP E/[A] data indicated that the antagonist effect of FPL 67085 did not consistently accord with simple competition: in some preparations depression of the asymptote was seen. Schild analysis of data combined from all preparations, regardless of the antagonist profile observed, gave an apparent pKB of 8.9 (slope parameter 0.90). 4. The potency of FPL 67085 was unaffected by the P1-purinoceptor antagonist, 8-sulphophenyltheophylline, was similar (IC50 0.6-3.8 nM) in human and rat washed platelets or whole blood and, in rat blood, did not change following 2-30 min incubation at 37 degrees C. 5. FPL 67085 was a weak (pA50 approximately 4.2) partial agonist in tissues containing P2X- or P2Y-purinoceptors, indicating some 30,000 fold selectivity for the P2T-subtype. 6. In anaesthetized rats, intravenous infusion of FPL 67085 produced rapidly-reversible, dose-related inhibition of ADP-induced platelet aggregation measured ex vivo (ID50 1.3 micrograms kg-1 min-1) with no significant effect on haemodynamics or circulating cell counts. 7. Thus, FPL 67085 is a potent, specific and selective inhibitor of ADP-induced platelet aggregation both in vitro and in vivo. As such, it represents a novel pharmacological tool to define the role of endogenous ADP in thrombosis and the potential of P2T-purinoceptor antagonists as a novel class of infusible anti-thrombotic agents for acute use in man.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Humphries RG,Tomlinson W,Clegg JA,Ingall AH,Kindon ND,Leff Pdoi
10.1111/j.1476-5381.1995.tb15925.xsubject
Has Abstractpub_date
1995-07-01 00:00:00pages
1110-6issue
6eissn
0007-1188issn
1476-5381journal_volume
115pub_type
杂志文章abstract:BACKGROUND AND PURPOSE:Rhythmical transient constrictions of the lymphatic vessels provide the means for efficient lymph drainage and interstitial tissue fluid balance. This activity is critical during inflammation, to avoid or limit oedema resulting from increased vascular permeability, mediated by the release of vari...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2009.00493.x
更新日期:2009-12-01 00:00:00
abstract::1. In decerebrated, non-spinalized rabbits, intrathecal administration of either of the selective 5-HT1A-receptor antagonists (S)WAY-100135 or WAY-100635 resulted in dose-dependent enhancement of the reflex responses of gastrocnemius motoneurones evoked by electrical stimulation of all myelinated afferents of the sura...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb16019.x
更新日期:1996-11-01 00:00:00
abstract::1. Inhibition of rat platelet aggregation by the nitric oxide (NO) donor MAHMA NONOate (Z-1-N-methyl-N-[6-(N-methylammoniohexyl)amino]diazen-1-ium-1,2-diolate) was investigated. The aims were to compare its anti-aggregatory effect with vasorelaxation, to determine the effects of the soluble guanylate cyclase inhibitor...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0704971
更新日期:2002-12-01 00:00:00
abstract::1. The purpose of the present study was to develop an experimental strategy for the quantification of the cardiovascular effects of non-selective adenosine receptor ligands at the adenosine A1 and A2a receptor in vivo. 2-Chloroadenosine (CADO) was used as a model compound. 2. Three groups of normotensive conscious rat...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb15412.x
更新日期:1996-05-01 00:00:00
abstract::1. The pathological features of Gram-positive shock can be mimicked by the co-administration of two cell wall components of Staphylococcus aureus, namely lipoteichoic acid (LTA) and peptidoglycan (PepG). This is associated with the expression of the inducible isoform of nitric oxide synthase (iNOS) in various organs. ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb16053.x
更新日期:1996-12-01 00:00:00
abstract::3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') administration to rats produces hyperthermia if they are housed in normal or warm ambient room temperature (Ta) conditions (>or=20 degrees C), but hypothermia when in cool conditions (Ta journal_title:British journal of pharmacology pub_type: 杂志文章 doi:10.1038/sj.bjp.0706318 更新日期:2005-09-01 00:00:00
abstract::1. The effect of trimebutine on the voltage-dependent inward Ca2+ current was investigated by the whole-cell voltage-clamp technique in single smooth muscle cells from rabbit ileum. 2. Trimebutine (3-100 microM) reduced the Ca2+ current in a concentration-dependent manner. The inhibitory effect on the Ca2+ current was...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1993.tb13823.x
更新日期:1993-09-01 00:00:00
abstract:BACKGROUND AND PURPOSE:The histamine H4 receptor is widely expressed in cells of immune origin and has been shown to play a role in a variety of inflammatory processes mediated by histamine. In this report, we describe the in vitro and in vivo anti-inflammatory properties of a potent histamine H4 receptor antagonist, A...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2009.00236.x
更新日期:2009-05-01 00:00:00
abstract::1. We investigated the role of nitric oxide (NO) in modulating spinal synaptic responses evoked by electrical and noxious sensory stimuli in the neonatal rat spinal cord in vitro. 2. Potentials were recorded extracellularly from a ventral root (L3-L5) of the isolated spinal cord preparation or spinal cord-saphenous ne...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb15600.x
更新日期:1996-08-01 00:00:00
abstract::1. [35S]t-butylbicyclophosphorothionate (TBPS) is a high affinity ligand for the picrotoxin site of GABA(A) receptors. Here we examined TBPS binding to the cloned receptors made of alpha 1, alpha 3 or alpha 6 in combination with beta 2 or beta 2 and gamma 2 subunits, in the presence of GABA and several allosteric liga...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb13185.x
更新日期:1994-08-01 00:00:00
abstract::1. To determine the role of G protein-coupled receptor kinases (GRKs) in the regulation of endogenous secretin receptor responsiveness, we have transiently overexpressed both wild-type (WT) and dominant negative mutant (DNM) GRKs in NG108-15 mouse neuroblastoma x rat glioma hybrid cells and investigated the effects of...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705101
更新日期:2003-02-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Although picrotoxin is a well-established antagonist of GABA(A) receptors, detailed studies of its action on inhibitory synaptic transmission have not previously been made. EXPERIMENTAL APPROACH:Electrophysiological techniques were used to study the action of picrotoxin on inhibitory postsynapti...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2009.00542.x
更新日期:2010-02-01 00:00:00
abstract::1. When the isolated small intestine of the rat is perfused via the mesenteric artery, an oxytocic principle (Gaddum's substance R) is released which is detectable in the perfusate after 30 min and is present in samples collected 8 h later. 2. The oxytocic activity of substance R is lost after boiling but is unaffecte...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1991.tb12278.x
更新日期:1991-04-01 00:00:00
abstract::Inhalation of cyclopropane in dogs, by the closed circuit method, for a fixed period, produced an emetic response during recovery from anaesthesia. Bilateral surgical ablation of the emetic chemoreceptor trigger zone of the area postrema rendered the dogs refractory to several times (3-6) the threshold emetic dose of ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1971.tb07174.x
更新日期:1971-09-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Mitochondrial aldehyde dehydrogenase (ALDH-2) has been shown to provide a pathway for bioactivation of organic nitrates and to be prone to desensitization in response to highly potent, but not to less potent, nitrates. We therefore sought to support the hypothesis that bioactivation by ALDH-2 cri...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0707116
更新日期:2007-02-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Psychological stress exacerbates symptoms of urinary bladder dysfunction; however, the underlying brain mechanisms are unclear. We have demonstrated that centrally administered bombesin, a stress-related neuropeptide, facilitates the rat micturition reflex. Brain bombesin-like peptides modulate t...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13941
更新日期:2017-09-01 00:00:00
abstract::1. Previous studies suggested that nitric oxide (NO) may cause hyperpolarization and relaxation of canine colonic smooth muscle by both cGMP-dependent and cGMP-independent mechanisms. This hypothesis was tested using 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), a novel inhibitor of NO-stimulated guanylate cycla...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0701487
更新日期:1997-11-01 00:00:00
abstract::1. Chronic benzodiazepine administration has been associated with tolerance and with downregulation of gamma-aminobutyric acidA (GABAA)-receptor binding and function. However, effects of individual benzodiazepines on brain regions have varied. 2. To compare the effects of chronic lorazepam and alprazolam, we have admi...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1990.tb14167.x
更新日期:1990-12-01 00:00:00
abstract::1. Sodium nitroprusside, S-nitroso-N-acetyl-D,L-penicillamine, Spermine NONOate and DEA NONOate raised cyclic GMP levels in bovine chromaffin cells in a time and concentration dependent manner with different potencies, the most potent being DEA/NO with an EC50 value of 0.38 +/- 0.02 microM. 2. Measurements of NO relea...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702607
更新日期:1999-06-01 00:00:00
abstract::1. The effects of acetylcholine (ACh) on membrane potential, relaxation and cyclic GMP levels were compared to the NO donor L-nitrosocysteine (Cys-NO) in segments of guinea-pig coronary artery. 2. ACh and Cys-NO produced concentration-dependent relaxations of muscles contracted with the H1 receptor agonist, 2-(2-amino...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb14851.x
更新日期:1994-04-01 00:00:00
abstract::The effects of infusions of eicosapentaenoic acid (EPA) (6 X 10(-8) mol min-1 and 15 X 10(-8) mol min-1) on the coronary constriction and the release of immunoreactive sulphidopeptide-leukotrienes (SP-LT), thromboxane B2(TXB2) and 6-keto-prostaglandin F1 alpha (PGF1 alpha) from perfused anaphylactic guinea-pig hearts ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1987.tb08961.x
更新日期:1987-02-01 00:00:00
abstract::1. The effect of bradykinin on the Na+-K+ pump of airway smooth muscle was investigated by measuring ouabain-sensitive (86)Rb(+) uptake in cultured guinea-pig tracheal smooth muscle cells. 2. Bradykinin induced a concentration-dependent increase in ouabain-sensitive (86)Rb(+) uptake, with an EC(50) of 3 nM (pD(2) = 8....
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0704198
更新日期:2001-08-01 00:00:00
abstract::1. The natriuretic and diuretic effects of atriopeptin III (125, 250 and 500 ng kg-1, i.v.) were studied in groups of rats anaesthetized with pentobarbitone which were either sham controls, unilaterally nephrectomized controls, adenine-fed or subtotal nephrectomy chronic renal failure models. 2. Atriopeptin III given ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1990.tb14701.x
更新日期:1990-02-01 00:00:00
abstract::For almost three decades intrathecal baclofen therapy has been the standard treatment for spinal cord injury spasticity when oral medication is ineffective or produces serious side effects. Although intrathecal baclofen therapy has a good clinical benefit-risk ratio for spinal spasticity, tolerance and the life-threat...
journal_title:British journal of pharmacology
pub_type: 评论,杂志文章
doi:10.1111/j.1476-5381.2010.00964.x
更新日期:2010-11-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Certain 5-lipoxygenase (5-LO) inhibitors exhibit anti-carcinogenic activities against 5-LO overexpressing tumour types and cultured tumour cells. It has been proposed therefore that 5-LO products significantly contribute to tumour cell proliferation. To date, the relationship between the inhibito...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2010.00915.x
更新日期:2010-10-01 00:00:00
abstract::1. The aim of the present study was to explore the contribution of adrenergic, sensory and nitrergic innervations to the inhibitory effects of the beta2-adrenoceptor agonist clenbuterol on responses to electrical field stimulation (EFS, 200 mA, 0.3 ms, 1-16 Hz, for 30 s, at 1 min interval) in rat mesenteric artery seg...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0701856
更新日期:1998-06-01 00:00:00
abstract::1. This study was done to characterize the influence of calcium channel blockade on renin secretion and renin gene expression in normal rats and rats with renovascular hypertension. To this end we studied the effects of the 1,4-dihydropyridine derivative, amlodipine, on plasma renin activity and renal renin m-RNA leve...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb15735.x
更新日期:1996-10-01 00:00:00
abstract::1. Effects of oestradiol on the electrical and mechanical properties of the rabbit basilar artery were investigated by use of microelectrode, patch-clamp and isometric tension recording methods. 2. Oestradiol (10 nM-100 microM) relaxed arterial tissue pre-contracted by excess [K]o solution (30 mM) in a concentration-d...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb15198.x
更新日期:1996-01-01 00:00:00
abstract::The effects of caffeine and procaine on noradrenergic transmission in the guinea-pig mesenteric artery were investigated by recording electrical responses of smooth muscle cells and by measuring the outflow of noradrenaline (NA) and 3,4-dihydroxyphenylglycol (DOPEG) induced by perivascular nerve stimulation. Caffeine ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1985.tb16149.x
更新日期:1985-03-01 00:00:00
abstract:BACKGROUND AND PURPOSE:This study represents a novel characterisation of KCNQ-encoded potassium channels in the vasculature using a variety of pharmacological and molecular tools to determine their role in contractility. EXPERIMENTAL APPROACH:Reverse transcriptase polymerase chain reaction (RT-PCR) experiments were un...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0707284
更新日期:2007-07-01 00:00:00