Abstract:
:1. The present study has compared the relative anti-aggregatory effect of various compounds which interfere with thromboxane (Tx) A2-dependent aggregation of human platelets in whole blood in vitro. These included the cyclo-oxygenase inhibitor aspirin, the TxA2 synthase inhibitor dazoxiben, the TxA2 (TP-) receptor blocking drug GR32191 and two compounds, R.68070 ((E)-5-[[[(3-pyridinyl) [3-(trifluoromethyl)phenyl]-methylen] amino]oxy] pentanoic acid) and CV-4151 [E)-7-phenyl-7-(3-pyridyl)-6-heptenoic acid), which possess both TP-receptor blocking and TxA2 synthase inhibitory activities in the same molecule. 2. GR32191, R.68070 and CV-4151 all antagonized aggregation to the TxA2 mimetic U-46619, with pA2 values of approximately 8.2, 5.4 and 4.8 respectively. This effect was specific, platelet aggregation induced by adenosine 5'-diphosphate (ADP) being unaffected by concentrations up to 10, 1000 and 300 microM respectively. In contrast, neither aspirin nor dazoxiben exhibited any measurable TP-receptor blocking activity. 3. The rank order of potency (pIC50) for inhibition of TxA2 formation in serum was R.68070 (7.4) greater than CV-4151 (6.9) greater than dazoxiben (5.7) greater than aspirin (5.3). In addition, all four drugs abolished collagen-induced platelet TxA2 formation. In contrast, GR32191 produced no consistent inhibition of TxA2 formation in either system up to concentrations of 10-30 microM. 4. The specificity of R.68070, CV-4151 and dazoxiben for TxA2 synthase was indicated by their ability to increase serum levels of prostaglandin E2 (PGE2) and PGD2 in parallel with decreases in TxA2 formation. This profile was not observed with aspirin or GR32191. However, high concentrations of R.68070 (100,microM) and CV-4151 (1000 microM) necessary for maximum TP-receptor blocking activity, produced substantially smaller increases in PGE2 and PGD2, consistent with an aspirin-like effect of these compounds upon cyclo-oxygenase. With dazoxiben (1000 microM), PGE2 and PGD2 levels remained elevated. 5. Aspirin inhibited collagen-induced platelet aggregation, the effect correlating with inhibition of TxA2 formation. Dazoxiben, whilst also achieving maximal inhibition of TxA2 formation, produced significantly less inhibition of aggregation than aspirin. In contrast, GR32191 (0.1-1O microM), at concentrations specific for TP-receptor blockade, produced a significantly greater antagonism of collagen-induced platelet aggregation than aspirin. This additional effect of GR32191 was absent in platelets pretreated with aspirin, indicating the probable involvement of an endogenous anti-aggregatory cyclo-oxygenase product in response to collagen stimulation. 6. R.68070 and CV-4151 also inhibited collagen-induced aggregation, with very high concentrations of R.68070 (100 microM) producing an effect equivalent to that of GR32191. 7. In contrast, the combination of GR32191 with either dazoxiben, R.68070 or CV-4151, at concentrations specific for TxA2 synthase, produced a synergistic inhibitory effect upon collagen-induced platelet aggregation which was greater than that achieved with either aspirin or any of the compounds used alone. Pretreatment of platelets with aspirin reversed this synergistic effect, consistent with it being dependent upon the formation and action of anti-aggregatory prostaglandins. 8. In conclusion, the present study has confirmed the superior platelet inhibitory profile of a combination of a TP-receptor blocking drug and a TxA2 synthase inhibitor to that of either activity alone. However, the maximum inhibitory effect of the currently available compounds, R.68070 and CV4151, which possess both activities in the same molecule, appears to be no greater in vitro than that obtained with the potent TP-receptor blocking drug, GR32191. This most probably reflects the inhibition by R.68070 and CV-4151 of platelet cyclo-oxygenase at the concentrations required for effective TP-receptor blockade which results in a reduction in the formation of anti-aggregatory prostanoids.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Watts IS,Wharton KA,White BP,Lumley Pdoi
10.1111/j.1476-5381.1991.tb12200.xsubject
Has Abstractpub_date
1991-02-01 00:00:00pages
497-505issue
2eissn
0007-1188issn
1476-5381journal_volume
102pub_type
杂志文章abstract:BACKGROUND AND PURPOSE:5-Hydroxytryptamine (5-HT) has been shown to control and modulate many physiological and behavioural functions in insects. In this study, we report the cloning and pharmacological properties of a 5-HT(1) receptor of an insect model for neurobiology, physiology and pharmacology. EXPERIMENTAL APPR...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2010.00638.x
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abstract::1 The action of iontophoretically administered lithium was studied on spinal Renshaw cells an interneurones and on supraspinal neurones in cerebral cortex, thalamus, hypothalamus and brain stem in anaesthetized cats and rats. 2 There was a correlation between the effects of Li+ and those of acetylcholine (ACh), althou...
journal_title:British journal of pharmacology
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doi:10.1111/j.1476-5381.1977.tb07740.x
更新日期:1977-06-01 00:00:00
abstract::1. Chronic treatment with a combined ETA/ETB endothelin receptor antagonist has been shown to reduce blood pressure in experimental rat models of hypertension in which endothelin-1 gene overexpression occurs in the walls of blood vessels, particularly small, resistance-sized arteries, but not in those genetic or exper...
journal_title:British journal of pharmacology
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abstract::Amyotrophic lateral sclerosis (ALS) is an adult onset disorder characterized by progressive neuromuscular junction (NMJ) dismantling and degeneration of motor neurons leading to atrophy and paralysis of voluntary muscles responsible for motion and breathing. Except for a minority of patients harbouring genetic mutatio...
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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...
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abstract::1. Tachycardia and bronchodilatation were produced by intravenous dimethylphenylpiperazinium iodide (DMPP) in the spinal or pithed cat. Responses other than those involving beta-adrenoceptors were minimized by appropriate blocking agents.2. With intact adrenals, both the tachycardia and bronchodilatation with 10 mug/k...
journal_title:British journal of pharmacology
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doi:10.1111/j.1476-5381.1973.tb08256.x
更新日期:1973-08-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Abdominal aortic aneurysm (AAA) is a degenerative disease with irreversible and progressive dilation of the artery. But there are few options for efficacious treatment except for traditional surgery. Probucol has been widely applied to treat hyperlipidaemia and atherosclerosis in clinic, but whet...
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abstract::The last five years have witnessed a remarkable resurgence of interest in myocardial reperfusion injury. Reperfusion is absolutely essential to salvage ischaemic myocardium but experimental and clinical studies show that reperfusion-associated injury may mask the full benefits of prompt reperfusion in acute myocardial...
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pub_type: 评论,杂志文章
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abstract::1. The pharmacological characteristics of cloned mammalian alpha 1A/D-, alpha 1B- and alpha 1C-adrenoceptor subtypes expressed in rat 1 fibroblasts were determined in comparison to the binding and functional properties of these subtypes in rat tissues. 2. Analysis of [3H]-prazosin binding to membrane homogenates from ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb14843.x
更新日期:1994-04-01 00:00:00
abstract::Cyclic adenosine monophosphate (cAMP) is one of the second messengers critically involved in the molecular mechanisms underlying memory formation. In the CNS, the availability of cAMP is tightly controlled by phosphodiesterase 4 (PDE4), a family of enzymes that degrades the cyclic nucleotide to inactive AMP. Among the...
journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
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abstract::The chemical trimethylcyclohexanol (TMC) is closely related to menthol, the major component of a terpene preparation with known choleretic and cholelitholytic activity. Its effects on hepatic cholesterol synthesis and bile secretion were examined in the rat. In both acute and long-term dosing experiments TMC significa...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1984.tb10759.x
更新日期:1984-01-01 00:00:00
abstract::1 Rats treated for seven days with seryl-trihydroxybenzylhydrazine (benserazide), and inhibitor of peripheral aromatic L-amino acid decarboxylase (500 mg/kg, daily, i.p.) alone or in combination with L-DOPA methylester (500 mg/kg, daily, i.p.) for seven days showed a moderate but significant decrease of liver aldehyde...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1977.tb16746.x
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abstract:BACKGROUND AND PURPOSE:AZ11645373 and N-{2-methyl-5-[(1R, 5S)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylcarbonyl]phenyl}-2-tricyclo[3.3.1.13,7]dec-1-ylacetamide hydrochloride (compound-22) are recently described P2X(7) receptor antagonists. In this study we have further characterized these compounds to determine their mecha...
journal_title:British journal of pharmacology
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更新日期:2009-04-01 00:00:00
abstract:BACKGROUND:Intrathecal (i.t.) injection of orexin A (OX-A) increases blood pressure and heart rate (HR), but the effects of OX-A on sympathetic and phrenic, nerve activity, and the baroreflex(es), somato-sympathetic and hypoxic chemoreflex(es) are unknown. EXPERIMENTAL APPROACH:Urethane-anaesthetized, vagotomized and ...
journal_title:British journal of pharmacology
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abstract::1 Very highly purified (greater than 100,000 u/mg) slow reacting substance of anaphylaxis (SRS-A) has been prepared by reversed phase high pressure liquid chromatographic (HPLC) techniques. 2 High resolution liquid chromatography suggests that SRS-A may exist in at least three distinct forms which are possible tautome...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1980.tb10696.x
更新日期:1980-01-01 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. Endothelin, a novel potent vasoconstrictor peptide produced by vascular endothelial cells stimulated anion secretion by a cultured secretory epithelium derived from the rat epididymis as measured by changes in short-circuit current (SCC). 2. Stimulation of the SCC was observed when endothelin was added to the basol...
journal_title:British journal of pharmacology
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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...
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更新日期:2003-05-01 00:00:00
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更新日期:1990-02-01 00:00:00
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abstract::1 The relationship of agonist efficacy to the rate of G protein-coupled receptor signaling desensitization is controversial. 2 Expressing inwardly rectifying potassium channels (GIRKs) in Xenopus oocytes, we have devised a signaling assay that clearly identifies CB1 cannabinoid receptor agonists with low intrinsic eff...
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abstract::1. Prostaglandin E2 (PGE2) is an autacoid that decreases proteoglycan synthesis, increases metalloprotease production by cultured chondrocytes, and can modulate some of the actions of interleukin-1 on cartilage. The objective of the present study was to characterize the subtype of prostaglandin E2 receptor present in ...
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abstract::1 The D3 dopamine receptor presumably activates Gi/Go subtypes of G-proteins, like the structurally analogous D2 receptor, but its signalling targets have not been clearly established due to weak functional signals from cloned receptors as heterologously expressed in mostly non-neuronal cell lines. 2 In this study, re...
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更新日期:1999-11-01 00:00:00
abstract::1. Bradykinin has multiple effects on differentiated NG108-15 neuroblastoma x glioma cells: it increases Ins(1,4,5)P3 production and intracellular Ca2+ concentration [Ca2+]i evokes a Ca2+ activated K+ current (IK(Ca)) and inhibits M current (IM). We studied the effect of the aminosteroid U73122 and the antibiotic neom...
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更新日期:1997-03-01 00:00:00