Abstract:
:1. The ability of a range of substituted imidazole compounds to inhibit mouse cerebellar neuronal nitric oxide synthase (nNOS), bovine aortic endothelial NOS (eNOS) and inducible NOS (iNOS) from lungs of endotoxin-pretreated rats was investigated. In each case the substrate (L-arginine) concentration employed was 120 nM. 2. 1-(2-Trifluoromethylphenyl) imidazole (TRIM) was a relatively potent inhibitor of nNOS and iNOS (IC50S of 28.2 microM and 27.0 microM respectively) but was a relatively weak inhibitor of eNOS (IC50, 1057.5 microM). The parent compound, imidazole, was a weak inhibitor of all three NOS isoforms (IC50S: nNOS, 290.6 microM; eNOS, 101.3 microM; iNOS, 616.0 microM). Substitution of imidazole with a phenyl group to yield I-phenylimidazole (PI) resulted in an isoform non-selective increase in inhibitory potency (IC50S: nNOS, 72.1 microM; eNOS, 86.9 microM; iNOS, 53.9 microM). Further substitution of the attached phenyl group resulted in an increase in nNOS and a decrease in eNOS inhibitory potency as in TRIM, 1-chlorophenylimidazole (CPI; IC50S: nNOS, 43.4 microM; eNOS, 392.3 microM; iNOS, 786.5 microM) and 1-(2,3,5,6-tetrafluorophenyl) imidazole (TETRA-FPI; IC50S; nNOS, 56.3 microM; eNOS, 559.6 microM; iNOS, 202.4 microM). 3. The ability of TRIM to inhibit mouse cerebellar nNOS activity in vitro was influenced by the concentration of L-arginine (0.12-10.0 microM) in the incubation medium. When mouse cerebellar nNOS was used as enzyme source a double reciprocal (Lineweaver-Burk) plot in the presence/absence of TRIM (50 microM) revealed a competitive inhibitory profile. The K(m) for L-arginine and the Ki for TRIM calculated from these data were 2.4 microM and 21.7 microM, respectively. The ability of TRIM to inhibit mouse cerebellar nNOS activity in vitro was unaffected by varying the time of exposure of the enzyme to TRIM from 0-60 min at 0 degree C. 4. TRIM exhibits potent antinociceptive activity in the mouse as evidenced by inhibition of acetic acid induced abdominal constrictions. The ED50 for TRIM following i.p. administration was 20 mg kg-1 (94.5 mumol kg-1). The antinociceptive effect of TRIM was reversed by pretreatment of animals with L-arginine (50 mg kg-1, i.p.) and was not accompanied by sedation, motor ataxia or behavioural changes (rearing, crossing, circling, dipping) as assessed by use of a box maze procedure. 5. L-NG nitro arginine methyl ester (L-NAME, 20 mg kg-1, i.v.) but not TRIM (0.5-20 mg kg-1, i.v.) increased mean arterial blood pressure (MAP) in the urethane-anaesthetized rat. 6. L-NAME (100 microM) potentiated the contractile response of the rabbit isolated aorta to phenylephrine (ED50; 0.084 +/- 0.01 microM in the presence and 0.25 +/- 0.05 microM in the absence of L-NAME; maximum response, 7.7 +/- 0.4 g in the presence and 5.6 +/- 0.5 g in the absence of L-NAME, n = 6, (P < 0.05) whilst TRIM (1-100 microM) was without effect. L-NAME (100 microM) but not TRIM (1-100 microM) also reduced carbachol-induced relaxation of the phenylephrine-precontracted rabbit aorta preparation. 7. L-NAME (50 microM) potentiated the vasoconstrictor effect of bolus-injected noradrenaline (10-1000 nmol) and reduced the vasodilator effect of carbachol (10 microM) added to the Krebs reservoir in the rat perfused mesentery preparation. L-NAME (50 microM) also reduced nitric oxide (NO) release (measured by chemiluminescence of nitrite in the Krebs perfusate) in response to noradrenaline (100 nmol; 53.8 +/- 4.0 pmol ml-1 in the presence and 84.8 +/- 8.0 pmol ml-1 in the absence of L-NAME, n = 15, P < 0.05) and carbachol (10 microM; 63.9 +/- 5.0 pmol ml-1 in the presence and 154.0 +/- 9.0 pmol ml-1 in the absence of L-NAME, n = 15, P < 0.05). TRIM (50 microM) did not affect either the vasoconstrictor response to noradrenaline or the vasodilator response to carbachol or the accompanying release of NO from the perfused rat mesentery.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Handy RL,Harb HL,Wallace P,Gaffen Z,Whitehead KJ,Moore PKdoi
10.1111/j.1476-5381.1996.tb16003.xsubject
Has Abstractpub_date
1996-09-01 00:00:00pages
423-31issue
2eissn
0007-1188issn
1476-5381journal_volume
119pub_type
杂志文章abstract:BACKGROUND AND PURPOSE:Screening of 12,000 compounds for binding affinity to the synaptic vesicle protein 2A (SV2A), identified a high-affinity pyrrolidone derivative, brivaracetam (ucb 34714). This study examined its pharmacological profile in various in vitro and in vivo models of seizures and epilepsy, to evaluate i...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/bjp.2008.198
更新日期:2008-08-01 00:00:00
abstract::1 The actions of 5-methoxytryptamine (5-MeOT), N,N-dimethyltryptamine (DMT), 5-hydroxy-N,N-dimethyltryptamine (bufotenine, 5-HODMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), and their interactions with 5-hydroxytryptamine (5-HT), acetylcholine, (-)-noradrenaline, and glutamate were studied by microiontophoresis...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1974.tb09609.x
更新日期:1974-03-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Pulmonary vascular dysfunction is a key event in acute lung injury. We recently demonstrated that PGE2 , via activation of E-prostanoid (EP)4 receptors, strongly enhances microvascular barrier function in vitro. The aim of this study was to investigate the beneficial effects of concomitant EP4 re...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13229
更新日期:2015-09-01 00:00:00
abstract::1. Bicyclic compounds with potential thymoleptic properties (Lu-compounds) have recently become available, and their effects on the membrane pumps of the central and peripheral monoamine neurones have now been tested and compared with those of the tricyclic antidepressant drugs.2. Biochemical and histochemical in vivo...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1969.tb08299.x
更新日期:1969-05-01 00:00:00
abstract::The cardiovascular actions of cannbinoids are complex. In general they cause vasorelaxation in isolated blood vessels, while in anaesthetised animals they cause multiphasic responses which involve an early bradycardia and long-lasting hypotension. However, in conscious animals, the picture is one of bradycardia follow...
journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1038/sj.bjp.0705725
更新日期:2004-05-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Sublesional osteoporosis predisposes individuals with spinal cord injury (SCI) to an increased risk of low-trauma fracture. The aim of the present work was to investigate the effect of treatment with resveratrol (RES) on sublesional bone loss in spinal cord-injured rats. EXPERIMENTAL APPROACH:Co...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.12301
更新日期:2013-10-01 00:00:00
abstract::1. The endothelial modulation of the relaxant responses to the nitric oxide (NO) donor sodium nitroprusside (SNP) and the KATP channel opener levcromakalim (LEM) and the interactions between these agents were analysed in isolated rat aorta. 2. LEM-induced relaxation was unchanged by endothelium removal or by the prese...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702924
更新日期:1999-12-01 00:00:00
abstract::1. Flexor withdrawal reflexes to noxious mechanical pinch stimuli were recorded as single motor unit activity in alpha-chloralose anaesthetized rats, by means of tungsten bipolar electrodes inserted percutaneously into hindlimb flexor muscles. The relative spinal and supraspinal contributions to mu- and kappa-opioid a...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1991.tb12402.x
更新日期:1991-09-01 00:00:00
abstract:BACKGROUND AND PURPOSE:SU4312, a potent and selective inhibitor of VEGF receptor-2 (VEGFR-2), has been designed to treat cancer. Recent studies have suggested that SU4312 can also be useful in treating neurodegenerative disorders. In this study, we assessed neuroprotection by SU4312 against 1-methyl-4-phenylpyridinium ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.12004
更新日期:2013-03-01 00:00:00
abstract::1. Caffeine has been widely used as a pharmacological tool to evaluate Ca(2+) release from the sarcoplasmic reticulum in isolated smooth muscle cells. However, in nervous tissue this drug also causes neurotransmitters release, which might cause additional effects when smooth muscle strips are evaluated. To assess this...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705348
更新日期:2003-07-01 00:00:00
abstract::The response to vasoactive agents of microvessels of the rat was tested in vivo by direct microscopic observation of the exteriorized mesentery and assessment of cutaneous vascular permeability changes with Evans blue. The constrictor response to a standard amount of noradrenaline in mesenteric microvessels was fully ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1984.tb16217.x
更新日期:1984-11-01 00:00:00
abstract::It was confirmed that morphine administration in vivo produced a selective decrease in the calcium content of synaptosomal fractions prepared from rat cerebral cortices. This effect was prevented by naloxone. 2 After morphine or naloxone, there were no changes in the sodium, potassium and magnesium contents of any of ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1976.tb10379.x
更新日期:1976-08-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Cannabis extracts and several cannabinoids have been shown to exert broad anti-inflammatory activities in experimental models of inflammatory CNS degenerative diseases. Clinical use of many cannabinoids is limited by their psychotropic effects. However, phytocannabinoids like cannabidiol (CBD), d...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2011.01379.x
更新日期:2011-08-01 00:00:00
abstract::Previous studies have provided evidence for the presence on B cell membrane of adenosine receptors (P1-purinoceptors) of the A1-subtype which inhibit insulin secretion. In this work we have investigated the implication of a guanosine triphosphate (GTP) binding protein (G protein) in the A1 purinoceptor-induced inhibit...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1989.tb11775.x
更新日期:1989-01-01 00:00:00
abstract::We have investigated the effects of methylenedioxymethamphetamine (MDMA, 'ecstasy'), i.v., on diastolic blood pressure (DBP) in pithed and pentobarbitone anaesthetized rats. In pithed rats, the non-selective 5-HT receptor antagonist methiothepin (0.1 mg kg(-1)) and the alpha2-adrenoceptor antagonists methoxyidazoxan a...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0704094
更新日期:2001-06-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Carboxylesterases (CEs) metabolize a wide range of xenobiotic substrates including heroin, cocaine, meperidine and the anticancer agent CPT-11. In this study, we have purified to homogeneity human liver and intestinal CEs and compared their ability with hydrolyse heroin, cocaine and CPT-11. EXPE...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2010.00700.x
更新日期:2010-08-01 00:00:00
abstract:BACKGROUND AND PURPOSE:We have previously shown that lipid mediators, produced by phospholipase D and C, are generated in OX(1) orexin receptor signalling with high potency, and presumably mediate some of the physiological responses to orexin. In this study, we investigated whether the ubiquitous phospholipase A(2) (PL...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2009.00535.x
更新日期:2010-01-01 00:00:00
abstract::The aim of the present study was to determine whether inhibition of cyclic nucleotide phosphodiesterase (PDE) modulates the stimulated generation of the cytokines, interleukin-4 (IL-4) and IL-13, from human basophils. This was addressed by evaluating the effects of both nonselective and selective inhibitors of PDEs on...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705892
更新日期:2004-08-01 00:00:00
abstract::1. The actions of bretylium tosylate on neuromuscular transmission in the rat phrenic nerve diaphragm preparation have been investigated by electro-2. On the guinea-pig ileum, threshold doses elicit repeated maximal spike contractions which are blocked by atropine. In the presence of atropine, higher concentrations of...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1971.tb07070.x
更新日期:1971-04-01 00:00:00
abstract::1. The psychoactive cannabinoids (-)-delta 9-tetrahydrocannabinol ((-)-delta 9-THC) and the 1,1-dimethyl-heptyl homologue of (-)-11-hydroxy-delta 8-tetrahydrocannabinol ((-)-DMH) both inhibited electrically-evoked contractions of the mouse isolated vas deferens and the myenteric plexus-longitudinal muscle preparation ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1992.tb09088.x
更新日期:1992-04-01 00:00:00
abstract::1. The effects of inhibiting endogenous nitric oxide (NO) synthesis with NG-monomethyl-L-arginine (L-NMMA) on the systemic and splanchnic circulation have been investigated in rats with experimental chronic portal hypertension, anaesthetized with ketamine. 2. Portal hypertension was induced by partial portal vein liga...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1992.tb14233.x
更新日期:1992-01-01 00:00:00
abstract::Constitutively active mu-opioid receptors (mu* receptors) are reported to be formed following prolonged agonist treatment of cells or whole animals. mu* receptors signal in the absence of activating ligand and a blockade of mu* activation of G-proteins by naloxone and naltrexone has been suggested to underlie the prof...
journal_title:British journal of pharmacology
pub_type: 评论,杂志文章
doi:10.1111/j.1476-5381.2009.00067.x
更新日期:2009-04-01 00:00:00
abstract::1. A technique for the close-arterial administration of substances to the rat stomach in vivo has been developed. 2. Intra-arterial infusion of platelet-activating factor (Paf, 10-50 ng kg-1 min-1 for 10 min) induced macroscopically assessed damage in the corpus mucosa, characterized as vasocongestion and necrosis. 3....
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1988.tb11425.x
更新日期:1988-01-01 00:00:00
abstract::1 The relative potencies of methotrimeprazine, (+)-methotrimeprazine, (+/-)-10-(3-dimethylamino-2-methylpropyl)-2-valeroyl phenothiazine hydrochloride (M & B 18,706) and (+)-M & B 18,706 in reducing the pressor action of noradrenaline in the spinal cat, reducing intercollicular decerebrate rigidity, and muscle spindle...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1974.tb09610.x
更新日期:1974-03-01 00:00:00
abstract::The interaction of a new nonribose ligand (LUF5831) with the human adenosine A1 receptor was investigated in the present study. Radioligand binding experiments were performed in the absence and presence of diverse allosteric modulators on both wild-type (wt) and mutant (T277A) adenosine A1 receptors. Thermodynamic dat...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0706655
更新日期:2006-03-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Cholecystokinin (CCK) is secreted by intestinal I cells and regulates important metabolic functions. In pancreatic islets, CCK controls beta cell functions primarily through CCK1 receptors, but the signalling pathways downstream of these receptors in pancreatic beta cells are not well defined. E...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13271
更新日期:2015-11-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Endogenous cannabinoids (endocannabinoids) in the periaqueductal grey (PAG) play a vital role in mediating stress-induced analgesia. This analgesic effect of endocannabinoids is enhanced by pharmacological inhibition of their degradative enzymes. However, the specific effects of endocannabinoids ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.12839
更新日期:2014-12-01 00:00:00
abstract::1. The possibility that tachykinin NK1 receptors are involved in the plasma extravasation evoked by intradermal (i.d.) injection of Phoneutria nigriventer venom (PNV) in rat dorsal skin in vivo has been investigated. 2. Local oedema formation induced by the i.d. injection of test agents was measured by the extravascul...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb15402.x
更新日期:1996-05-01 00:00:00
abstract::1 Nine antibiotic compounds in common use were studied to determine their ability to affect intestinal motility in vitro, in the guinea-pig ileum and rabbit colon. 2 Ampicillin, doxycycline, mecillinam and metronidazole were without effect over a concentration range which included typical serum levels found when these...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1981.tb10453.x
更新日期:1981-06-01 00:00:00
abstract::In this issue of the BJP, Green et al. suggest that animal data could not be used to predict the adverse effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans and that MDMA did not produce 5-HT neurotoxicity in the human brain. This proposal was, however, not accompanied by a review of the empirical evidence i...
journal_title:British journal of pharmacology
pub_type: 评论,杂志文章
doi:10.1111/j.1476-5381.2012.01941.x
更新日期:2012-07-01 00:00:00