Abstract:
:1. We have investigated the inhibitory effects of RP 73401 (piclamilast) and rolipram against human monocyte cyclic AMP-specific phosphodiesterase (PDE4) in relation to their effects on prostaglandin (PG)E2-induced cyclic AMP accumulation and lipopolysaccharide (LPS)-induced TNF alpha production and TNF alpha mRNA expression. 2. PDE4 was found to be the predominant PDE isoenzyme in the cytosolic fraction of human monocytes. Cyclic GMP-inhibited PDE (PDE3) was also detected in the cytosolic and particulate fractions. Reverse transcription polymerase chain reaction (RT-PCR) of human monocyte poly (A+) mRNA revealed amplified products corresponding to PDE4 subtypes A and B of which the former was most highly expressed. A faint band corresponding in size to PDE4D was also observed. 3. RP 73401 was a potent inhibitor of cytosolic PDE4 (IC50: 1.5 +/- 0.6 nM, n = 3). (+/-)-Rolipram (IC50: 313 +/- 6.7 nM, n = 3) was at least 200 fold less potent than RP 73401. R-(-)-rolipram was approximately 3 fold more potent than S-(+)-rolipram against cytosolic PDE4. 4. RP 73401 (IC50: 9.2 +/- 2.1 nM, n = 6) was over 50 fold more potent than (+/-)-rolipram (IC50: 503 +/- 134 nM, n = 6) ) in potentiating PGE2-induced cyclic AMP accumulation. R-(-)-rolipram (IC50: 289 +/- 121 nM, n = 5) was 4.7 fold more potent than its S-(+)-enantiomer (IC50: 1356 +/- 314 nM, n = 5). A strong and highly-significant, linear correlation (r = 0.95, P < 0.01, n = 13) was observed between the inhibitory potencies of a range of structurally distinct PDE4 inhibitors against monocyte PDE4 and their ED50 values in enhancing monocyte cyclic AMP accumulation. A poorer, though still significant, linear correlation (r = 0.67, P < 0.01, n = 13) was observed between the potencies of the same compounds in potentiating PGE2-induced monocyte cyclic AMP accumulation and their abilities to displace [3H]-rolipram binding to brain membranes. 5. RP 73401 (IC50: 6.9 +/- 3.3 nM, n = 5) was 71 fold more potent than (+/-)-rolipram (IC50: 490 +/- 260 nM, n = 4) in inhibiting LPS-induced TNF alpha release from monocytes. R-(-)-rolipram (IC50: 397 +/- 178 nM, n = 3) was 5.2-fold more potent than its S-(+)- enantiomer (IC50: 2067 +/- 659 nM, n = 3). As with cyclic AMP, accumulation a closer, linear correlation existed between the potency of structurally distinct compounds in suppressing TNF alpha with PDE4 inhibition (r = 0.93, P < 0.01, n = 13) than with displacement of [3H]-rolipram binding (r = 0.65, P < 0.01, n = 13). 6. RP 73401 (IC50: 2 nM) was 180 fold more potent than rolipram (IC50: 360 nM) in suppressing LPS (10 ng ml-1)-induced TNF alpha mRNA. 7. The results demonstrate that RP 73401 is a very potent inhibitor of TNF alpha release from human monocytes suggesting that it may have therapeutic potential in the many pathological conditions associated with over-production of this pro-inflammatory cytokine. Furthermore, PDE inhibitor actions on functional responses are better correlated with inhibition of PDE4 catalytic activity than displacement of [3H]-rolipram from its high-affinity binding site, suggesting that the native PDE4 in human monocytes exists predominantly in a 'low-affinity' state.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Souness JE,Griffin M,Maslen C,Ebsworth K,Scott LC,Pollock K,Palfreyman MN,Karlsson JAdoi
10.1111/j.1476-5381.1996.tb15450.xsubject
Has Abstractpub_date
1996-06-01 00:00:00pages
649-58issue
3eissn
0007-1188issn
1476-5381journal_volume
118pub_type
杂志文章abstract::The abilities of prostaglandin E1 (PGE1), PGE2, PGD2 and PGF2 alpha to antagonize striatal dopamine function were assessed following bilateral and unilateral injections into the striata of the rat and guinea-pig. Three tests were used to assess the effects of the bilateral injections, ability to antagonize dyskinetic ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1985.tb11095.x
更新日期:1985-08-01 00:00:00
abstract::Effects of hypoxia on atrioventricular conduction were investigated in the Langendorff-perfused isolated heart of the rabbit with various extracellular calcium concentrations ([Ca2+]) as well as in the presence of verapamil, nifedipine, N-(6-aminohexyl)-5-chloro-1-naphthalenesulphonamide (W-7) and chlorpromazine. The ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1986.tb09496.x
更新日期:1986-05-01 00:00:00
abstract::1. Vanadium compounds can mimic actions of insulin through alternative signalling pathways. The effects of three organic vanadium compounds were studied in non-ketotic, streptozotocin-diabetic rats: vanadyl acetylacetonate (VAc), vanadyl 3-ethylacetylacetonate (VEt), and bis(maltolato)oxovanadium (VM). A simple inorga...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702311
更新日期:1999-01-01 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::1. We have studied the mechanical response of circular strips of the guinea-pig ileum to tachykinins and characterized the receptors involved by means of receptor-selective agonists. 2. The strips responded to both substance P (SP) and neurokinin A (NKA), as well as to [Pro9]-SP sulphone (selective NK1-receptor agonis...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1990.tb14195.x
更新日期:1990-12-01 00:00:00
abstract::1. N-formyl peptides (e.g. fMLP; N-formyl-L-methionyl-L-leucyl-phenylalanine) are potent mediators for inflammatory reactions. We report functional expression in Xenopus oocytes of human fMLP-R98 cDNA, without co-expression of the promiscuous G-protein subunit, Galpha-16. 2. Stimulation of voltage-clamped oocytes (-70...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0704592
更新日期:2002-03-01 00:00:00
abstract::The distribution of beta-adrenoceptor subtypes in slide-mounted sections of guinea-pig kidney has been examined by the technique of in vitro labelling combined with autoradiography. Binding of (-)-[125I]-cyanopindolol (Cyp) to kidney sections equilibrated and dissociated slowly, was saturable and stereoselective with ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1985.tb08867.x
更新日期:1985-06-01 00:00:00
abstract::Midbrain dopaminergic (DA) neurones sustain important physiological functions such as control of motricity, signalling of the error in prediction of rewards and modulation of emotions and cognition. Moreover, their degeneration leads to Parkinson's disease and they may be dysfunctional in other pathological states, su...
journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1038/sj.bjp.0706328
更新日期:2005-09-01 00:00:00
abstract::We examined the mechanisms underlying leukotriene D4- (LTD4) induced constriction of human small (300 - 500 micron i.d.) bronchioles, and the effect of LTD4 on ion currents and Ca2+ transients in smooth muscle cells (SMC) isolated from these bronchioles. LTD4 caused a concentration-dependent bronchoconstriction with a...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0704076
更新日期:2001-05-01 00:00:00
abstract::1. The pharmacological profile of LR-B/081, (methyl 2-[[4-butyl-2-methyl- 6-oxo-5-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1(6H)- pyrimidinyl]methyl]-3-thiophenecarboxylate), a novel antagonist at the angiotensin II (AII) AT1-receptor, was studied in vitro and in vivo. 2. In rabbit aortic strips incubated w...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1995.tb13323.x
更新日期:1995-03-01 00:00:00
abstract::1. Anaesthetized, open-chest dogs were subjected to 60 min of left circumflex coronary artery occlusion followed by 90 min of reperfusion. Endothelium-dependent and -independent relaxant responses of the isolated coronary arterial rings were then investigated. 2. The endothelium-dependent, acetylcholine-induced relaxa...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1992.tb09018.x
更新日期:1992-03-01 00:00:00
abstract::A large range of neuroadaptations develop in response to chronic opioid exposure and these are thought to be more or less critical for expression of the major features of opioid addiction: tolerance, withdrawal and processes that may contribute to compulsive use and relapse. This review considers these adaptations at ...
journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1038/bjp.2008.100
更新日期:2008-05-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Chromosomal instability is not only a hallmark of cancer but also an attractive therapeutic target. A diverse set of mitotic kinases maintains chromosomal stability. One of these is monopolar spindle 1 (Mps1, also known as TTK), which is essential for chromosome alignment and for the spindle asse...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13782
更新日期:2017-06-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Due to their potent bronchodilator properties, beta(2)-adrenoceptor agonists are a mainstay of therapy in asthma. However, the effects of beta(2)-adrenoceptor agonists on inflammation are less clear. Accordingly, we have investigated the effects of beta(2)-adrenoceptor agonists on inflammatory me...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2010.00708.x
更新日期:2010-05-01 00:00:00
abstract::1. The effects of methylflavonolamine hydrochloride (4'-methyl-7-(2-hydroxy-3-isopropylamino-propoxy)-flavone hydrochloride, MFA) were investigated and compared with verapamil and papaverine on rabbit isolated aortic strips, which were contracted by noradrenaline, calcium and potassium. 2. Pre-incubation for 25 min wi...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1988.tb11637.x
更新日期:1988-08-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Calu-3 cells are derived from serous cells of human lung submucosal glands, a prime target for therapy in cystic fibrosis (CF). Calu-3 cells can be cultured to form epithelia capable of transepithelial transport of chloride. A CF Calu-3 cell is not available. EXPERIMENTAL APPROACH:A retroviral v...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0707175
更新日期:2007-04-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Injury to the lung parenchyma is a constitutional feature shared by many lung diseases. The protein, phosphatase and tensin homologue deleted on chromosome Ten (PTEN) is a major suppressor of phosphoinositide-3 kinase/Akt signalling, a vital survival pathway in lung parenchymal cells. Based on th...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2008.00020.x
更新日期:2009-01-01 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
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2010.01102.x
更新日期:2011-02-01 00:00:00
abstract::1. Male rats treated with guanethidine 25 mg/kg daily for eight weeks had no demonstrable ejaculatory function immediately after cessation of treatment. Four weeks later, ejaculatory function had returned in two-thirds of the males, and after eight weeks, all males were able to deposit sperm in the vagina. However, fe...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1973.tb08219.x
更新日期:1973-05-01 00:00:00
abstract::Noradrenaline (NA) and adrenaline (Ad) are modulators of cytokine production. Here we investigated the role of these neurotransmitters in the regulation of macrophage inflammatory protein (MIP)-1alpha expression. Pretreatment of RAW 264.7 macrophages with NA or Ad decreased, in a concentration-dependent manner (1 nM-1...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702179
更新日期:1998-11-01 00:00:00
abstract::1. A study has been made of serum, mixed and parotid salivary levels attained in normal volunteers following oral dosage of 500 mg phenoxymethylpenicillin tablets, 500 mg crushed phenoxymethylpenicillin tablets in capsules, 500 mg ampicillin, 500 mg cloxacillin and 500 mg cephalexin.2. High mixed saliva levels were ob...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1971.tb07173.x
更新日期:1971-09-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Endothelial cell proliferation, migration and adhesion are necessary for the formation of new blood vessels. We reported previously that baicalein strongly inhibited proliferation of rat heart endothelial cells and here we assess effects on migration and adhesion of these cells. EXPERIMENTAL APP...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0707345
更新日期:2007-08-01 00:00:00
abstract::The ionic mechanism underlying the effect of (-)-baclofen in the hippocampus was investigated using guinea-pig brain slices. (-)-Baclofen either perfused or applied directly by microiontophoresis hyperpolarized the membrane and decreased the membrane input resistance of pyramidal cells in a dose-dependent manner. The ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1985.tb17377.x
更新日期:1985-04-01 00:00:00
abstract::We performed intracellular recordings from a rat corticostriatal slice preparation in order to compare the electrophysiological effects of the classical antiepileptic drug (AED) phenytoin (PHT) and the new AEDs lamotrigine (LTG) and gabapentin (GBP) on striatal neurons. PHT, LTG and GBP affected neither the resting me...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702361
更新日期:1999-02-01 00:00:00
abstract::1. The effects of capsaicin on voltage-gated Ca2+ currents (ICa), and intracellular Ca2+ concentrations [( Ca2+]i) in cultured dorsal root ganglion (DRG) neurones of the rat were examined in vitro by use of combined patch clamp-microfluorometric recordings. 2. Under voltage-clamp conditions, capsaicin (0.1-10 microM) ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1990.tb12725.x
更新日期:1990-10-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Excitation-transcriptional coupling involves communication between plasma membrane ion channels and gene expression in the nucleus. Calcium influx through L-type Ca(2+) channels induces phosphorylation of the transcription factor, cyclic-AMP response element binding protein (CREB) and downstream ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2009.00599.x
更新日期:2010-03-01 00:00:00
abstract::1. The effects of melanotrophin release inhibiting factor (MIF) and its cyclic analogue cyclo (Leu-Gly) on tolerance to the analgesic effect of morphine were studied in male Sprague-Dawley rats. 2. Tolerance to morphine was induced by implantation of four morphine pellets (each containing 75 mg of morphine free base) ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1981.tb09152.x
更新日期:1981-04-01 00:00:00
abstract:BACKGROUND AND PURPOSE:There is increasing evidence that potassium channels are involved in the cardiovascular dysfunction of sepsis. This evidence was obtained after the systemic inflammation, cardiovascular dysfunction and organ damage had developed. Here we have studied the consequences of early interference with po...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2011.01324.x
更新日期:2011-07-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Here, we have compared the neurochemical profile of three new cathinones, butylone, mephedrone and methylone, in terms of their potential to inhibit plasmalemmal and vesicular monoamine transporters. Their interaction with 5-HT and dopamine receptors and their psychostimulant effect was also stud...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2012.01998.x
更新日期:2012-09-01 00:00:00
abstract::The effects of the alpha- and beta-isomers of flupenthixol on 5-hydroxytryptamine (5-HT)-induced platelet aggregation and on 5-HT and dopamine uptake were investigated. Alpha-Flupenthixol was 185 times more potent than the beta-isomer as an inhibitor of platelet aggregation. In contrast both isomers were equipotent a...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1975.tb07432.x
更新日期:1975-12-01 00:00:00