Abstract:
:The platelet-lowering drug anagrelide inhibits bone marrow megakaryocytopoiesis by an unknown mechanism. Recently, it was found that anagrelide is bio-transformed in humans into two major metabolites (6,7-dichloro-3-hydroxy-1,5 dihydro-imidazo[2,1-b]quinazolin-2-one (BCH24426) and 2-amino-5,6-dichloro-3,4,-dihydroquinazoline (RL603). Whether these metabolites have biological activities that may underlie the mode of action of the parent drug is presently unclear. To clarify this question here we have compared the activities of anagrelide, BCH24426 and RL603 on the growth and differentiation of CD34(+) haematopoietic progenitor cells in liquid culture and on the migration of differentiated megakaryocytes. Incubation with either anagrelide, BCH24426 or RL603 did not affect the early expansion of CD34(+) cells stimulated by thrombopoietin. In contrast, both anagrelide and BCH24426 potently inhibited the development of megakaryocytes (IC(50) +/- s.e.m. = 26 +/- 4 and 44 +/- 6 nM, respectively), whereas RL603 showed no significant effect. Anagrelide and BCH24426 did not affect erythroid or myelomonocytic differentiation stimulated by erythropoietin or granulocyte-macrophage colony-stimulating factor, demonstrating the selectivity of these compounds against the megakaryocytic lineage. Neither anagrelide nor its metabolites showed a significant effect on the migratory response of megakaryocytes towards stromal cell-derived factor-1alpha. Although BCH24426 was shown to be considerably more potent than anagrelide as an inhibitor of phosphodiesterase type III (PDEIII) (IC(50) = 0.9 vs 36 nM) this activity did not correlate with the potency of inhibition of megakaryocyte development. Furthermore, other PDEIII inhibitors of widely differing potency were shown to have negligible effects on megakaryocytopoiesis. Taken together our results demonstrate that anagrelide and BCH24426 target a cellular event involved specifically in the megakaryocyte differentiation programme, which is independent of PDEIII inhibition.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Wang G,Franklin R,Hong Y,Erusalimsky JDdoi
10.1038/sj.bjp.0706341subject
Has Abstractpub_date
2005-10-01 00:00:00pages
324-32issue
3eissn
0007-1188issn
1476-5381pii
0706341journal_volume
146pub_type
杂志文章abstract::The peptides, neurotensin, substance P, somatostatin, and bombesin, several analogues and fragments of neurotensin and compound 48/80, all caused the secretion of both endogenous 5-hydroxytryptamine (5-HT) and histamine. There was no differential effect of any of the secretagogues tested on the secretion of 5-HT and h...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1984.tb10069.x
更新日期:1984-02-01 00:00:00
abstract::1. The hyperpolarization of the resting membrane potential, Vm, induced by isoprenaline in the lumbrical muscle fibres of the mouse, was investigated by use of intracellular microelectrodes. 2. In normal Krebs-Henseleit solution (potassium concentration: K+o = 5.7 mM, 'control'), Vm was -7.40 +/- 0.2 mV; lowering K+o ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1995.tb15940.x
更新日期:1995-12-01 00:00:00
abstract::Muscarinic receptors in the rat cerebral cortex, reacted with p-chloromercuribenzoate (PCMB) under different conditions (Phase I and II), have modified binding sites. These exhibit remarkable changes in the structural dependence of the binding of drugs. In Phase I, the structure-binding profile of agonists for both th...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1983.tb11066.x
更新日期:1983-09-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Orally administered withanoside IV (a compound isolated from the roots of Withania somnifera) improved memory deficits in mice with a model of Alzheimer's disease induced by the amyloid peptide Abeta(25-35). Sominone, an aglycone of withanoside IV, was identified as an active metabolite after ora...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2009.00313.x
更新日期:2009-08-01 00:00:00
abstract:BACKGROUND AND PURPOSE:The bladder urothelium is now known to have active properties. Our aim was to investigate the contractile properties of the urinary mucosa in response to the tachykinin neurokinin A (NKA) and carbachol. EXPERIMENTAL APPROACH:Discrete concentration-response curves for carbachol and NKA were obtai...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/bjp.2008.29
更新日期:2008-04-01 00:00:00
abstract::BACKGROUND AND PURPOSE The transepithelial absorption of Na(+) in the lungs is crucial for the maintenance of the volume and composition of epithelial lining fluid. The regulation of Na(+) transport is essential, because hypo- or hyperabsorption of Na(+) is associated with lung diseases such as pulmonary oedema or cys...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2012.01909.x
更新日期:2012-07-01 00:00:00
abstract::1. We studied the effects of various K+ channel blockers on the vasodilator responses of guinea-pig isolated basilar arteries to nitrergic nerve stimulation, the nitric oxide (NO) donor sodium nitroprusside (SNP), and the membrane permeable guanosine-3',5'-cyclic monophosphate (cyclic GMP) analogue 8-bromo-cyclic GMP ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0701552
更新日期:1998-01-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Pelitinib is a potent irreversible EGFR TK inhibitor currently in clinical trials for the treatment of lung cancer. Hyperthermia has been applied concomitantly with chemotherapy and radiotherapy to enhance treatment outcome. In this study, we investigated the ability of the combination of pelitin...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13189
更新日期:2015-08-01 00:00:00
abstract::Rats were placed on either a low sodium intake (low sodium diet 0.025% dry weight, tap water for drinking) or a high sodium intake (normal sodium diet 0.45% dry weight, 0.9% saline for drinking) for 10 days. The pressor-response curve to angiotensin II in rats previously on a high sodium intake was shifted to the left...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1985.tb11111.x
更新日期:1985-12-01 00:00:00
abstract::1. The electrical activity of guinea-pig pelvic ganglion cells following iontophoretically applied cholinergic drugs, alone and during orthodromic nerve stimulation via the hypogastric nerve, has been recorded intracellularly.2. Iontophoretic application of nicotine (Nic) and acetylcholine (ACh) reduced membrane resis...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1971.tb09932.x
更新日期:1971-01-01 00:00:00
abstract::1. The haemodynamic effects of propranolol, practolol and 4-hydroxypropranolol have been compared in anaesthetized dogs both at free heart rates and at heart rates fixed by electrical pacing. All three drugs produced a fall in heart rate at the lowest dose of 0.09 mg/kg.2. Practolol caused less change in dP/dt, cardia...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1972.tb08076.x
更新日期:1972-06-01 00:00:00
abstract::1. Acute SR 58611A (0.25 mg kg-1), was effective in reducing the blood glucose response to a glucose tolerance test (GTT) in normal lean (control) and spontaneously obese/diabetic CBA/Ca mice and to be equipotent to 1.25 mg kg-1 glibenclamide in lean mice. 2. Neither brown (BAT) nor white (WAT) adipose tissue lipogene...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702946
更新日期:1999-12-01 00:00:00
abstract::1. Changes induced in the electrocorticogram by the bilateral perfusion of (+)-amphetamine into the mesencephalic reticular formation (MRF) have been studied in cat encéphale isolé preparations. 2. (+)-Amphetamine, applied for 5 min in the MRF, mimicked the electrocortical desynchronization induced by the perfusion of...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1977.tb08424.x
更新日期:1977-11-01 00:00:00
abstract::1. We have investigated the influence of endothelial damage on the cerebrovascular reactivity to 5-hydroxytryptamine (5-HT) and some selective 5-HT agonists in canine basilar artery. 2. 5-HT, alpha-methyl 5-HT, GR 43175 (3-[2-dimethyl amino] ethyl-N-methyl-1H-indole-5-methane sulphonamide) and 5-carboxamidotryptamine ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1989.tb11797.x
更新日期:1989-01-01 00:00:00
abstract::1 Contractile responses produced by the alpha 1-adrenoceptor selective agonist, phenylephrine, and the alpha 2-adrenoceptor selective agonists, oxymetazoline and clonidine, have been compared to those produced by noradrenaline (non selective) in the rat aorta. 2 The relative order of potency of the agonists was noradr...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1982.tb09337.x
更新日期:1982-12-01 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::1. The aim of this study was to determine the conditions under which the alpha2-adrenoceptor agonist UK14304 produces vasoconstriction in the porcine isolated ear artery. 2. UK14304 (0.3 microM) produced a small contraction of porcine isolated ear arteries which was 7.8+/-3.3% of the response to 60 mM KCl. Similar siz...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0701935
更新日期:1998-07-01 00:00:00
abstract::1. Female mice of the Hough/Porton and Tuck/TO strains were found to be more sensitive than male mice to the diuretic effects of oral and intravenous doses of ethacrynic acid. 2. The sensitivity of Hough/Porton male mice to ethacrynic acid was increased after pretreatment with stilboestrol and the sensitivity of femal...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1977.tb07536.x
更新日期:1977-08-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Post-operative ileus (POI) is induced by intestinal inflammation. Here, we aimed to clarify the effects of 5-HT3 receptor antagonists against POI. EXPERIMENTAL APPROACH:We administered three 5-HT3 receptor antagonists, ondansetron, tropisetron and palonosetron, to a mouse model of POI induced by...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13006
更新日期:2015-02-01 00:00:00
abstract::1. Previous patch clamp studies of oesophageal circular muscle cells showed that nitric oxide (NO) modulated the opening of Ca2(+)-activated K+ channels involved in mediating the inhibitory junction potentials (i.j.ps). This study clarified the role of Ca2+ release from the superficial sarcoplasmic reticulum (SR) in t...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb15661.x
更新日期:1996-08-01 00:00:00
abstract::1. The role of nitic oxide (NO) derived from L-arginine in the regional vasodilator effects of endothelin-1 has been investigated in anaesthetized, spontaneously hypertensive (SH) rats in which autonomic reflexes were abolished by ganglion blockade. The experimental design incorporated animals infused with phenylephri...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1992.tb09049.x
更新日期:1992-03-01 00:00:00
abstract::1. Different 5-hydroxytryptamine (5-HT) receptor subtypes mediate different behavioural responses. Compounds acting at more than one 5-HT receptor exert behavioural effects which may be the result of response competition or a specific interaction between pathways within the CNS. Therefore the mutual interaction betwee...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1990.tb14138.x
更新日期:1990-11-01 00:00:00
abstract::1. Fluoxetine (Prozac) is widely used as an antidepressant drug and is assumed to be a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI). Claims that its beneficial psychotropic effects extend beyond those in treatment of depression have drawn clinical and popular attention to this compound, raising the q...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0701545
更新日期:1997-12-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Gain of function mutations in TRPC6 channels can cause autosomal dominant forms of focal segmental glomerulosclerosis (FSGS). Validated inhibitors of TRPC6 channels that are biologically active on FSGS-related TRPC6 mutants are eagerly sought. EXPERIMENTAL APPROACH:We synthesized new TRPC6-inhib...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13977
更新日期:2017-11-01 00:00:00
abstract:BACKGROUND AND PURPOSE:The use of tubulin-binding compounds, which act in part by inhibiting tumour angiogenesis, has become an integral strategy of tumour therapy. Recently, tubulysins were identified as a novel class of natural compounds of myxobacterial origin, which inhibit tubulin polymerization. As these compound...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2012.02037.x
更新日期:2012-11-01 00:00:00
abstract::The effects of the angiotensin-converting-enzyme inhibitor (ACEI) ramiprilat, the angiotensin II type 1 receptor antagonist (AT(1)A) candesartan, and the combination of both drugs on infarct size (IS) resulting from regional myocardial ischaemia were studied in pigs. Both ACEI and AT(1)A reduce myocardial IS by a brad...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0703544
更新日期:2000-09-01 00:00:00
abstract::The effects of injection of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA) and N-ethyl-3,4-methylenedioxyamphetamine (MDEA) (all 20 mg kg(-1)) on blood pressure, heart rate, core body temperature and locomotor activity in conscious rats were investigated using radiotelemetry. MDMA and MD...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0706688
更新日期:2006-04-01 00:00:00
abstract::1 The beta-adrenoceptor agonist isoprenaline normally causes only a small and inconsistent increase in the membrane potential of cells in guinea-pig liver slices, in contrast to the large hyperpolarizations seen with alpha-agonists. However, after a selective alpha-adrenoceptor agonist has been applied, the response t...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1977.tb06991.x
更新日期:1977-01-01 00:00:00
abstract::1. We investigated the role of two conserved basic residues in the second transmembrane helix arginine 172 (R172) and lysine 179 (K179) of the VPAC(2) receptor. 2. Vasoactive intestinal polypeptide (VIP) activated VPAC(2) receptors with an EC(50) value of 7 nM, as compared to 150, 190 and 4000 nM at R172L, R172Q and K...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0704195
更新日期:2001-08-01 00:00:00
abstract::1. The mechanism by which neuropeptide Y (NPY) potentiates the vasoconstriction induced by alpha 1-adrenoceptor agonists was investigated in 3rd generation mesenteric arterioles of the rat. 2. At a maximally active concentration, nitrendipine (10(-6) M) displaced to the right the concentration-response curves to norad...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1990.tb14714.x
更新日期:1990-02-01 00:00:00