Abstract:
:We have studied the recovery of receptor binding and of isoprenaline-stimulated cyclic AMP responses after chronic (2-5 days) exposure of tissue-cultured living rat heart cells to several beta-adrenoceptor antagonists. Most experiments were performed with [3H]- (+/-)-carazolol and [3H]-(+/-)-CGP 12177, as prototypes of high affinity lipophilic and hydrophilic ligands respectively. Chronic antagonist treatment did not alter the total number of receptors nor did it cause intracellular accumulation of the ligands. At the end of the treatment, radiolabelled antagonists were displaced either by 'infinite' dilution of the incubation medium or by competitive displacement with the non-labelled ligand (-)-timolol. In dilution assays dissociation of carazolol from specific sites was biphasic with t 1/2 values of 41 +/- 14 and 219 +/- 15 min. Dissociation of CGP 12177 was monophasic with t 1/2 of 102 +/- 2 min. Timolol enhanced the dissociation rates of both radioligands and suppressed the slow phase of carazolol dissociation. Isoprenaline-stimulated cyclic AMP formation did not recover in parallel with the release of the two antagonists from receptor binding sites. To reach about 80% of control values for receptor availability or cyclic AMP response required 3 h and 24 h washout periods, respectively, after carazolol (0.2 nM) treatment, or 1.5 and 12 h washout periods after CGP 12177 (4 nM) treatment. Such a 'decoupling' effect was not observed during recovery from chronic exposure to the antagonists, timolol and propranolol. We conclude that some antagonists cause a novel form of desensitization that is not linked to their partial agonistic potency. Moreover, carazolol-type drugs seem to induce an additional isomeric form of the beta-receptor that is not recognized by other antagonists. These observations could explain the well known discrepancy between long duration of action and rapid removal from the circulation of several antagonists in current therapeutic use.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Becker C,Porzig Hdoi
10.1111/j.1476-5381.1984.tb10814.xsubject
Has Abstractpub_date
1984-07-01 00:00:00pages
745-55issue
3eissn
0007-1188issn
1476-5381journal_volume
82pub_type
杂志文章abstract::1 Picrotoxin selectively and reversibly suppressed the inhibitory action of gamma-aminobutyric acid (GABA), but not that of glycine, taurine or beta-alanine, on the frequency of spontaneous spike discharges in guinea-pig cerebellar slices. Strychnine reversibly suppressed the inhibitory action of glycine, taurine or b...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1976.tb07650.x
更新日期:1976-05-01 00:00:00
abstract::1 Groups of mice were pretreated with the 5-hydroxytryptamine (5-HT) depletors, fenfluramine or p-chlorophenylalanine (PCPA), followed by pethidine or morphine. 2 Fenfluramine alone produced a short lasting analgesia but PCPA was without any effect. 3 Pethidine and morphine both increased hot plate reaction times meas...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1982.tb09177.x
更新日期:1982-04-01 00:00:00
abstract::The effects of aconitine, an Aconitum alkaloid, on spontaneous inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs respectively) were investigated in the mechanically dissociated rat ventromedial hypothalamic (VMH) neurons in which native presynaptic nerve terminals remained intact. Under current-clamp co...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0704517
更新日期:2002-02-01 00:00:00
abstract::1. The possible roles of endothelial and smooth muscle cell hyperpolarization and nitric oxide (NO) in endothelium-dependent relaxation were examined in isolated rings of pig right coronary artery. 2. The effects of hyperpolarization were prevented with high K+ (30-125 mM), isotonic Krebs solutions. Functional antagon...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb13110.x
更新日期:1994-06-01 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::It has been proposed that the vagus nerve plays a role in mediating cholecystokinin-8 (CCK-8) effect on such gastric functions as motility, emptying and gastric acid secretion. To examine the contribution of the efferent pathways in realizing these effects, efferent mass activity in the ventral gastric vagal nerve in ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0703270
更新日期:2000-04-01 00:00:00
abstract::The effects of local perivascular application of dopamine to rat pial arterioles. (20-40 micrometer i.d.) were examined in situ, at the microcirculatory level, by use of a high-resolution closed circuit television microscope recording system. Local application of very low, physiological doses (1 to 10 pg) of dopamine ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1980.tb07900.x
更新日期:1980-08-01 00:00:00
abstract::1 The vasopressor response to prostaglandin F2 alpha (PGF2 alpha) and to ((15S)-hydroxy-11 alpha, 9 alpha-(epoxymethano)-prosta-5Z, 13E-dienoic acid) (U-46619) in the canine isolated lung lobe was significantly attenuated following the administration of verapamil. 2 The pressor response to arachidonic acid (AA) was no...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1981.tb16777.x
更新日期:1981-05-01 00:00:00
abstract::1. The effects of the intravenous injection of Kö 1173, a new anticonvulsant drug, phenytoin and procainamide were studied on three types of cardiac arrhythmia in dogs.2. Ventricular ectopic beats produced by intravenous injection of adrenaline in anaesthetized dogs respired with halothane were abolished by Kö 1173, 0...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1972.tb08114.x
更新日期:1972-08-01 00:00:00
abstract::1. Morphine-like analgesic drugs caused depression of twitches of the isolated guinea-pig ileum in response to transmural electrical stimulation. The drugs tested were the narcotic analgesics codeine, diamorphine, fentanyl, morphine, morphine-N-oxide, normorphine, oxymorphone, pethidine, phenazocine and phenoperidine ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1969.tb10580.x
更新日期:1969-10-01 00:00:00
abstract::1. Openers of ATP-sensitive K(+) channels are of interest in several therapeutic indications including overactive bladder and other lower urinary tract disorders. This study reports on the in vitro and in vivo characterization of a structurally novel naphthylamide N-[2-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethy...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705908
更新日期:2004-09-01 00:00:00
abstract::1. We have investigated the in vitro interaction between chloride ions and endothelium as revealed by alterations in vascular contractility and smooth muscle cell membrane potential in isolated pulmonary arteries from Dahl salt-resistant normotensive and salt-sensitive hypertensive rats. 2. Exposure to nitro-l-arginin...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705703
更新日期:2004-03-01 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::1 We previously reported that four lignans isolated from the bark of Machilus thunbergii Sieb. et Zucc. (Lauraceae) protected primary cultures of rat cortical neurons from neurotoxicity induced by glutamate. 2 Among the lignans, meso-dihydroguaiarectic acid (MDGA) and licarin A significantly attenuated glutamate-induc...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0706380
更新日期:2005-11-01 00:00:00
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...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702905
更新日期:1999-11-01 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:BACKGROUND AND PURPOSE:Highly vascularized ovarian carcinoma secretes the putative endocannabinoid and GPR55 agonist, L-α-lysophosphatidylinositol (LPI), into the circulation. We aimed to assess the involvement of this agonist and its receptor in ovarian cancer angiogenesis. EXPERIMENTAL APPROACH:Secretion of LPI by t...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13196
更新日期:2015-08-01 00:00:00
abstract::1. The effects of the non-selective endothelin (ET) receptor (ETA/ETB) antagonist, bosentan, on sciatic nerve dysfunction in experimental diabetes were investigated. 2. Rats with 5-6 weeks untreated streptozotocin-diabetes exhibited characteristic slowed motor nerve conduction velocity (mean +/- s.d., 36.6 +/- 3.4 m s...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1995.tb15888.x
更新日期:1995-05-01 00:00:00
abstract::1. The effects of myocardial ischaemia/reperfusion were tested on the coronary vasorelaxant responses to agonists selective for the A1 and A2 adenosine receptor subtypes in the dog. The left anterior descending (LAD) coronary artery was occluded distal to the first diagonal branch. The occlusion was maintained for 1 h...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb14877.x
更新日期:1994-04-01 00:00:00
abstract::1. The influence of feeding 2 levels of sotalol on the incidence of beta-aminopropionitrile (BAPN)-induced aortic ruptures of immature turkeys was determined.2. Four of 22 turkeys fed 0.12% sotalol and 0.07% BAPN died of aortic ruptures, but 6 of 21 turkeys fed only BAPN died of the syndrome.3. Blood pressure, heart r...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1972.tb08095.x
更新日期:1972-07-01 00:00:00
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 A procedure involving two guinea-pig isolated hearts perfused in series is described for detecting in the recipient heart the release of a possible coronary vasodilator metabolite from the donor heart. 2 Adrenaline and isoprenaline stimulated the rate and force of contraction and produced a multiphasic coronary vasc...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1976.tb07696.x
更新日期:1976-09-01 00:00:00
abstract:BACKGROUND AND PURPOSE:The human, rat, and mouse P2X(7) receptors have been previously characterized, and in this study we report the cloning and pharmacological properties of the guinea pig orthologue. EXPERIMENTAL APPROACH:A cDNA encoding for the guinea pig P2X(7) receptor was isolated from a guinea pig brain librar...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0707596
更新日期:2008-02-01 00:00:00
abstract::In intact mesenteric arteries, increasing [K(+)]o by 5 mM hyperpolarized both endothelial and smooth muscle cells. Subsequent exposure to 10 microM phenylephrine depolarized both cell types which were then repolarized by a 5 mM increase in [K(+)]o. In endothelium-denuded vessels, increasing [K(+)]o by 5 mM hyperpolari...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0704256
更新日期:2001-09-01 00:00:00
abstract:BACKGROUND AND PURPOSE:(-)-Englerin A (EA) is a potent cytotoxic agent against renal carcinoma cells. It achieves its effects by activation of transient receptor potential canonical (TRPC)4/TRPC1 heteromeric channels. It is also an agonist at channels formed by the related protein, TRPC5. Here, we sought an EA analogue...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.14128
更新日期:2018-03-01 00:00:00
abstract::1. Inhibition of human polymorphonuclear leucocyte (PMN) function by adenosine was studied with respect to effects of adenosine on intracellular cyclic AMP and calcium during the PMN respiratory burst. 2. The adenosine analogue 5'-N-ethylcarboxamide-adenosine (NECA) and L-N6-phenyl-isopropyl-adenosine (L-PIA) inhibite...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1989.tb12028.x
更新日期:1989-07-01 00:00:00
abstract::1. Cumulative concentration-response curves (CRC) to prostaglandin E1 (PGE1), PGE2, PGD2 and PGF2alpha (0.01-30 microM) and to the thromboxane A2 (TXA2) receptor agonist U-46619 (0.01-30 microM) were constructed in human isolated detrusor muscle strips both in basal conditions and during electrical field stimulation. ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0701903
更新日期:1998-07-01 00:00:00
abstract::1 The effects of opioids on synaptic transmission in cat sacral parasympathetic colonic ganglia were studied in vitro, using intracellular electrophysiological techniques. Electrical stimulation of the pelvic nerve evoked fast excitatory postsynaptic potentials (e.p.s.ps), which were blocked by hexamethonium and tetro...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1987.tb11340.x
更新日期:1987-10-01 00:00:00
abstract::1 Mechanical and electrical responses to stimulation of the parasympathetic and sympathetic nerves were compared in the trachea isolated from normal guinea-pigs and from guinea-pigs sensitized to albumin and exposed repeatedly to inhaled albumin (a model of bronchial asthma). 2 Sensitized trachealis exhibited mechanic...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1987.tb11385.x
更新日期:1987-12-01 00:00:00
abstract::1. Peroxynitrite, a potent cytotoxic oxidant formed by the reaction of nitric oxide with superoxide anion, and hydroxyl radical, formed in the iron-catalysed Fenton reaction, are important mediators of reperfusion injury. In in vitro studies, DNA single strand breakage, triggered by peroxynitrite or by hydroxyl radica...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0701234
更新日期:1997-07-01 00:00:00