Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: DrugBank:APRD00345 (ICI)
 5,388 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Exposure of slices of cerebral cortex from guinea pigs to electrical pulses for 10s or to noradrenaline, 5-hydroxytryptamine or histamine increases the rate of phosphorylation of unidentified proteins in the tissue; the increases in protein phosphorylation due to electrical pulses and noradrenaline were non-additive, whereas the increases due to pulses and 5-hydroxytryptamine or histamine were additive. 2. The stimulating effects of electrical pulses and noradrenaline on protein phosphorylation were antagonized by the beta-adrenergic blocking agents L-propranolol, dichloroisoprenaline, practolol and ICI 66082, but not by the alpha-adrenergic blocking agents, phentolamine and phenoxybenzamine. 3. The increase in protein phosphorylation associated with electrical pulses was antagonized by 10 mum-trifluoperazine and 0.5 mum-prostaglandin E1. 4. It is postulated that under the experimental conditions used the action of electrical pulses on protein phosphorylation is mediated by noradrenaline acting through a beta-adrenergic receptor mechanism probably involving adenylate cyclase.
 ...
PMID:Protein phosphorylation in respiring slices of guinea-pig cerebral cortex. Evidence for a role for noradrenaline and adenosine 3':5'-cyclic monophosphate in the increased phosphorylation observed on application of electrical pulses. 0 16

The present study investigated the effects of celiprolol a novel beta 1-antagonist with partial beta 2-agonist activity on the human failing heart. Experiments were performed on isolated electrically driven atrial and ventricular cardiac preparations and in membrane preparations from the left ventricles of nine patients (four with dilated cardiomyopathy; five with ischemic cardiomyopathy) undergoing cardiac transplantation for terminal heart failure. Celiprolol produced a negative inotropic effect in atrial and ventricular heart muscle. However, in the presence of forskolin--which activates the catalyst of the adenylate cyclase-or the cAMP phosphodiesterase inhibitor milrinone, celiprolol produced concentration-dependent positive inotropic effects and positive lusitropic effects. Experiments with the beta 1-and beta 2-selective antagonists CGP 207.12A and ICI 118.551, respectively, suggest that the positive inotropic response is mediated by beta 2-adrenoceptors. In radioligand binding experiments, a selectivity of 15.7 [-Gpp(NH)p] or 23.9 [+Gpp(NH)p] as judged from the Ki values--of binding to beta 2-adrenoceptors was measured in the failing human ventricular myocardium. Competition curves with celiprolol alone and in the presence of the guanine nucleotide Gpp(NH)p revealed no evidence for agonist activity at beta 1- or beta 2-adrenoceptors. It is concluded that amplification of the cAMP response is able to unmask partial agonist activity of celiprolol in the failing human heart at beta 2-adrenoceptors. The inotropic measurements are a more sensitive approach than radioligand binding studies. Whether the pharmacological profile of celiprolol will be useful in conditions like heart failure is questionable with respect to the potential downregulation of beta 2-adrenoceptors by its partial agonist activity.
 ...
PMID:Positive inotropic effects due to partial agonistic activity of the beta-adrenoceptor antagonist celiprolol following amplification of cAMP formation in failing human myocardium. 127 96

Beta-adrenergic receptors on cultured human retinal pigment epithelium were demonstrated by the binding of [125I]cyanopindolol. Its pharmacologic specificity was also examined. Specific [125I]cyanopindolol binding was saturable, with a dissociation constant of 130 pM and a receptor density of 12 fmol per one-half million cells, which is equivalent to 14,000 receptor sites per retinal pigment epithelial cell. Agonists competed for specific [125I]cyanopindolol binding, with the following rank order of potencies: (-)-isoproterenol > (-)-epinephrine > (-)-norepinephrine. Beta 2-selective antagonist ICI-118551 was approximately 3 log orders more potent than the beta 1-selective antagonist, betaxolol. These receptors were also coupled to an adenylate cyclase. These results suggest strongly that cultured human retinal pigment epithelial cells possess beta 2-adrenergic receptors. The potential significance of these findings with regard to retinal pigment epithelial functions is discussed herein.
 ...
PMID:Human retinal pigment epithelial cells possess beta 2-adrenergic receptors. 133 Jun 65

The influence of maturation and aging on beta receptors in rat liver was studied. Competition binding experiments with the nonselective beta-antagonist propranolol and the subtype selective antagonists ICI 118,551 (beta 2) ICI 89,406 (beta 1), and CGP 20,712A (beta 1) revealed the presence of a mixed beta 1 and beta 2 receptor population in crude plasma membrane preparations from livers of newborn, mature, and senescent rats. The percentage of beta 1 receptors was lowest in livers from newborn rats and was increased in livers from mature and senescent rats. This increase is caused by a decrease in beta 2 receptor density on maturation, although the beta 1 receptor density is nearly constant throughout the life span of the rat. Isoproterenol-stimulated adenylate cyclase activity was inhibited in livers from senescent rats by propranolol and ICI 118,551 and to a lesser extent by ICI 89,406 and CGP 20,712A. The isoproterenol-stimulated glucose output in hepatocytes from senescent rats was inhibited concentration dependently by propranolol, ICI 118,551, ICi 89,406, and CGP 20,712A. From these results we conclude that beta 1 and beta 2 receptors are present in livers from rats of the three age groups and that the beta 1 to beta 2 receptor ratio is increased in livers from mature and senescent rats compared with newborn rats. Both beta receptor subtypes are linked to the cAMP second messenger system in newborn and senescent rats; beta 1 and beta 2 receptors are equally involved in the regulation of glycogenolysis in hepatocytes from senescent rats.
 ...
PMID:Influence of age on the beta 1- and beta 2-adrenergic receptors in rat liver. 133 56

1. Triiodothyronine (T3; 1.0 mg/kg per day subcutaneously) was administered to 10 dogs for 14 days; 10 saline-treated dogs served as controls. T3-treated dogs showed the expected physiological responses of hyperthyroidism; further, chronotropic responses to isoprenaline in vivo were significantly increased in T3-treated dogs. 2. Beta-adrenoceptor subtype density was measured in membrane preparations by displacement of 125I-iodocyanopindolol binding by the selective beta 2-adrenoceptor antagonist, ICI 118, 551. T3 treatment led to a 93% increase in right atrial beta 1-adrenoceptor density and a 141% increase in left ventricular beta 1-adrenoceptor density; beta 2-adrenoceptor densities in right atrial, left ventricular and lung membranes were unchanged. 3. T3-treatment did not change basal or maximally stimulated adenylate cyclase activities in left ventricular membranes. 4. Thus, the cardiovascular changes in experimental hyperthyroidism in dogs were accompanied by an increased chronotropic response in vivo to isoprenaline and an increased beta 1-adrenoceptor density in atrial and ventricular membranes. However, there was no corresponding change in basal or maximal responsiveness of adenylate cyclase in ventricular membranes.
 ...
PMID:Cardiac beta-adrenoceptor changes in experimental hyperthyroidism in dogs. 133 80

In severe asthma attacks beta 2-sympathomimetics lose part of their therapeutic efficiency. To elucidate this loss of efficiency in an experimental model we compared the relaxant potency of salbutamol (SAL), fenoterol (FEN), formoterol (FOR), and (-)-isoprenaline (ISO) in guinea pig tracheae partially and maximally precontracted by 0.1 and 60 mumol/L carbachol, respectively. In partially precontracted tracheae the beta 2-sympathomimetics exerted maximum relaxation in comparison with ISO and low EC50S (nmol/L) for relaxation (SAL, 20; FEN, 5.6; FOR, 0.28; and ISO, 2.5). In maximally precontracted tracheae, however, the beta 2-sympathomimetics were only partial agonists for relaxation with reduced intrinsic activities (%) in comparison to ISO (SAL, 59%; FEN, 61%; FOR, 76%) and significantly increased EC50S (nmol/L) for relaxation (SAL, 130; FEN, 57; FOR, 3.0; ISO, 37). To investigate if the high relaxant potency of FOR is correlated with a higher binding affinity and/or a higher intrinsic activity for adenylate cyclase stimulation than for FEN and SAL, we performed experiments in receptor membranes from guinea pig lung. Binding competition of SAL, FEN, and FOR with [3H]ICI 118,551 for lung beta 2-adrenoceptors yielded dissociation constants (KD) of 320 (SAL), 120 (FEN), and 7.6 (FOR) nmol/L, which exhibited the same ranking as EC50S for relaxation. Concentrations of SAL, FEN, and FOR equivalent to 100 KD of the respective dissociation constants stimulated beta 2-adrenoceptor-coupled adenylate cyclase with different intrinsic activities (%) incomparison to ISO (SAL, 61%; FEN, 63%; FOR, 89%) matching intrinsic activities for relaxation. From these experiments it may be concluded that FOR might improve drug therapy of severe asthma not only due to its long mode of action discovered in clinical studies but also due to its high intrinsic activity and receptor affinity.
 ...
PMID:Formoterol, fenoterol, and salbutamol as partial agonists for relaxation of maximally contracted guinea pig tracheae: comparison of relaxation with receptor binding. 135 70

The release of GnRH evoked by norepinephrine (NE) was studied in GT1 GnRH neuronal cell lines in superfusion and static cultures. GnRH release from static cultured GT1-7 cells was stimulated by NE in a dose-dependent fashion. This effect was mimicked by the nonsubtype-selective beta-adrenergic agonist isoproterenol and blocked by the beta-adrenergic antagonist propranolol and the beta 1-adrenergic subtype-specific antagonist CGP 20712A. However, the stimulation of GnRH release by NE was not affected by the beta 2-, alpha-, alpha 1-, or alpha 2-adrenergic antagonists ICI 118.551, phentolamine, prazosin, or yohimbine, respectively. Superfusion of GT1-1 cells with NE for 60-100 min resulted in rapid and sustained increases in GnRH secretion. The NE-stimulated GnRH release showed a higher amplitude and longer duration than the spontaneous GnRH pulses characteristic of GT1-1 cells. In parallel to the stimulation of GnRH release, NE also rapidly increased (first observed at 60 sec) the intracellular concentration of cAMP in isobutylmethylxanthine-pretreated GT1-1 and GT1-7 cells in a dose-dependent fashion. The stimulation of intracellular cAMP concentration was also mimicked by isoproterenol and blocked by propranolol and CGP 20712A. In addition, GT1 cells express beta 1- but not beta 2-adrenergic receptor mRNA, as probed by Northern blot analysis. These results demonstrate a direct stimulatory effect of NE on GnRH neurons. The pharmacological evidence and the mRNA analysis are consistent with NE acting through a beta 1-adrenergic receptor positively coupled to adenylate cyclase.
 ...
PMID:Beta 1-adrenergic regulation of the GT1 gonadotropin-releasing hormone (GnRH) neuronal cell lines: stimulation of GnRH release via receptors positively coupled to adenylate cyclase. 135 2

The pharmacological properties of BRL 37,344 (sodium-4-(2'-[2-hydroxy-2- (3-chloro-phenyl)ethylamino]-propyl)phenoxyacetatesesquihydrate), a beta 3-selective agonist, and CGP 12,177A) (-)-4-(3-t-butyl amino-2-hydroxypropoxy) benzimidazole-2-one], a non-selective beta-antagonist, recently characterized as a partial beta 3-agonist in rat adipose tissue, were studied in comparison with isoproterenol, a non-selective beta-agonist, in plasma membranes prepared from the livers of newborn rats. Competition binding curves obtained with [125I]iodocyanopindolol ([125I]CYP) as ligand and isoproterenol or BRL 37,344 as competitor were characterized by the presence of a high and a low affinity binding site; the high affinity binding site was no longer detectable when guanidylimidobisphosphate (GppNHp) was present in the incubation mixture. Competition curves with CGP 12,177A were monophasic and independent of GppNHp. In the presence of 10(-7) M of the beta 2-selective antagonist ICI 118,551 [erythro-(+/-)-1-(7-methylindan-4-yloxy)-3-isopropylamino butan-2-ol], a concentration which blocks most of the beta 2-receptors, ligand binding was reduced to 32% of its maximum. Under these conditions, isoproterenol further displaced the ligand, and competition curves still displayed the high and the low affinity binding sites; BRL 37,344, however, caused no further displacement of ligand, except at the highest concentrations. This suggests that BRL 37,344 occupies only the ICI 118,551-sensitive binding sites, i.e. beta 2-receptors. Isoproterenol and BRL 37,344 both stimulated adenylate cyclase (EC 4.6.1.1) activity concentration dependently, although the stimulating effect of BRL 37,344 was about half of what was found for isoproterenol. Furthermore, BRL 37,344 inhibited concentration dependently the isoproterenol-induced stimulation of adenylate cyclase, and the inhibition was dependent on the concentration of isoproterenol. The stimulating effect of isoproterenol and BRL 37,344 on adenylate cyclase was blocked by ICI 118,551, whereas the beta 1-selective antagonist CGP 20,712A ((+/-)-(2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino)-3-[4-(1-methy l-4- trifluoromethyl-2-imidazolyl)-phenoxy]-2-propanolmethane sulphonate) was ineffective. CGP 12,177A failed to stimulate adenylate cyclase activity. From these results we suggest that BRL 37,344 acts as a beta 2-partial agonist in rat liver. The results obtained with CGP 12,177A are typical for a non-selective beta-antagonist. We therefore conclude that there is no pharmacological evidence for the presence of beta 3-receptors in livers from newborn rats.
 ...
PMID:Pharmacological characterization of a beta 3-receptor agonist (BRL 37,344) and a partial agonist (CGP 12,177A) in neonatal rat liver plasma membranes. 136 33

The derivatives of proenkephalin A were measured in acid extracts of rat lacrimal glands by specific radioimmunoassay. Glands from adult male rats contained all four derivatives of the opiate precursor. The content in the gland of proenkephalin A-derived peptides Met5-enkephalin, Leu5-enkephalin, Met5-enkephalin Arg6-Phe7 and Met5-enkephalin Arg6-Gly7-Leu8 indicates tissue specific processing with an enhancement of the heptapeptide. The effect of enkephalins on the activity of adenylate cyclase in lacrimal membranes was measured and compared with the effect of the synthetic enkephalin analogue D-ala2-methionine enkephalinamide (DALA) that inhibits both lacrimal protein secretion and lacrimal adenylate cyclase. In the presence of the peptidase inhibitors thiorphan and bestatin, the inhibition of forskolin-stimulated adenylate cyclase activity by Met5-enk, Leu5-enk, Met5-enk Arg6-Phe7 and DALA were identical. Maximum inhibition was approximately 35% at a dose of 50 microM enkephalin. Addition of the octapeptide, Met5-enk Arg6-Gly7-Leu8 resulted in decreased adenylate cyclase activity; however, the effect was not statistically significant. Activation of delta opioid receptors by the endogenous enkephalins is indicated by the reversal of adenylate cyclase inhibition in the presence of the delta-receptor antagonist ICI 174864. The data support the physiological significance of in vitro inhibition of lacrimal secretion by DALA and indicate a possible role for endogenous enkephalins in lacrimal function.
 ...
PMID:Proenkephalin A derivatives in lacrimal gland: occurrence and regulation of lacrimal function. 152 77

The interaction of [(-)-4-(3-t-butylamino-2-hydroxy-propoxy)benzimidazol-2-one] (CGP 12177) (CGP) with receptors that couple to adenylate cyclase was examined in membrane homogenates from rat interscapular brown adipose tissue (IBAT). Although typically regarded as a beta adrenoceptor antagonist, CGP stimulated adenylate cyclase activity with an activation constant of about 3 microM. Consistent with its classification as an antagonist, CGP inhibited norepinephrine-stimulated cyclase activity and did so at concentrations that had little or no stimulatory effect. CGP also inhibited activity stimulated by the atypical agonist [(R*,R*)-4-[2-[[2[(3-chlorophenyl)-2- hydroxyethyl]amino]propyl]phenyl]phenoxyacetic acid (BRL 37344), but only at CGP concentrations that stimulated activity when tested alone. The beta-1-selective antagonist ICI 89,406 blocked norepinephrine-stimulated adenylate cyclase activity, but did not inhibit the activity stimulated by CGP. Together, these results indicate that CGP modulates IBAT adenylate cyclase by interacting with two receptors. One is the beta-1 receptor of which CGP is a high-affinity antagonist. The second appears to be an atypical receptor of which CGP is a partial agonist.
 ...
PMID:CGP 12177A modulates brown fat adenylate cyclase activity by interacting with two distinct receptor sites. 167 92


1 2 3 4 5 6 7 8 9 10 Next >>