Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. DL-Propranolol, L-propranolol, DL-alprenolol, pindolol (LB46), practolol, ICI 66082, sotalol and oxprenolol all produced prolonged falls in blood pressure and heart rate after intracerebroventricular administration in conscious normotensive cats. 2. Transient initial pressor responses and tachycardias were observed after intracerebroventricular infusions of all the beta-adrenoceptor antagonists used, except ICI 66082. 3. D-Propranolol, D-alphrenolol, procaine and lignocaine all produced initial increases in blood pressure and heart rate but did not subsequently cause any reduction in either blood pressure or heart rate. 4. The time of maximum hypotension and bradycardia after intracerebroventricular infusion of beta-adrenoceptor antagonists coincided with the maximum inhibition of the centrally mediated tachycardia observed after intracerebroventricular isoprenaline.
Clin Sci Mol Med Suppl 1975 Jun
PMID:The brain as a possible site for the cardiovascular effects of beta-adrenoceptor blocking agents in cats. 2 78

Prostaglandin F2 alpha (PGF2 alpha) binds specifically to a partially purified membrane preparation from rat corpora lutea. The high affinity, low capacity binding component asa a Kd = 4.7 nM and has a capacity of 0.38 pmol/mg protein. Binding kinetics were temperature-dependent with an association rate constant of 2.5 x 10(5) 1/mol-sec and a dissociation rate constant of 4.3 x 10(-4) sec-1 at 22 degrees C. Little competition for binding was shown by other prostaglandins and prostaglandin metabolites; the PGF2 alpha analogue ICI 81008 (16-m-trifluoromethylphenyl-prostaglandin F2 alpha) showed a binding affinity similar to that of PGF2 alpha. The specific binding of PGF2 alpha to luteal cell membranes was confirmed by electron microscopy using a ferritin--PGF2 alpha conjugate. Ferritin--PGF2 alpha was found predominantly on luteal cell surfaces; little binding occurred on other types of cells present. These data demonstrate specific binding of PGF2 alha to rat luteal membranes. It is suggested that the luteolytic action of PGF2 alpha in the rat may be receptor-mediated.
Mol Cell Endocrinol 1979 Jan
PMID:Specific binding of prostaglandin F2 alpha to membranes of rat corpora lutea. 22 Dec 85

The interaction of tamoxifen (ICI 46,474), a synthetic antiestrogen, with uterine cytosol proteins of immature calf and rat has been studied directly using the tritiated compound labeled with a high specific activity. The binding complexes were measured by the dextrancoated charcoal, protamine sulfate and hydroxyapatite assays. Scatchard plots revealed a single class of high-affinity (KD congruent to 1.7 nM) binding sites, with a binding capacity similar to that of estradiol. Competitive experiments showed the same binding specificity for estrogens and antiestrogens. Sucrose gradient analysis revealed an 8S binding protein which could be partially proteolysed by trypsin into a 4S binding protein. Kinetic studies showed that the association rate of tamoxifen was 5 times lower than that of estradiol and reacted according to a second order kinetics. The first-order kinetics of dissociation was considerably higher than that of estradiol, giving a half-dissociation time of 20--40 min at 0--2 degrees C. In some cases tamoxifen displayed two slopes of dissociation, but the proportion of the slow-dissociating complex was always inferior to that found with estradiol. In contrast to estradiol, the kinetic constants ratio (k-/k+) gave a calculated dissociation constant, similar to that determined in equilibrium conditions (KD), agreeing with a simple reactional scheme. We conclude that the antiestrogen tamoxifen binds directly to the 8S cytosol receptor for estrogens and not to another receptor for the antagonists. In contrast to estradiol, the antagonist is rapidly dissociated from the receptor sites and is unable to protect them against thermal inactivation. The affinity of tamoxifen for its receptor sites as determined directly is surprisingly high when compared to its affinity evaluated indirectly by competitive experiments. It is then suggested that the two ligands either bind on two different sites of the same protein or induce a different conformational change of the same binding site.
Mol Cell Endocrinol
PMID:High-affinity binding of the antiestrogen [3H]tamoxifen to the 8S estradiol receptor. 68 Mar 40

1. Atenolol (ICI 66.082, Tenormin) is a new beta-adrenoreceptor-blocking agent, devoid of intrinsic sympathomimetic and membrane-stabilizing properties. It does not cross the blood-brain barrier. 2. Atenolol given to hypertensive patients in initial open trials reduced arterial blood pressure significantly. 3. A double-blind comparison between atenolol and placebo in forty-five patients with essential hypertension demonstrated that atenolol gave a statistically significant reduction of blood pressure (delta 28/15 mmHg, P less than 0-005). 4. The optimum anti-hypertensive dose of atenolol in patients with mild to moderately severe essential hypertension was 200 mg daily. 5. Atenolol was compared with propranolol in thirty patients with essential hypertension. No statistically significant differences of anti-hypertensive effect were observed between the two drugs. 6. Long-term results (up to 2 years) in 117 hypertensive patients indicate that drug tolerance is good. No serious toxic effects were observed. 7. In four of twelve hypertensive patients with obstructive airways disease atenolol had to be withdrawn owing to deterioration of ventilatory function.
Clin Sci Mol Med Suppl 1976 Dec
PMID:Clinical evaluation of atenolol in hypertension. 79 59

The antiestrogen tamoxifen has been successfully used to control estrogen receptor (ER) and progesterone receptor positive breast cancer. However, the development of antiestrogen resistance is frequently observed in patients following long term treatment. We have studied the development of antiestrogen resistance in vitro and established an antiestrogen resistant variant of MCF-7 cells (clone 5C) after long term culture in estrogen free medium. The growth of clone 5C cells was not altered by either estradiol-17 beta or the antiestrogens 4-hydroxytamoxifen and ICI 164,384. Estrogen-stimulated progesterone receptor and reporter gene expression were markedly reduced in 5C cells compared to wild type MCF-7 cells. Only minor alteration in the levels of ER and no alteration in the affinity of ER for ligand were found in 5C cells. No mutation of ER cDNA in 5C cells was detected by polymerase chain reaction and DNA sequencing. This study demonstrates that change(s) in ER-mediated gene expression rather than the amino acid sequence of the ER itself may be associated with the development of at least one form of antiestrogen resistance.
Mol Cell Endocrinol 1992 Dec
PMID:An estrogen receptor positive MCF-7 clone that is resistant to antiestrogens and estradiol. 130

An expression system that utilized yeast copper metallothionein promoter and ubiquitin fusion technology to express the human estrogen receptor gene in yeast is described. We have studied the biochemical and transcriptional regulatory properties of the human estrogen receptor. The biochemical properties of the yeast expressed receptors are identical to the receptors isolated from human tissue. Estradiol mediated activation of transcription by the receptor was studied by a reporter beta-galactosidase gene where expression was under the control of estrogen response elements. Using this expression system and a hyperpermeable yeast strain we have studied the effects of various antiestrogens on the regulation of estrogen receptor function. We demonstrate that tamoxifen and ICI 164,384 are capable of binding to the receptor but neither antiestrogen was able to block the estradiol mediated increase in transcription. In fact, both antiestrogens exerted weak agonist activity in this system.
J Steroid Biochem Mol Biol 1992 Aug
PMID:Human estrogen receptor regulation in a yeast model system and studies on receptor agonists and antagonists. 132 95

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.
Mol Pharmacol 1992 Oct
PMID:Influence of age on the beta 1- and beta 2-adrenergic receptors in rat liver. 133 56

Primary cultures of precursor cells from mouse and rat brown adipose tissue (BAT) were used to study the effect of a new beta-agonist (ICI D7114) on the uncoupling protein (UCP) gene expression. ICI 215001 (the active metabolite of D7114) increased the expression of UCP and its mRNA in brown adipocytes differentiating in vitro in a dose-dependent manner. This stimulating effect was not inhibited by propranolol, a non-specific beta-antagonist, but was partially reduced by bupranolol, a beta 3-antagonist. No expression of UCP mRNA was ever induced by ICI 215001 in white adipocytes differentiated in vitro. It was concluded that the drug could affect the brown adipose cells through a beta 3-pathway. It could clearly modulate the expression of UCP in brown adipocytes differentiated in vitro, but was not able by itself to turn on the gene.
Mol Cell Endocrinol 1992 Jul
PMID:Regulation of UCP gene expression in brown adipocytes differentiated in primary culture. Effects of a new beta-adrenoceptor agonist. 135 51

The presence of beta 2-adrenoceptors in the sheep ventricular myocardium was assessed by the radioligand binding technique and functional studies. In membrane preparations, the competition curve between [3H]-dihydroalprenolol and the selective beta 1-antagonist CGP 20712A (0.1 nM-1 mM) was clearly biphasic, and revealed the presence of two different binding sites showing an affinity (pKD) for CGP 20712A of 9.5 +/- 0.9 and 4.5 +/- 0.4, respectively. The relative proportion of beta 1:beta 2 adrenoceptors was about 70:30 in both the right and left ventricle. In ventricular trabeculae driven at 1Hz, isoprenaline (1-300 nM) caused a dose-dependent increase in the force of contraction, the maximum effect being 298 +/- 26 mg, associated with reduction of time to peak tension (t1, clinotropic effect) and relaxation time (t2, 298 +/- 26 mg, associated with reduction of time to peak tension (t1, clinotropic effect) and relaxation time (t2, lusitropic effect). The inotropic dose-response curve for isoprenaline was significantly shifted to the right by pretreatment of the preparations with 0.1 microM CGP 20712A or with the selective beta 2-antagonist ICI 118551 (50 nM). In the presence of CGP 20712A (0.1 microM), isoprenaline, up to a concentration of 10 microM, did not affect either t1 or t2; on the other hand, pretreatment of the preparations with ICI 118551 (50 nM) fully antagonized the clinotropic but not the lusitropic effect of isoprenaline. In the presence of CGP 20712A procaterol (0.01-10 microM), a beta 2-adrenoceptor agonist, induced a positive intropic effect which was not associated with any significant modifications in t1 or t2. This effect was completely abolished by ICI 118551 (50 nM). The positive inotropic action of isoprenaline (1 microM) was associated with a significant decrease in action potential duration measured at -60 mV (220 +/- 8 and 193 +/- 10 ms in the absence and presence of isoprenaline, respectively; P less than 0.05). In the presence of CGP 20712A (0.1 microM) alone, isoprenaline (1 microM) still induced a significant increase in contractility but the action potential profile was only slightly affected. The effects of isoprenaline were fully antagonized by the simultaneous presence of CGP 20712A and ICI 118551 (10 nM). It is concluded that both beta 1- and beta 2-adrenoceptors appear to coexist in sheep ventricular myocardium where their stimulation mediates a positive inotropic effect. However, their functional role on the relaxation phase of the twitch may be different.
J Mol Cell Cardiol 1992 Jul
PMID:Beta 1- and beta 2-adrenoceptors in sheep cardiac ventricular muscle. 135 82

Hypogonadal (hpg) mutant mice, with a congenital deficiency of hypothalamic gonadotrophin-releasing hormone (GnRH), and testicular feminized (tfm) mice, which lack a functional androgen receptor, were used to study the effects of the potent GnRH agonist 'Zoladex' (ICI 118630; D-Ser (Bu(t))6, Azgly10-GnRH) on pituitary and gonadal function. Zoladex (0.5 mg) in a sustained-release lactide-glycolide copolymer depot was administered subcutaneously under anaesthesia and was left in place for 7 days, after which time the effects of the drug upon pituitary and serum gonadotrophin concentrations, glycoprotein hormone subunit mRNAs and testicular morphology were investigated. At the pituitary level, Zoladex treatment resulted in a substantial reduction in LH content in normal males, and LH content was depressed in hpg mice even below the basal levels normally found in these mutants. Pituitary LH content in the Zoladex-treated animals was depressed in the tfm groups, but not to the same levels as those found in the normal and castrated normal mice. Zoladex treatment at the time of castration prevented the post-operative elevation in serum LH associated with castration alone. In the androgen-deficient tfm mouse, Zoladex did not depress the normally elevated serum LH levels. Serum LH in the hpg animals was, in all cases, below the limit of detection of the assay. Pituitary FSH content was depressed into the hpg range in both the normal and castrated animals, but there was no further depression in the hpg mice. The pituitary content was reduced in the tfm mice, again the effects not being as dramatic as in the normal and castrated animals. Serum FSH content, as measured by radioimmunoassay, was depressed by 50% in normal mice; there was no reduction in the hpg mice, however. With regard to pituitary gonadotrophic hormone gene expression, Zoladex administration to normal mice caused a dramatic reduction in LH beta mRNA content, to a level approximating that found in untreated hpg mice. The drug also depressed LH beta mRNA in the castrated group to the hpg range when given at the time of castration, whereas in untreated castrated mice there was a significant increase in LH beta mRNA. In the tfm mouse, which can be considered as a model for long-term failure of androgen feedback, Zoladex again induced a fall in LH beta mRNA, but not to the same extent as in the normal and normal castrated group. Zoladex had no effect on the already low levels of LH beta mRNA found in hpg mice.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Endocrinol 1992 Jun
PMID:Effects of the gonadotrophin-releasing hormone agonist 'Zoladex' upon pituitary and gonadal function in hypogonadal (hpg) male mice: a comparison with normal male and testicular feminized (tfm) mice. 138 60


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