Gene/Protein Disease Symptom Drug Enzyme Compound
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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.
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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

1. Responses of cerebral cortical neurones to the microiontophoretic application of acetylcholine, noradrenaline, cyclic adenosine 3',5'-monophosphate (cyclic AMP) and cyclic guanosine 3',5'-monophosphate (cyclic GMP) were examined.2. The application of acetylcholine and cyclic GMP to identified pyramidal tract neurones resulted in an increased frequency of firing in a large number of cells. Upon application of both substances to cells which could not be identified as pyramidal tract cells, a reduction in the frequency of spontaneous firing was sometimes observed.3. Careful current controls had no effect on the cells discussed here, indicating that the observed responses were not due to the iontophoretic currents. Also, the electro-osmotic ejection of cyclic GMP (outward current) produced similar changes of cell firing to those which followed iontophoretic application (inward current).4. The microiontophoretic application of atropine resulted in a blockade of acetylcholine responses while leaving responses to cyclic GMP unaffected. This suggests that cyclic GMP was not acting indirectly by releasing acetylcholine from presynaptic endings.5. Ejection of cyclic GMP from solutions containing calcium ions produced responses comparable to those produced by cyclic GMP alone. It is unlikely therefore that cyclic GMP was causing excitation by chelating calcium.6. Applications of noradrenaline and cyclic AMP produced a reduction in the spontaneous discharge rate of most neurones tested.7. Phosphodiesterase inhibitors such as ICI 63,197 caused a potentiation of the noradrenaline responses of pyramidal tract neurones.8. 5'-adenosine monophosphate produced a powerful depression of all cells to which it was applied. This action was blocked by aminophylline, suggesting the effect was mediated through an adenosine receptor. Responses to cyclic AMP were usually not abolished, but were reduced by about 50% in amplitude.9. These results are consistent with the hypothesis that cyclic AMP may mediate some neuronal effects of noradrenaline and cyclic GMP may mediate some effects of acetylcholine. The results are also consistent with the suggestion that the two nucleotides may sometimes mediate opposite cellular responses to humoral stimuli.
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PMID:Microiontophoretic studies of the effects of cylic nucleotides on excitability of neurones in the rat cerebral cortex. 19 28

Viloxazine hydrochloride (ICI 58,834, VIVALAN) a chemically novel antidepressant, shows selective inhibition of noradrenaline uptake into mouse heart in vivo and into rat brain in vitro. The noradrenaline uptake inhibitory activity resides primarily in one of the two optically active isomers, and it is suggested that in the conformation adopted for uptake by noradrenaline, the aryl and the amino groups are trans. In a comparison of in vivo and in vitro potency, tri- and tetracyclic antidepressants exhibit a good correlation. However, viloxazine possesses higher in vivo activity than would be expected from in vitro studies. The latter finding cannot be readily explained on the basis of known pharmacokinetic or metabolic factors.
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PMID:Effects of viloxazine, its optical isomers and its major metabolites on biogenic amine uptake mechanisms in vitro and in vivo. 72 46

Radioligand-binding experiments were performed with crude membrane homogenates (CMH) from human skin in order to investigate the epidermal beta-adrenergic receptor (beta AR) density. CMH were prepared from leftovers of split-thickness skin grafts by sequential homogenization and centrifugation procedures to yield essentially epidermal fragments. Saturation experiments with the non-selective beta-adrenoceptor antagonist (-)-[125I]-iodocyanopindolol (ICYP) as radioligand showed saturable specific binding isotherms. Scatchard transformation of the data demonstrated high-affinity binding of ICYP to a single class of beta AR (Bmax = 80 +/- 10 fmol/mg protein; KD = 8 pM +/- 0.9; n = 8). beta AR antagonists displaced ICYP in a monophasic displacement pattern. The IC50 values were (nmol/1) propranolol (non-selective) 24.8; ICI 118,551 (beta 2 selective) 14.7; CGP-12177 (non-selective) 28.9; bisoprolol (beta 1 selective) 1500; CGP-20712A (beta 1 selective) 8990. beta AR agonists displaced ICYP with a potency ranking isoprenaline greater than adrenaline greater than noradrenaline. We conclude that epidermal crude membrane homogenates prepared from human split-thickness skin contain a high population of beta 2-adrenergic receptors. These receptors may be studied to further investigate the nature of human epidermal beta-adrenergic mechanisms.
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PMID:Binding of beta-adrenergic receptors in human skin. 131 66

[45Ca2+] Uptake was studied in response to adrenaline, isoprenaline, noradrenaline, and (Bu)2cAMP in platelets from patients with anorexia nervosa. In both controls and anorectics, adrenaline, isoprenaline, noradrenaline, and (Bu)2cAMP stimulated [45Ca2+] uptake. In receptor subtype characterisation studies on control platelets, adrenaline-stimulated [45Ca2+] uptake was blocked by yohimbine (an alpha 2-adrenoceptor antagonist) and the specific beta 2-adrenoceptor antagonist ICI 118,551, but not by atenolol (a beta 1-antagonist). Isoprenaline action was blocked by ICI 118,551, but not by yohimbine. Noradrenaline-stimulated [45Ca2+] uptake was blocked by yohimbine but not by ICI 118,551. In platelets from anorectic patients, there was a significant increase in noradrenaline-stimulated [45Ca2+] uptake, a significant diminution in adrenaline and isoprenaline-stimulated [45Ca2+] uptake, but no significant difference in (Bu)2cAMP-stimulated [45Ca2+] uptake, when compared with controls. Basal uptake was also significantly enhanced in anorectics and was found to be inhibited with verapamil but not adrenoceptor antagonist. These data firstly indicate that both alpha 2- and beta 2-adrenoceptor activation elicits [45Ca2+] uptake by platelets. It is proposed that this stimulated [45Ca2+] uptake does not reflect changes in cytosolic Ca2+ but to localized changes of Ca2+ at the plasma membrane, possibly associated with receptor activation, per se. The respective increase and decrease of alpha- and beta-adrenoceptor activity in platelets from anorectic patients is in accord with other reports of changes of adrenoceptor number and type in platelets and other cells from anorectic patients. There may also be an increase in calcium channel activity in platelets from anorectics.
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PMID:Differential changes in alpha- and beta-adrenoceptor linked [45Ca2+] uptake in platelets from patients with anorexia nervosa. 134 46

The aim of the present study was to investigate beta-adrenoceptor modulation of noradrenaline release from sympathetic nerves in superfused cortical kidney slices of 4-week-old spontaneously hypertensive rats (SHR) and age-matched controls (WKY). After preincubation with 3H-noradrenaline the kidney slices were electrically stimulated in superfusion chambers. The stimulation induced (S-I) outflow of radioactivity was mainly composed of unmetabolized 3H-noradrenaline in both strains and thus taken as an index of noradrenaline release. There was a frequency-dependent (1.25-20 Hz) increase in the S-I outflow of radioactivity. At all stimulation frequencies tested S-I outflow of radioactivity was similar or even slightly lower in SHR than in WKY kidney slices in either the absence or presence of cocaine (10 mumol/l). The non-selective beta-adrenoceptor agonists isoprenaline (0.1 mumol/l) and adrenaline (0.01 and 0.1 mumol/l) enhanced S-I outflow of radioactivity. The facilitatory effects of isoprenaline (0.1 mumol/l) and adrenaline (0.1 mumol/l) were blocked by the selective beta 2-adrenoceptor antagonist ICI 118551 (0.1 mumol/l) but not by the selective beta 1-adrenoceptor antagonist atenolol (0.3 mumol/l). The cell-permeable cAMP analogue 8-bromo-cAMP (300 mumol/l) enhanced S-I outflow of radioactivity to a similar extent in both SHR and WKY kidney slices. A combination of 8-bromo-cAMP (300 mumol/l) and adrenaline (0.1 mumol/l) did not enhance S-I outflow of radioactivity to a greater extent than 8-bromo cAMP (300 mumol/l) alone in both strains.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of beta 2-adrenoceptors by isoprenaline and adrenaline enhances noradrenaline release in cortical kidney slices of young spontaneously hypertensive rats. 134 53

The potencies of the beta 1-adrenoceptor agonist, noradrenaline, and the beta 2-adrenoceptor agonist, fenoterol, at beta-adrenoceptors in portal vein were examined using preparations isolated from control, methimazole-treated or l-thyroxine-treated rats. Tissues were preincubated with phenoxybenzamine (1 mumol/l) to block alpha-adrenoceptors and neuronal and extraneuronal uptake. Fenoterol was approximately 400 times more potent than noradrenaline (-log IC50 7.85 vs. 5.26) in inhibiting the spontaneous contractions of the portal vein. The beta 2-adrenoceptor antagonist, ICI 118,551, was approximately 3000 fold more potent than the beta 1-adrenoceptor antagonist, atenolol, in blocking the effects of fenoterol (pA2 9.32 and 5.88 respectively) and 400 times more potent in antagonising noradrenaline (pA2 8.96 vs. 6.23). Treatment of rats with methimazole led to decreased myogenic tone, and treatment with thyroxine to increased tone. beta-Adrenoceptor binding densities and the relative potencies of the agonists and antagonists used were unaffected by methimazole treatment. Thyroxine administration was also without effect on the relative potencies of these compounds. Our data indicate that although the portal vein is a target tissue for thyroxine, as indicated by its influence on myogenic tone, the beta-adrenoceptor population in this preparation, confirmed to be of the beta 2-subtype, is unaffected.
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PMID:Classification of the beta-adrenoceptor subtype in the rat portal vein: effect of altered thyroid hormone levels. 135 Sep 95

Isoprenaline (0.1 microM), in the presence of phentolamine (1 microM) to block autoinhibitory alpha-adrenoceptors, significantly increased the efflux of radioactivity produced by field stimulation (2 Hz for 60 s) from rat isolated atria in which the noradrenergic transmitter stores had been labelled with [3H]noradrenaline. This facilitatory effect of isoprenaline on noradrenergic transmission was not affected by the selective beta 1-adrenoceptor antagonist CGP 20712A (0.3 microM). However, the selective beta 2-adrenoceptor antagonist ICI 118551 (0.1 microM) not only abolished the facilitatory effect of isoprenaline but reversed it to an inhibitory effect, indicating that the prejunctional beta-adrenoceptors subserving facilitation of noradrenergic transmission in rat atria are of the beta 2-subtype. The inhibitory effect of isoprenaline that was revealed by blockade of beta 2-adrenoceptors was abolished by atenolol (3 microM) in a concentration which markedly reduced the effect of isoprenaline on the rate of atrial beating. This finding suggests that activation of beta 1-adrenoceptors on atrial myocytes by isoprenaline may have resulted in release of one or more substance(s) which inhibited stimulation-induced release of noradrenaline, presumably by activating prejunctional receptors. The inhibitory effect of isoprenaline on noradrenergic transmission was not affected by the prostaglandin synthesis inhibitor indomethacin (10 microM) suggesting that prostaglandins were not involved.
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PMID:An inhibitory effect of isoprenaline on stimulation-induced noradrenaline release from rat atria. 135 62

In patients with chronic heart failure cardiac beta-1 adrenoceptors are reduced, whereas beta-2 adrenoceptor changes vary depending on the etiology of the disease. Beta Adrenoceptor agonists can be used for short-term inotropic support in chronic heart failure; their clinical efficacy might depend on which beta adrenoceptor subtype(s) mediates their positive inotropic effect. Thus, the beta adrenoceptor subtype(s) involved in the positive inotropic effects of clinically used beta adrenoceptor agonists was characterized on isolated electrically driven human right atria by the use of the selective beta-1 adrenoceptor antagonist CGP 20712 A (300 nmol/l) and/or the selective beta-2 adrenoceptor antagonist ICI 118,551 (30 nmol/l). Epinine evoked positive inotropic effects through stimulation of beta-1 and beta-2 adrenoceptors to about the same degree, whereas dobutamine acted mainly at beta-1 adrenoceptors but had a significant beta-2 adrenoceptor component. Both agonists were full agonists causing the same maximum increase in contractile force (Emax) as did isoprenaline or Ca++ (Emax = 1.0). In contrast, denopamine was a partial selective beta-1 adrenoceptor agonist (Emax = 0.75-0.85). Dopamine was in the presence of uptake1-blockade (by 5 mumol/l phenoxybenzamine) a partial agonist (Emax = 0.60-0.70) acting selectively at beta-1 adrenoceptors; in the absence of uptake1-blockade, however, dopamine was a full agonist, indicating that part of its positive inotropic effect is indirect via the release of endogenous noradrenaline. Xamoterol did not exert positive inotropic effects, but concentration-dependently slightly decreased basal force of contraction.
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PMID:Characterization of the beta adrenoceptor subtype(s) mediating the positive inotropic effects of epinine, dopamine, dobutamine, denopamine and xamoterol in isolated human right atrium. 135 51

1. The effect of several adrenoceptor agonists and antagonists on the spontaneous and stimulus-evoked release of [3H]noradrenaline was studied in rat isolated portal vein. 2. Yohimbine (10(-6)M) increased the stimulus-evoked [3H]noradrenaline efflux. Adrenaline alone (3 x 10(-6)M) was without effect, while it increased the resting efflux when added together with yohimbine. 3. Propranolol alone was without effect on the release of [3H]noradrenaline. When added (2 x 10(-6)M) at the same time as yohimbine, it reduced the stimulation-induced 3H efflux. When added before adrenaline and yohimbine, propranolol (10(-5)M) reduced both spontaneous and stimulus-evoked release of [3H]noradrenaline. 4. The effect of several beta-blocking drugs was measured on the enhancing effect of yohimbine on the stimulation-evoked 3H efflux. The beta 1-adrenoceptor blocking drugs: atenolol (5 x 10(-6) and 10(-5) M), metoprolol (5 x 10(-6) and 10(-5) M), like the more selective bisoprolol (2 x 10(-6) and 4 x 10(-6) M) inhibited yohimbine activity. Likewise, propranolol (2 x 10(-6) and 5 x 10(-6)M) and the beta 2-adrenoceptor blocker ICI 118551 exhibited an antagonistic effect. 5. These results indicate the possibility for noradrenaline to activate presynaptic beta-adrenoceptors in rat portal vein. They show an interaction between the presynpatic alpha 2- and beta-adrenoceptor mediated systems in the release of noradrenaline. They suggest the presence and the activity of facilitatory beta 1-adrenoceptors.
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PMID:Modulation of noradrenergic transmission in the rat isolated portal vein: role of prejunctional alpha 2-adrenoceptors and beta-adrenoceptors. 135 78


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