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)

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

A method is described for assessing the selectivity of compounds for beta 1- and beta 2-adrenoceptors in vivo. The potency of selective beta-adrenoceptor agonists to increase heart rate and decrease uterine contractions in pithed rats and in isolated tissues was determined. The order of potency both in vivo (i.v. route) and in vitro was: isoprenaline greater than noradrenaline greater than salbutamol on heart rate, and isoprenaline greater than salbutamol greater than noradrenaline on uterine relaxation. Fenoterol, salbutamol, and BRL 26830A/28410, but not denopamine, (i.p.) route were more potent stimulants of uterine relaxation than of heart rate in pithed rats and in vitro. The abilities of atenolol (beta 1-selective), ICI 118551 (beta 2-selective) and propranolol (non selective between beta 1- and beta 2-adrenoceptors) to inhibit responses to isoprenaline on heart rate and uterine contractions in vivo were also assessed. The effects of isoprenaline on heart rate were selectively antagonized by atenolol while those on the uterus were selectively antagonized by ICI 118551. These results show that beta 1-adrenoceptors mediate increases in heart rate and that beta 2-adrenoceptors mediate uterine relaxation in the pithed rat. They further show that the activity of compounds at these tissues can be used to assess their selectivity for beta 1- or beta 2-adrenoceptors in vivo.
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PMID:Method for assessing the activity of drugs at beta 1- and beta 2-adrenoceptors in the same animal. 290 5

The effects of fenoterol and salbutamol on isometric force of contraction were studied in isolated, electrically driven human papillary muscle preparations. Fenoterol increased force of contraction at concentrations of 1 mumol l-1 and higher. The maximally effective concentration of fenoterol (100 mumol l-1) increased force of contraction by about 130%. The positive inotropic effect of fenoterol was not influenced by 0.1 mumol l-1 prazosin. The beta 1-selective antagonist atenolol (2 mumol l-1) and the beta 2-selective antagonist ICI 118551 (1 mumol l-1) shifted the concentration-response curve of fenoterol to the right, indicating that beta 1- and beta 2-adrenoceptors may contribute to the positive inotropic effect of fenoterol. In contrast to fenoterol, salbutamol increased force of contraction only by about 11% at 100 mumol l-1. The results indicate that: (1) fenoterol exerts a direct positive inotropic effect in the human heart which may support the beneficial effects of the reduction of systemic vascular resistance in patients with congestive heart failure; (2) this positive inotropic effect of fenoterol is mediated by beta 1- and beta 2-adrenoceptors; (3) the clinically observed improvement of cardiac performance in the case of salbutamol is presumably not due to any direct positive inotropic effect.
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PMID:Effects of the beta 2-adrenoceptor agonists fenoterol and salbutamol on force of contraction in isolated human ventricular myocardium. 397 72

Fenoterol (beta 2-agonist) and several analogs stimulated swine adipose tissue lipolysis in addition to epinephrine, norepinephrine and isoproterenol. Lipolytic activity was inhibited by propranolol (beta 1 + beta 2) greater than metoprolol (beta 1) greater than ICI 118,551 (beta 2) greater than practolol (beta 1) much greater than butoxamine (beta 2) regardless of the agonist used in the test system. The swine adipose adrenoceptor is not readily classified into a beta 1 or beta 2 subtype. It may be unique or the classification systems devised in laboratory animals may not be applicable across species.
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PMID:Specificity of beta-adrenergic control of lipolysis in swine adipose tissue. 614 79

EC50 and relative intrinsic activity values were obtained for isoprenaline, fenoterol, salbutamol, prenalterol and three new beta-adrenoceptor agonists, BRL 28410, BRL 35113 and BRL 35135 on rat white adipocyte lipolysis, rat atrial rate and tension, rat uterus tension and guinea-pig tracheal tension. Fenoterol and salbutamol were selective for tracheal and uterine responses, prenalterol was selective for atrial responses, but BRL 28410, BRL 35113 and BRL 35135 were selective for the adipocyte lipolytic response. pA2 values for propranolol, practolol, ICI 118,551 and sotalol were obtained on adipocytes, atria and trachea. pA2 values for propranolol and sotalol were much lower on adipocytes than on atria or trachea. The pA2 value for practolol was lower on adipocytes than on atria and the pA2 value for ICI 118,551 was lower on adipocytes than on trachea. Both agonist and antagonist studies therefore suggest that the rat adipocyte lipolytic receptor does not fit into the current beta 1/beta 2-adrenoceptor classification.
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PMID:The rat lipolytic beta-adrenoceptor: studies using novel beta-adrenoceptor agonists. 614 97

We studied the effects of selective beta-adrenoceptor agonists on the cholinergic and non-adrenergic non-cholinergic (excitatory NANC) contractions elicited by electrical field stimulation of guinea pig main bronchi in vitro. Addition of the selective beta 2-adrenoceptor agonists, fenoterol and salbutamol, and the selective beta 3-adrenoceptor agonist, BRL 37344 (4-[2-[(2-hydroxy-2-(3-chlor-phenyl)ethyl)amino]-propyl]-phenoxyac etic acid), induced a dose-dependent inhibition of the cholinergic contraction (pD2 7.89, 6.71 and 4.56, respectively) and the excitatory NANC response (pD2 9.11, 8.16 and 7.42, respectively). Fenoterol- and BRL 37344-induced inhibition of the excitatory NANC response was blocked with high potency (pKB 8.77 and 9.07, respectively) by the selective beta 2-adrenoceptor antagonist, ICI 118,511 (erythro-1-(7-methylindan-4-yloxy)-3-(isopropylamino)-but an-2-ol). A comparable contraction induced by neurokinin A (2 or 5 nM) was also inhibited by fenoterol, salbutamol and BRL 37344, but at significantly higher concentrations than for the inhibition of the excitatory NANC response (pD2 8.72, 7.56 and 6.66, respectively). Such a preferential inhibition of electrical field stimulation- versus agonist-induced effects was not observed for cholinergic contractions (pD2 versus methacholine-induced tone 7.86, 6.93 and 5.10, respectively). The results clearly exclude the involvement of beta 3-adrenoceptors in these responses. Furthermore they show that beta 2-adrenoceptors are involved in the prejunctional inhibition of excitatory NANC contractions, presumably via modulation of tachykinin release from sensory nerves, and solely in the postjunctional inhibition of cholinergic contractions.
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PMID:Beta 2- but not beta 3-adrenoceptors mediate prejunctional inhibition of non-adrenergic non-cholinergic contraction of guinea pig main bronchi. 779 55

The aim of the study was to further explore the prejunctional beta-adrenoceptor-mediated control mechanism of noradrenaline release from sympathetic nerves in response to preganglionic nerve stimulation (PNS) and local nerve stimulation of the portal vein, respectively, in the pithed rat. Baseline values as well as the increments of mean arterial blood pressure (delta-BP), heart rate (delta-HR) and plasma noradrenaline levels (delta-NA) in response to four PNS episodes (0.8 Hz, 3 ms, 75 V for 45 s at 20 min intervals), respectively, were evaluated. Fenoterol administration (0.25 mg/kg, i.v.) reduced significantly the basal blood pressure but did not alter delta-BP in response to PNS. Basal heart rate markedly increased after fenoterol without any further change in heart rate induced by PNS. The beta 1-selective antagonist CGP 20712A attenuated delta-BP in response to PNS and prevented the fenoterol-induced increase in basal heart rate. The beta 2-selective antagonist ICI 118,551 per se did not change the blood pressure and heart rate values, but antagonized the fenoterol-induced decrease in basal blood pressure. Fenoterol enhanced plasma delta-NA in response to PNS by 105% in comparison to the corresponding control value. This effect of fenoterol could be blocked by pretreatment with ICI 118,551 but not with CGP 20712A (a selective beta 1-adrenoceptor antagonist) which per se did not significantly change plasma delta-NA. Repeated local stimulation of the portal vein (S1-S3, 2 Hz, 3 ms, 10 mA, for 120 s at 30 min intervals) increased portal plasma noradrenaline without changing mean blood pressure and heart rate in pithed rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pre- and postganglionic stimulation-induced noradrenaline overflow is markedly facilitated by a prejunctional beta 2-adrenoceptor-mediated control mechanism in the pithed rat. 796 7

Using electrical field stimulation of epithelium-denuded intact guinea pig tracheal tube preparations, we studied the presence and role of prejunctional beta2-adrenoceptors by measuring evoked endogenous acetylcholine (ACh) and norepinephrine (NE) release directly. Analysis of ACh and NE was through two HPLC systems with electrochemical detection. Electrical field stimulation (150 mA, 0.8 ms, 16 Hz, 5 min, biphasic pulses) released 29.1 +/- 2.5 pmol ACh/g tissue and 70.2 +/- 6.2 pmol NE/g tissue. Preincubation for 15 min with the selective beta2-adrenoceptor agonist fenoterol (1 microM) increased both ACh and NE overflow to 178 +/- 28 (P < 0.01) and 165 +/- 12% (P < 0.01), respectively, of control values, increases that were abolished completely by the selective beta2-adrenoceptor antagonist ICI-118551 (1 microM). Further experiments with increasing fenoterol concentrations (0.1-100 microM) and different preincubation periods (1, 5, and 15 min) showed a strong and concentration-dependent facilitation of NE release, with maximum response levels decreasing (from nearly 5-fold to only 2.5-fold of control value) with increasing agonist contact time. In contrast, sensitivity of facilitatory beta2-adrenoceptors on cholinergic nerves to fenoterol gradually increased when the incubation period was prolonged; in addition, a bell-shaped concentration-response relationship was found at 15 min of preincubation. Fenoterol concentration-response relationships (15-min agonist preincubation) in the presence of atropine and yohimbine (1 microM each) were similar in the case of NE release, but in the case of ACh release, the bell shape was lost. The results indicate a differential capacity and response time profile of facilitatory prejunctional beta2-adrenoceptors on adrenergic and cholinergic nerve terminals in the guinea pig trachea and suggest that the receptors on adrenergic nerves are more susceptible to desensitization.
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PMID:Facilitatory beta2-adrenoceptors on cholinergic and adrenergic nerve endings of the guinea pig trachea. 1007 Jan 5

Histamine, released from activated mast cells, causes bronchoconstriction mediated by H(1) receptors, whereas beta(2)-agonists are widely used for the relief of bronchoconstriction. In this study, we examined the effects of the beta(2)-adrenoceptor agonist, fenoterol, on the expression of H(1) receptors at the mRNA and protein levels, and functional responses. Incubation of bovine tracheal smooth muscle with fenoterol (10(-7) M) for 2 h increased H(1) receptor mRNA (maximum approximately 190%). The number of H(1) receptors was increased after 12 and 18 h without any change in binding affinity. In the contraction experiments, the concentration-response curves for histamine-induced contraction were shifted significantly to the left after 18-h exposure to fenoterol, consistent with the increase in receptor number. The fenoterol-induced increase in H(1) receptor mRNA was concentration-dependent and was abolished by propranolol and ICI 118551, but not by CGP 20712A, indicating that fenoterol acts via beta(2)-adrenoceptors. These effects were mimicked by other cAMP-elevating agents forskolin and prostaglandin E(2), and by the stable cAMP analog 8-bromo-cAMP. Cycloheximide alone produced superinduction of H(1) receptor mRNA and augmented the fenoterol-induced increase in H(1) receptor mRNA. Fenoterol increased both the stability and the transcription rate of H(1) receptor mRNA. Pretreatment with dexamethasone did not prevent fenoterol-induced up-regulation of H(1) receptor mRNA. Thus, fenoterol increases the expression of airway smooth muscle H(1) receptors via activation of the cAMP system through increased gene transcription and mRNA stability. This mechanism may be involved in the adverse responses encountered with the clinical use of short-acting beta(2)-agonists.
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PMID:Up-regulation of airway smooth muscle histamine H(1) receptor mRNA, protein, and function by beta(2)-adrenoceptor activation. 1077 67

Agonists at beta2 adrenoceptors are used widely as bronchodilators in treating bronchial asthma. These agents also may have important anti-inflammatory effects on eosinophils in asthma. We examined whether widely prescribed beta2-adrenoceptor agonists differ in ability to suppress stimulus-induced eosinophil effector functions such as superoxide anion (O2-) generation and degranulation. To examine involvement of cellular adhesion in such responses, we also investigated effects of beta2 agonists on cellular adhesion and on CD11b expression by human eosinophils. O2- was measured using chemiluminescence. Eosinophil degranulation and adhesion were assessed by a radioimmunoassay for eosinophil protein X (EPX). CD11b expression was measured by flow cytometry. Fenoterol inhibited platelet-activating factor (PAF)-induced O2- generation by eosinophils significantly more than salbutamol or procaterol. Fenoterol partially inhibited PAF-induced degranulation by eosinophils similarly to salbutamol or procaterol. Fenoterol inhibited phorbol myristate acetate (PMA)-induced O2- generation and degranulation by eosinophils, while salbutamol or procaterol did not. Fenoterol inhibition of PMA-induced O2- generation was not reversed by ICI-118551, a selective beta2-adrenoceptor antagonist. Fenoterol, but not salbutamol or procaterol, significantly inhibited PAF-induced eosinophil adhesion. Fenoterol inhibited O2- generation and degranulation more effectively than salbutamol or procaterol; these effects may include a component involving cellular adhesion. Inhibition also might include a component not mediated via beta2 adrenoceptors.
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PMID:Inhibition by fenoterol of human eosinophil functions including beta2-adrenoceptor-independent actions. 1245 31


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