α<sub>1</sub>‐Adrenoceptor function and autoradiographic distribution in human asthmatic lung

Spina, Dom; Rigby, Paul; Paterson, J. W.; Goldie, Roy G.

doi:10.1111/j.1476-5381.1989.tb12006.x

Cited by 30 publications

(3 citation statements)

References 36 publications

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“…Radioligand binding studies using [ 3 H]prazosin have demonstrated the presence of α 1 -adrenoceptors in membranes prepared from a number of tissues, including brain [48], liver [49,50], kidney [51][52][53] and smooth muscle [54][55][56], but not from lung [57]. For a radioligand to be useful in vivo the number of targeted receptors must be high relative to non-specific binding sites.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of [11C]GB67, a novel radioligand for imaging myocardial α1-adrenoceptors with positron emission tomography

et al. 2000

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Dysfunction of the sympathetic nervous system underlies a number of myocardial disorders. Positron emission tomography (PET) offers a way of assessing receptor function non-invasively in humans, but there are no PET radioligands for assessing myocardial alpha-adrenoceptors. GB67, a structural and pharmacological analogue of the alpha 1-adrenoceptor antagonist prazosin, was labelled with positron-emitting carbon-11 (t1/2 = 20.4 min) by 11C-methylation of N-desmethylamido-GB67 (GB99). [11C]GB67 was injected intravenously into conscious rats. Serial arterial blood samples were taken. Rats were killed and tissues removed to determine radioactivity. The percentages of unchanged [11C]GB67 and its radioactive metabolites in plasma and tissues were assessed by HPLC. Plasma clearance of radioactivity was rapid. Myocardial uptake was maximal at 1-2 min and decreased slowly during 60 min. Predosing with adrenoceptor antagonists demonstrated selectivity for myocardial alpha 1-adrenoceptors. GB67 and prazosin blocked uptake of radioactivity; the non-selective antagonist, phentolamine, partially blocked uptake; the alpha 2-adrenoceptor antagonist, RX 821002, only blocked uptake at high dose and the beta-adrenoceptor antagonist, CGP 12177, had no effect. Additionally, injection of prazosin at 20 min after radioligand displaced radioactivity. In vivo competition curves obtained by injecting [11C]GB67 with varying amounts of either unlabelled GB67 or its precursor GB99 were fitted to a competitive binding model to provide estimates of the maximum number of binding sites (Bmax) and half saturation doses (K) for myocardium. Assuming a tissue protein content of 10%, the values of Bmax [approximately 13 pmol.(g tissue)-1[ were similar to those ]50-170 fmol.(mg protein)-1] reported for myocardial alpha 1-adrenoceptors assessed in vitro. Both GB67 and its precursor GB99 had high affinity for alpha 1-adrenoceptors [KGB67 = 1.5 nmol.(kg body weight)-1, KGB99 = 4.8 nmol.(kg body weight)-1]. HPLC demonstrated four radioactive metabolites in plasma. [11C]GB67 was 80% of the radioactivity at 5 min and 50% at 45 min. No radioactive metabolites were detected in myocardium up to 60 min after injection. [11C]GB67 was assessed in two male human volunteers. PET demonstrated high myocardial uptake. The profile of radioactive metabolites in plasma was comparable to that in the rat, although metabolism was slower in humans. Thus, [11C]GB67 is a promising radioligand for assessing alpha 1-adrenoceptors in human myocardium with PET.

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Section: Discussionmentioning

confidence: 99%

Evaluation of [11C]GB67, a novel radioligand for imaging myocardial α1-adrenoceptors with positron emission tomography

et al. 2000

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“…Whilst various studies have focused on the effects of disease states such as asthma on contractile function mediated via α‐adrenoceptors (Kneussel & Richardson, 1978; Szentivanyi, 1979; 1980; Goldie et al ., 1985; Spina et al ., 1989), little research has been directed towards determining the effects of ageing in the normal functioning of these systems.…”

Section: Introductionmentioning

confidence: 99%

Age and region‐dependent contraction to α‐adrenoceptor agonists in rat and guinea‐pig isolated trachea

Preuss

Rigby

Goldie

1998

British J Pharmacology

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1 The in¯uence of age and of region on a-adrenoceptor-mediated contraction to (7)-adrenaline and (7)-noradrenaline was examined in rat (4 ± 136 weeks) and guinea-pig (2 ± 156 weeks) isolated tracheal ring preparations with particular emphasis on the early (up to 12 weeks) maturation phase. 2 In rat tracheal rings, signi®cant regional variation was observed with respect to maximal (7)-adrenaline-induced contraction, such that the greatest activity was seen in ring preparations from the laryngeal end of the trachea. Tracheal rings from the carinal end responded very poorly or were unresponsive to (7)-adrenaline, depending on animal age. These regional di erences were seen across the age range. The potencies of (7)-adrenaline and (7)-noradrenaline remained unchanged with respect to animal age, but the maximum contractile tension that developed in response to these agonists increased with increasing animal age in all regions of the trachea. 3 In guinea-pig isolated tracheal tissue, maximum contractile responses (E max ) to (7)-adrenaline and (7)-noradrenaline remained unchanged with increasing animal age. In addition, there was no evidence for a region-dependence in the responsiveness of tracheal tissue to a-adrenoceptor-mediated contraction in this species. 4 In both guinea-pig and rat isolated tracheal tissue, a-adrenoceptor-mediated contraction appeared to involve the activation of a 1 -adrenoceptors.

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“…The · 1 -adrenergic receptor, which mediates the contraction of smooth muscle, is relatively sparse and may only be demonstrated under certain conditions [34][35][36][37][38]. Prejunctional · 2 -adrenergic receptors (autoreceptors) may inhibit the release of both norepinephrine and of NPY from adrenergic nerves and the release of tachyki-nins from sensory nerves [39][40][41].…”

Section: Sympathetic Nervous Systemmentioning

confidence: 99%

Autonomic Innervation of Human Airways: Structure, Function, and Pathophysiology in Asthma

Velden¹,

Hulsmann

1999

Neuroimmunomodulation

126

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The human airways are innervated via efferent and afferent autonomic nerves, which regulate many aspects of airway function. It has been suggested that neural control of the airways may be abnormal in asthmatic patients, and that neurogenic mechanisms may contribute to the pathogenesis and pathophysiology of asthma. In this review, the autonomic innervation of the human airways and possible abnormalities in asthma are discussed. The parasympathetic nervous system is the dominant neuronal pathway in the control of airway smooth muscle tone. Stimulation of cholinergic nerves causes bronchoconstriction, mucus secretion, and bronchial vasodilation. Although abnormalities of the cholinergic innervation have been suggested in asthma, thus far the evidence for cholinergic dysfunction in asthmatic subjects is not convincing. Sympathetic nerves may control tracheobronchial blood vessels, but no innervation of human airway smooth muscle has been demonstrated. β-Adrenergic receptors, however, are abundantly expressed on human airway smooth muscle and activation of these receptors causes bronchodilation. The physiological role of β-adrenergic receptors is unclear and their function seems normal in asthmatic patients. Inhibitory nonadrenergic noncholinergic (NANC) nerves, containing vasoactive intestinal peptide and nitric oxide, may be the only neural bronchodilator pathways in human airways. Although a dysfunction of inhibitory NANC nerves has been proposed in asthma, thus far no differences in inhibitory NANC responses have been found between asthmatics and healthy subjects. Excitatory NANC nerves, extensively studied in animal airways, have also been detected in human airways. In animal studies, stimulation of excitatory NANC nerves causes bronchoconstriction, mucus secretion, vascular hyperpermeability, cough, and vasodilation, a process called ‘neurogenic inflammation’. Recent studies have demonstrated an interaction between the excitatory NANC nervous system and inflammatory cells. Neuropeptides may influence the recruitment, proliferation, and activation of leukocytes. On the other hand, inflammatory cells may modulate the neuronal phenotype and function. The functional relevance of the excitatory NANC nervous system and its interaction with the immune system in asthma still remains to be elucidated.

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α₁‐Adrenoceptor function and autoradiographic distribution in human asthmatic lung

Cited by 30 publications

References 36 publications

Evaluation of [11C]GB67, a novel radioligand for imaging myocardial α1-adrenoceptors with positron emission tomography

Evaluation of [11C]GB67, a novel radioligand for imaging myocardial α1-adrenoceptors with positron emission tomography

Age and region‐dependent contraction to α‐adrenoceptor agonists in rat and guinea‐pig isolated trachea

Autonomic Innervation of Human Airways: Structure, Function, and Pathophysiology in Asthma

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α1‐Adrenoceptor function and autoradiographic distribution in human asthmatic lung

Cited by 30 publications

References 36 publications

Evaluation of [11C]GB67, a novel radioligand for imaging myocardial α1-adrenoceptors with positron emission tomography

Evaluation of [11C]GB67, a novel radioligand for imaging myocardial α1-adrenoceptors with positron emission tomography

Age and region‐dependent contraction to α‐adrenoceptor agonists in rat and guinea‐pig isolated trachea

Autonomic Innervation of Human Airways: Structure, Function, and Pathophysiology in Asthma

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α₁‐Adrenoceptor function and autoradiographic distribution in human asthmatic lung