Localization of β-adrenoreceptors in mammalian lung by light microscopic autoradiography

Barnes, Peter J.; Basbaum, Carol; Nadel, Jay A.; Roberts, James M.

doi:10.1038/299444a0

Cited by 124 publications

(40 citation statements)

References 14 publications

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“…Clearly the most urgent objective is to obtain much more precise information on the cellular localisation of P-adrenoceptor subtypes in the airways. The recent use of light microscope autoradiography in ferret lung with [3H]-dihydroalprenolol (Barnes, Basbaum, Nadel & Roberts, 1982) has revealed that high densities of P-adrenoceptors are associated with alveoli and airway smooth muscle, particularly the smooth muscle of the smaller airways (bronchioles). It will be important now to extend this approach to examine receptor subtypes in the airways of several species.…”

Section: Discussionmentioning

confidence: 99%

β‐Adrenoceptor heterogeneity in guinea‐pig airways: comparison of functional and receptor labelling studies

Carswell

Nahorski

1983

British J Pharmacology

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Section: Discussionmentioning

confidence: 99%

β‐Adrenoceptor heterogeneity in guinea‐pig airways: comparison of functional and receptor labelling studies

Carswell

Nahorski

1983

British J Pharmacology

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“…Recent studies in anaesthetized rats have given results for uptake of (-)-[3H]-CGP 12177 in lung and heart and for (Kawai et al, 1986), muscle (Watson-Wright & Wilkinson, 1986, fat (Lacasa et al, 1985) and proximal tubules in kidney (Morgunov & Hirsch, 1990). Other radiolabelled ligands have shown the presence of P-adrenoceptors in the aorta and trachea (Barnes et al, 1982). Another factor which may complicate the delivery of the ligand to tissues is that there are reports that CGP 12177 has a partial agonist effect in vitro Becker & Porzig, 1984).…”

Section: Animalsmentioning

confidence: 99%

Demonstration of the suitability of CGP 12177 for in vivo studies of β‐adrenoceptors

Law¹

1993

British J Pharmacology

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Positron emission tomography (PET) with appropriate radioligands offers the possibility of studying receptors non‐invasively in man. The suitability of CGP 12177, a hydrophilic non‐selective β‐adrenoceptor antagonist which can be labelled with the positron emitter 11C, as a ligand for in vivo studies of β‐adrenoceptors was assessed in rats. [3H]‐CGP 12177 was injected into the tail veins of restrained conscious rats. Serial blood samples were taken from tail arteries to determine clearance from plasma. Rats were killed and tissues removed to determine tissue uptake. Radioactivity was assessed by liquid scintillation counting. The uptake of (−)‐[3H]‐CGP 12177 in various tissues was compared to that of (±)‐[3H]‐CGP 12177. Maximum tissue:plasma ratios obtained for the (−)‐enantiomer in lung, heart and liver were 170, 42 and 13 compared with 60, 15 and 12 for the racemate. Prior injection of excess unlabelled (±)‐CGP 12177 blocked the uptake of both (−)‐ and (±)‐[3H]‐CGP 12177 in lung and heart but not liver, tissue:plasma ratios for both tracers being reduced to 7, 3 and 7 respectively. Clearance of (−)‐[3H]‐CGP 12177 from plasma was rapid during the first 5 min but showed only small changes during 5 to 90 min. Uptake in lung and heart reached a maximum at 1 to 5 min and showed a slow decrease during 5–90 min. Prior injection of unlabelled (±)‐CGP 12177 reduced uptake in lung and heart to 10% and 20% respectively. Injection of unlabelled (±)‐CGP 12177 at 15 min displaced ∼75% of the radioactivity by 90 min. (±)‐Propranolol had a similar effect to that of unlabelled (±)‐CGP 12177. Prior injection reduced uptake of radioactivity in lung and heart to 15% and 20% respectively. Injection of (±)‐propranolol at 15 min displaced ∼60% of the radioactivity by 90 min indicating that the tracer binds to β‐adrenoceptor sites in vivo. In vivo saturation curves, obtained by injection of (−)‐[3H]‐CGP 12177 with increasing amounts of unlabelled (−)‐CGP 12177, gave values of Bmax for lung of ∼45 pmol per g wet weight of tissue and for heart of ∼ 6 pmol per g wet weight of tissue. KD could only be expressed as nmol injected per kg body weight, that for lung (2.5 nmol kg−1) being greater than that for heart (1.3 nmol kg−1). Competition studies carried out by co‐injecting (−)‐[3H]‐CGP 12177 with unlabelled (±)‐CGP 12177 or (−)‐propranolol gave similar values for Bmax (lung 44 pmol g−1, heart 6 pmol g−1,). Values of KD for (±)‐CGP 12177 (lung 4.7 pmol kg−1, heart 2.6 pmol kg−1) were approximately twice those for (−)‐CGP 12177. Values of KD for (−)‐propranolol (lung 38 nmol kg−1, heart 104 nmol kg−1) were greater. The results show that (−)‐[3H]‐CGP 12177 is a suitable ligand for assessing β‐adrenoceptors in vivo.

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“…In contrast to GR, a soluble intracellular receptor that resides in the cytosolic compartment when unliganded (1)(2)(3)(4), the ␤ 2 -adrenergic receptor (␤ 2 -AR) constitutes a plasma membrane-anchored, G-protein-coupled receptor with seven transmembrane spanning domains (14,15). The ␤ 2 -AR is highly expressed in fibroblasts, vascular smooth muscle cells (USMCs), and epithelial cells of the human lung (14,16). Signal transduction by ␤ 2 -AR occurs upon ligand binding via activation of adenylate cyclase, which increases the concentration of intracellular cAMP (14).…”

mentioning

confidence: 99%

Ligand-independent Activation of the Glucocorticoid Receptor by β2-Adrenergic Receptor Agonists in Primary Human Lung Fibroblasts and Vascular Smooth Muscle Cells

Eickelberg

Roth

Lörx

et al. 1999

Journal of Biological Chemistry

365

208

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The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor present in most cell types. Upon ligand binding, the GR is activated and translocates into the nucleus where it transmits the anti-inflammatory actions of glucocorticoids. Here, we describe the ligand-independent activation of GR by the ␤ 2 -adrenergic receptor (␤ 2 -AR) agonists, salbutamol and salmeterol, in primary human lung fibroblasts and vascular smooth muscle cells. Immunohistochemistry demonstrated expression of GR and the ␤ 2 -AR by fibroblasts and vascular smooth muscle cells. Treatment of the cells with the ␤ 2 -AR agonists, salbutamol or salmeterol, resulted in translocation of GR into the nucleus beginning at 30 min, as shown by immunohistochemistry and Western blotting of cytosolic and nuclear cell extracts. In comparison, activation of GR induced by the corticosteroids dexamethasone and fluticasone occurred at the same time after treatment (30 min) but resulted in a more complete depletion of GR from the cytosolic compartment. Electrophoretic mobility shift assays confirmed that nuclear GR, activated by both ␤ 2 -AR agonists and glucocorticoids, actively bound to the GR consensus sequence (GR element). Functional activation of the GR was confirmed by a Luciferase reporter gene assay, using a GR driven promoter fragment from the p21 (WAF1/CIP1) gene. The effects of the ␤ 2 -AR agonists, salbutamol and salmeterol, were dependent upon binding to the ␤ 2 -AR, because blocking of ␤ 2 -AR with propranolol abrogated GR activation. GR activation appeared to involve cAMP. In summary, these data show that ␤ 2 -AR agonists are potent activators of GR. Ligandindependent activation of GR by ␤ 2 -AR agonists may substantially mediate the anti-inflammatory actions of these drugs observed in vitro and in vivo.

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Localization of β-adrenoreceptors in mammalian lung by light microscopic autoradiography

Cited by 124 publications

References 14 publications

β‐Adrenoceptor heterogeneity in guinea‐pig airways: comparison of functional and receptor labelling studies

β‐Adrenoceptor heterogeneity in guinea‐pig airways: comparison of functional and receptor labelling studies

Demonstration of the suitability of CGP 12177 for in vivo studies of β‐adrenoceptors

Ligand-independent Activation of the Glucocorticoid Receptor by β2-Adrenergic Receptor Agonists in Primary Human Lung Fibroblasts and Vascular Smooth Muscle Cells

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