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Title: Autoradiographic localization of beta-adrenoceptors in asthmatic human lung

Abstract

The autoradiographic distribution and density of beta-adrenoceptors in human non-diseased and asthmatic bronchi were investigated using (125I)iodocyanopindolol (I-CYP). Analysis of the effects of the beta-adrenoceptor antagonists on I-CYP binding demonstrated that betaxolol (20 nM, beta 1-selective) had no significant effect on specific grain density in either nonasthmatic or asthmatic human bronchus, whereas ICI-118551 (20 nM, beta 2-selective) inhibited I-CYP binding by 85 +/- 9% and 89 +/- 3%, respectively. Thus, homogeneous populations of beta 2-adrenoceptors existed in bronchi from both sources. Large populations of beta-adrenoceptors were localized to the bronchial epithelium, submucosal glands, and airway smooth muscle. Asthmatic bronchial tissue featured epithelial damage with exfoliated cells associated with luminal mucus plugs. A thickened basement membrane and airway smooth muscle hyperplasia were also evident. High levels of specific I-CYP binding were also detected over asthmatic bronchial smooth muscle, as assessed by autoradiography and quantitation of specific grain densities. Isoproterenol and fenoterol were 10- and 13-fold less potent, respectively, in bronchi from asthmatic lung than in those from nonasthmatic lung. However, this attenuated responsiveness to beta-adrenoceptor agonists was not caused by reduced beta-adrenoceptor density in asthmatic airways. A defect may exist in the coupling between beta-adrenoceptors and postreceptor mechanisms in severely asthmaticmore » lung.« less

Authors:
; ; ;  [1]
  1. (Univ. of Western Australia, Nedlands, Perth (Australia))
Publication Date:
OSTI Identifier:
5026080
Resource Type:
Journal Article
Resource Relation:
Journal Name: American Review of Respiratory Disease; (USA); Journal Volume: 140:5
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; ASTHMA; PATHOGENESIS; RECEPTORS; BIOLOGICAL LOCALIZATION; SYMPATHOMIMETICS; AUTORADIOGRAPHY; BIOCHEMICAL REACTION KINETICS; BRONCHI; IODINE 125; LUNGS; MAN; ANIMALS; AUTONOMIC NERVOUS SYSTEM AGENTS; BETA DECAY RADIOISOTOPES; BODY; DAYS LIVING RADIOISOTOPES; DISEASES; DRUGS; ELECTRON CAPTURE RADIOISOTOPES; INTERMEDIATE MASS NUCLEI; IODINE ISOTOPES; ISOTOPES; KINETICS; MAMMALS; MEMBRANE PROTEINS; NUCLEI; ODD-EVEN NUCLEI; ORGANIC COMPOUNDS; ORGANS; PRIMATES; PROTEINS; RADIOISOTOPES; REACTION KINETICS; RESPIRATORY SYSTEM; RESPIRATORY SYSTEM DISEASES; VERTEBRATES; 550901* - Pathology- Tracer Techniques

Citation Formats

Spina, D., Rigby, P.J., Paterson, J.W., and Goldie, R.G. Autoradiographic localization of beta-adrenoceptors in asthmatic human lung. United States: N. p., 1989. Web. doi:10.1164/ajrccm/140.5.1410.
Spina, D., Rigby, P.J., Paterson, J.W., & Goldie, R.G. Autoradiographic localization of beta-adrenoceptors in asthmatic human lung. United States. doi:10.1164/ajrccm/140.5.1410.
Spina, D., Rigby, P.J., Paterson, J.W., and Goldie, R.G. 1989. "Autoradiographic localization of beta-adrenoceptors in asthmatic human lung". United States. doi:10.1164/ajrccm/140.5.1410.
@article{osti_5026080,
title = {Autoradiographic localization of beta-adrenoceptors in asthmatic human lung},
author = {Spina, D. and Rigby, P.J. and Paterson, J.W. and Goldie, R.G.},
abstractNote = {The autoradiographic distribution and density of beta-adrenoceptors in human non-diseased and asthmatic bronchi were investigated using (125I)iodocyanopindolol (I-CYP). Analysis of the effects of the beta-adrenoceptor antagonists on I-CYP binding demonstrated that betaxolol (20 nM, beta 1-selective) had no significant effect on specific grain density in either nonasthmatic or asthmatic human bronchus, whereas ICI-118551 (20 nM, beta 2-selective) inhibited I-CYP binding by 85 +/- 9% and 89 +/- 3%, respectively. Thus, homogeneous populations of beta 2-adrenoceptors existed in bronchi from both sources. Large populations of beta-adrenoceptors were localized to the bronchial epithelium, submucosal glands, and airway smooth muscle. Asthmatic bronchial tissue featured epithelial damage with exfoliated cells associated with luminal mucus plugs. A thickened basement membrane and airway smooth muscle hyperplasia were also evident. High levels of specific I-CYP binding were also detected over asthmatic bronchial smooth muscle, as assessed by autoradiography and quantitation of specific grain densities. Isoproterenol and fenoterol were 10- and 13-fold less potent, respectively, in bronchi from asthmatic lung than in those from nonasthmatic lung. However, this attenuated responsiveness to beta-adrenoceptor agonists was not caused by reduced beta-adrenoceptor density in asthmatic airways. A defect may exist in the coupling between beta-adrenoceptors and postreceptor mechanisms in severely asthmatic lung.},
doi = {10.1164/ajrccm/140.5.1410},
journal = {American Review of Respiratory Disease; (USA)},
number = ,
volume = 140:5,
place = {United States},
year = 1989,
month =
}
  • /sup 125/I-Human calcitonin gene-related peptide (hCGRP) binding sites were localized in human and guinea pig lungs by an autoradiographic method. Scatchard analysis of saturation experiments from slide-mounted sections of guinea pig lung displayed specific /sup 125/I-hCGRP binding sites with a dissociation constant (Kd) of 0.72 +/- 0.05 nM (mean +/- S.E.M., n = 3) and a maximal number of binding sites (Bmax) of 133.4 +/- 5.6 fmol/mg protein. In both human and guinea pig lung, autoradiography revealed that CGRP binding sites were widely distributed, with particularly dense labeling over bronchial and pulmonary blood vessels of all sizes and alveolar walls.more » Airway smooth muscle and epithelium of large airways was sparsely labeled but no labeling was found over submucosal glands. This localization corresponds well to the reported pattern of CGRP-like immunoreactive innervation. The findings of localization of CGRP binding sites on bronchial and pulmonary blood vessels indicate that CGRP may be important in the regulation of airway and pulmonary blood flow.« less
  • beta-Adrenoceptors were localized and characterized in valve leaflets of the rat heart. Sixteen micrometer-thick tissue sections containing the mitral and aortic valves were incubated with (-)3-(/sup 125/I)iodocyanopindolol followed by autoradiography with computerized microdensitometry and comparison with /sup 125/I-labeled standards. beta-Adrenoceptors were present in all the valves studied. The selective beta 1-adrenoceptor antagonist CGP 20712 A (100 nM) displaced not more than 20% of the total binding sites, suggesting that most of the beta-adrenoceptors in the valve leaflets are of the beta 2-subtype. Forskolin-binding sites were detected in the mitral valve leaflet by incubation of adjacent tissue sections with (12-/sup 3/H)forskolin.more » Our results indicate that catecholamines could regulate the function of the heart valves through stimulation of beta 2-adrenoceptors.« less
  • Characteristics of beta-adrenoceptors were analyzed using radioligand-binding techniques with 3H-dihydroalprenolol in lung specimens from 11 children with pulmonary hypertension (median age, three years) undergoing surgical repair of congenital heart defects and four pediatric control subjects (median age, five years) undergoing thoracotomy for removal of neoplasms or cysts. Scatchard analysis of 3H-DHA binding to lung membranes showed similar values of the dissociation constant in both groups (Kd = 0.72 +/- 0.22 nM in patients vs 1.22 +/- 0.22 nM in controls; p = NS). The receptor density was significantly increased in patients in comparison with controls, with respective values of 164more » +/- 19 and 95 +/- 13 fmol/mg of protein (p less than 0.025), and correlated directly with mean pulmonary arterial pressure (r = 0.82; p less than 0.0005). No significant relationship was observed between receptor number and pulmonary arterial medial thickness. Thus, the increase in receptor density in these patients may be related to adaptative changes in cells other than vascular smooth muscle.« less
  • Functional organ bath experiments and tritium-labelled ligand binding studies were used to investigate the relationship between {beta}-adrenoceptor-mediated relaxation and the total number of {beta}-adrenoceptors in human lung parenchymal tissue and bronchial tissue. Sensitivity to the {beta}-adrenoceptor agonist isoprenaline varied almost 10-fold for lung parenchymal preparations and 35-fold for bronchial preparations between patients. The total number of ({sup 3}H) DHA labelled {beta}-adrenoceptors varied almost 6-fold for lung parenchymal membrane preparations and less than 2-fold for bronchial tissue membrane preparations between patients. Comparison of sensitivity to isoprenaline and {beta}-adrenoceptor number for lung parenchymal tissue from the same patient demonstrated a negative correlationmore » suggesting that {beta}-adrenoceptor-mediated sensitivity of lung parenchymal tissue is inversely related to the number of {beta}-adrenoceptors. However, there was an absence of correlation between sensitivity to isoprenaline and {beta}-adrenoceptor number in bronchial tissue from the same patient.« less
  • Specific binding of (/sup 125/I)-(-)-cyanopindolol to human tracheal smooth muscle membranes was saturable, stereo-selective and of high affinity (K/sub d/ = 5.3 +/- 0.9 pmol/l and R/sub T/ = 78 +/- 7 fmol/g tissue). The ..beta../sub 1/-selective antagonists atenolol and LK 203-030 inhibited specific (/sup 125/I)-(-)-cyanopindolol binding according to a one binding site model with low affinity in nearly all subjects, pointing to a homogeneous BETA/sub 2/-adrenoceptor population. In one subject using LK 203-030 a small ..beta../sub 1/-adrenoceptor subpopulation could be demonstrated. The beta-mimetics isoprenaline, fenoterol, salbutamol and terbutaline recognized high and low affinity agonist binding sites. Isoprenaline's pK/sub H/-more » and pK/sub L/-values for the high and low affinity sites were 8.0 +/- 0.2 and 5.9 +/- 0.3 respectively. In functional experiments isoprenaline relaxed tracheal smooth muscle strips having intrinsic tone with a pD/sub 2/-value of 6.63 +/- 0.19. 32 references, 4 figures, 2 tables.« less