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Investigation of the inverse agonism effect of nadolol on the Gs signaling pathway
Author(s) -
Peng Hui,
Bond Richard A.,
Knoll Brian
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.724.11
Subject(s) - nadolol , agonist , receptor , prostaglandin e2 receptor , endocrinology , inverse agonist , medicine , pharmacology , chemistry , propranolol
Nadolol is a nonselective beta‐adrenergic receptor (¦ÂAR) blocker with inverse agonist activity at ¦Â2‐ARs. Previous studies in human embryonic kidney 293 cells over‐expressing human ¦Â2AR showed an initial increase in the number of inactive state of receptors (R) after acute nadolol treatment, and an increase in the number of active state of receptors (R*) with decreased receptor degradation after chronic treatment. In this study, further experiments indicated that chronic treatment with isoproterenol significantly decreased cellular level of Gs while chronic nadolol treatment had no effect. In organ bath experiments using the tracheal rings from an asthmatic mouse model we investigated the effects of nadolol on other Gs‐coupled receptors. Nadolol treatment produced an enhanced relaxation response mediated by the prostacyclin receptor (IP) agonist cicaprost and prostaglandin E2 receptor (EP2) agonist CAY 10399, in addition to the ¦ÂAR agonist isoproterenol. In isolated airway smooth muscle cells, western blot data suggested chronic treatment with nadolol increased the levels of IP and EP2 receptors. These data suggest that nadolol enhances Gs signaling through the ¦Â2‐AR, IP and EP2 receptors and this enhancement of bronchorelaxant responses may contribute to the beneficial effects of chronic nadolol treatment in murine asthma model.