Phosphodiesterase 4 and tolerance to beta 2-adrenoceptor agonists in asthma.
beta 2-Adrenoceptor agonists provide a mainstay in the treatment of asthma worldwide. However, despite their ability to provide symptomatic relief, chronic or repeated exposure to beta 2-adrenoceptor agonists does not resolve asthmatic inflammation, because of the rapid development of tolerance by pro-inflammatory and immune cells of the lung. The prevailing belief is that tolerance to the so-called non-bronchodilator actions of beta 2-adrenoceptor agonists is largely attributable to direct receptor desensitization mediated by G protein receptor-coupled kinases and/or cAMP-dependent protein kinase. Here, Mark Giembycz suggests another, largely ignored, explanation for beta 2-adrenoceptor desensitization that is based on the accelerated degradation of cAMP by phosphodiesterase.
Giembycz
M A
MA
Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK.
D015105:3',5'-Cyclic-AMP Phosphodiesterases; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004361:Drug Tolerance; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D010727:Phosphoric Diester Hydrolases / Q000096:biosynthesis / Q000378:metabolism*
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D018927:Anti-Asthmatic Agents; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4