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Current Drug Targets - Inflammation & Allergy


ISSN (Print): 1568-010X
ISSN (Online): 1568-010X

Regulation of Inducible Nitric Oxide Synthase by cAMP-Elevating Phosphodiesterase Inhibitors

Author(s): M. Markovic, Dj. Miljkovic and V. Trajkovic

Volume 2, Issue 1, 2003

Page: [63 - 79] Pages: 17

DOI: 10.2174/1568010033344471

Price: $65


Among the numerous genes controlled by cyclic adenosine monophosphate (cAMP) / protein kinase A signalling machinery is the gene encoding the inducible nitric oxide synthase (iNOS), an enzyme catalyzing the synthesis of a highly reactive free radical nitric oxide (NO). While being a major microbicidal and tumoricidal molecule, iNOS-derived NO has also been implicated in tissue destruction, as well as in regulation of inflammatory / immune cell function in various disorders associated with excessive inflammation. A feasible way for cAMP-dependent therapeutic control of inflammation, including iNOS-mediated NO synthesis, could involve the administration of drugs that block the enzymatic activity of cAMP-degrading phosphodiesterases (PDE). Indeed, cAMP-elevating PDE inhibitors can influence iNOS activation in different cell types in vitro, and their potent anti-inflammatory effects in experimental disease models and clinical studies were frequently accompanied with profound modulation of NO production. A set of conflicting data has been generated over the years, ranging from strong suppression to marked enhancement of NO release by cAMP-increasing PDE inhibitors, depending on celltype, iNOS stimuli, and / or the agents used. The present review summarizes the data on iNOS modulation by cAMP-elevating PDE inhibitors and possible mechanisms behind it, speculating on its contribution to the therapeutic effects of these drugs.

Keywords: camp, inos, nitric oxide, phosphodiesterase, inflammation

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