Regulation of inducible nitric oxide synthase by cAMP-elevating phospho-diesterase inhibitors.
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 cell-type, 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.
Markovic
M
M
Institute of Microbiology and Immunology, School of Medicine, Belgrade, Yugoslavia.
Miljkovic
Dj
Dj
Trajkovic
V
V
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000378:metabolism; D002986:Clinical Trials as Topic; D000242:Cyclic AMP / Q000096:biosynthesis* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D012772:Shock, Septic / Q000188:drug therapy / Q000378:metabolism
D010726:Phosphodiesterase Inhibitors; D000242:Cyclic AMP; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D006152:Cyclic GMP