Interactions between cAMP- and cGMP-dependent protein kinase inhibitors and phosphodiesterase IV inhibitors on arachidonate release from human monocytes.
The effects of specific inhibitors of cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG) on the inhibitory activity of phosphodiesterase (PDE) type IV inhibitors and of the cell permeable analogue of cAMP, db-cAMP, were investigated on fMLP-induced arachidonate release from human monocytes. When monocytes were preincubated with the combined PKA/PKG inhibitor H8 (10(-6) to 10(-4) M) or the selective PKG inhibitor Rp-8-cpt-cGMPs (10(-6) to 10(-4) M) a concentration-dependent reduction of the inhibitory effect of db-cAMP (10(-3) M), rolipram (10(-5) M) and Ro 20-1724 (10(-5) M) was noted. When monocytes were preincubated with the selective PKA inhibitor H89 (10(-6) to 10(-4) M), only a small inhibition of the effect of db-cAMP and no inhibition of the effects of rolipram and Ro 20-1724 were observed. The present data indicate that db-cAMP and PDE IV inhibitors elicit an in vitro anti-inflammatory activity by a PKA-independent mechanism, which do not appear to be mainly mediated via the PKG activation.
Hichami
A
A
Laboratoire de Pharmacodynamie et de Pharmacologie Moléculaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes, France.
Boichot
E
E
Germain
N
N
Coqueret
O
O
Lagente
V
V
D016718:Arachidonic Acid / Q000378:metabolism*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004347:Drug Interactions; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism
D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D016718:Arachidonic Acid; D011494:Protein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases