Effects of phosphodiesterase inhibitors on L-arginine pathways in rat alveolar macrophages.
Effects of phosphodiesterase inhibitors on L-arginine-dependent pathways in rat alveolar macrophages, inducible nitric oxide (NO) synthase (iNOS) and arginase, were studied. Culture of rat alveolar macrophages in the presence of lipopolysaccharides (20 h) caused an increase of arginase activity (by 135%) and nitrite concentration (fourfold). The nonselective phosphodiesterase inhibitor IBMX (2-isobutyl-1-methylxanthine) enhanced arginase activity by 35% and nitrite accumulation by 130%. IBMX caused a clear increase in iNOS protein levels and a relatively smaller increase in iNOS mRNA. The effect of IBMX on nitrite accumulation was largely attenuated by the protein kinase A inhibitor K 5720. The phosphodiesterase 4 inhibitor rolipram enhanced nitrite accumulation more effectively than the phosphodiesterase 3 inhibitor siguadozan (about 50% and 20% of IBMX effect, respectively), whereas the phosphodiesterase 3/4 inhibitor benzafendrine was as effective as IBMX. In conclusion, in rat alveolar macrophages, phosphodiesterase 4 and, to a smaller extent, phosphodiesterase 3 play a role in the control of iNOS-mediated NO synthesis.
Koschorreck
Sahra
S
Institute of Pharmacology and Toxicology, University of Bonn, Reuterstr. 2b, D-53113 Bonn, Federal Republic of Germany.
Wenzel
Folker
F
Fuhrmann
Margarita
M
Racké
Kurt
K
D000818:Animals; D001120:Arginine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D010726:Phosphodiesterase Inhibitors; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat