Attenuation by phosphodiesterase inhibitors of lipopolysaccharide-induced thromboxane release and bronchoconstriction in rat lungs.
Exposure of perfused rat lungs to lipopolysaccharides (LPS) causes induction of cyclooxygenase-2 followed by thromboxane (TX)-mediated bronchoconstriction (BC). Recently, phosphodiesterase (PDE) inhibitors have received much interest because they not only are bronchodilators but also can suppress release of proinflammatory mediators. In the present study, we investigated the effect of three different PDE inhibitors on TX release and BC in LPS-exposed perfused rat lungs. The PDE inhibitors used were motapizone (PDE III specific), rolipram (PDE IV specific), and zardaverine (mixed PDE III and IV specific). At 5 microM, a concentration at which all three compounds selectively block their respective PDE isoenzyme, rolipram (IC50 = 0.04 microM) and zardaverine (IC50 = 1.8 microM) largely attenuated the LPS-induced BC, whereas motapizone was almost ineffective (IC50 = 40 microM). In contrast to LPS, BC induced by the TX-mimetic U46619 was prevented with comparable strength by motapizone and rolipram. In LPS-treated lungs, the TX release was reduced to 50% of controls by rolipram and zardaverine but was unaltered in the presence of 5 microM motapizone. Increasing intracellular cAMP through perfusion of db-cAMP or forskolin (activates adenylate cyclase) also reduced TX release and BC. We conclude that PDE inhibitors act via elevation of intracellular cAMP. Although both PDE III and PDE IV inhibitors can relax airway smooth muscle, in the model of LPS-induced BC, PDE IV inhibitors are more effective because (in contrast to PDE III inhibitors) they also attenuate TX release.
Uhlig
S
S
Biochemical Pharmacology, University of Konstanz, Konstanz, Germany. SUhlig@fz-borstel.de
Featherstone
R L
RL
Held
H D
HD
Nüsing
R
R
Schudt
C
C
Wendel
A
A
D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D000242:Cyclic AMP / Q000502:physiology; D005260:Female; D008070:Lipopolysaccharides / Q000633:toxicity*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013931:Thromboxanes / Q000378:metabolism*
D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D013931:Thromboxanes; D000242:Cyclic AMP