ATTENUATION BY PHOSPHODIESTERASE INHIBITORS OF LIPOPOLYSACCHARIDE-INDUCED THROMBOXANE RELEASE AND BRONCHOCONSTRICTION IN RAT

Exposure of perfused rat lungs to lipopolysaccharides (LPS) causes ind uction of cyclooxygenase-2 followed by thromboxane (TX)-mediated bronc hoconstriction (HC). 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 o n TX release and BC in LPS-exposed perfused rat lungs. The PDE inhibit ors used were motapizone (PDE III specific), rolipram (PDE IV specific ), and zardaverine (mixed PDE III and IV specific). At 5 mu M, a conce ntration at which all three compounds selectively block their respecti ve PDE isoenzyme, rolipram (lC(50) = 0.04 mu M) and zardaverine (IC50 = 1.8 mu M) largely attenuated the LPS-induced BC, whereas motapizone was almost ineffective (IC50 = 40 mu M). In contrast to LPS, BC induce d by the TX-mimetic U46619 was prevented with comparable strength by m otapizone and rolipram. In LPS-treated lungs, the TX release was reduc ed to 50% of controls by rolipram and zardaverine but was unaltered in the presence of 5 mu M motapizone. Increasing intracellular cAMP thro ugh perfusion of db-cAMP or forskolin (activates adenylate cyclase) al so reduced TX release and BC. We conclude that PDE inhibitors act via elevation of intracellular cAMP. Although both PDE III and PDE IV inhi bitors carl 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.