EFFECT OF SELECTIVE PHOSPHODIESTERASE TYPE-IV INHIBITOR, ROLIPRAM, ONFLUID AND CELLULAR-PHASES OF INFLAMMATORY RESPONSE

The antiinflammatory activity of rolipram, a selective inhibitor of th e cyclic AMP-specific phosphodiesterase (PDE IV), was studied. Rolipra m did not inhibit 5-lipoxygenase activity but did inhibit human monocy te production of leukotriene B4 (LTB4, IC50, 3.5 muM). Likewise, murin e mast cell release of leukotriene C4 and histamine was inhibited. In vivo, rolipram inhibited arachidonic acid-induced inflammation in the mouse, while the low K(m)-cyclic-GMP PDE inhibitor, zaprinast, did not inhibit. Rolipram had a modest effect on LTB, production in the mouse , but markedly reduced LTB4-induced PMN infiltration. Beta-adrenergic receptor activation of adenylate cyclase was important for rolipram an tiinflammatory activity since beta blockade abrogated arachidonic acid -induced inflammation. Thus, the antiinflammatory profile of rolipram is novel and may result from inhibition of PMN function and perhaps va soactive amine release and leukotriene biosynthesis. These actions may be dependent upon endogenous beta-adrenergic activity and are likely mediated through inhibition of PDE IV.