INVOLVEMENT OF CYCLIC-AMP IN THE EFFECTS OF PHOSPHODIESTERASE-IV INHIBITORS ON ARACHIDONATE RELEASE FROM MONONUCLEAR-CELLS

The effects of selective phosphodiesterase inhibitors, cyclic AMP (cAM P) elevating agents and stable analogues of cyclic nucleotides, on the release of arachidonate induced by N-formyl-Met-Leu-Phe (fMLP) were i nvestigated on human peripheral blood mononuclear cells. The selective phosphodiesterase TV inhibitors, rolipram and Ro 20-1724, and the non -selective phosphodiesterase inhibitor, theophylline, elicited a conce ntration-dependent inhibition of arachidonate release (EC(50) = 1.3 X 10(-6) M, 3.2 X 10(-6) M and 3.7 X 10(-4) M respectively). The selecti ve phosphodiesterase III inhibitor, milrinone (10(-5) M), only caused a slight effect while the phosphodiesterase V inhibitor, zaprinast (10 (-5) M), the beta(2)-adrenoceptor agonists, salbutamol and fenoterol ( 10(-5) M), failed to inhibit arachidonate release. Forskolin (10(-5) M ) and N-6,2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (db-cAMP, 10(-3) M) elicited a moderate inhibition. Forskolin increased the eff ects of rolipram and Ro 20-1724 (EC(50) = 4.5 X 10(-7) M and 4 X 10(-7 ) M respectively). Incubation of the cells with rolipram (10(-8) to 10 (-5) M), Ro 20-1724 (10(-8) to 10(-5) M), forskolin (10(-5) M) or salb utamol (10(-5) M) alone, induced a moderate increase or no increase at all in intracellular cAMP. However, in the presence of forskolin, rol ipram (10(-8) to 10(-6) M) and Ro 20-1724 (10(-8) to 10(-6) M) induced a significant and concentration-dependent increase in intracellular l evels of cAMP. These results suggest that the potent inhibition of ara chidonate release from mononuclear cells by selective phosphodiesteras e IV inhibitors may be due to increases in discrete pools of intracell ular cAMP.