EFFECT OF SELECTIVE PHOSPHODIESTERASE INHIBITORS ON RESPONSE OF OVINEPULMONARY-ARTERIES TO PROSTAGLANDIN E-2

Several adenosine 3',5'-cyclic monophosphate (cAMP)-hydrolyzing phosph odiesterase isozymes are present in the pulmonary vasculature. The pre sent study was designed to determine the effect of selective inhibitor s of phosphodiesterase subtypes on prostaglandin E-2 (PGE(2))-induced relaxation of isolated fourth-generation pulmonary arteries of newborn lambs. PGE(2) and forskolin caused pulmonary arteries to relax and in duced an increase in the intracellular cAMP content in the vessels. Th e relaxation and change in cAMP content were augmented by milrinone an d rolipram, inhibitors of phosphodiesterase type 3 (PDE3) and type 4 ( PDE4), respectively. The augmentation in relaxation and the increase i n cAMP content caused by milrinone plus rolipram was greater than the sum of the responses caused by either of the inhibitors alone. Methoxy methyl-1-methyl-3-(2-methylpropyl)xanthine, an inhibitor of phosphodie sterase type 1, had no effect on relaxation and change in cAMP induced by PGE(2) and forskolin. Acetylcholine alone had no effect on cAMP co ntent in the vessels but augmented the relaxation and the increase in cAMP induced by PGE(2) and forskolin in arteries with endothelium. Thi s effect was not observed in arteries without endothelium or in arteri es with endothelium treated with N-G-nitro-L-arginine. These results s uggest that PDE3 and PDE4 are the primary enzymes hydrolyzing cAMP of pulmonary arteries of newborn lambs and that an inhibition of both PDE 3 and PDE4 would result in a greater effect than that caused by inhibi tion of either one of the subtype isozymes alone. Furthermore, endothe lium-derived nitric oxide may enhance cAMP-mediated relaxation by inhi bition of PDE3.