Interactions between nitric oxide and arachidonic acid in lung epithelial cells: Possible roles for peroxynitrite and superoxide

This study investigated interactions between nitric oxide synthesis and phospholipase A₂ (PLA₂) activation in lung epithelial cells. Nitrite formation, inducible nitric oxide synthase expression, and [ ³H]arachidonic acid (AA) release were determined following treatment with: (1) the nitric oxide synthase inhibitors N^G-nitro-L-arginine methyl esther (L-NAME) and aminoguanidine; (2) arachidonyl trifluoromethyl ketone (AACOCF₃), a specific cytosolic PLA₂ inhibitor; (3) S-morpholinosydnonimine (SIN-1), a nitric oxide donor which provokes peroxynitrite formation; (4) trolox, a free radical scavenger, and (5) the AA release agonists calcium ionophore, phorbol 12-myristate 13-acetate, and sodium vanadate. The results demonstrated that (1) L-NAME and aminoguanidine inhibited agonist-induced AA release by 40 and 65%, respectively; (2) AACOCF₃ inhibited nitrite formation and inducible nitric oxide synthase expression in a dose-dependent manner; (3) SIN-1, together with AA release agonists, significantly increased the AA output, and (4) trolox counteracted the SIN-1 effects. Our results demonstrate cross talk between nitric oxide synthase and PLA₂ pathways, with a possible intermediary role for peroxynitrite and superoxide.