Contribution of lipoxygenase and cyclooxygenase metabolites in the modulation of cyclic nucleotides in the guinea pig myometrium. Differential effects of carbachol and ionophore A23187.

Accumulation of cyclic GMP in estradiol-treated immature guinea pig myometrium was enhanced by carbachol, ionophore A23187, unsaturated fatty acids and their hydroperoxides. Cyclic AMP content was elevated only by arachidonic acid, A23187 and PGI2. Eicosatetraynoic acid (TYA), but not indomethacin prevented all cyclic GMP responses. The effects of A23187 and arachidonate on cyclic AMP were accompanied by a parallel increase (2-3 fold) in the generation of PGI2 by the myometrium. Both events were similarly reduced by indomethacin, TYA, 15-hydroperoxyarachidonic acid and tranylcypromine, suggesting that PGI2 was involved. Omission of Ca2+ or addition of mepacrine or p-bromophenacylbromide abolished the stimulatory effects of A23187 and carbachol on cyclic GMP as well as the A23187-induced elevations in both PGI2 and cyclic AMP generation. Thus, with both exogenous arachidonate as well as with endogenous fatty acid, released through an apparent phospholipase A2-induced activation process, the lipoxygenase pathway was associated with an activation of the cyclic GMP system and the cyclooxygenase pathway, via PGI2 generation, with an activation of the cyclic AMP system. Carbachol failed to alter both cyclic AMP content and the release of PGI2 suggesting a cholinergic receptor-mediated fatty acid release process, selectively coupled to the lipoxygenase route.