Effects of H-89, an inhibitor of protein kinase A, on the acetylcholine release from myenteric plexus of guinea pig ileum.

In order to clarify the involvement of cyclic AMP-dependent protein kinase (protein kinase A) in acetylcholine (ACh) release from myenteric plexus of guinea pig ileum, the effect of H-89, a specific inhibitor of protein kinase A, on the ACh release was investigated. H-89 (0.1-10 microM) inhibited the spontaneous and nicotine-induced release of ACh in a concentration dependent manner. It at 1 microM decreased both kinds of release of ACh to almost half of the control, but it did not affect the ACh release evoked by electrical field stimulation and by 5-hydroxytryptamine. H-89 had no significant effect on the indomethacin (IND), an inhibitor of PG synthesis, -insensitive component of the spontaneous and nicotine-induced release of, ACh. OP-41483, an analog of PGI2 and forskolin, an activator nicotine-induced release of, ACh. OP-41483, an analog of PGI2 and forskolin, an activator of adenylate cyclase, reversed the inhibitory effect of IND on the ACh release. H-89 at 1 microM completely inhibited the reverse effects of OP-41483 and forskolin. These results suggest that activation of protein kinase A is essential for modulation of the nicotine-induced and spontaneous ACh release from myenteric plexus of guinea pig ileum and the activity of protein kinase A is regulated by endogenous PGs via intracellular cyclic AMP level.