Vol. 286, Issue 3, 1222-1230, September 1998

Inhibitory Effects of Nitric Oxide Donors on Nitric Oxide Synthesis in Rat Gastric Myenteric Plexus

Kenji Hosoda , Toku Takahashi, Masayuki A. Fujino and Chung Owyang

Department of Internal Medicine (K.H., T.T., C.O.), University of Michigan Medical Center, Ann Arbor, Michigan and First Department of Medicine (K.H., M.F.), Yamanashi Medical University, Yamanashi, Japan

We investigated whether nitric oxide (NO) exerts an inhibition on its own synthesis in the gastric myenteric plexus in rats. Nonadrenergic, noncholinergic relaxations in response to transmural electrical stimulation (TS) were markedly antagonized by N^G-nitro-L-arginine methyl ester, (10⁴ M) and abolished by tetrodotoxin (10⁶ M). Pretreatment with various NO donors {3-morpholino-sydnonymide [SIN-1 (3 × 10⁷ to 3 × 10⁶ M)], S-nitroso-N-acetylpenicillamine (10⁶ to 10⁵ M), sodium nitroprusside (10⁸ to 3 × 10⁸ M) and 8-bromoquanosine 3',5'-cyclic monophosphate [8-bromo-cGMP (10⁶ to 3 × 10⁶ M)]} significantly inhibited TS-evoked nonadrenergic, noncholinergic relaxations in a dose-dependent manner. In contrast, vasoactive intestinal polypeptide (10⁸ M)-induced relaxations were not affected by SIN-1 or 8-bromo-cGMP. TS evoked a significant increase in ³H-citrulline formation, which was completely abolished by calcium-free medium, N^G-nitro-L-arginine methyl ester, (10⁴ M) and tetrodotoxin (10⁶ M). ³H-citrulline formation evoked by TS was significantly inhibited by SIN-1 (10⁷ to 10⁵ M) and 8-bromo-cGMP (10⁷ to 10⁵ M) in a dose-dependent manner. The inhibitory effect of SIN-1 was partially prevented by 1H-[1,2,4]oxadiazolo[3,4-a]quinoxalin-1-one (10⁵ M), a guanylate cyclase inhibitor. We conclude that NO synthesis in the gastric myenteric plexus is negatively regulated by NO and cGMP. This suggests an autoregulatory feedback mechanism of NO synthesis in the gastric myenteric plexus.