THE ROLE OF THE L-ARGININE/NITRIC OXIDE PATHWAY FOR RELAXATION OF THE HUMAN LOWER ESOPHAGEAL SPHINCTER

Smooth muscle specimens were taken from the oesophagogastric junction (OGJ) in patients operated on for gastrointestinal malignancies not involving the OGJ. The smooth muscle bundles of the inner, circular layer of the OGJ were richly innervated by fine nerve fibres staining positively for NADPH diaphorase. The outer longitudinal layer had a markedly lower number of NADPH-diaphorase positive nerve fibres. When the preparations were suspended in organ baths for recording of isometric tension, they developed active tension. Transmural field stimulation (TMS) induced frequency-dependent relaxations, which were abolished by N-G-nitro-L-arginine (L-NNA; 10(-4) M), and were often converted to atropine-sensitive contractions. The effect of L-NNA was concentration-dependent, and the concentration-response curve for L-NNA was shifted to the right by L-arginine pre-incubation. The enantiomer N-G-nitro-D-arginine (10(-4) M) also showed inhibitory actions on the responses to TMS, but significantly less than L-NNA. Relaxant responses to vasoactive intestinal polypeptide (VIP), forskolin, and sodium nitroprusside were unaffected by L-NNA pre-incubation. Exposure to a 124 mM K+ solution resulted in a biphasic relaxation of the preparations. This relaxation was not seen in preparations treated with scorpion venom (20 mu g ml(-1)) or L-NNA (10(-4) hr). Instead, a contractile response to 124 mM K+ solution was found. The results suggest that NANC responses to electrical stimulation of nerves in the human OGJ are mediated by a product generated from L-arginine. Moreover, the inhibitory biphasic response to 124 mM K+ is dependent on the release of this mediator, which seems capable of relaxing the muscle independently of changes in K+ conductance.