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

Smooth muscle specimens were taken from the oesophagogastric junction (OGJ) in patients operated on for gastrointestinal malignancies not in volving the OGJ. The smooth muscle bundles of the inner, circular laye r of the OGJ were richly innervated by fine nerve fibres staining posi tively for NADPH diaphorase. The outer longitudinal layer had a marked ly lower number of NADPH-diaphorase positive nerve fibres. When the pr eparations were suspended in organ baths for recording of isometric te nsion, they developed active tension. Transmural field stimulation (TM S) induced frequency-dependent relaxations, which were abolished by N- G-nitro-L-arginine (L-NNA; 10(-4) M), and were often converted to atro pine-sensitive contractions. The effect of L-NNA was concentration-dep endent, and the concentration-response curve for L-NNA was shifted to the right by L-arginine pre-incubation. The enantiomer N-G-nitro-D-arg inine (10(-4) M) also showed inhibitory actions on the responses to TM S, but significantly less than L-NNA. Relaxant responses to vasoactive intestinal polypeptide (VIP), forskolin, and sodium nitroprusside wer e unaffected by L-NNA pre-incubation. Exposure to a 124 mM K+ solution resulted in a biphasic relaxation of the preparations. This relaxatio n 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 elec trical stimulation of nerves in the human OGJ are mediated by a produc t generated from L-arginine. Moreover, the inhibitory biphasic respons e to 124 mM K+ is dependent on the release of this mediator, which see ms capable of relaxing the muscle independently of changes in K+ condu ctance.