Parallel pathways mediate inhibitory effects of vasoactive intestinal polypeptide and nitric oxide in canine fundus

1 The gastric adaptation reflex is activated by the release of non-adrenerg ic, non-cholinergic (NANC) inhibitory transmitters, including nitric oxide (NO) and vasoactive intestinal polypeptide (VIP). The role of NO in this re flex is not disputed, but some investigators suggest that NO synthesis is s timulated by VIP in post-junctional cells or in nerve terminals. We investi gated whether the effects of these transmitters are mediated by independent pathways in the canine gastric fundus. 2 VIP and NO produced concentration-dependent relaxation of the canine fund us. N-omega-nitro-L-arginine (L-NNA) reduced relaxation induced by electric al field stimulation (EFS; 0.5-8 Hz), but had no effect on responses to exo genous VIP acid sodium nitroprusside (SNP, 10 mu M). 3 Oxyhaemoglobin reduced relaxations produced by EFS and SNP. Oxyhaemoglobi n also reduced relaxation responses to low concentrations of VIP (<10 nM), but these effects were non-specific and mimicked by methaemoglobin which ha d no effect on nitrergic responses. 4 A blocker of guanylyl cyclase, 1H-[1,2,4]oxidiazolo [4,3,-a]quinoxalin-1- one, (ODQ) inhibited responses to EFS, SNP and DETA/NONOate (an NO donor), but had no effect on responses to VIP. cis-N-(2-phenylcyclopentil)-azacyclo tridec-1en-2-amine monohydrochloride (MDL 12,330A), a blocker of adenylyl c yclase, reduced responses to EFS, VIP and forskolin, but did not affect res ponses to SNP. 5 Levels of cyclic GMP were enhanced by the NO donor S-nitroso-n-acetylpeni cillamine (SNAP) but were unaffected by VIP (1 mu M). The increase in cycli c GMP in response to SNAP was blocked by ODQ. 6 The results suggest that at least two transmitters, possibly NO and VIP, mediate relaxation responses in the canine fundus. NO and VIP mediate respo nses via cyclic GMP- and cyclic AMP-dependent mechanisms, respectively. No evidence was found for a serial cascade in which VIP is coupled to NO-depen dent responses.