Gastrointestinal (GI) smooth muscle cell activity is controlled by contractile cholinergic neurons and relaxant non-adrenergic non-cholinergic (NANC) neurons in the myenteric plexus between the circular and longitudinal muscle layer. Decreased or increased NANC relaxation might be involved in the pathophysiology of functional GI motility disorders. Vasoactive intestinal polypeptide (VIP) and nitric oxide (NO) are the primary inhibitory NANC neurotransmitters. As classic neurotransmitters, VIP is stored in vesicles in the nerve endings, while NO is synthetized on demand by the neuronal isoform of NO synthase (nNOS). The VIP/nNOS co-localization in myenteric neurons, reported for various regions of the GI tract in different species, suggests that VIP and NO are co-transmitters. At the presynaptic level, VIP and NO can induce each others release. Most clear-cut evidence for this mechanism was obtained in isolated myenteric ganglia where VIP induced NO release, and NO facilitated VIP release. At the postsynaptic level, many studies support that VIP and NO are parallel co-transmitters, acting via the adenylate cyclase/3'5' adenosine cyclic monophosphate (cAMP) and guanylate cyclase/3'5' cyclic guanosine monophosphate pathway respectively. Mainly based on results obtained in isolated GI smooth muscle cells, a serial postsynaptic VIP/NO interaction model was proposed, whereby VIP is the principle neurotransmitter, acting partially via a VPAC receptor and the adenylate cyclase/cAMP pathway but also by induction of muscular NO production. Recent results suggest that the capacity of VIP to release NO from isolated smooth muscle cells is related to the induction of inducible NOS (iNOS) in the cells during the isolation procedure. The relative contribution of NO and VIP to GI NANC relaxation differs upon tissue and nerve firing frequency, so that interference with either of them will lead to varying effects.

1 The interaction between nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) was investigated in isolated circular smooth muscle cells and strips of the guinea-pig gastric fundus. 2 VIP induced a concentration-dependent inhibition of carbachol-induced contraction in smooth muscle cells with a maximum at 10 76 M. The relaxation by 10 76 M VIP was inhibited for 79.1+5.8% (mean+s.e.mean) by the NO-synthase (NOS) inhibitor L-N G -nitroarginine (L-NOARG; 10 74 M) in a L-arginine reversible way. Also the inducible NOS (iNOS) selective inhibitor N-(3-(acetaminomethyl)-benzyl)acetamide (1400 W; 10 76 M) inhibited the VIP-induced relaxation, but its inhibitory e ect was not reversed by L-arginine. 3 When cells were incubated with the guanylyl cyclase inhibitor 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ, 10 76 M), the protein kinase A-inhibitor (R)-p-cyclic adenosine-3',5'-monophosphothioate ((R)-p-cAMPS, 10 76 M) and the glucocorticoid dexamethasone (10 75 M), the relaxant e ect of VIP was decreased by respectively 80.9+7.6, 77.0+11.6 and 87.1+4.5%. 4 In circular smooth muscle strips of the guinea-pig gastric fundus, the VIP (10 79 ± 10 77 M)-induced relaxations were not signi®cantly in¯uenced by 10 74 M L-NOARG, 10 76 M 1400 W, 10 76 M ODQ and 10 75 M dexamethasone. 5 These results suggest that iNOS, possibly induced by the procedure to prepare the smooth muscle cells, is involved in the relaxant e ect of VIP in isolated smooth muscle cells but not in smooth muscle strips of the guinea-pig gastric fundus. This study illustrates the importance of the experimental method when studying the in¯uence of NOS inhibitors on the relaxation induced by VIP in gastrointestinal smooth muscle preparations.

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