THE ROLE OF NITRIC-OXIDE (NO) IN 5-HT-INDUCED RELAXATIONS OF THE GUINEA-PIG STOMACH

In a previous study we showed that the relaxations induced after vagal stimulation of the guinea-pig stomach are mediated via nitric oxide ( NO) or a NO-related substance. Intra-arterial injection (i.a.) of 5-hy droxytryptamine (5-HT) also induced relaxations in the guinea-pig stom ach. Since it has been shown that in the guinea-pig colon 5-HT-induced relaxations are mediated via NO the aim of this study was to establis h whether NO is involved in the 5-HT-induced relaxations in the guinea -pig stomach. Intra-arterial injection of 5-HT induced dose-dependent relaxations of the stomach. Since atropine and alpha- and beta-adrenoc eptor blocking agents did not influence the relaxation and since tetro dotoxin (TTX) blocked the relaxations, this effect is mediated via NAN C-neurons. Administration of a NO-synthase-inhibitor N(G)-nitro-L-argi nine (L-NNA) concentration-dependently reduced the 5-HT-induced relaxa tions. Haemoglobin (a NO-scavanger) did not affect the relaxations to 5-HT, while addition of methylene blue, an inhibitor of soluble guanyl ate cyclase, reduced the relaxations by 50%. Addition of an opioid rec eptor agonist (loperamide), a 5-HT, antagonist (methiothepin or meterg oline) or a 5-HT4 receptor agonist (cisapride) or -antagonist (tropise tron in micromolar concentrations) inhibited the 5-HT-induced relaxati ons. Neither the 5-HT4 receptor agonist renzapride, nor the novel 5-HT 4 receptor antagonist SDZ 205-557, affected the relaxations to 5-HT. T hese data indicate that 5-HT-induced relaxations of the guinea-pig sto mach are mediated via NANC-inhibitory nerves on which inhibitory opioi d-receptors are present. The use of selective agonists and antagonists indicates that 5-HT does not act via 5-HT2, 5-HT3 or 5-HT4 receptors. 5-HT may act via 5-HT1 receptors but the subtype involved, if any, ha s not yet been identified. The inhibitory neurotransmitter which is in volved is NO or a NO-related substance.