INHIBITION BY NITRIC-OXIDE AND CYCLIC-GMP OF 5-HYDROXYTRYPTAMINE RELEASE FROM THE VASCULARLY PERFUSED GUINEA-PIG SMALL-INTESTINE

The effects of nitric oxide (NO) on the spontaneous release of 5-hydro xytryptamine (5-HT) were studied in the in vitro vascularly perfused g uinea-pig small intestine. The NO donor SIN-1 concentration-dependentl y decreased 5-HT release with an EC50 of 1.34 mu M, whereas the NO syn thase inhibitor N-G-nitro-L-arginine (100 mu M) was without effect. Th e inhibition by SIN-1 of 5-HT release was enhanced by superoxide dismu tase (150 U/ml) and antagonized by the selective inhibitor of soluble guanylyl cyclase, ODQ (1 mu M). Tetrodotoxin (1 mu M) prevented the in hibition by SIN-1 of 5-HT release, which suggests that the effect of S IN-1 is indirectly mediated via release of an inhibitory neurotransmit ter. Substance P could be excluded as inhibitory transmitter because t he effect of SIN-1 remained unchanged in the presence of the NK1 recep tor antagonist CP 99994 (100 nM). The cyclic GMP analogue, 8-bromo cyc lic GMP (300 mu M), also decreased basal release of 5-HT, but this dec rease was not tetrodotoxin-sensitive. It is concluded that NO inhibits the release of 5-HT from enterochromaffin cells via release of an ent eric neurotransmitter. Acetylcholine (via nicotinic receptors) and sub stance P (via NK1 receptors) are not involved in the NO-mediated inhib ition. The inhibition of 5-HT outflow by NO is due to the activation o f soluble guanylyl cyclase. 8-Bromo cyclic GMP inhibited 5-HT release by a direct effect on the enterochromaffin cells. (C) 1998 Elsevier Sc ience Ltd. All rights reserved.