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-hydroxytryptamine (5-HT) were studied in the in vitro vascularly perfused guinea-pig small intestine. The NO donor SIN-1 concentration-dependently decreased 5-HT release with an EC50 of 1.34 microM, whereas the NO synthase inhibitor N(G)-nitro-L-arginine (100 microM) was without effect. The inhibition by SIN-1 of 5-HT release was enhanced by superoxide dismutase (150 U/ml) and antagonized by the selective inhibitor of soluble guanylyl cyclase, ODQ (1 microM). Tetrodotoxin (1 microM) prevented the inhibition by SIN-1 of 5-HT release, which suggests that the effect of SIN-1 is indirectly mediated via release of an inhibitory neurotransmitter. Substance P could be excluded as inhibitory transmitter because the effect of SIN-1 remained unchanged in the presence of the NK1 receptor antagonist CP 99994 (100 nM). The cyclic GMP analogue, 8-bromo cyclic GMP (300 microM), also decreased basal release of 5-HT, but this decrease was not tetrodotoxin-sensitive. It is concluded that NO inhibits the release of 5-HT from enterochromaffin cells via release of an enteric neurotransmitter. Acetylcholine (via nicotinic receptors) and substance P (via NK1 receptors) are not involved in the NO-mediated inhibition. The inhibition of 5-HT outflow by NO is due to the activation of soluble guanylyl cyclase. 8-Bromo cyclic GMP inhibited 5-HT release by a direct effect on the enterochromaffin cells.
Department of Pharmacology, University of Mainz, Germany.
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D000818:Animals; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005730:Ganglionic Blockers / Q000494:pharmacology; D006168:Guinea Pigs; D007421:Intestine, Small / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D019335:Nitroarginine / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010477:Perfusion; D011810:Quinoxalines / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013373:Substance P / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D005730:Ganglionic Blockers; D010069:Oxadiazoles; D011810:Quinoxalines; D012702:Serotonin Antagonists; D019335:Nitroarginine; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D012701:Serotonin; D013373:Substance P; D013779:Tetrodotoxin; C002385:linsidomine; D008981:Molsidomine; D006152:Cyclic GMP