Background: Serotonin (5-hydroxytryptamine [5-HT]) has been shown to induce chloride secretion through a nonadrenergic/noncholinergic neural pathway, mediated by a 5-HT(3) receptor. We hypothesized that 5-HT(3)-induced Cl(-) secretion is ultimately mediated by nitric oxide (NO).
Methods: Unstripped sheets of rat distal colon were mounted in Ussing chambers and short-circuited. The 5-HT(3) receptor agonist, 2-methyl-5-HT, was added in the absence and presence of the NO synthase inhibitor, L-NAME. Companion studies involved the addition of sodium nitroprusside to tissue that was incubated with or without tetrodotoxin.
Results: L-NAME caused a significant reduction in the 2-methyl-5-HT-induced change in circuit current, in a concentration-dependent manner. Sodium nitroprusside caused a change in circuit current over baseline in 5 minutes. The addition of tetrodotoxin did not significantly alter the change in circuit current; however, the apical Cl(-) channel blocker, anthracene-9-carboxylic acid, abolished this response.
Conclusions: Neurally mediated Cl(-) secretion in response to 2-methyl-5-HT is inhibited by an NO synthase inhibitor. Exogenous NO mimics this response, which is unaffected by tetrodotoxin. These data suggest that neurally mediated serotoninergic Cl(-) secretion is, in part, mediated by NO. The ability of exogenous NO to induce a change in circuit current in the presence of tetrodotoxin suggests that NO is a final neurotransmitter in this neural-mucosal reflex and therefore acts directly on the enterocyte to induce secretion.