The long-term objective of this application is to examine the physiologic role of endogenous serotonin (5-hydroxytryptamine or 5-HT) of mucosal origin in the regulation of intestinal mucosal transport. Studies of patients with carcinoid syndrome have demonstrated that, when elevated, circulating 5-HT is a potent secretagogue for water and chloride ion secretion. The hypothesis is that 5-HT, physiologically released from enterochromaffin cells of the gut, induces secretion directly by acting on adjacent crypt enterocytes, or indirectly by releasing transmitters from enteric neurons (neural action) or other secretagogues from adjacent cells (paracrine action). The two main models are rat distal colon and human proximal jejunum. Accordingly, the specific aims are to characterize: I) the mechanisms of 5-HT release from the mucosa, using high performance liquid chromatography with electrochemical detection (HPLC-EC) to measure 5-HT release from chambered mucosal sheets and crypt fragments or from vascularly perfused segments of intestine; 2) 5-HT receptor types on isolated, dispersed enterocytes and enterocyte and neural membranes, using radioligand binding techniques and measurement of intracellular messengers; 3) the neural and non-neural mechanisms of 5-HT-induced transport change in chambered mucosal sheets under short circuit conditions and in isolated enterocytes using radiolabeled-ions or fluorescent techniques; and 4) the sensory enteric neuronal involvement in both 5-HT release from the mucosa and in 5-HT-induced transport changes. The latter aim will be pursued in chambered mucosal sheets using the sensory neurotoxin, capsaicin, and preferential receptor antagonists for the major neurotransmitters found in enteric sensory neurons (substance P, neurokinin A and calcitonin-gene-related peptide). It is hoped that a better understanding of the physiologic role of intestinal mucosal 5-HT will lead to improved understanding of normal and abnormal human intestinal transport.
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