SEROTONIN INDUCES CL- SECRETION IN HUMAN JEJUNAL MUCOSA IN-VITRO VIA A NONNEURAL PATHWAY AT A 5-HT4 RECEPTOR

We examined the effect of 5-hydroxytryptamine (5-HT) on Na+ and Cl- flux (J) and short-circuit current (I-sc) in human jejunal mucosa. Segments of jejunum, taken at the time of gastric bypass surgery, were stripped of the seromuscular layers (and attached neural ganglia) and mounted as flat mucosal sheets in Ussing chambers under short-circuit conditions. 5-HT (0.1-100 mu M) produced a concentration-dependent rise in I-sc (mean effective concn = 2.5 mu M). Using Na-22 and Cl-36, We measured Aux across control tissues and in those exposed to 5-HT. 5-HT decreased both net J(Na) and J(Cl) and increased I-sc (-1.1 +/- 0.6, -1.7 +/- 0.6, and 0.6 +/- 0.1 mu eq.cm(-2).h(-1), respectively). Thus the 5-HT-induced rise in I-sc could be accounted for by reduced net J(Na) and J(Cl). 5-HT induced a significant (P < 0.05) Cl- secretion (serosal-to-mucosal flux) when glucose was included in the buffer bathing the mucosal surface. Neither tetrodotoxin, the adrenergic receptor antagonists prazosin and propranolol, nor the cholinergic receptor antagonists atropine and hexamethonium inhibited the change (Delta) in I-sc induced by 5-HT. 5-Methoxytryptamine (5-MeOT) and zacopride, known 5-HT4 receptor agonists, induced significant Delta I-sc. The 5-HT receptor antagonists N-acetyl-5-hydroxytryptophyl-5-hydroxytryptamine (5-HT1P ketanserin (5-HT2), and ICS-205-930 (preferential for 5-HT3 at 0.1 mu M) had no effect on Delta I-sc. However, ICS-205-930 (1.0 mu M) inhibited in a similar manner the Delta I-sc induced by 5-HT [log(10) of the dissociation constant (pK(B)) of the antagonist-receptor complex was 6.2] and 5-MeOT (pK(B) 6.5), a finding indicating 5-HT4 receptor antagonism. We conclude that 5-HT induces electrogenic Cl- secretion in chambered human jejunal mucosa by a nonneural pathway through a 5-HT4-like receptor.