We examined the effect of 5-hydroxytryptamine (5-HT) on Na+ and Cl- flux (J) and short-circuit current (Isc) 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 microM) produced a concentration-dependent rise in Isc (mean effective concn = 2.5 microM). Using 22Na and 36Cl, we measured flux across control tissues and in those exposed to 5-HT. 5-HT decreased both net JNa and JCl and increased Isc (-1.1 +/- 0.6, -1.7 +/- 0.6, and 0.6 +/- 0.1 mueq.cm-2.h-1, respectively). Thus the 5-HT-induced rise in Isc could be accounted for by reduced net JNa and JCl. 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 Isc induced by 5-HT. 5-Methoxytryptamine (5-MeOT) and zacopride, known 5-HT4 receptor agonists, induced significant delta Isc. 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 microM had no effect on delta Isc.(ABSTRACT TRUNCATED AT 250 WORDS)