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- fl ux (J) and short-circuit current (I-sc) in human jejunal mucosa. Segme nts of jejunum, taken at the time of gastric bypass surgery, were stri pped of the seromuscular layers (and attached neural ganglia) and moun ted as flat mucosal sheets in Ussing chambers under short-circuit cond itions. 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 mea sured Aux across control tissues and in those exposed to 5-HT. 5-HT de creased 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 (seros al-to-mucosal flux) when glucose was included in the buffer bathing th e mucosal surface. Neither tetrodotoxin, the adrenergic receptor antag onists prazosin and propranolol, nor the cholinergic receptor antagoni sts atropine and hexamethonium inhibited the change (Delta) in I-sc in duced 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 k etanserin (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) inhibit ed 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 antago nism. We conclude that 5-HT induces electrogenic Cl- secretion in cham bered human jejunal mucosa by a nonneural pathway through a 5-HT4-like receptor.