CYCLIC-AMP-DEPENDENT ANION SECRETION IN HUMAN SMALL AND LARGE-INTESTINE

Cyclic AMP-dependent Cl- secretion is the major secretion pathway in h uman intestine. The aim of the present study was to examine mechanisms involved in cAMP-dependent anion secretion in human small and large i ntestine. Surgical resection specimens from both jejunum and distal co lon were studied under short circuited conditions, Addition of the pho sphodiesterase inhibitor IBMX induced an increase in the short-circuit current (Isc) equivalent to the net increase in Cl- secretion. The Is c was inhibited by diphenylamine decarboxylate (DPC; Cl- channel block er), bumetanide (basolateral Na+/K+/2Cl(-) cotransporter), BaCl2 (baso lateral K+ channel) and Cl- free buffer in both segments and indometha cin (cyclo-oxygenase inhibitor) in colon alone. Diphenylamine decarbox ylate appears to directly inhibit secretion in jejunum, although its i nhibitory effect is possibly mediated by inhibition of cyclo-oxygenase in the colon. A small component of IBMX-stimulated Isc was inhibited by acetazolamide. Cyclic AMP-dependent secretion is largely apical Cl- secretion, although a small component appears to be HCO3. Secretion i s dependent on basolateral K+ channels and Na+/K+/2Cl(-) cotransporter s and, in the colon, is inhibited by indomethacin, implying a role for cyclo-oxygenase metabolites. The chloride channel blocker DPC inhibit s secretion in both areas. This class of compounds may have potential for treatment of secretory diarrhoea.