Reversal of cyclic AMP mediated intestinal secretion by ethacrynic acid

Ethacrynic acid (EA) has been reported to reduce cholera toxin induced intestinal fluid secretion in the intact animal. The authors explored the nature of this inhibition in vitro by measuring unidirectional, transmural fluxes of ²²Na and ³⁶Cl across isolated rabbit ileal mucosa. Under control conditions (short circuited mucosa bathed in bicarbonate Ringer), there was net absorption of Na and Cl. Theophylline (10 mM), cyclic AMP (5 mM), and cholera toxin (added in vivo) abolished net Na flux and produced net Cl secretion. In the presence of either theophylline or cAMP, addition of 0.1 mM EA to the serosal bathing solution abolished net Cl secretion and restored net Na absorption. Cholera toxin treated mucosa was exposed to 0.05 and 1.0 mM EA. The lower concentration restored net Na absorption but did not significantly reduce Cl secretion. The higher concentration abolished net transport of both Na and Cl. Short circuit current and Na flux measurements in the presence and absence of glucose indicated that 0.1 mM EA does not inhibit glucose coupled Na transport. Short circuit current measurements in the presence of 1.0 mM EA suggested that even this concentration of EA does not inhibit glucose coupled Na transport. Thus EA appears to specifically inhibit Cl (or NaCl) secretion without inhibiting the absorptive Na 'pump'. The antisecretory effect of 0.1 mM EA does not appear to result from inhibition of adenylate cyclase since secretion stimulated by addition of 5 mM cAMP was abolished. Furthermore, 0.1 mM EA did not significantly reduce theophylline augmented and cholera toxin augmented cAMP levels in ileal mucosa. It is concluded that EA interacts specifically with the active Cl (or NaCl) secretory mechanism of the small intestine at a step beyond generation of cAMP.