Inhibition of Escherichia coli heat-stable enterotoxin by indomethacin and chlorpromazine

Purified heat-stable enterotoxin (ST) from a porcine strain of enterotoxigenic Escherichia coli activates guanylate cyclase in particulate fractions of rat intestinal tissue and induces fluid accumulation in suckling mice. These effects of ST were examined in the presence of either indomethacin or chlorpromazine. We also examined the effects of these two drugs on fluid accumulation in suckling mice induced by the 8-bromo analog of cyclic guanosine monophosphate. Either indomethacin or chlorpromazine reduced ST activation of guanylate cyclase. Both drugs also reduced intestinal fluid accumulation in suckling mice that resulted from submaximal doses of ST (both P<0.001). However, there was no reduction in fluid secretion by either drug when a maximally effective dose of ST was used, suggesting that inhibition of fluid secretion by both drugs can be overcome by increasing the ST dose and that a threshold level of guanylate cyclase activity results in maximal secretory response. Both drugs also reduced basal guanylate cyclase activity in rat intestinal tissue and fluid secretion in suckling mice. Chlorpromazine also reduced intestinal secretion mediated by 8-bromo cyclic guanosine monophosphate (P<0.001). These findings indicate that chlorpromazine interferes with the effects of ST both before and after its activation of guanlylate cyclase, whereas indomethacin interferes with ST only before its activation of guanlylate cyclase.