Abstract

The secretory effect of cholera toxin (CT) in the small intestine involves increased levels ofboth 3',5'-cyclic adenosine monophosphate (cAMP) and prostaglandin E2 (PGE2), which stimulate chloride ion (Cl^-) and fluid secretion. It was observed that L-histidine reduces fluid accumulation by 54.3% (p<.001) in the lumina of intestinal segments injected with CT. To understand the mechanism of this effect, the direct interaction of L-histidine and PGE2 was investigated using biochemical and physiological methodologies. Intraperitoneal and intraluminal injection ofL-histidine markedly reduced the fluid accumulation induced by CT. Chromatography of PGE2-histidine mixtures by reverse-phase C-18 HPLC revealed the conversion of PGE2 to a new molecular species. Further analysis by mass spectrometry showed that the mass of this product was consistent with that of a complex ofPGE2 and L-histidine with a stoichiometry of 1.0. To determine the physiological significance of the reaction, the effect of L-histidine on PGE2-induced sodium transport was examined in the epidermis of the frog Xenopus mounted in a modified Ussing chamber. L-histidine inhibited both basal and PGE2-induced sodium transport. 1 JlM PGE2 increased the steady-state Na⁺-dependent short-circuit current (1 ) by 12% (the maximum PGE2-induced change in I was 18:!:3%, n=5, p<.01), and 1 JlM PGE2 plus 10 mM histidine decreased Isc to 38:!:10% of control (n=5, p<.025). In conclusion, these data suggest that the protective action of histidine on CT-induced fluid secretion is attributable to a covalent reaction between histidine and PGE2. Whether histidine might be beneficial in the treatment of cholera and other intestinal diseases merits further examination.