Studies on the mechanism of Salmonella typhimurium enterotoxin-induced diarrhoea.

The unidirectional fluxes of Na+ and Cl- were studied in Salmonella typhimurium enterotoxin-treated rats. There was net secretion of Na+ and Cl- in toxin-treated animals, while in control animals there was net absorption of these ions. In the presence of the Ca(2+)-ionophore, there was net secretion of Na+ and Cl- in the control group, while the ionophore enhanced the secretion of these ions in experimental animals. The calcium channel blocker, verapamil, decreased the secretion induced by salmonella toxin, but could not reverse the secretion to absorption. There was no difference in the net absorption of Ca2+ in both the control and experimental animals. There was a significant increase in the intracellular free calcium concentrations in enterocytes isolated from toxin-treated rat intestines as compared to that in enterocytes isolated from control animals. In the presence of PMA (phorbol-12-myristated-13-acetate) there was net secretion of Na+ and Cl- in the control group, while in the experimental group there was no change in the fluxes of these ions. The selective, potent inhibitor of protein kinase C, H-7 (1-(5-isoquinolinylsulphonyl)-2-methylpiperazine) reversed the secretion of Na+ and Cl- in the toxin-treated group to absorption. The addition of indomethacin also inhibited the secretion induced by salmonella toxin, but failed to reverse it to absorption. However, the addition both H-7 and indomethacin to the experimental group had a partial additive effect. These studies demonstrate that the Salmonella enterotoxin-mediated fluid secretion involves protein kinase C and the arachidonic acid metabolites and perhaps does not involve the extracellular calcium pools.