Objective: Modulation of potassium ion permeability of the enterocyte membrane is thought to maintain the electrical gradient for chloride ion secretion, the assumed basis for secretory diarrhoeal disease. This hypothesis was examined by testing the ability in vivo glibenclamide, a chloride and potassium channel blocker, clotrimazole, a potassium channel blocker and cromokalim, a potassium channel opener for their ability to alter the ability of E.coli STa enterotoxin to inhibit jejunal fluid absorption in the anaesthetised rat. Methods: Luminal uptake of fluid in vivo was measured by volume recovery from the jejunum of the anaesthetised rat (70 mg/kg i.p. Sagatal) after STa exposure and in the presence of the above agents. All procedures were carried out in conformity with UK legislation. Data are given as the mean plus the standard error of the mean with the number of loop experiments in parenthesis. Significance was tested by 't'-test. Results: The unchallenged jejunum absorbed fluid at a rate of 98.8 ± 6 (8) ul/cm/hr. In the STa (80 ng/ml) challenged loop, there was a significantly lesser (p<0.001) rate of 33.2. ± 8.1 (9) ul/cm/hr absorption, that was also significantly higher (p< 0.001) than zero absorption. No potassium channel active agent when perfused luminally with STa was able to restore to normal the low rates of fluid absorption after STa challenge. Clotrimazole, glibenclamide and cromakalim had significant effects on the cardiovascular system in vivo when given as an i.v bolus dose and also on rabbit ileum motility in vitro. Intravenous glibenclamide, and clotrimazole also failed to restore STa challenged fluid absorption. Cromakalim worsened (p<0.05) STa inhibited fluid absorption to 10.3 ± 6.8 (5) ul/cm/hr. Conclusion: These compounds were identified as likely anti-secretory agents in vitro by their ability to reduce short-circuit current elevation after STa exposure back to pre-challenge levels. These findings do not support the concept of electrogenic chloride ion secretion as the basis for diarrhoeal disease.