The Effect of Bacterial Enterotoxins on Intestinal Weak Electrolyte Absorption

McEwan, Gordon Thomas Alexander (1987) The Effect of Bacterial Enterotoxins on Intestinal Weak Electrolyte Absorption. PhD thesis, University of Glasgow.

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Weakly dissociable compounds partition into lipid membranes by non-ionic diffusion. The 'microclimate hypothesis' predicts that the rate of weak electrolyte absorption from the small intestine is determined by the pH prevailing at the mucosal surface. This pH will determine the proportion of unionised: ionised species presented to the brush border membrane. In rat and human jejunum, the mucosal surface pH is significantly lower than neutral luminal fluid and is relatively resistant to bulk pH changes. This tends to favour weak acid absorption but hinders the uptake of weak bases. There are indications that some types of small bowel derangement might disrupt the mechanisms maintaining this low mucosal surface pH, or 'acid microclimate' resulting in its dissipation. If the microclimate hypothesis applies, any change in the mucosal surface pH should be accompanied by alterations to weak electrolyte absorption. To test this the present study undertook to find a method of altering the intestinal microclimate pH in rats in vivo with a view to investigating the effects of a surface pH shift on the absorption of a number of weakly dissociable drugs. Using an in vivo perfusion chamber, the pH at the intestinal mucosal surface could be measured with ease confirming previous findings that a low pH exists in the jejunum while a neutral value was observed in the ileum. Measurements with liquid ion exchange (LIX) pH microelectrodes in vitro demonstrated that a pH gradient exists along jejunal but not ileal villi. In the jejunum, the lowest pH values were detected in the upper villus region below the villus tips. Exposing the intestinal mucosa to E. coli STa enterotoxin or its synthetic, peptide analogue, STh(6-19), resulted in a rapid, reversible elevation of the intestinal microclimate pH to values significantly higher than those measured in unchallenged tissue. In the jejunum, this alkalinisation was most prominent in the upper villus region which had previously demonstrated the lowest pH values. The observation that 8-bromo cGMP has very similar effects on mucosal surface pH to STa suggests that this mucosal surface alkalinisation is mediated through cGMP. The additional finding that theophylline, a phosphodiesterase inhibitor, prevented the surface pH from returning to control values after enterotoxin removal provided further evidence for this. The 8-bromo analogue of cAMP induced a considerably lesser surface pH elevation than its cGMP counterpart. Forskolin and cholera toxin, both potent adenylate cyclase activators, ellicited similar small intestinal surface pH elevations. This suggests that cGMP-dependent secretory processes are more capable of inducing surface pH changes than those dependent on cAMP. However, in the presence of theophylline both forskolin and cholera toxin elevated the mucosal surface pH to values similar to those attained after STa challenge. Theophylline alone had no effect on the mucosal surface pH. Since STa was the most potent and reliable effector of surface pH changes it was used as a tool to test the microclimate hypothesis. Solutions of five weakly dissociable drugs were perfused through in vivo loops of rat jejunum in the presence or absence of STa. Two weak acids (salicylic acid and phenytoin) and three weak bases (amphetamine, morphine and lignocaine) were investigated. In these experiments STa reduced the absorption of both weak acids while enhancing the absorption of all three weak bases. These changes were confirmed by similar alterations to drug appearance in the peripheral blood indicating that total drug transfer was affected by STa. Enhanced weak base absorption was despite unfavourable net fluid secretion. These results are in accordance with prediction using the microclimate hypothesis in that the alterations to weak electrolyte absorption are consistent with an STa-induced elevation of the intestinal microclimate pH. This conclusion was strengthened by the observation that a combination of forskolin and theophylline, which had very similar effects to STa on mucosal surface pH also caused a similar enhancement of lignocaine absorption. Therefore the present experiments provide evidence in favour of the microclimate hypothesis, that the microclimate pH is a primary determinant of weak electrolyte absorption rate. The similarities between rat and human intestine suggest that these observations may have direct relevence to considerations of drug absorption in human small intestinal disease.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Physiology, Pharmacology
Date of Award: 1987
Depositing User: Enlighten Team
Unique ID: glathesis:1987-77610
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jan 2020 11:53
Last Modified: 14 Jan 2020 11:53

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