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Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California, USA
1Correspondence: h2dong{at}ucsd.edu
Thank you for the opportunity to respond to comments raised by one of your readers regarding our manuscript, "Heat-stable enterotoxin of Escherichia coli (STa) can stimulate duodenal HCO3– secretion via a novel GC-C- and CFTR-independent pathway (1)
". With two currently published manuscripts on this topic, we have performed many experiments using multiple well validated in vitro and in vivo methods (including pH stat, back-titration and CO2-sensitive electrode methods) to measure STa-stimulated duodenal HCO3– secretion in the absence of CFTR function (1
, 2)
. However, the reader’s concern about the involvement of Na+/H+ exchange (NHE) is valid. Studies have shown that inhibition of NHE produces an increase in measurable duodenal HCO3– (3
, 4)
, which can be at least partially attenuated by inhibition of CFTR (4)
. Thus, when measuring HCO3– one must determine if this is due solely to HCO3– secretion, inhibition of H+ absorption, or a combination of the two.
In our current study, we used 1 mM amiloride to examine if inhibition of NHE was responsible for our observed increase in HCO3–. Despite the fact that amiloride at a concentration of 1 mM fails to affect the mucosal surface pH in rat proximal jejunum (5)
, it inhibits the activity of NHE by 72% in mouse duodenal epithelial cells (6)
. Although not reported in our manuscript, addition of amiloride (1 mM) caused a significant increase in recorded HCO3– that had peaked or stabilized prior to STa addition (P<0.05), reflecting inhibition of H+ absorption. Subsequent addition of STa (in the presence of amiloride) produced a further increase in HCO3–, which was not significantly different than STa stimulation in the absence of amiloride (these are the values reported in the manuscript). Subsequently, our ability to abolish this response with DIDS, make us confident in our conclusions that in the absence of CFTR (and GC-C), STa stimulates HCO3– secretion via Cl–/HCO3– exchange, not inhibition of NHE.
An additional important point to remember is that our findings in the duodenum may not hold true for other segments of the small intestine. Each segment of the intestine (duodenum, jejunum, and ileum) has variations in morphological structure, expression of receptors/transporters/signaling components, and function. To date, the majority of studies examining the effect of STa on intestinal transport have been performed using the jejunum. While it is tempting to apply lessons learned from other parts of the intestine, the proximal duodenum and jejunum have different physiological functions (although the distal duodenum and proximal jejunum may be quite similar). The primary purpose of the duodenum is to neutralize acidic gastric contents for digestion and protection of the intestinal mucosa. In contrast, the jejunum’s main function is for the absorption of digested components and the reabsorption of water. It is likely that these functional differences account for different responses to STa.
FOOTNOTES
The opinions expressed in editorials, essays, letters to the editor, and other articles comprising the Up Front section are those of the authors and do not necessarily reflect the opinions of FASEB or its constituent societies. The FASEB Journal welcomes all points of view and many voices. We look forward to hearing these in the form of op-ed pieces and/or letters from its readers addressed to journals{at}faseb.org.
REFERENCES
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