Do Acid Sensing Ion Channels Contribute to Heartburn?

It is now well established that patients with gastroesophageal reflux disease - both erosive
and non-erosive forms - have on esophageal biopsy a lesion in esophageal stratified squamous
epithelium known as 'dilated intercellular spaces (DIS). This lesion has importance because
it reflects an increase in paracellular permeability due to acid damage to the tight
junctions [1]. Moreover, the increase in paracellular permeability in non-eroded esophageal
epithelium provides a plausible explanation for why heartburn occurs during episodes of acid
reflux (or esophageal acid perfusion) in those with nonerosive reflux disease (NERD) but not
in healthy subjects, and that is because luminal acid is now able to diffuse between cells
in quantities sufficient to acidify the intercellular space [2]. Further, the lowering of
intercellular pH is the likely trigger for heartburn by its ability to stimulate
pain-sensing neurons (nociceptors) within the esophageal mucosa; with the signal from these
neurons being transmitted to the CNS for heartburn perception. Clinical and experimental
evidence support these concepts in that antacid ingestion relieves and proton pump
inhibitors (PPIs) prevent heartburn in most patients and when PPIs control heartburn, they
also lead to resolution of DIS in squamous epithelium [3]. Moreover, it is increasingly
likely that many NERD patients classified as PPI-partial responders develop heartburn
through the same mechanism as PPI-complete responders with NERD. This is because PPIs only
raise gastric pH to ~pH 5, and even such 'weakly-acidic' refluxates have been shown to be
associated with heartburn [4]. The reason for this is that in the presence of a broken
epithelial barrier, weakly acidic refluxates are still able to acidify the intercellular
space to levels sufficient to activate the nociceptors - the latter the case since the
nociceptors can be activated even at pHs as modestly acidic as pH 6.0-pH 7.0 (see below).

The esophageal mucosa has two nociceptors that are candidates to mediate heartburn in NERD.
These are: a) a capsaicin-sensitive, transient receptor potential vanilloid receptor
(TRPV)-1, and b) an amiloride-inhibitable, acid-sensing ion channel (ASIC), subtype 2. Both
nociceptor types innervate the esophageal mucosa and are activated by small declines in
environmental (intercellular) pH [5,6]. Recently, a role for TRPV-1 was sought in the
causation of heartburn during esophageal acid perfusion [7]. This was done by perfusing the
esophagus with capsaicin in quantities presumed sufficient to desensitize TRPV-1 and then
perfusing with acid to see if it blocked heartburn. The results, however, were negative in
that acid still elicited heartburn. From this, one can conclude that heartburn is either not
mediated by TRPV-1 or that capsaicin failed to adequately desensitize TRPV-1. We propose to
test the hypothesis that capsaicin's failure to block heartburn in these subjects was
because the actual nociceptors mediating heartburn are mucosal ASICs rather than TRPV-1. The
hypothesis will be tested in a double-blind crossover study designed to determine if
esophagal perfusion with the ASIC-inhibitor, amiloride, can block heartburn elicited by
acid-perfusion in PPI-complete responders and PPI-partial responders with NERD [8]. The
expectation is that, when compared to placebo, amiloride, which readily diffuses across
intact esophageal epithelium, will reduce the frequency and both prolong the onset and
reduce the severity of heartburn elicitable by esophageal acid perfusion. Such an outcome
would provide support for mucosal ASICs, rather than TRPV-1, as mediator of heartburn in
NERD, and raise interest in ASICs as a potential therapeutic target for that subset with
NERD that are PPI-partial responders.