Do Acid Sensing Ion Channels Contribute to Heartburn?
Condition: Gastroesophageal Reflux Disease; Heartburn
MeSH terms: Gastroesophageal Reflux; Heartburn
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this research study is to learn about whether treating the esophagus with
      amiloride reduces either the frequency or the time to onset of acid-induced heartburn in
      patients with nonerosive reflux disease. In particular, we are looking at people who have
      either had complete relief while using a Proton Pump Inhibitor (PPI) or who have only had
      some relief of symptoms while on a PPI.
    

Detailed description: 
      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.
    

Intervention name(s): Amiloride; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): dosage form: intraesophageal amiloride infusion dosage: liquid 1 mM amiloride concentration duration: 5 minute infusion given once frequency: 1 time; dosage form: intraesophageal saline infusion dosage: normal Saline (0.91% w/v of NaCl) duration: 5 minutes given once frequency: 1 time
Other intervention name(s): Midamor
Intervention MeSH terms: Amiloride
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Gastroesophageal reflux disease; Heartburn