title: A pH-sensitive, neurogenic pathway mediates disease severity in a model of post-ERCP pancreatitis.
abstract: BACKGROUND
  Endoscopic retrograde cholangiopancreatography (ERCP) has a high risk of pancreatitis although the underlying mechanisms are unclear. Transient receptor potential vanilloid 1 (TRPV1) is a cation channel expressed on C and Adelta fibres of primary sensory neurons and is activated by low pH. TRPV1 activation causes release of inflammatory mediators that produce oedema and neutrophil infiltration. We previously demonstrated that neurogenic factors contribute to the pathogenesis of pancreatitis. Resiniferatoxin (RTX) is a TRPV1 agonist that, in high doses, defunctionalises C and Adelta fibres. When we discovered that the pH of radio-opaque contrast solutions used for ERCP was 6.9, we hypothesised that low pH may contribute to the development of contrast-induced pancreatitis via activation of TRPV1.
  
  
  METHODS
  Rats underwent equal pressure pancreatic ductal injection of contrast solutions at varying pH with or without RTX.
  
  
  RESULTS
  Contrast solution (pH 6.9) injected into the pancreatic duct caused a significant increase in pancreatic oedema, serum amylase, neutrophil infiltration, and histological damage. Solutions of pH 7.3 injected at equal pressure caused little damage. The severity of the pancreatitis was significantly increased by injection of solutions at pH 6.0. To determine if the effects of low pH were mediated by TRPV1, RTX was added to the contrast solutions. At pH levels of 6.0 and 6.9, RTX significantly reduced the severity of pancreatitis.
  
  
  CONCLUSIONS
  Contrast solutions with low pH contribute to the development of pancreatitis through a TRPV1-dependent mechanism. It is possible that increasing the pH of contrast solution and/or adding an agent that inhibits primary sensory nerve activation may reduce the risk of post-ERCP pancreatitis.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Noble
authors.forename: J
authors.initials: J
authors.lastname: Romac
authors.forename: S R
authors.initials: SR
authors.lastname: Vigna
authors.forename: R A
authors.initials: RA
authors.lastname: Liddle
mesh_terms: D000818:Animals; D002760:Cholangiopancreatography, Endoscopic Retrograde / Q000009:adverse effects*; D003287:Contrast Media / Q000009:adverse effects* / Q000737:chemistry; D004224:Diterpenes / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D008297:Male; D020078:Neurogenic Inflammation / Q000150:complications; D009475:Neurons, Afferent / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects*; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D050916:TRPV Cation Channels / Q000494:pharmacology
chemical_list: D003287:Contrast Media; D004224:Diterpenes; D050916:TRPV Cation Channels; C024353:resiniferatoxin