Treatment with proton pump inhibitors induces tolerance to histamine-2 receptor antagonists in Helicobacter pylori-negative patients

Scand J Gastroenterol. 1998 Dec;33(12):1244-8. doi: 10.1080/00365529850172313.


Background: Treatment with H2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) induces hypergastrinemia and causes rebound hypersecretion of gastric acid after treatment, and during treatment with H2RAs tolerance develops. In the present study we investigated whether a treatment period with a PPI induced tolerance to an H2RA.

Methods: Thirteen patients with esophagitis were given omeprazole for 90 days. Twenty-four-hour pH monitorings without and with ranitidine were performed before and after treatment with omeprazole. Blood samples and biopsy specimens from the oxyntic mucosa were analyzed for gastrin, histamine, and chromogranin A.

Results: An increase in mucosal histamine and a reduction in the effect of ranitidine on gastric pH was found 14 days after discontinuing omeprazole compared with before treatment in Helicobacter pylori-negative but not in H. pylori-positive patients.

Conclusions: Treatment with omeprazole reduces the effect of ranitidine in H. pylori-negative patients. This is caused by an increase in histamine released by the enterochromaffin-like cell secondarily to hypergastrinemia, corresponding to the tolerance towards H2RAs seen in patients with Zollinger-Ellison syndrome.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Aged
  • Chromogranin A
  • Chromogranins / metabolism
  • Drug Tolerance
  • Esophagitis / drug therapy*
  • Esophagitis / microbiology*
  • Esophagitis / physiopathology
  • Female
  • Gastric Acid / metabolism
  • Gastrins / metabolism
  • Gastroesophageal Reflux / drug therapy
  • Gastroesophageal Reflux / microbiology
  • Gastroesophageal Reflux / physiopathology
  • Gastrointestinal Agents / therapeutic use*
  • Helicobacter Infections / physiopathology*
  • Helicobacter pylori*
  • Histamine H2 Antagonists / therapeutic use*
  • Histamine Release
  • Humans
  • Hydrogen-Ion Concentration
  • Male
  • Middle Aged
  • Omeprazole / therapeutic use*
  • Proton Pump Inhibitors*
  • Ranitidine / therapeutic use*


  • Chromogranin A
  • Chromogranins
  • Gastrins
  • Gastrointestinal Agents
  • Histamine H2 Antagonists
  • Proton Pump Inhibitors
  • Ranitidine
  • Omeprazole