title: Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine.
abstract: BACKGROUND
  Proton pump inhibitors (PPIs) are gastric acid-suppressing agents widely prescribed for the treatment of gastroesophageal reflux disease. Recently, several studies in patients with acute coronary syndrome have raised the concern that use of PPIs in these patients may increase their risk of major adverse cardiovascular events. The mechanism of this possible adverse effect is not known. Whether the general population might also be at risk has not been addressed.
  
  
  RESULTS
  Plasma asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. Elevated plasma ADMA is associated with increased risk for cardiovascular disease, likely because of its attenuation of the vasoprotective effects of endothelial nitric oxide synthase. We find that PPIs elevate plasma ADMA levels and reduce nitric oxide levels and endothelium-dependent vasodilation in a murine model and ex vivo human tissues. PPIs increase ADMA because they bind to and inhibit dimethylarginine dimethylaminohydrolase, the enzyme that degrades ADMA.
  
  
  CONCLUSIONS
  We present a plausible biological mechanism to explain the association of PPIs with increased major adverse cardiovascular events in patients with unstable coronary syndromes. Of concern, this adverse mechanism is also likely to extend to the general population using PPIs. This finding compels additional clinical investigations and pharmacovigilance directed toward understanding the cardiovascular risk associated with the use of the PPIs in the general population.
authors.affiliation: Department of Cardiovascular Sciences, Texas Methodist Hospital Research Institute, Houston, TX 77030, USA.
authors.forename: Yohannes T
authors.initials: YT
authors.lastname: Ghebremariam
authors.forename: Paea
authors.initials: P
authors.lastname: LePendu
authors.forename: Jerry C
authors.initials: JC
authors.lastname: Lee
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Erlanson
authors.forename: Anna
authors.initials: A
authors.lastname: Slaviero
authors.forename: Nigam H
authors.initials: NH
authors.lastname: Shah
authors.forename: James
authors.initials: J
authors.lastname: Leiper
authors.forename: John P
authors.initials: JP
authors.lastname: Cooke
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D064098:Esomeprazole / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D005764:Gastroesophageal Reflux / Q000188:drug therapy*; D006801:Humans; D064747:Lansoprazole / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D054328:Proton Pump Inhibitors / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D012307:Risk Factors; D014664:Vasodilation / Q000187:drug effects
chemical_list: D015415:Biomarkers; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; C018524:N,N-dimethylarginine; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D000581:Amidohydrolases; C059999:dimethylargininase; D064098:Esomeprazole
keywords: N,N dimethylarginine; dimethylarginine dimethylaminohydrolase; endothelium; nitric oxide; proton pump inhibitors