Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine.

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Ghebremariam YT, LePendu P, Lee JC, Erlanson DA, Slaviero A, Shah NH, Leiper J, Cooke JP

Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine.

Circulation. 2013 Aug 20;128(8):845-53. doi: 10.1161/CIRCULATIONAHA.113.003602. Epub 2013 Jul 3.

PubMed ID

23825361 [ View in PubMed

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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. METHODS AND 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.

DrugBank Data that Cites this Article

Drugs

Pantoprazole

Esomeprazole

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Dexlansoprazole	N(G),N(G)-dimethylarginine dimethylaminohydrolase 1	Protein	Humans	Unknown	Not Available	Details
Esomeprazole	N(G),N(G)-dimethylarginine dimethylaminohydrolase 1	Protein	Humans	Unknown	Not Available	Details
Pantoprazole	N(G),N(G)-dimethylarginine dimethylaminohydrolase 1	Protein	Humans	No	Inhibitor	Details