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Pharmacotherapy. 2021 Jan 19. doi: 10.1002/phar.2504. Online ahead of print.

Association of proton pump inhibitor use with
endothelial function and metabolites of the nitric
oxide pathway: a cross-sectional study
Michael Nolde  1   2 , Martin Bahls  3   4 , Nele Friedrich  4   5 , Marcus Dörr  3   4 , Tobias Dreischulte  6 , 
Stefan B Felix  3   4 , Ina-Maria Rückert-Eheberg  1   7 , Nayeon Ahn  1   2 , Ute Amann  2 , 
Edzard Schwedhelm  8   9 , Henry Völzke  4   10 , Markus M Lerch  11 , Jakob Linseisen  1   2 , 
Christa Meisinger  1   2 , Sebastian E Baumeister  1   2
Affiliations
PMID: 33465818 DOI: 10.1002/phar.2504
Abstract
Objective: Long-term intake of proton pump inhibitors (PPIs) might increase the risk of
cardiovascular events. One suggested mechanism is that PPIs inhibit the enzyme dimethylarginine
dimethylaminohydrolase (DDAH), and thereby block the degradation of endothelial asymmetrical
dimethylarginine (ADMA). Excess ADMA in turn leads to impaired endothelial nitric oxide (NO)
generation. So far, this mechanism has only been established in human cell cultures. This study
examined that pathway in a human population. Previous studies that examined this pathway in
human populations measured circulating ADMA, and found no association with PPI use and excess
plasma ADMA. But in a recent study plasma ADMA was not correlated with intracellular ADMA. We
therefore focused on changes in plasma citrulline as an indicator for potential DDAH inhibition.
Methods: We analyzed the association between regular daily PPI intake and flow-mediated dilation
(FMD) of the brachial artery as well as plasma concentrations of citrulline, arginine, ADMA, and
symmetric dimethylarginine using inverse probability weighting to adjust for confounding and
censoring. Data that had been collected between 2008 and 2012 of 1,298 participants from two
independent cohorts of the population-based Study of Health in Pomerania was used.
Results: 87 participants (57.5% female) were regular daily users of PPIs. In the fully adjusted
models, associations were identified for FMD and plasma citrulline concentrations. PPI users
revealed a 0.99% (95% CI: -1.96 to -0.02) lower FMD and 3.03 µmol/l (95% CI: -4.96 to -1.10) lower
plasma citrulline levels as compared to non-users.
Conclusion: Our data provide evidence that long-term intake of PPIs might inhibit human DDAH
activity, resulting in impaired endothelial NO production and reduced vascular function. In the long
run this might explain an increased risk for cardiovascular diseases associated with long-term PPI
use.
Keywords: citrulline; endothelium; flow-mediated dilation; nitric oxide; proton pump inhibitor.
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