Response to Letters Regarding Article, “Unexpected Effect of Proton Pump Inhibitors: Elevation of the Cardiovascular Risk Factor Asymmetric Dimethylarginine”

We thank the authors for their positive comments and amplifying remarks in response to our article in Circulation .1 We agree with the authors that the proton pump inhibitors (PPIs) may adversely influence cardiovascular physiology in multiple ways. We found that PPIs reduce the enzymatic activity of dimethylarginine dimethylaminohydrolase. In this way, PPIs increase plasma levels of asymmetrical dimethylarginine (ADMA).1 Because it inhibits the generation of vascular nitric oxide (NO), ADMA would be expected to increase platelet interaction with the vessel wall. Chyrchel and colleagues correctly point out that our findings may explain why PPIs attenuate the benefit of clopidogrel, as well as other P2Y12 antiplatelet agents not dependent on CYP2C19 for their activity.We thank Montenegro and Lundberg for pointing out that NO may be generated in the stomach by the reduction of ingested nitrite, an effect that depends on low gastric pH. Dietary nitrate and nitrite …