Human dimethylarginine dimethylaminohydrolase 1 inhibition by proton pump inhibitors and the cardiovascular risk marker asymmetric dimethylarginine: in vitro and in vivo significance

Abstract

Proton pump inhibitor (PPI)-induced inhibition of dimethylarginine dimethylaminohydrolase 1 (DDAH1), with consequent accumulation of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA), might explain the increased cardiovascular risk with PPI use. However, uncertainty exists regarding whether clinical PPI concentrations significantly inhibit DDAH1 under linear initial rate conditions, and whether PPI-induced DDAH1 inhibition significantly increases ADMA in humans. DDAH1 inhibition by esomeprazole, omeprazole, pantoprazole, lansoprazole and rabeprazole was determined by quantifying DDAH1-mediated L-citrulline formation in vitro. Plasma ADMA was measured in PPI users (n = 134) and non-users (n = 489) in the Hunter Community Study (HCS). At clinical PPI concentrations (0.1–10 μmol/L), DDAH1 retained >80% activity vs. baseline. A significant, reversible, time-dependent inhibition was observed with lansoprazole (66% activity at 240 min, P = 0.034) and rabeprazole (25% activity at 240 min, P < 0.001). In regression analysis, PPI use was not associated with ADMA in HCS participants (beta 0.012, 95% CI −0.001 to 0.025, P = 0.077). Furthermore, there were no differences in ADMA between specific PPIs (P = 0.748). At clinical concentrations, PPIs are weak, reversible, DDAH1 inhibitors in vitro. The lack of significant associations between PPIs and ADMA in HCS participants questions the significance of DDAH1 inhibition as a mechanism explaining the increased cardiovascular risk reported with PPI use.

Association of proton pump inhibitor use with endothelial function and metabolites of the nitric oxide pathway: A cross‐sectional study

“…In line with previous studies, there was no association between PPI intake and plasma levels of ADMA. [8][9][10] We are not aware of any studies that assessed the effect of PPI intake on plasma SDMA or arginine, and our data showed no relationship between these variables.…”

“…So far, all efforts to reproduce these findings in human studies were without success. [8][9][10] One possible reason for this is that the plasma concentration of ADMA does not reflect the intracellular endothelial ADMA concentration very well. 11 ADMA might therefore not be the best choice to measure the effect of PPIs on endothelial citrulline, arginine, ADMA, and symmetric dimethylarginine using inverse probability weighting to adjust for confounding and censoring.…”

Safety of Long-Term Proton Pump Inhibitors: Facts and Myths

“…The mechanisms by which PPIs can affect the various pathways involved in the pathogenesis of the cardiovascular disease are complex (64)(65)(66) . By inhibiting dimethylarginine dimethylaminohydrolase (ADHD), they reduce the degradation of plasma asymmetric dimethylarginine (ADMA) by altering nitric oxide-dependent vasodilation.…”

Use of proton pump inhibitors and risk of ischemic events in the general population

“…The most credited hypothesis derived from the observation that an impairment of NOS (Nitric Oxide Synthase) pathway resulting in a promotion of ischemic conditions (16,31,32). In fact, all PPI class members can directly inhibit dimethylarginine dimethylaminohydrolase (DDAH) (31) activity.…”