Abstract 230: Angiotensin-Converting Enzyme Inhibition Increases ADMA Concentration in Patients on Hemodialysis

Abstract

Endothelial dysfunction occurs commonly in patients with end-stage renal disease (ESRD) and is associated with increased cardiovascular morbidity and mortality. Asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxidase synthase, is elevated in patients with chronic kidney disease and contributes to endothelial dysfunction in ESRD. In the general population, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) decrease ADMA levels, but no study has compared the effect of these drugs in patients with ESRD on hemodialysis. We therefore evaluated the effect of one-week treatment with ramipril (5 mg/d), valsartan (160 mg/d) and placebo on ADMA levels in fifteen patients on hemodialysis in a previously published double-blind, placebo-controlled, 3X3 cross-over study. We found that ADMA levels were increased at baseline and throughout the dialysis session during ramipril treatment (Figure 1, p<0.001 compared to both placebo and valsartan). Ramipril did not increase ADMA levels in a study of patients without ESRD, suggesting that factors related to ESRD or hemodialysis contribute to the ACE inhibitor-induced increase in ADMA levels. We have previously shown that ACE inhibition increases bradykinin (BK) levels during hemodialysis. Therefore, we evaluated the effect of BK on ADMA production in A549 cells; incubation with BK increased intracellular ADMA concentration through bradykinin B2- receptor (B2R) stimulation (Figure 2). In conclusion, ACE inhibition increases ADMA in patients on hemodialysis. Studies in vitro suggest that this could occur through a bradykinin-mediated increase in ADMA production.