Angiotensin converting enzyme inhibition increases ADMA concentration in patients on maintenance hemodialysis--a randomized cross-over study

Jorge L Gamboa, Mias Pretorius, Katie C Sprinkel, Nancy J Brown, T Alp Ikizler, Jorge L Gamboa, Mias Pretorius, Katie C Sprinkel, Nancy J Brown, T Alp Ikizler

Abstract

Background: Endothelial dysfunction occurs in patients with end-stage renal disease (ESRD) and is associated with increased cardiovascular morbidity and mortality. Asymmetric dimethylarginine (ADMA) 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 maintenance hemodialysis (MHD).

Methods: We evaluated the effect of 1-week treatment with ramipril (5 mg/d), valsartan (160 mg/d), and placebo on ADMA levels in 15 patients on MHD in a double-blind, placebo-controlled, three x three cross-over study.

Results: We found that ADMA levels were increased at baseline and throughout the dialysis session during ramipril treatment (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. We have previously shown that ACE inhibition increases bradykinin (BK) levels during hemodialysis. We therefore evaluated the effect of bradykinin on ADMA production in A549 cells; a cell line that expresses BK receptors. Incubation with BK increased intracellular ADMA concentration through BK B2-receptor stimulation.

Conclusion: These data indicate that short-term ACE inhibition increases ADMA in patients on MHD whereas ARBs do not. In vitro studies further suggest that this may occur through BK-mediated increase in ADMA production during ACE inhibition.

Trial registration: Clinicaltrials.gov NCT00732069 August 6 2008 and NCT00607672 February 4 2008.

Figures

Fig. 1
Fig. 1
Effect of 1 week treatment with ramipril, valsartan and placebo on (a) asymmetric dimethylarginine (ADMA) and (b) symmetric dimethylarginine in patients with end-stage renal disease during hemodialysis
Fig. 2
Fig. 2
Effect of 1 week treatment with ramipril, valsartan and placebo on (a) arginine levels and (b) ratios of arginine- to-asymmetric dimethylarginine (ADMA) in patients with end-stage renal disease during hemodialysis
Fig. 3
Fig. 3
Effect of 1 week treatment with ramipril, candesartan and placebo on (a) asymmetric dimethylarginine (ADMA), b symmetric dimethylarginine, c arginine levels, and (d) arginine-to-asymmetric dimethylarginine (ADMA) ratios in patients with no history of end-stage renal disease
Fig. 4
Fig. 4
Effect of bradykinin (BK, 20nM) incubation on intracellular asymmetric dimethylarginine (ADMA) levels in human adenocarcinoma cell (A549). HOE stands for HOE-140, a bradykinin B2 receptor inhibitor (1 μM). Bradykinin B1 inhibition (B1 inh) was performed using the B1 receptor antagonist Lys (Des-Arg9-Leu8) BK (1 μM). Bars represent mean ± standard deviation

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