Abstract
BackgroundEndothelial 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).MethodsWe 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.ResultsWe 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.ConclusionThese 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 registrationClinicaltrials.gov NCT00732069 August 6 2008 and NCT00607672 February 4 2008Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-015-0162-x) contains supplementary material, which is available to authorized users.
Highlights
Endothelial dysfunction occurs in patients with end-stage renal disease (ESRD) and is associated with increased cardiovascular morbidity and mortality
Effect of hemodialysis and treatment on methylarginines Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels decreased by 30 min, reached a nadir at 1 h after the initiation of hemodialysis (Fig. 1), and remained lower at the end of hemodialysis (4 h)
ADMA levels were significantly higher at baseline and throughout dialysis during ramipril treatment (Fig. 1) compared to treatment with either placebo or valsartan
Summary
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. Patients undergoing maintenance hemodialysis (MHD) exhibit accelerated atherosclerosis and are at high risk of developing cardiovascular events, even after controlling for traditional risk factors [1,2,3]. Certain non-traditional factors, such as oxidative stress and inflammation, have been implicated in the pathogenesis of atherosclerosis of end-stage renal disease (ESRD) [4]. Endothelial dysfunction is commonly present in patients with ESRD and is associated with an increased risk of atherosclerotic events [8]. Increased levels of asymmetric dimethylarginine (ADMA), a potent inhibitor of endothelial nitric oxide synthase, can contribute to endothelial dysfunction.
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