Effects of amlodipine and valsartan on oxidative stress and plasma methylarginines in end-stage renal disease patients on hemodialysis

Abstract

Patients with end-stage renal disease (ESRD) receiving hemodialysis (HD) treatment have a markedly shortened life expectancy in large part owing to cardiovascular disease (CVD), not explained by established risk factors. We tested the hypothesis that therapy with valsartan, an angiotensin receptor blocker and amlodipine, an antioxidant calcium channel blocker will reduce oxidative stress and the plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase. We confirmed that compared with age- and gender-matched healthy controls, ESRD patients have excessive oxidative stress and arginine methylation as indexed by elevated plasma levels of oxidation products of lipids (13-hydroxyoctadecadienoic acid (13-HODE)), thiols (oxidized:reduced glutathione, oxidized glutathione (GSSG):GSH), proteins, and nucleic acids, and the methylation products ADMA and symmetric dimethylarginine (SDMA). We undertook a double blind, crossover study of equi-antihypertensive treatment with amlodipine and valsartan for 6 weeks each to test our hypothesis. Both treatments significantly reduced GSSG:GSH, 8-hydroxy 2-deoxyguanosine, ADMA, and SDMA levels and amlodipine reduced 13-HODE. We conclude that hypertensive patients with ESRD receiving HD have evidence of extensive oxidation of lipids, thiols, proteins, and nucleic acids and methylation of arginine that could contribute to CVD. Many of these changes can be reduced by short-term treatment with amlodipine and valsartan.

Comparative Effects of Angiotensin-Converting Enzyme Inhibition and Angiotensin-Receptor Blockade on Inflammation during Hemodialysis

“…In contrast, a previous study showed that oxidative stress levels decreased in hemodialysis patients after 6-week treatment with valsartan. 44 The discrepancy with our study may reside in the duration of the treatment. Although this study does not address the mechanism for the effect of valsartan and ramipril on F 2 -isoprostanes, we observed that increasing blood flow increases F 2 -isoprostanes in the human forearm vasculature.…”

ADMA Levels Correlate with Proteinuria, Secondary Amyloidosis, and Endothelial Dysfunction

“…14,15 Because the kidneys provide a significant route for clearance of methylarginines, 16,17 it is perhaps not surprising that ADMA 18 and SDMA concentrations increase in CKD patients even without proteinuria, 19,20 or that proteinuria with reduced renal function is associated with both elevated ADMA and endothelial dysfunction. 10,21,22 However, the patients in our study all had a nearly normal renal function.…”

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

“…Pharmacological agents that have been tested for their ability to modify ADMA levels in humans include drugs that interfere with the renin-angiotensin system (RAS) by either blocking the formation [angiotensin-converting enzyme (ACE) inhibitors] or pharmacological action [angiotensin receptor blockers (ARBs)] of angiotensin II (ANG II). Although some investigators found significant reductions of ADMA levels in patients treated with RAS-blocking agents (2,4,9,15,16,27,42), other studies have failed to confirm these findings (10,40). Sound interpretation of the aforementioned clinical trials is complicated due to differences in study design, study cohorts, treatment regimen, and the use of different bioanalytical methods to determine ADMA levels.…”

“…Briefly, all animals were trained on alternate days over a period of 2 wk to get accustomed to the device. Final measurements were performed before pump implantation and on days 2,3,7,14,21, and 28 after surgery. A total of 20 consecutive readings of systolic blood pressure (SBP) and heart rate were recorded and averaged.…”