Effects of amlodipine and valsartan on oxidative stress and plasma methylarginines in end-stage renal disease patients on hemodialysis
2006; Elsevier BV; Volume: 70; Issue: 12 Linguagem: Inglês
10.1038/sj.ki.5001983
ISSN1523-1755
AutoresShakil Aslam, T Santha, Anna Leone, Christopher S. Wilcox,
Tópico(s)Renin-Angiotensin System Studies
ResumoPatients 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. 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. Cardiovascular disease (CVD) accounts for over 50% of the annual mortality of patients with end-stage renal disease (ESRD) on maintenance dialysis.1.US Renal Data System, USRDS Annual Data Report: Atlas of End-Stage Renal Disease in the United States,National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases2005Google Scholar The prevalence of the traditional cardiovascular risk factors, diabetes mellitus, hypertension, smoking, and dyslipidemias, is high in this patient population.2.Zoccali C. Mallamaci F. Tripepi G. Traditional and emerging cardiovascular risk factors in end-stage renal disease.Kidney Int. 2003; 85: S105-S110Abstract Full Text Full Text PDF Scopus (168) Google Scholar However, the HEMO study concluded that systolic blood pressure, smoking, or male gender were not associated with an increased risk of CVD, whereas diastolic blood pressure was actually inversely related.3.Cheung A.K. Sarnak M.J. Yan G. et al.Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients.Kidney Int. 2000; 58: 353-362Abstract Full Text Full Text PDF PubMed Scopus (630) Google Scholar Hypercholesterolemia was associated with an increased risk of coronary artery disease but not cerebrovascular or peripheral vascular disease. More recently, a controlled trial of lipid lowering with atorvastatin in hypercholesterolemic diabetic patients on hemodialysis (HD) reported no beneficial effect on cardiovascular events.4.Wanner C. Krane V. Marz W. et al.Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.N Engl J Med. 2005; 353: 238-248Crossref PubMed Scopus (2047) Google Scholar These findings have prompted an interest in nontraditional risk factors to explain the epidemiology of CVD in ESRD population. These risk factors include oxidative stress,5.Himmelfarb J. Stenvinkel P. Ikizler T.A. Hakim R.M. The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia.Kidney Int. 2002; 62: 1524-1538Abstract Full Text Full Text PDF PubMed Scopus (946) Google Scholar abnormal calcium and phosphate metabolism,6.Ganesh S.K. Stack A.G. Levin N.W. et al.Association of elevated serum PO(4), CaxPO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients.J Am Soc Nephrol. 2001; 12: 2131-2138Crossref PubMed Scopus (1432) Google Scholar hyperhomocysteinemia,7.Mallamaci F. Zoccali C. Tripepi G. et al.Hyperhomocysteinemia predicts cardiovascular outcomes in hemodialysis patients.Kidney Int. 2002; 61: 609-614Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar malnutrition and inflammation syndrome, and the accumulation of the nitric oxide synthase inhibitor, asymmetric dimethylarginine (ADMA).8.Vallance P. Leone A. Calver A. et al.Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.Lancet. 1992; 339: 572-575Abstract PubMed Scopus (1880) Google Scholar ADMA is an independent predictor of endothelial dysfunction and CVD both in patients with ESRD and the general population. It is associated with a three-fold increased risk of future severe cardiovascular events and mortality in patients on HD9.Zoccali C. Bode-Boger S. Mallamaci F. et al.Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study.Lancet. 2001; 358: 2113-2117Abstract Full Text Full Text PDF PubMed Scopus (929) Google Scholar and a four-fold increased risk of acute coronary events in clinically healthy, nonsmoking men.10.Valkonen V.P. Paiva H. Salonen J.T. et al.Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine.Lancet. 2001; 358: 2127-2128Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar In patients with chronic kidney disease, ADMA is a strong predictor of progression of chronic kidney disease and mortality.11.Ravani P. Tripepi G. Malberti F. et al.Asymmetrical dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease: a competing risks modeling approach.J Am Soc Nephrol. 2005; 16: 2449-2455Crossref PubMed Scopus (333) Google Scholar,12.Fliser D. Kronenberg F. Kielstein J.T. et al.Asymmetric dimethylarginine and progression of chronic kidney disease: the mild to moderate kidney disease study.J Am Soc Nephrol. 2005; 16: 2456-2461Crossref PubMed Scopus (290) Google Scholar Therefore, it represents a novel therapeutic target for clinical interventions. The pathogenesis of elevated ADMA levels is not understood in patients with ESRD. Data from experimental models suggest that oxidative stress increases the activity of protein arginine methyltransferases (PRMTs)13.Boger R.H. Sydow K. Borlak J. et al.LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases.Circ Res. 2000; 87: 99-105Crossref PubMed Scopus (454) Google Scholar which methylate arginine moieties on proteins and inhibits NG, NG-dimethylarginine-dimethylaminohydrolase (DDAH) activity14.Leiper J. Murray-Rust J. McDonald N. Vallance P. S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase.Proc Natl Acad Sci USA. 2002; 99: 13527-13532Crossref PubMed Scopus (265) Google Scholar which specifically metabolizes ADMA. However, effects of oxidative stress reduction on elevated plasma levels of methylarginines in chronic kidney disease are not known. Oxidative stress is the outcome of complex interactions between oxidants and antioxidant defense pathways that damage thiols, lipids, proteins, and nucleic acids. Although the presence of oxidative stress is well documented in patients with chronic kidney disease,15.Himmelfarb J. McMonagle E. McMenamin E. Plasma protein thiol oxidation and carbonyl formation in chronic renal failure.Kidney Int. 2000; 58: 2571-2578Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar,16.Annuk M. Zilmer M. Lind L. et al.Oxidative stress and endothelial function in chronic renal failure.J Am Soc Nephrol. 2001; 12: 2747-2752PubMed Google Scholar there is currently no consensus on a single ideal marker of oxidative stress. Furthermore, effects of antihypertensive therapy on oxidative stress have not been studied prospectively in ESRD patients. Oxidation products of lipids, proteins, thiols, and DNA are the most commonly measured parameters in clinical studies.15.Himmelfarb J. McMonagle E. McMenamin E. Plasma protein thiol oxidation and carbonyl formation in chronic renal failure.Kidney Int. 2000; 58: 2571-2578Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar, 16.Annuk M. Zilmer M. Lind L. et al.Oxidative stress and endothelial function in chronic renal failure.J Am Soc Nephrol. 2001; 12: 2747-2752PubMed Google Scholar, 17.Ikizler T.A. Morrow J.D. Roberts L.J. et al.Plasma F2-isoprostane levels are elevated in chronic hemodialysis patients.Clin Nephrol. 2002; 58: 190-197Crossref PubMed Google Scholar, 18.Satoh M. Yamasaki Y. Nagake Y. et al.Oxidative stress is reduced by the long-term use of vitamin E-coated dialysis filters.Kidney Int. 2001; 59: 1943-1950Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 19.Oberg B.P. McMenamin E. Lucas F.L. et al.Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease.Kidney Int. 2004; 65: 1009-1016Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar 13-Hydroxyoctadecadienoic acid (13-HODE) is a linoleic acid peroxidation product generated by the action of 15-lipoxygenase and by non-enzymatic oxidation. It is a stable parameter of lipid peroxidation that has been implicated in the pathogenesis of atherosclerosis.20.Belkner J. Wiesner R. Kuhn H. Identification of oxidatively modified lipids in atherosclerotic lesions of human aortas.Agents Actions. 1992; 37: 78-84PubMed Google Scholar Although two trials of antioxidants reported a reduction in CVD events in HD patients, these trials did not measure the markers of oxidative stress or inflammation, thereby making their interpretation somewhat uncertain.21.Boaz M. Smetana S. Weinstein T. et al.Secondary prevention with antioxidants of cardiovascular disease in end stage renal disease (SPACE): randomised placebo-controlled trial.Lancet. 2000; 356: 1213-1218Abstract Full Text Full Text PDF PubMed Scopus (895) Google Scholar,22.Tepel M. van der G.M. Statz M. et al.The antioxidant acetylcysteine reduces cardiovascular events in patients with end-stage renal failure: a randomized, controlled trial.Circulation. 2003; 107: 992-995Crossref PubMed Scopus (334) Google Scholar Treatment of HD patients with antagonists of renin–angiotensin system reduces oxidative stress in observational studies.23.de Cavanagh E.M. Ferder L. Carrasquedo F. et al.Higher levels of antioxidant defenses in enalapril-treated versus non-enalapril-treated hemodialysis patients.Am J Kidney Dis. 1999; 34: 445-455Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar Angiotensin II acting on AT1 receptors increases superoxide generation in part by activating nicotinamide adenine dinucleotide phosphate oxidase.24.Chabrashvili T. Kitiyakara C. Blau J. et al.Effects of ANG II type 1 and 2 receptors on oxidative stress, renal NADPH oxidase, and SOD expression.Am J Physiol Regul Integr Comp Physiol. 2003; 285: R117-R124Crossref PubMed Scopus (280) Google Scholar The dihydropyridine calcium channel blocker (CCB) amlodipine exerts strong antioxidant actions in vitro in lipid-laden cell membranes independent of its CCB action,25.Mason R.P. Walter M.F. Trumbore M.W. et al.Membrane antioxidant effects of the charged dihydropyridine calcium antagonist amlodipine.J Mol Cell Cardiol. 1999; 31: 275-281Abstract Full Text PDF PubMed Scopus (124) Google Scholar but the relevance of this to treatment of oxidative stress in vivo has not been studied in ESRD patients. Although the antagonists of the renin-angiotensin system and CCBs are the most widely prescribed antihypertensive agents in patients on maintenance HD,26.Agarwal R. Nissenson A.R. Batlle D. et al.Prevalence, treatment, and control of hypertension in chronic hemodialysis patients in the United States.Am J Med. 2003; 115: 291-297Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar their antioxidant properties have not been prospectively studied. Furthermore, the effects of these antioxidant agents on methylarginine metabolism have not been explored in this population. Therefore, we hypothesized that in stable ESRD patients on maintenance HD, valsartan (an angiotensin receptor blocker) and amlodipine (a CCB) will lower oxidative stress, and that this will be associated with a reduction in the plasma levels of ADMA independent of blood pressure lowering. This was investigated in a double-blind crossover trial of equally antihypertensive therapy with these two agents. A total of 30 patients were enrolled. Twenty-three patients completed the study; seven patients withdrew from the study owing to consent withdrawal (three), transfer to another facility (one), and hospitalization unrelated to the study (three). Four patients were excluded from the final analysis owing to administration of intravenous iron during one of the study phases. This left 19 patients who comprised the study population. They were matched with an equal number of healthy controls. The baseline characteristics of the patients and the controls are shown in Tables 1 and 2. There were no current smokers in either group. The maximum dose of valsartan (320 mg daily) and amlodipine (10 mg daily) was achieved in all study subjects.Table 1Patient characteristicsVariablePatients (n=19)Controls (n=19)P-valueAge (years)57.9±2746.5±60.07—GenderF=12F=14—M=8M=6—Time on dialysis (months)46±31——Etiology of ESRD Hypertension12—— Diabetes mellitus4—— HIV-AN2—— Lupus nephritis1—— Unknown1——AN, associated nephropathy; ESRD, end-stage renal disease; F, female; HIV, human immunodeficiency virus; M, male. Open table in a new tab Table 2Biomarkers of oxidative stress and L-arginine metabolism in patients with ESRD on maintenance HD and healthy controlsParameterControls (n=19)ESRD patients (n=19)P-valuePlasma 13-HODE (nmol/ml)210.4±15.9428.3±26.8<0.0001 Protein carbonyl (ng/mg)0.07±0.010.17±0.01<0.0001 8-HO2dG (ng/ml)1.88±0.142.85±0.220.0013 HS-CRP (mg/l)0.07±0.0080.84±0.360.034 L-arginine (μmol/l)95.3±3.286.7±4.80.15 ADMA (μmol/l)0.59±0.031.94±0.12<0.0001 SDMA (μmol/l)0.65±0.043.2±0.3<0.0001Whole blood GSSG:GSH (× 100)1.23±0.542.9±1.20.04ADMA, asymmetric dimethylarginine; ESRD, end-stage renal disease; GSH, glutathione; HD, hemodialysis; 13-HODE, 13-hydroxyoctadecadienoic acid; 8-HO2dG, 8-hydroxy 2-deoxyguanosine; HS-CRP, high-sensitivity C-reactive protein; SDMA, symmetric dimethylarginine. Open table in a new tab AN, associated nephropathy; ESRD, end-stage renal disease; F, female; HIV, human immunodeficiency virus; M, male. ADMA, asymmetric dimethylarginine; ESRD, end-stage renal disease; GSH, glutathione; HD, hemodialysis; 13-HODE, 13-hydroxyoctadecadienoic acid; 8-HO2dG, 8-hydroxy 2-deoxyguanosine; HS-CRP, high-sensitivity C-reactive protein; SDMA, symmetric dimethylarginine. After 6 weeks of therapy, both amlodipine and valsartan lowered 13-HODE by 29.7 and 14.4% (P=0.09 for valsartan), 8-hydroxy 2-deoxyguanosine by 21 and 19.5%, ADMA by 38.1 and 39.2%, SDMA by 41.6 and 37.5%, and GSSG:GSH by 40 and 79%, respectively (Table 3). Neither treatment had any significant effect on plasma protein carbonyl content, high-sensitivity C-reactive protein, or L-arginine. A total of 10 patients received valsartan first and nine patients received amlodipine first. Data were also analyzed according to the order in which the study drugs were administered and we detected no carry-over effect. Additional antihypertensive drugs were used in all three phases of the study to maintain the target blood pressure level. During the amlodipine and valsartan phases, the drugs used in the run-in period were withdrawn as required to maintain a stable target BP, whereas the study drugs were titrated up to full dose. Drugs used in the run-in, amlodipine, and valsartan phases of the study were as follows: clonidine in four, two, and two patients, labetalol in 12, 12, and 10 patients, and doxazosin in one, one, and one patient, respectively and were not statistically different. Blood pressure measured before HD three times a week was strictly similar during the run-in and intervention phases (Figure 1). Sixteen patients completed the 44-h ambulatory blood pressure monitoring. This confirmed that there was no difference in systolic (139±5.9 vs 137±5.9 mmHg), diastolic (80±3.7 vs 77.6±3.0 mmHg), or mean arterial pressure (102±3.8 vs 99.3±3.4 mmHg) between amlodipine and valsartan therapy, respectively (Figure 2).Table 3Effects of therapy with amlodipine and valsartan on parameters of oxidative stress and methylarginines in 19 patients on HDParameterBaselineAmlodipineValsartanP-value (ANOVA)Plasma 13-HODE (nmol/ml)428.3±26.8301.0±14.0*Significant at P<0.05.366.8±15.80.002 Protein carbonyl (ng/mg)0.17±0.010.16±0.010.17±0.010.81 8-HO2dG (ng/ml)2.97±0.222.34±0.2*Significant at P<0.05.2.39±0.15*Significant at P<0.05.0.028 HS-CRP (mg/l)0.84±0.361.4±0.921.33±0.50.83 L-arginine (μmol/l)86.7±4.878.2±4.879.3±5.50.4 ADMA (μmol/l)1.94±0.121.2±0.16*Significant at P<0.05.1.18±0.1*Significant at P<0.05.<0.0001 SDMA (μmol/l)3.2±0.31.87±0.24*Significant at P<0.05.2.0±0.23*Significant at P<0.05.0.001Whole blood GSSG:GSH (× 100)2.9±3.11.8±1.3*Significant at P<0.05.0.6±0.1*Significant at P<0.05.0.02ADMA, asymmetric dimethylarginine; ANOVA, analysis of variance; GSH, glutathione; HD, hemodialysis; 13-HODE, 13-hydroxyoctadecadienoic acid; 8-HO2dG, 8-hydroxy 2-deoxyguanosine; HS-CRP, high-sensitivity C-reactive protein; SDMA, symmetric dimethylarginine.* Significant at P<0.05. Open table in a new tab Figure 2Results of 44-h interdialytic ambulatory blood pressure monitoring. (aml, amlodipine; val, valsartan).View Large Image Figure ViewerDownload (PPT) ADMA, asymmetric dimethylarginine; ANOVA, analysis of variance; GSH, glutathione; HD, hemodialysis; 13-HODE, 13-hydroxyoctadecadienoic acid; 8-HO2dG, 8-hydroxy 2-deoxyguanosine; HS-CRP, high-sensitivity C-reactive protein; SDMA, symmetric dimethylarginine. We confirmed previous reports of oxidative stress and elevated plasma levels of ADMA and SDMA in patients with ESRD.15.Himmelfarb J. McMonagle E. McMenamin E. Plasma protein thiol oxidation and carbonyl formation in chronic renal failure.Kidney Int. 2000; 58: 2571-2578Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar, 16.Annuk M. Zilmer M. Lind L. et al.Oxidative stress and endothelial function in chronic renal failure.J Am Soc Nephrol. 2001; 12: 2747-2752PubMed Google Scholar, 17.Ikizler T.A. Morrow J.D. Roberts L.J. et al.Plasma F2-isoprostane levels are elevated in chronic hemodialysis patients.Clin Nephrol. 2002; 58: 190-197Crossref PubMed Google Scholar, 18.Satoh M. Yamasaki Y. Nagake Y. et al.Oxidative stress is reduced by the long-term use of vitamin E-coated dialysis filters.Kidney Int. 2001; 59: 1943-1950Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 19.Oberg B.P. McMenamin E. Lucas F.L. et al.Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease.Kidney Int. 2004; 65: 1009-1016Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar We detected widespread oxidation of all major biomolecules (lipids, protein, thiols, and DNA). The main new finding is that equi-antihypertensive therapy with amlodipine and valsartan led to significant reductions in many parameters of oxidative stress, and in plasma levels of ADMA and SDMA. We report 13-HODE as a new marker of lipid peroxidation in this patient population. High levels of 13-HODE cholesterol esters are found in atherosclerotic plaques in humans atheromas20.Belkner J. Wiesner R. Kuhn H. Identification of oxidatively modified lipids in atherosclerotic lesions of human aortas.Agents Actions. 1992; 37: 78-84PubMed Google Scholar where it may have a pathogenetic role. Linoleic acid is the most abundant polyunsaturated fatty acid in phospholipids including low-density lipoprotein, where its abundance is about seven times that of arachidonic acid.27.Esterbauer H. Gebicki J. Puhl H. Jurgens G. The role of lipid peroxidation and antioxidants in oxidative modification of LDL.Free Radic Biol Med. 1992; 13: 341-390Crossref PubMed Scopus (2099) Google Scholar Furthermore, it is the predominantly oxidized polyunsaturated fatty acid in phospholipids.28.Jira W. Spiteller G. Carson W. Schramm A. 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Formation of 9-hydroxyoctadecadienoic acid from linoleic acid in endothelial cells.J Biol Chem. 1989; 264: 6823-6830Abstract Full Text PDF PubMed Google Scholar We found that amlodipine was more effective in lowering plasma levels of 13-HODE than valsartan. Amlodipine is highly lipophilic and accumulates in cell membranes, where it can inhibit lipid peroxidation independent of its action as CCB.25.Mason R.P. Walter M.F. Trumbore M.W. et al.Membrane antioxidant effects of the charged dihydropyridine calcium antagonist amlodipine.J Mol Cell Cardiol. 1999; 31: 275-281Abstract Full Text PDF PubMed Scopus (124) Google Scholar Within the phospholipid bilayer of the cell membrane, the charged amino pole of amlodipine is positioned next to the oppositely charged groups whereas the hydrophobic pole is buried in the membrane hydrocarbon core, thereby aligning the dihydropyridine conjugated ring with phospholipid acyl chains which are an important target for peroxidation. Amlodipine scavenges free oxygen radicals by donating two abstractable hydrogen atoms associated with its aromatic ring, thereby breaking the lipid peroxidation chain reaction.33.Mason R.P. Campbell S.F. Wang S.D. Herbette L.G. Comparison of location and binding for the positively charged 1,4-dihydropyridine calcium channel antagonist amlodipine with uncharged drugs of this class in cardiac membranes.Mol Pharmacol. 1989; 36: 634-640PubMed Google Scholar Evidence of an in vivo antioxidant action of amlodipine on lipids was provided by an approximately 30% reduction in the plasma levels of 13-HODE in our study. The evidence of lipid oxidation in patients on HD was accompanied by evidence of oxidation of thiols, proteins, and nucleic acids. GSH is an important intracellular antioxidant that modulates vascular tone by scavenging free oxygen radicals. Intracoronary administration of GSH in high-risk individuals improves coronary endothelial vasomotor function.34.Kugiyama K. Ohgushi M. Motoyama T. et al.Intracoronary infusion of reduced glutathione improves endothelial vasomotor response to acetylcholine in human coronary circulation.Circulation. 1998; 97: 2299-2301Crossref PubMed Scopus (87) Google Scholar We confirmed an increased oxidation of GSH in ESRD patients. We found a significant reduction in the oxidized fraction of GSH with valsartan and amlodipine, which indicates an improvement in the redox milieu. A similar reduction in GSH oxidation is also seen in patients with essential hypertension treated with candesartan and amlodipine.35.Muda P. Kampus P. Zilmer M. et al.Effect of antihypertensive treatment with candesartan or amlodipine on glutathione and its redox status, homocysteine and vitamin concentrations in patients with essential hypertension.J Hypertens. 2005; 23: 105-112Crossref PubMed Scopus (18) Google Scholar Neither treatment had an effect on elevated plasma levels of high-sensitivity C-reactive protein, or protein carbonyl. The relatively short duration of our study may explain the lack of a reduction in these parameters. We limited the duration of each study arm to 6 weeks to avoid the high drop-out rate owing to concurrent illnesses and requirement for intravenous iron in this population, which could confound the oxidative stress parameters.36.Drueke T. Witko-Sarsat V. Massy Z. et al.Iron therapy, advanced oxidation protein products, and carotid artery intima-media thickness in end-stage renal disease.Circulation. 2002; 106: 2212-2217Crossref PubMed Scopus (328) Google Scholar Compartmentalization of the oxidative processes within the cells may also explain some of the differences in the oxidative stress parameters and may limit the ability of these drugs to exert antioxidant effects. We confirmed the reports of increased plasma levels of ADMA and SDMA, with unchanged L-arginine, in HD patients.8.Vallance P. Leone A. Calver A. et al.Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.Lancet. 1992; 339: 572-575Abstract PubMed Scopus (1880) Google Scholar However, a new finding was the marked reduction in the plasma levels of these methylarginines during treatment with amlodipine and valsartan. Methylarginines result form methylation of the arginine residues in proteins by PRMTs using s-adenosylmethionine as a methyl donor.37.McBride A.E. Silver P.A. State of the arg: protein methylation at arginine comes of age.Cell. 2001; 106: 5-8Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar Upon hydrolysis of the proteins, free methylarginines appear in the cytosol. The asymmetrically methylated arginines (ADMA and N-monomethyl-L-arginine), but not SDMA, inhibit nitric oxide synthase. ADMA, in addition, upregulates the expression of lectin-like OxLDL receptor in cultured human monocytes, leading to a 2.4-fold increase in the intracellular concentration of OxLDL.38.Smirnova I.V. Kajstura M. Sawamura T. Goligorsky M.S. Asymmetric dimethylarginine upregulates LOX-1 in activated macrophages: role in foam cell formation.Am J Physiol Heart Circ Physiol. 2004; 287: H782-H790Crossref PubMed Scopus (86) Google Scholar DDAH hydrolyses ADMA to citrulline and dimethylamine which is its major route of its elimination, whereas SDMA is eliminated principally by renal excretion.39.Kimoto M. Whitley G.S. Tsuji H. Ogawa T. Detection of NG,NG-dimethylarginine dimethylaminohydrolase in human tissues using a monoclonal antibody.J Biochem (Tokyo). 1995; 117: 237-238Crossref PubMed Scopus (148) Google Scholar The absence of renal excretion accounts for the higher plasma levels of SDMA than ADMA in patients with ESRD. Both isoforms of DDAH (1 and 2) are inhibited by oxidation and nitrosation.14.Leiper J. Murray-Rust J. McDonald N. Vallance P. S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase.Proc Natl Acad Sci USA. 2002; 99: 13527-13532Crossref PubMed Scopus (265) Google Scholar In this study, both
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