Asymmetric Dimethylarginine, L-Arginine, and Endothelial Dysfunction in Essential Hypertension

Perticone, Francesco; Sciacqua, Angela; Maio, Raffaele; Perticone, Maria; Maas, Renke; Böger, Rainer H.; Tripepi, G.; Sesti, Giorgio; Zoccali, Carmine

doi:10.1016/j.jacc.2005.04.040

Cited by 238 publications

(188 citation statements)

References 38 publications

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“…We did not observe any relationship between ANG II-induced hypertension and plasma ADMA levels. Evidence for an association between high blood pressure and elevated ADMA levels comes from small clinical studies (29,35). Other reports, including several large-scale clinical studies, did not confirm such an association (25,31).…”

Section: Discussionmentioning

confidence: 99%

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

Jacobi¹,

Maas²,

Cordasic³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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RH, Hilgers KF. Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice. Am J Physiol Heart Circ Physiol 294: H1058-H1066, 2008. First published December 21, 2007 doi:10.1152/ajpheart.01103.2007.-The aim of the present study was to investigate the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) in angiotensin II (ANG II)-induced hypertension and target organ damage in mice. Mice transgenic for the human DDAH1 gene (TG) and wild-type (WT) mice (each, n ϭ 28) were treated with 1.0 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ANG II, 3.0 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ANG II, or phosphate-buffered saline over 4 wk via osmotic minipumps. Blood pressure, as measured by tail cuff, was elevated to the same degree in TG and WT mice. Plasma levels of ADMA were lower in TG than WT mice and were not affected after 4 wk by either dose of ANG II in both TG and WT animals. Oxidative stress within the wall of the aorta, measured by fluorescence microscopy using the dye dihydroethidium, was significantly reduced in TG mice. ANG II-induced glomerulosclerosis was similar between WT and TG mice, whereas renal interstitial fibrosis was significantly reduced in TG compared with WT animals. Renal mRNA expression of protein arginine methyltransferase (PRMT)1 and DDAH2 increased during the infusion of ANG II, whereas PRMT3 and endogenous mouse DDAH1 expression remained unaltered. Chronic infusion of ANG II in mice has no effect on the plasma levels of ADMA after 4 wk. However, an overexpression of DDAH1 alleviates ANG II-induced renal interstitial fibrosis and vascular oxidative stress, suggesting a blood pressure-independent effect of ADMA on ANG II-induced target organ damage. dimethylarginine dimethylaminohydrolase; hypertension; transgenic ASYMMETRIC DIMETHYLARGININE (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is increasingly recognized as a potential risk factor and prognostic biomarker in cardiovascular disease (38). Thus far, elevated ADMA levels have been associated with all established cardiovascular risk factors (38). Furthermore, recent data from genetic mouse models indicate a causal role for ADMA in the pathophysiology of vascular disease (7,19). ADMA derives from the posttranslational methylation of L-arginine residues within proteins catalyzed by enzymes called protein arginine methyltransferases (PRMTs). Upon proteolysis, methylarginines are released into the circulation. Although ϳ15% of ADMA are excreted via the urine, the major elimination occurs through enzymatic degradation (ϳ85%) (1). The enzyme dimethylarginine dimethylaminohydrolase (DDAH), of which two isoforms with distinct tissue distribution have been described, catalyzes the hydrolysis of ADMA to L-citrulline and dimethylamine (38).Thus far, clinical studies have mostly addressed the prognostic value of ADMA in cardiovascular or kidney disease as well as the impact of pharmacological interventions aimed at lowering ADMA levels ...

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Section: Discussionmentioning

confidence: 99%

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

Jacobi¹,

Maas²,

Cordasic³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…ADMA might be an intrinsic factor involved in vasodilative function, 6,19) and many studies have reported a close relation between a decrease in ADMA levels and improvement of vascular endothelial function. 25) Therefore, telmisartan can be expected to improve vascular endothelial function, at least in part, via a decrease in ADMA levels.…”

Section: Discussionmentioning

confidence: 97%

“…Subsequently, the brachial ankle PWV (baPWV) was obtained by dividing the length of blood vessels between the heart and inferior limb (L, which was obtained from the height using a regression formula) by PTT (baPWV = L/PTT cm/second). 19,20) In the present study, a higher value of baPWV, which was obtained at the bilateral arteries in the inferior limbs, was employed. Although values with a lot of noise were obtained again, recording was successfully performed in all subjects.…”

Section: Methodsmentioning

confidence: 99%

Telmisartan Decreases Plasma Levels of Asymmetrical Dimethyl-L-Arginine and Improves Lipid and Glucose Metabolism and Vascular Function

et al. 2009

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SummaryTelmisartan is an angiotensin II receptor blocker (ARB) and also an activator of peroxisome proliferator-activated receptor-γ (PPAR-γ). We investigated whether telmisartan improves vascular endothelial function in patients with essential hypertension with the production of endothelial nitric oxide synthase (eNOS) through PPAR-γ.Telmisartan was administered to 15 patients with essential hypertension. To assess vascular function, asymmetric dimethylarginine (ADMA), an eNOS inhibitor synthesized by endothelial cells, and the pulse-wave velocity (PWV) were measured. The serum levels of lipid, glucose, and glycohemoglobin (HbA1c) were also evaluated before and after treatment. Telmisartan therapy significantly decreased the blood pressure and total-and LDL-cholesterol levels. HbA1c was also significantly improved but not in fasting plasma glucose. The serum levels of ADMA were significantly decreased (0.48 ± 0.08 to 0.42 ± 0.05 nmol/mL; P = 0.01). PWV values were significantly decreased by telmisartan from 1,822.5 ± 352.3 to 1,661.5 ± 299.8 cm/second (P = 0.04*). Telmisartan decreased PWV presumably via the activation of PPAR-γ , suggesting that this agent improves vascular endothelial function via its pleiotropic effects, a mechanism that is different from its hypotensive effects. (Int Heart J 2009; 50: 73-83) Key words: Telmisartan, Vascular endothelial function, Essential hypertension, PPAR-γ , ADMA THE impairment of endothelium causes atherosclerosis, 1) and consequently cerebrovascular and cardiovascular accidents, and is related to poor clinical outcome. Nitric oxide (NO) is a potent vasodilator produced by nitric oxide synthase (NOS) in endothelium, and controls vascular function via regulation of its metabolism.2,3) As a factor regulating NOS activity in vivo, asymmetric dimethylarginine (ADMA), an endogeneous competitive inhibitor of NOS activFrom the

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“…17) Reduction of high serum ADMA levels has been recommended as a therapeutic target for conditions associated with endothelial dysfunction. [8][9][10][11] Statin drugs are known to upregulate the expression of endothelial NO synthase and improve endothelial function. 18) On the other hand, different statin treatments have been associated with different effects on serum ADMA levels in hypercholesterolemic patients.…”

Section: Discussionmentioning

confidence: 99%

“…7) Serum ADMA levels are elevated in conditions associated with endothelial dysfunction, such as diabetes mellitus, hypertension, hypercholesterolemia, and coronary artery disease. [8][9][10][11] In patients with MetS, which is also a condition associated with endothelial dysfunction, elevated ADMA levels have also been shown. 12) Fluvastatin is a synthetic, competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase.…”

mentioning

confidence: 99%

Short Term Fluvastatin Treatment Lowers Serum Asymmetric Dimethylarginine Levels in Patients With Metabolic Syndrome

Oğuz

Uzunlulu

2008

Int. Heart J.

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SUMMARYElevated concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are associated with endothelial dysfunction. Metabolic syndrome (MetS) is also a condition associated with impaired endothelial function. To test the hypothesis that lipid lowering treatment with a statin lowers ADMA levels, we investigated the effect of fluvastatin treatment on serum ADMA levels in patients with MetS.A total of 85 hypercholesterolemic MetS patients (53 females, 32 males; mean age, 55.8 ± 9.1 years) were included in this prospective, randomized, controlled study. Patients were randomly assigned to either the treatment (n = 42) or control group (n = 43). Recommendations for lifestyle modification were provided to both groups. In addition, the patients in the treatment group received fluvastatin, extended release tablets, 80 mg/day, orally for 6 weeks. Serum levels of ADMA and lipids were assessed at baseline and at the completion of treatment. High performance liquid chromatography was used to measure serum ADMA concentrations.In the fluvastatin group, there was a significant reduction in serum ADMA levels compared to baseline (from 1.57 ± 1.07 µmol/L to 1.17 ± 1.41 µmol/L, P < 0.05), whereas in the control group no significant change was observed (from 1.06 ± 0.46 µmol/L to 1.24 ± 1.38 µmol/L, P > 0.05). There was a statistically significant difference between the groups in terms of mean percent change from baseline (P = 0.047). Fluvastatin treatment for hypercholesterolemia in patients with MetS is associated with a decrease in serum ADMA levels at 6 weeks. This finding is consistent with known beneficial effects of statin treatment on endothelial function in hypercholesterolemic patients. (Int Heart J 2008; 49: 303-311) Key words: Asymmetric dimethylarginine, Fluvastatin, Metabolic syndrome METABOLIC syndrome (MetS) is characterized by a cluster of cardiometabolic risk factors including hypertension, atherogenic dyslipidemia, hyperglycemia, and prethrombotic/proinflammatory conditions, 1) and represents a significant risk factor for the development of coronary heart disease, myocardial inFrom the

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Asymmetric Dimethylarginine, L-Arginine, and Endothelial Dysfunction in Essential Hypertension

Abstract: The main finding in this study is that in essential hypertensives the L-arginine and endogenous inhibitor of nitric oxide synthase, ADMA, are inversely related to endothelial function.

Cited by 238 publications

References 38 publications

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

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

Telmisartan Decreases Plasma Levels of Asymmetrical Dimethyl-L-Arginine and Improves Lipid and Glucose Metabolism and Vascular Function

Short Term Fluvastatin Treatment Lowers Serum Asymmetric Dimethylarginine Levels in Patients With Metabolic Syndrome

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