Asymmetric dimethylarginine, oxidative stress, and vascular nitric oxide synthase in essential hypertension

Abstract

-We reported impaired endotheliumderived relaxation factor/nitric oxide (EDRF/NO) responses and constitutive nitric oxide synthase (cNOS) activity in subcutaneous vessels dissected from patients with essential hypertension (n ϭ 9) compared with normal controls (n ϭ 10). We now test the hypothesis that the patients in this study have increased circulating levels of the cNOS inhibitor, asymmetric dimethylarginine (ADMA), or the lipid peroxidation product of linoleic acid, 13-hydroxyoctadecadienoic acid (HODE), which is a marker of reactive oxygen species. Patients had significantly (P Ͻ 0.001) elevated (means Ϯ SD) plasma levels of ADMA (P ADMA, 766 Ϯ 217 vs. 393 Ϯ 57 nmol/l) and symmetric dimethylarginine (P SDMA: 644 Ϯ 140 vs. 399 Ϯ 70 nmol/l) but similar levels of L-arginine accompanied by significantly (P Ͻ 0.015) increased rates of renal ADMA excretion (21 Ϯ 9 vs. 14 Ϯ 5 nmol/ mol creatinine) and decreased rates of renal ADMA clearance (18 Ϯ 3 vs. 28 Ϯ 5 ml/min). They had significantly increased plasma levels of HODE (P HODE: 309 Ϯ 30 vs. 226 Ϯ 24 nmol/l) and renal HODE excretion (433 Ϯ 93 vs. 299 Ϯ 67 nmol/mol creatinine). For the combined group of normal and hypertensive subjects, the individual values for plasma levels of ADMA and HODE were both significantly (P Ͻ 0.001) and inversely correlated with microvascular EDRF/NO and positively correlated with mean blood pressure. In conclusion, elevated levels of ADMA and oxidative stress in a group of hypertensive patients could contribute to the associated microvascular endothelial dysfunction and elevated blood pressure. blood pressure; 13-hydroxyoctadecadienoic acid; endothelium-derived relaxation factor/nitric oxide; albuminuria MOST OF THE ESTABLISHED AND nontraditional cardiovascular risk factors are associated with endothelial dysfunction (3,5,7,18,45). This includes those with essential hypertension in some (29,33,34,35,39,42,50), but not all, studies (54). Endothelial function depends on the integrity of constitutive nitric oxide synthase (cNOS) and the availability and vascular signaling of its product, nitric oxide (NO). Endothelial dysfunction is of clinical importance since it predisposes to the development of hypertension and atherosclerosis and consequently is a predictor of subsequent adverse cardiovascular events (34).Endothelial dysfunction has been ascribed to two principal factors. One is an enhanced vascular generation of superoxide anion (O 2 ⅐ Ϫ ) that bioinactivates endothelial-derived NO (5), thereby reducing endothelial function and forming peroxynitrite (ONOO Ϫ ). Peroxynitrite itself can nitrosate and inactivate prostacyclin synthase (46), which is an additional pathway mediating endothelium-dependent relaxation. A second factor is generation of asymmetric dimethylarginine (ADMA), which inhibits nitric oxide synthase (6) and inhibits the cellular uptake of L-arginine by the cationic amino acid transporters (CATs) (8).We have studied endothelial function and cNOS activity directly in subcutaneous resistance vessels dissected from glute...

Reactive oxygen species and vascular biology: implications in human hypertension

“…148 Additionally, normotensive subjects with a family history of hypertension have greater H 2 O 2 production than blood pressure-matched normotensives without a family history of hypertension, suggesting that there may be a genetic component that leads to elevated production of H 2 O 2 . 149,150 Plasma levels of asymmetric dimethylarginine (endothelial nitric oxide synthase inhibitor) and the lipid peroxidation product of linoleic acid, 13-hydroxyoctadecadienoic acid, a marker of ROS production, were inversely correlated with microvascular endothelial dysfunction and elevated blood pressure in hypertensive patients. To further support a relationship between oxidative stress and blood pressure, Van et al 151 recently showed that myeloperoxidase is positively and independently associated with blood pressure and that this association is strongest in subjects with increased levels of oxidative markers.…”

Morphometric changes of the left ventricle and characteristics of peripheral hemodynamics in patients with drug resistant hypertension

“…Кроме того, перегрузка ЛЖ давлением, нарушения диастолической функции ЛЖ приводят к перегрузке ЛП и сопровождаются увеличением его размера, который у пациентов с РАГ стремится к предельным значениям, достижение которого увеличивает риск развития фибрилляции предсердий [20]. Таким об-разом, у пациентов с резистентной артериальной ги-пертензией отмечается сформировавшаяся, прогно-стически наиболее неблагоприятная концентрическая гипертрофия миокарда левого желудочка, что является наиболее значимым фактором риска сердечно-со-судистых осложнений, в том числе со смертельным исходом [21,22]. Огромную роль в развитии не-обратимых изменений в миокарде при АГ в виде его гипертрофии ЛЖ и интерстициального фиброза иг-рает состояние МЦР.…”

Asymmetric dimethylarginine and homocysteine in exudative age-related macular degeneration

“…In order that increased level of ADMA can have the important role in the pathogenesis of atherosclerosis and E-ARMD. [10][11][12][13][14] Dimethylarginine dimethylaminohydrolase (DDAH) is an enzyme that it degrades methylarginine, specifically ADMA. The activity of DDAH is impaired by oxidative stress, permitting ADMA to accumulate.…”

“…11,15,27,28 High level of ADMA can also induce oxidative damage in vascular tissues results in endothelial dysfunction. 10,12 Endothelial function depends on the integrity of constitutive NOS and the availability and vascular signaling of its product, NO. 12 Vallance et al 29 reported a large increase in serum concentrations of ADMA in patients with CKD and end-stage renal disease and showed that ADMA inhibited NOS and that ADMA and cationic amino acid transferase.…”

“…10,12 Endothelial function depends on the integrity of constitutive NOS and the availability and vascular signaling of its product, NO. 12 Vallance et al 29 reported a large increase in serum concentrations of ADMA in patients with CKD and end-stage renal disease and showed that ADMA inhibited NOS and that ADMA and cationic amino acid transferase. Selley 30 demonstrated that Hcy inhibits the activity of DDAH in cultured neuronal granule cells, causing the accumulation of ADMA and the inhibition of NO synthesis.…”