Plasma concentrations of endogenous inhibitor of nitric oxide synthesis in normal pregnancy and pre-eclampsia

Fickling, S. A.; Williams, David; Vallance, Patrick; Nussey, Stephen; Whitley, Guy

doi:10.1016/0140-6736(93)92335-q

Cited by 156 publications

(101 citation statements)

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“…Methylated analogues of arginine such as asymmetric dimethylarginine (ADMA) and N-mono methylarginine (L-NMMA) are competitive inhibitors of NO synthesis. Free ADMA is found in plasma and urine of healthy individuals and is synthesised by the post-translational methylation of protein arginine residues and liberated upon their hydrolysis (Kakimoto and Akazawa, 1970;Fickling et al, 1993). The intracellular concentration of ADMA reaches levels sufficient to inhibit NO synthesis (Macallister et al, 1994) and can be modulated by changes in the activity of the enzyme dimethylarginine dimethylaminohydrolase (DDAH) (Ogawa et al, 1989;Macallister et al, 1996).…”

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confidence: 99%

Dimethylarginine dimethylaminohydrolase I enhances tumour growth and angiogenesis

et al. 2002

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Angiogenesis is a prerequisite for tumour progression and is highly regulated by growth factors and cytokines a number of which also stimulate the production of nitric oxide. Asymmetric dimethylarginine is an endogenous inhibitor of nitric oxide synthesis. Asymmetric dimethylarginine is metabolised by dimethylarginine dimethylaminohydrolase. To study the effect of dimethylarginine dimethylaminohydrolase on tumour growth and vascular development, the rat C6 glioma cell line was manipulated to overexpress the rat gene for dimethylarginine dimethylaminohydrolase I. Enhanced expression of dimethylarginine dimethylaminohydrolase I increased nitric oxide synthesis (as indicated by a two-fold increase in the production of cGMP), expression and secretion of vascular endothelial cell growth factor, and induced angiogenesis in vitro. Tumours derived from these cells grew more rapidly in vivo than cells with normal dimethylarginine dimethylaminohydrolase I expression. Immunohistochemical and magnetic resonance imaging measurements were consistent with increased tumour vascular development. Furthermore, dimethylarginine dimethylaminohydrolase activity was detected in a series of human tumours. This data demonstrates that dimethylarginine dimethylaminohydrolase plays a pivotal role in tumour growth and the development of the tumour vasculature by regulating the concentration of nitric oxide and altering vascular endothelial cell growth factor production.

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Dimethylarginine dimethylaminohydrolase I enhances tumour growth and angiogenesis

et al. 2002

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“…[8][9][10] In addition, Savvidou et al reported that elevated ADMA concentrations preceded preeclampsia. ADMA was higher at 23-25 weeks in women who later developed preeclampsia, and interestingly ADMA was also elevated in other women with abnormal uterine artery Doppler measurements including women who later had a pregnancy with a growth restricted infant in the absence of preeclampsia.…”

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confidence: 99%

Elevated asymmetric dimethylarginine concentrations precede clinical preeclampsia, but not pregnancies with small-for-gestational-age infants

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et al. 2008

American Journal of Obstetrics and Gynecology

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Objective-The purpose of this study was to investigate maternal plasma concentrations of asymmetric dimethylarginine (ADMA) in mid-pregnancy and at the time of disease in women who develop preeclampsia compared to women with uncomplicated pregnancies and women with SGA infants.Study design-Plasma samples were collected at mid-pregnancy and at the time of delivery from 31 women with uncomplicated pregnancies, 12 women with SGA infants and 15 women with preeclampsia. ADMA and L-arginine were measured by high-pressure liquid chromatography. Conclusions-Maternal ADMA concentrations are higher in mid-pregnancy in women who develop preeclampsia compared to uncomplicated controls and SGA. Elevated ADMA prior to clinical onset of preeclampsia suggests a role of this NOS inhibitor in the pathophysiology of preeclampsia. Results-Maternal

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“…10 The reduction in NO bioavailability may be due in part to the action of a circulating endogenous NO synthase inhibitor, N G ,N G -dimethylarginine (asymmetric dimethylarginine; ADMA). [23][24][25][26] Intra-arterial administration of ADMA causes vasoconstriction in forearm vessels 27 via inhibition of endothelium-derived NO synthesis. We and others have demonstrated high levels of ADMA in urine from hypertensive rats, 28 in plasma from hypercholesterolemic rabbits, 29 in patients with peripheral arterial occlusive disease, 30 and in the regenerating endothelium of balloon-injured vessels.…”

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Endogenous Nitric Oxide Synthase Inhibitor

et al. 1999

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Background-Exposure to risk factors such as hypertension or hypercholesterolemia decreases the bioavailability of endothelium-derived nitric oxide (NO) and impairs endothelium-dependent vasodilation. Recently, a circulating endogenous NO synthase inhibitor, asymmetric dimethylarginine (ADMA), has been detected in human plasma. The purpose of this study was to examine the relationship between plasma ADMA and atherosclerosis in humans. Methods and Results-Subjects (nϭ116; age, 52Ϯ1 years; male:female ratio, 100:16) underwent a complete history and physical examination, determination of serum chemistries and ADMA levels, and duplex scanning of the carotid arteries. These individuals had no symptoms of coronary or peripheral artery disease and were taking no medications. Univariate and multivariate analyses revealed that plasma levels of ADMA were positively correlated with age (PϽ0.0001), mean arterial pressure (PϽ0.0001), and ⌺ glucose (an index of glucose tolerance) (Pϭ0.0006). Most intriguingly, stepwise regression analysis revealed that plasma ADMA levels were significantly correlated to the intima-media thickness of the carotid artery (as measured by high-resolution ultrasonography). Conclusions-This study reveals that plasma ADMA levels are positively correlated with risk factors for atherosclerosis.Furthermore, plasma ADMA level is significantly correlated with carotid intima-media thickness. Our results suggest that this endogenous antagonist of NO synthase may be a marker of atherosclerosis.

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Plasma concentrations of endogenous inhibitor of nitric oxide synthesis in normal pregnancy and pre-eclampsia

Cited by 156 publications

References 3 publications

Dimethylarginine dimethylaminohydrolase I enhances tumour growth and angiogenesis

Dimethylarginine dimethylaminohydrolase I enhances tumour growth and angiogenesis

Elevated asymmetric dimethylarginine concentrations precede clinical preeclampsia, but not pregnancies with small-for-gestational-age infants

Endogenous Nitric Oxide Synthase Inhibitor

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