Studies on the catabolism of NG-methylarginine, NG, NG-dimethylarginine and NG, NG-dimethylarginine in the rabbit

McDermott, J.R.

doi:10.1042/bj1540179

Cited by 188 publications

(93 citation statements)

References 15 publications

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“…14 Asymmetric dimethylarginine (ADMA) is a naturally occurring L-arginine analogue derived from the proteolysis of proteins containing methylated arginine residues. [15][16][17] When administered acutely, ADMA inhibits purified NO synthase catalytic activity, endothelium-derived NO bioavailability, and endothelium-dependent NO-mediated vascular response, all of which are reversed by L-arginine (but not by D-arginine). 5,18,19 Plasma concentrations of ADMA have been found to be elevated in patients with arteriosclerosis, 20 as well as with coronary risk factors, such as hypertension 21 or hypercholesterolemia, 22 and elevated ADMA levels are associated with impaired endothelium-dependent NO-mediated vasodilation.…”

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confidence: 99%

Asymmetric Dimethylarginine Produces Vascular Lesions in Endothelial Nitric Oxide Synthase–Deficient Mice

Suda

Tsutsui

Morishita

et al. 2004

ATVB

171

124

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Objective-Asymmetric dimethylarginine (ADMA) is widely believed to be an endogenous nitric oxide synthase (eNOS) inhibitor. However, in this study, we examined our hypothesis that the long-term vascular effects of ADMA are not mediated by inhibition of endothelial NO synthesis. Methods and Results-ADMA was infused in wild-type and eNOS-knockout (KO) mice by osmotic minipump for 4 weeks. In wild-type mice, long-term treatment with ADMA caused significant coronary microvascular lesions. Importantly, in eNOS-KO mice, treatment with ADMA also caused an extent of coronary microvascular lesions that was comparable to that in wild-type mice. These vascular effects of ADMA were not prevented by supplementation of L-arginine, and vascular NO production was not reduced by ADMA treatment. Treatment with ADMA caused upregulation of angiotensin-converting enzyme (ACE) and an increase in superoxide production that were comparable in both strains and that were abolished by simultaneous treatment with temocapril (ACE inhibitor) or olmesartan (AT 1 receptor antagonist), which simultaneously suppressed vascular lesion formation. Key Words: asymmetric dimethylarginine Ⅲ arteriosclerosis Ⅲ nitric oxide Ⅲ endothelial nitric oxide synthase Ⅲ mice E ndothelium-derived nitric oxide (NO), synthesized from L-arginine by endothelial NO synthase (eNOS), has several important antiatherogenic actions. 1-5 Indeed, reduction of endothelial NO synthesis (endothelial dysfunction) predisposes the blood vessel to arteriosclerosis, 1-5 and the eNOS-deficient (eNOS-KO) mice exhibit accelerated vascular lesion formation. 6,7 As pharmacological tools to inhibit endothelial NO synthesis, synthetic L-arginine analogues have been used in vitro and in vivo. Among them, N -nitro-L-arginine methyl ester (L-NAME) is the most frequently used agent. [1][2][3][4][5] Long-term treatment with L-NAME is known to cause arteriosclerotic coronary lesions, especially at microvascular levels, in experimental animals. 8,9 This model with L-NAME is regarded as a useful animal model for examining the protective roles of endothelium-derived NO in the pathogenesis of arteriosclerosis. 8,9 See cover However, it is controversial whether these vascular effects of L-NAME are caused primarily by the inhibition of endothelial NO synthesis for the following reasons: first, the importance of endothelium-derived NO decreases as the vessel size becomes smaller, 10 whereas L-NAME-induced vascular lesions are prominent at microvascular levels; 8 second, long-term treatment with L-NAME does not reduce eNOS activity; 11 third, multiple actions of L-NAME other than simple inhibition of NO synthesis have been reported. 12,13 The most appropriate way to address this issue is to use mice that are deficient in the eNOS gene and to examine whether long-term treatment with L-NAME causes coronary vascular lesions in those mice. We have recently shown that treatment with L-NAME causes a comparable extent of Conclusions-These

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confidence: 99%

Asymmetric Dimethylarginine Produces Vascular Lesions in Endothelial Nitric Oxide Synthase–Deficient Mice

Suda

Tsutsui

Morishita

et al. 2004

ATVB

171

124

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“…Further studies established that methylated L-Arg molecules also occur freely in body fluids (2)(3)(4)(5) and various tissues (6,7). Although degradation of Arg-methylated proteins has been shown to be a source of free MMA and ADMA (8,9), a direct methylation of L-Arg via a so far unknown pathway has also been suggested (10,11). The y ϩ membrane transporter system is apparently involved in the uptake or release of MMA and ADMA (11,12).…”

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confidence: 99%

Structural and Functional Characterization of the Zn(II) Site in Dimethylargininase-1 (DDAH-1) from Bovine Brain

Knipp¹,

Charnock²,

Garner³

et al. 2001

Journal of Biological Chemistry

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were first found as a result of post-translational modifications of Arg residues, mainly in DNA-and RNA-binding proteins (1). Further studies established that methylated L-Arg molecules also occur freely in body fluids (2-5) and various tissues (6, 7). Although degradation of Arg-methylated proteins has been shown to be a source of free MMA and ADMA (8, 9), a direct methylation of L-Arg via a so far unknown pathway has also been suggested (10, 11). The y ϩ membrane transporter system is apparently involved in the uptake or release of MMA and ADMA (11,12).Nitric-oxide synthase (NOS), which generates the free radical NO from L-Arg, exists in at least three isoforms that are involved in different biological processes. The two constitutive isoforms, nNOS (neuronal) and eNOS (endothelial), produce NO for neurotransmission and cardiovascular regulation, respectively, and are predominantly regulated by cytosolic Ca 2ϩ levels (13). It is well established that MMA and ADMA are endogenous competitive inhibitors of NOS (9,11,14). The intracellular L-Arg levels and the corresponding K m value of NOS are such that the production of NO should not depend on L-Arg supplementation (15). However, in biological studies, the addition of L-Arg increased the production of NO (16), a phenomenon called the "Arg paradox." In this context, it may be noted that recent in vitro studies have shown that the concomitant presence of varying, yet physiologically relevant, levels of MMA and ADMA dramatically affects NOS activity (17).The enzyme dimethylargininase (L-N ,N -dimethylarginine dimethylaminohydrolase (DDAH), EC 3.5.3.18) hydrolyzes both MMA and ADMA to L-citrulline (L-Cit), CH 3 NH 2 , and (CH 3 ) 2 NH, respectively (18). It has been established that DDAH regulates NOS by controlling the levels of MMA and ADMA (10). DDAH exists in at least two isoforms (19), both of which are cytosolic proteins (20). Whereas DDAH-1 is expressed predominantly in tissues containing nNOS (21-25), DDAH-2 is mainly found in tissues expressing eNOS (19,25). The role of DDAH-1 in the regulation of nNOS is also evident from recent studies showing that both proteins are up-regulated in injured neurons (26).The increased levels of MMA and ADMA in plasma and urine have been found in several diseases that are linked to vascular dysfunction characterized by low NO levels, e.g. uremia, atherosclerosis, hypercholesterolemia, diabetes mellitus, hypertension, and homocysteinemia (27). Moreover, increased levels of ADMA in plasma have been discussed as a risk factor for atherosclerosis (3,4,9). In contrast, NO overproduction apparently leads to diseases such as septic shock and migraine. In these cases, clinical studies using MMA as a drug have been or are currently being conducted (28,29).The above studies clearly indicate the importance of DDAH in NO metabolism. Previously, we have demonstrated that DDAH-1 from bovine brain is a monomeric (31.2 kDa) Zn(II)-containing protein (30) and that the Zn(II) is not involved in the * This work was supported in part by the Olga...

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“…About 20% of the clearance of these compounds is due to renal excretion. The remaining 80% of clearance is largely due the action of the cytoplasmic enzyme dimethylarginine dimethylaminohydrolase (DDAH); [54] which is expressed ubiquitously as two isoforms [55]. This enzyme is exquisitely sensitive to oxidative stress because it expresses a sulfhydryl group in its catalytic site [56].…”

Section: L-arginine: Rationale For Its Use In Vascular Diseasesmentioning

confidence: 99%

Herbal Viagra and nitric oxide: how hard is the evidence?

Cooke¹

2010

Cureus

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Studies on the catabolism of NG-methylarginine, NG, NG-dimethylarginine and NG, NG-dimethylarginine in the rabbit

Cited by 188 publications

References 15 publications

Asymmetric Dimethylarginine Produces Vascular Lesions in Endothelial Nitric Oxide Synthase–Deficient Mice

Asymmetric Dimethylarginine Produces Vascular Lesions in Endothelial Nitric Oxide Synthase–Deficient Mice

Structural and Functional Characterization of the Zn(II) Site in Dimethylargininase-1 (DDAH-1) from Bovine Brain

Herbal Viagra and nitric oxide: how hard is the evidence?

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