Angiotensin-Converting Enzyme Activity is Involved in the Mechanism of Increased Endogenous Nitric Oxide Synthase Inhibitor in Patients With Type 2 Diabetes Mellitus.

Itō, Akira; Egashira, Kensuke; Narishige, Takahiro; Muramatsu, Kouhei; Takeshita, Akira

doi:10.1253/circj.66.811

Cited by 74 publications

(48 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…7,25,26 Endothelium-dependent vasodilatation has also been found to be impaired in patients with OSAS, 15,27-29 but their plasma ADMA concentrations were not determined in those studies. In the present study, endothelium-dependent vasodilatation was ameliorated with the improvement of apnea by nCPAP.…”

Section: Discussionmentioning

confidence: 96%

Amelioration of Vascular Endothelial Dysfunction in Obstructive Sleep Apnea Syndrome by Nasal Continuous Positive Airway Pressure-Possible Involvement of Nitric Oxide and Asymmetric NG, NG-Dimethylarginine-

Ohike

Kozaki

Iijima

et al. 2005

Circ J

145

View full text Add to dashboard Cite

ndothelial dysfunction is recognized as an early phase of arteriosclerosis 1 and an important cause of that dysfunction is impaired nitric oxide (NO) release from the endothelium. Endothelial NO is a key regulator of vascular homeostasis; it induces vasorelaxation by generating cyclic GMP in the underlying smooth muscle cells, and prevents monocyte adhesion to the endothelium, platelet activation, and smooth muscle cell proliferation. Hence, impaired NO release from injured endothelial cells is regarded as an initiator and promoter of arteriosclerosis.Endothelial NO is produced when L-arginine is con- February 2005 verted to L-citrulline by the enzyme endothelial nitric oxide synthase (eNOS). Endothelial NOS is inhibited by endogenous inhibitors, NG-monomethyl-L-arginine (L-NMMA) and asymmetric dimethylarginine (ADMA), which are structural analogues of L-arginine. 2,3 Plasma ADMA is eliminated by renal excretion and by degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). 4 Increased plasma concentration of ADMA is associated with hypertension, 5 pulmonary hypertension, 6 hypercholesterolemia, 7,8 carotid intima -media thickening, 9 severe peripheral artery occlusive disease, 10 and the clustering of coronary risk factors. 9 These findings suggest that ADMA is responsible for endothelial dysfunction. Obstructive sleep apnea syndrome (OSAS) has been recently attracting attention as a significant disorder. Frequent apnea/hypopnea attacks followed by arousal results in insufficient sleep at night, causing daytime sleepiness, leading to work inefficiency, and even traffic accidents. In addition, OSAS often accompanies hypertension, obesity, glucose intolerance, and dyslipidemia, all of which are factors in metabolic syndrome. Hence, OSAS is recognized as a risk factor for cardiovascular disease. 11-14 It has been Background Asymmetric NG,NG-dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide (NO) synthase and its plasma concentration is elevated in patients with cardiovascular risk factors, including hyperlipidemia, hypertension, diabetes, and hyperhomocysteinemia. Obstructive sleep apnea syndrome (OSAS) has been attracting attention as a risk factor for cardiovascular disorders because it often accompanies hypertension, obesity, glucose impairment, and dyslipidemia, all of which are factors in metabolic syndrome and risk factors for cardiovascular disease. Methods and ResultsIn the present study, flow-mediated vasodilatation (FMD) of the brachial artery and plasma concentrations of ADMA were measured before and after nasal continuous positive airway pressure (nCPAP) therapy, which abrogates apnea, in 10 male patients aged 36-69 years old, who were given a diagnosis of OSAS by polysomnography. The percent FMD (%FMD) improved significantly from 3.3±0.3% to 5.8±0.4% (p<0.01) and 6.6±0.3% (p<0.01), before, 1 week, and 4 weeks after nCPAP, respectively. At the same time, the plasma NOx concentrations, metabolites of NO, tended to increase, bu...

show abstract

Section: Discussionmentioning

confidence: 96%

Amelioration of Vascular Endothelial Dysfunction in Obstructive Sleep Apnea Syndrome by Nasal Continuous Positive Airway Pressure-Possible Involvement of Nitric Oxide and Asymmetric NG, NG-Dimethylarginine-

Ohike

Kozaki

Iijima

et al. 2005

Circ J

145

View full text Add to dashboard Cite

show abstract

“…Pharmacological agents that have been tested for their ability to modify ADMA levels in humans include drugs that interfere with the renin-angiotensin system (RAS) by either blocking the formation [angiotensin-converting enzyme (ACE) inhibitors] or pharmacological action [angiotensin receptor blockers (ARBs)] of angiotensin II (ANG II). Although some investigators found significant reductions of ADMA levels in patients treated with RAS-blocking agents (2,4,9,15,16,27,42), other studies have failed to confirm these findings (10,40). Sound interpretation of the aforementioned clinical trials is complicated due to differences in study design, study cohorts, treatment regimen, and the use of different bioanalytical methods to determine ADMA levels.…”

mentioning

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

View full text Add to dashboard Cite

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 ...

show abstract

“…Hipertansiyon ve tip 2 diabetes mellitusda vasküler disfonksiyon ve insülin direnci varlığının en erken belirteçlerinden birisi plazma ADMA düzeylerinde-ki yüksekliktir [46]. Renin-anjiotensin-aldesteron sistemi blokörleri tip 2 diabetes mellitus hastalarında ve esansiyel hipertansiyon hastalarında plazma ADMA seviyelerini düşürür [47,48]. Kronik böbrek hastalarında ACE inhibitörü ramipril ile anjiotensin reseptör antagonisti valsartan kıyaslanmış ve her iki ilacın da endotelyal disfonksiyonu iyileştirmede ve yükselmiş ADMA seviyelerini azaltmada eşit oranda etkin oldukları bulunmuştur [49].…”

Section: çEşitli Klinik Durumlarda Adma Ve öNemiunclassified

Metabolism of asymmetric dimethylarginine and its clinical significance

Erbil¹,

Kurt²,

Yaman³

et al. 2012

Turk J Bioch

View full text Add to dashboard Cite

ÖZETAsimetrik dimetilarjinin nitrik oksit sentaz enziminin endojen inhibitörüdür. Nitrik oksit endotel bağımlı vazodilatasyon, damar duvarındaki düz kas proliferasyonu, hücre-hücre etkileşimleri, platelet adezyon ve agregasyonunun inhibisyonu ile monosit adezyonu inhibisyonu gibi düzenleyici fonksiyonlara sahiptir. Arjinin amino asitinin modifiye bir formu olan asimetrik dimetilarjinin, metilenmiş proteinlerin proteolizi sonucu oluşur. Hücrede oluşan ve salınan net asimetrik dimetilarjinin miktarı, arjinin metilasyonu, metillenmiş arjinin içeren proteinlerin yıkımı, dimetilarjinin dimetilaminohidrolaz enzimi ile metabolizasyonu ve hücreden atılımı oranları arasındaki dengeye bağlıdır. Hücre içinde oluşan asimetrik dimetilarjininin neredeyse tamamı dimetilarjinin dimetilaminohidrolaz enzimi tarafından yıkılırken küçük miktardaki asimetrik dimetilarjinin, katyonik amino asit taşıyıcıları tarafından hücreden kan dolaşımına taşınır. Plazmaya geçen asimetrik dimetilarjinin ya böbreklerden değişime uğramadan idrar ile atılmakta ya da başlıca karaciğer ve böbrekte olmak üzere tekrar hücre içine alınarak dimetilarjinin dimetilaminohidrolaz enzimi tarafından metabolize edilmektedir. Plazma asimetrik dimetilarjinin seviyesi, çeşitli avantaj ve dezavantajları bulunması ile birlikte, yüksek performanslı sıvı kromatografisi, kütle spektrometresi ve ELISA ile ölçülebilir. Plazmadaki asimetrik dimetilarjininin biyolojik olarak aktif olup olmadığı kesin olarak bilinmemektedir. Ancak literatürde pek çok klinik durumda plazma asimetrik dimetilarjinin konsantrasyonunun yüksek olduğunu gösteren çalışmalar mevcuttur. Bölümümüzde yapılan klinik ve deneysel çalışmalarda da literatürle uyumlu olarak kronik böbrek hastalığı, hipertansiyon, endometriosis ve şizofreni hastalarında yüksek olarak bulunmuştur. Özellikle, nitrik oksit gibi, kardiyovasküler sistem üzerine birçok düzenleyici etkisi bulunan bir molekülün sentezini inhibe etmesi nedeni ile günümüzde yeni bir kardiyovasküler risk faktörü olarak değerlendirilmektedir. Endotel disfonksiyonuna yol açması ve endotel disfonksiyonun birçok hastalığın patogenezinde önemli olması, yakın gelecekte de asimetrik dimetilarjinin üzerine araştırmaların devam edeceğine işaret etmektedir. Anahtar Sözcükler: Asimetrik dimetilarjininin, nitrik oksit, dimetilarjinin dimetilaminohidrolaz, endotel disfonksiyonu Çıkar çatışması: Yazarların çıkar çatışması bulunmamaktadır. ABSTRACTAsymmetric dimethylarginine is an endogenous inhibitory of nitric oxide synthase enzyme. Nitric oxide has regulatory functions such as endothelial dependent vasodilatation, smooth muscle proliferation in vessel wall, cell-cell interactions, platelet aggregation and adhesion inhibition and monosit adhesion inhibition. Asymmetric dimethylarginine, a modified form of arginine amino acid, is produced by proteolysis of methylated proteins. Net amount of produced and released ADMA depends on the balance between arginine methylation, degradation of proteins containing methylated arginine and metabolism by the enzyme dimetilarjinin di...

show abstract

Angiotensin-Converting Enzyme Activity is Involved in the Mechanism of Increased Endogenous Nitric Oxide Synthase Inhibitor in Patients With Type 2 Diabetes Mellitus.

Cited by 74 publications

References 28 publications

Amelioration of Vascular Endothelial Dysfunction in Obstructive Sleep Apnea Syndrome by Nasal Continuous Positive Airway Pressure-Possible Involvement of Nitric Oxide and Asymmetric NG, NG-Dimethylarginine-

Amelioration of Vascular Endothelial Dysfunction in Obstructive Sleep Apnea Syndrome by Nasal Continuous Positive Airway Pressure-Possible Involvement of Nitric Oxide and Asymmetric NG, NG-Dimethylarginine-

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

Metabolism of asymmetric dimethylarginine and its clinical significance

Contact Info

Product

Resources

About