Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P50583 (asymmetrical)
 12,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Circulating urotensin (UTN) is increased in patients with heart failure and in patients with renal diseases, and UTN antagonism is currently considered as a potential treatment for these conditions. Contrary to this contention, studies in end-stage renal disease suggest that, perhaps because of interference with sympathetic and NO systems, UTN may be cardioprotective. Therefore, we investigated the relationship between circulating UTN and echocardiographic parameters of left ventricular function (midwall fractional shortening), left atrial volume, and myocardial geometry (mean wall thickness and relative wall thickness) in 191 patients with end-stage renal disease. UTN was associated directly (r=0.39; P<0.001) with left ventricular systolic function and inversely with left atrial volume (r=-0.40; P<0.001) and the muscular component of the left ventricular (UTN versus mean wall thickness: r=-0.30, P<0.001; UTN versus relative wall thickness: r=-0.32, P<0.001). Adjustment for a series of 11 risk factors produced a relatively small change in the strength of these relationships. However, further adjustment for plasma norepinephrine or, particularly so, for the endogenous inhibitor of NO synthase asymmetrical dimethyl arginine produced a 33% to 50% decrease in the strength of such associations. Of note, there was a strong UTN-asymmetrical dimethyl arginine interaction in determining midwall fractional shortening (P=0.001) and mean wall thickness (P=0.006). These data support the hypothesis that high UTN is cardioprotective in end-stage renal disease and that interference by UTN with sympathetic activity and NO synthesis represents an intermediate mechanism mediating the favorable echocardiographic profile of patients with high UTN. Additional mechanistic insights may be needed before launching long-term clinical trials with UTN antagonists in patients with end-stage renal disease.
Hypertension 2008 Feb
PMID:Urotensin II and cardiomyopathy in end-stage renal disease. 1808 53

Patients with chronic kidney disease frequently exhibit a sustained overactivity of the sympathetic nervous system (SNA) which is caused by neurohormonal mechanisms arising in the failing kidney. Additional potential mechanisms underlying SNA overactivity include increased levels of angiotensin II and asymmetrical dimethylarginine. Overactivity of the SNA contributes to hypertension and cardiovascular complications, and it is postulated to be a predictor of mortality in the presence of cardiovascular diseases such as asymptomatic left-ventricular dysfunction and chronic congestive heart failure. The activity of the SNA can be estimated by measurements of plasma and by spillover rates of norepinephrine (NE), microneurography (MSNA) in sympathetic muscle nerve fibers, and power spectral analysis of heart-rate and blood-pressure variability. An increase in SNA, as measured by MSNA, was found in many types of human hypertension. The pathogenesis of hypertension in renal failure is complex, and arises from the interaction of hemodynamic and neuroendocrine factors. The potential effect of erythropoietin treatment on SNA or baroreceptor activity is still unclear.
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PMID:Sympathetic overactivity in uremia. 1808 57

Telmisartan, in addition to blocking angiotensin (Ang) II type 1 receptor (AT(1)R), activates peroxisome proliferator activated receptor gamma (PPARgamma) signaling that interferes with nitric oxide (NO) system. Because aging of endothelial cells (ECs) is hallmarked by a reduction in NO synthesis, we hypothesized that telmisartan increases NO formation by regulated asymmetrical dimethylarginine (ADMA)-dimethylarginine dimethylaminohydrolase (DDAH)-system through blocking AT(1)R and activating PPARgamma signaling. To test this hypothesis, ECs were cultured with telmisartan, eprosartan, Ang II, and GW9662 (PPARgamma antagonist) until the twelfth passage. During the process of aging, PPARgamma protein expression decreased significantly, whereas the expression of AT(1)R increased. Telmisartan reversed these effects and dose-dependently decreased reactive oxygen species and 8-iso-prostaglandin (PG) F(2alpha) formation. This effect was associated with an upregulated activity and protein expression of DDAH, accompanied by a decrease in ADMA concentration, an increase in NO metabolites, and delayed senescence. Blockade of PPARgamma signaling by GW9662 or PPARgamma small-interference RNA prevented the effect of telmisartan on ADMA-DDAH-NO system. Coincubation with Ang II did not affect the effect of telmisartan-delayed senescence, whereas Ang II itself accelerated endothelial aging. Moreover, AT(1)R blocker eprosartan that did not influence PPARgamma protein expression had no effect on ADMA system and senescence. We have demonstrated that telmisartan mainly by activating PPARgamma signaling can alter the catabolism and release of ADMA as an important cardiovascular risk factor. We therefore propose that telmisartan translationally and posttranslationally upregulated DDAH expression via activation of PPARgamma signaling, causing ADMA to diminish and increase NO synthesis sufficient to delay senescence.
Hypertension 2008 Mar
PMID:Effect of telmisartan on nitric oxide--asymmetrical dimethylarginine system: role of angiotensin II type 1 receptor gamma and peroxisome proliferator activated receptor gamma signaling during endothelial aging. 1825 Mar 62

Environmental tobacco smoke (ETS) acutely affects peripheral and coronary vascular tone. Whether ETS exerts specific deleterious effects on aortic wave reflection through nicotine exposure, whether they persist after ETS cessation, and whether the smoke environment impairs microvascular function and increases asymmetrical dimethyl-arginine levels are not known. We tested these hypotheses in a randomized, crossover study design in 11 healthy male nonsmokers. The effects of 1 hour of exposure to ETS, as compared with a nontobacco smoke and normal air, on augmentation index corrected for heart rate and skin microvascular hyperemia to local heating were examined. Augmentation index increased both during (P=0.01) and after (P<0.01) the ETS session but remained unchanged in the nontobacco smoke session when compared with normal air. Nicotine levels after the exposure were related to the peak rise in augmentation index (r=0.84; P<0.01), denoting a predominant role of nicotine in ETS vascular effects. This was confirmed in a second set of experiments (n=14), where the sublingual administration of nicotine was associated with an acute impairment in wave reflection as compared with placebo (P=0.001). Both ETS and nontobacco smokes increased plasma asymmetrical dimethyl-arginine levels (P<0.001), but only ETS reduced the late rise in skin blood flow in response to heating (P=0.03). In conclusion, passive smoking specifically increases aortic wave reflection through a nicotine-dependent pathway and impairs microvascular function, even after the end of the exposure. However, both tobacco and nontobacco passive smoking inhalation increase plasma asymmetrical dimethyl-arginine levels.
Hypertension 2008 Jun
PMID:Acute effects of passive smoking on peripheral vascular function. 1900 Nov 86

Dimethylarginine dimethylaminohydrolase (DDAH) is an enzyme that metabolizes asymmetrical N(G),N(G)-dimethyl-L-arginine (ADMA) and N(G)-monomethyl-L-arginine (MMA), which are competitive endogenous inhibitors of NO synthase. However, it remains unknown whether NO itself influences DDAH activity and/or ADMA/MMA contents to regulate NO generation via a biofeedback mechanism. The present study was designed to examine the effects of NO on intracellular ADMA and MMA contents and DDAH gene expression levels and enzymatic activities in cultured rat aortic endothelial cells. The NO donors SNAP and NOR3 did not influence DDAH-1 expression but increased DDAH-2 mRNA and protein levels in concentration-dependent manners. SNAP upregulated DDAH enzymatic activity and reduced the MMA and ADMA contents but did not affect the symmetrical N(G),N'(G)-dimethyl-L-arginine and L-arginine levels, thereby negating a mediatory role for system y(+) in ADMA/MMA downregulation. The cGMP agonists 8-bromo-cGMP and C-type natriuretic peptide also stimulated DDAH-2 gene and protein expression levels and DDAH activity and increased the amount of nitrite/nitrate released into the culture supernatants. SNAP-induced DDAH-2 gene expression and DDAH activity were significantly inhibited by a protein kinase G inhibitor, KT5823, and a soluble guanylate cyclase inhibitor, ODQ, suggesting a mediatory role for cGMP in NO-induced DDAH-2 expression. Suppression of DDAH-2 mRNA using small interfering RNA technology abrogated NO-induced DDAH-2 expression. These data demonstrate that NO acts on endothelial cells to induce DDAH-2 expression via a cGMP-mediated process to reduce ADMA/MMA. Thus, the DDAH-2-ADMA/MMA-endothelial NO synthase regulatory pathway and NO-induced cGMP constitute a positive feedback loop that ultimately serves to maintain NO levels in the endothelial environment.
Hypertension 2008 Nov
PMID:Nitric oxide upregulates dimethylarginine dimethylaminohydrolase-2 via cyclic GMP induction in endothelial cells. 1882 64

Endogenous NO synthase inhibitors (end-NOSIs) have been associated with cardiovascular risk factors and atherosclerosis. In addition, end-NOSIs may directly cause hypertension through hemodynamic effects. We aimed to examine the association between end-NOSI asymmetrical dimethylarginine (ADMA) and N-guanidino-monomethyl-arginine (NMMA), subclinical atherosclerosis, and arterial hemodynamics. We studied 922 adults participating in a population-based study (PREVENCION Study) and examined the correlation between end-NOSI/L-arginine and arterial hemodynamics, carotid-femoral pulse wave velocity, and carotid intima-media thickness using linear regression. ADMA, NMMA, and L-arginine were found to be differentially associated with various classic cardiovascular risk factors. ADMA and NMMA (but not L-arginine) were significant predictors of carotid intima-media thickness, even after adjustment for cardiovascular risk factors, C-reactive protein, and renal function. In contrast, ADMA and NMMA did not predict carotid-femoral pulse wave velocity, blood pressure, or hemodynamic abnormalities. Higher L-arginine independently predicted systolic hypertension, higher central pulse pressure, incident wave amplitude, central augmented pressure, and lower total arterial compliance but not systemic vascular resistance or cardiac output. We conclude that ADMA and NMMA are differentially associated with cardiovascular risk factors, but both end-NOSIs are independent predictors of carotid atherosclerosis. In contrast, they are not associated with large artery stiffness, hypertension, or hemodynamic abnormalities. Our findings are consistent with a role for asymmetrical arginine methylation in atherosclerosis but not in large artery stiffening, hypertension, or long-term hemodynamic regulation. L-arginine is independently associated with abnormal pulsatile (but not resistive) arterial hemodynamic indices, which may reflect abnormal L-arginine transport, leading to decreased intracellular bioavailability for NO synthesis.
Hypertension 2008 Dec
PMID:Endogenous nitric oxide synthase inhibitors, arterial hemodynamics, and subclinical vascular disease: the PREVENCION Study. 1885 83

A 66-year-old Taiwanese aboriginal male had complained of right-side blurred vision for 2 months, especially when reading. He had a 10-year history of hypertension and cardiovascular disease. His best-corrected visual acuity was 20/25 in each eye. Ophthalmoscopy revealed asymmetrical cupping, but a normal disc. Humphrey perimetry showed an upper homonymous paracentral quadrantanopic defect. Brain magnetic resonance imaging showed an infarction in the left lower calcarine area over the extrastriate (V2/V3) cortical area and a narrowing of the left middle and posterior cerebral arteries due to severe arteriosclerosis.
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PMID:Homonymous central quadrantanopia caused by an extrastriate (v2/v3) infarction: a case report. 1892 58

A 83-year-old woman presented with a 25-year history of hypertension which was long-standing, uncontrolled, severe hypertension because of irregular oral administration of antihypertensive drug underwent an echocardiographic examination as part of an evaluation of hypertension. She described chest distress associated with activity, syncope for three times in the past one year. On physical examination, she was in no acute distress, with a regular pulse rate and blood pressure of 185/115 mmHg. On auscultation, her lung fields were clear. There was a III/VI late peaking crescendo/decrescendo systolic murmur along the left sternal border radiating to the apex, which increased with standing and Valsalva's maneuver and decreased with squatting. There was no report of provocative maneuvers performed during auscultation. There was no edema. Transthoracic echocardiography showed a hyperdynamic left ventricle with markedly increased left ventricular wall thicknesses and asymmetrical septal hypertrophy. M-mode echocardiography showed systolic anterior motion of the mitral valve apparatus and midsystolic closure of the aortic valve. A dynamic left ventricular outflow tract obstruction was present, with a resting maximal instantaneous gradient of 55 mmHg. With the Valsalva maneuver, the gradient increased to 114 mmHg. No any factors that could cause hypertension were found at kidney, adrenal gland and renal artery etc. by ultrasound and multislice compute tomography.
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PMID:Valsalva maneuver, uncontrolled hypertension, asymmetric septal hypertrophy and dynamic outflow obstruction: a case report. 1915 78

We assessed effect of antihypertensive drugs from various classes on humoral parameters of endothelial function - levels of asymmetrical dimethyl-arginine (ADMA) and metabolites of nitrous oxide (MNO) - in 106 patients with I-II degree arterial hypertension before and after 2 weeks of treatment. Two weeks treatment with various antihypertensive drugs did not lead to significant changes of ADMA levels. However antihypertensive drugs from various classes produced different effects on levels of MNO. Combination antihypertensive preparation indapamide and perindopril caused significant elevation of MNO level in patients with I-II degree arterial hypertension what appears to be indirect reflection of augmentation of nitrous oxide formation and improvement of endothelial function.
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PMID:[Effect of antihypertensive drugs on some humoral parameters of endothelial function]. 1946 32

The blood-brain barrier (BBB) impedes the influx of intravascular compounds from the blood to the brain. Few blood-borne macromolecules are transferred into the brain because vesicular transcytosis in the endothelial cells is considerably limited and the tight junction is located between the endothelial cells. At the first line of the BBB, the endothelial glycocalyx which is a negatively charged, surface coat of proteoglycans, and adsorbed plasma proteins, contributes to the vasculoprotective effects of the vessels wall and are involved in maintaining vascular permeability. In the endothelial cytoplasm of cerebral capillaries, there is an asymmetrical array of metabolic enzymes such as alkaline phosphatase, acid phosphatase, 5'-nucleotidase, adenosine triphosphatase, and nucleoside diphosphatase and these enzymes contribute to inactivation of substrates. In addition, there are several types of influx or efflux transporters at the BBB, such as P-glycoprotein (P-gp), multidrug resistance associated protein, breast cancer resistance protein, organic anion transporters, organic cation transporters, organic cation transporter novel type transporters, and monocarboxylic acid transporters. P-gp, energy-dependent efflux transporter protein, is instrumental to the barrier function. Several findings recently reported indicate that endothelial P-gp contributes to efflux of undesirable substances such as beta-amyloid protein from the brain or periarterial interstitial fluid, while P-gp likely plays a crucial role in the genesis of multiple vascular abnormalities that accompany hypertension. In this review, influx and efflux mechanisms of drugs at the BBB are also reviewed and how medicines pass the BBB to reach the brain parenchyma is discussed.
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PMID:Mechanisms of the penetration of blood-borne substances into the brain. 1994 73


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