Melatonin prevents hypertension and increased asymmetric dimethylarginine in young spontaneous hypertensive rats

Nitric oxide (NO) deficiency is associated with development of hypertension. We examined whether melatonin protects against the blood pressure increase is because of the restoration of the NO pathway. Spontaneous hypertensive rats (SHR) and control normotensive Wistar Kyoto (WKY) rats aged 4 weeks were assigned to four groups (N=6 for each group): untreated SHR and WKY, melatonin-treated SHR and WKY. Melatonin-treated rats received 0.01% melatonin in drinking water for 8 wks. All rats were sacrificed at 12 wk of age. SHR had higher blood pressure than WKY, which melatonin prevented. Plasma asymmetric dimethylarginine (ADMA) levels were elevated in SHR, combined with a reduction in plasma L-arginine to ADMA ratio (AAR). In the kidney, L-arginine, ADMA, and AAR were not different between SHR and WKY rats, whereas L-citrulline level was increased in SHR. Melatonin decreased plasma ADMA level and restored plasma AAR. Renal dimethylarginine dimethylaminohydrolase (DDAH, ADMA-metabolizing enzyme) activity was lower in SHR than WKY rats, which melatonin therapy prevented. Also, melatonin elevated both L-arginine and ADMA but reduced L-citrulline level in the kidney in SHR, which was associated with the prevention of reduced renal argininosuccinate lyase (ASL) expression in SHR. Moreover, melatonin reduced the degree of oxidative damaged DNA product, 8- hydroxydeoxyguanosine (8-OHdG) immunostaining in SHR. The observed antihypertensive effects of melatonin in young SHR are because of the restoration of the NO pathway by reduction of plasma ADMA, restoration of plasma AAR, preservation of renal L-Arg availability, and attenuation of oxidative stress.     

Uncomplicated type 1 diabetes is associated with increased asymmetric dimethylarginine concentrations

CONTEXT: Asymmetric dimethylarginine (ADMA) has recently emerged as an independent risk marker for cardiovascular disease, but studies investigating the ADMA levels in type 1 diabetes mellitus (DM) are scarce. OBJECTIVE: We aimed to evaluate plasma ADMA, L-arginine concentrations, and L-arginine to ADMA ratio in uncomplicated type 1 diabetic patients and controls. DESIGN AND SUBJECTS: Forty patients with type 1 DM who did not have clinical evidence of vascular complications and 35 healthy controls were included in the study. RESULTS: Plasma ADMA concentrations were higher (2.6 +/- 1.9 vs. 1.7 +/- 0.7 micromol/liter, P < 0.01), and L-arginine levels were lower (79.3 +/- 22.6 vs. 89.6 +/- 19.4 micromol/liter, P < 0.05) in the diabetic group, compared with controls. The L-arginine to ADMA ratio was also lower in the diabetic group (38.7 +/- 17.1 vs. 62.0 +/- 27.9, P < 0.0001). In diabetic patients, logADMA correlated positively with body mass index (BMI) (P = 0.01), fasting blood glucose (P = 0.006), and low-density lipoprotein cholesterol (LDL-c) (P = 0.01) and negatively with high-density lipoprotein cholesterol (P = 0.03). L-arginine to ADMA ratio correlated negatively with BMI (P = 0.004), fasting blood glucose (P = 0.02), and LDL-c (P = 0.01) and positively with high-density lipoprotein cholesterol (P = 0.04). In controls, logADMA and L-arginine to ADMA ratio correlated with BMI and LDL-c (P < 0.05). In regression analysis, BMI predicted 15% variance of ADMA levels (P = 0.02). CONCLUSIONS: We demonstrated that ADMA increases and L-arginine to ADMA ratio decreases, even before the development of vascular complications in type 1 DM.     

Association between asymmetric dimethylarginine and indices of vascular function in patients with essential hypertension

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and is associated with endothelial dysfunction. The aim of the present study was to investigate the relationship between ADMA, indices of arterial stiffness, endothelial function and carotid artery intima-media thickness (IMT) in hypertension patients. Eighty middle-aged (47 ± 10 years) untreated patients with mild to moderate essential hypertension underwent routine physical examination, pulse wave analysis (PWA), measurement of aortic pulse wave velocity (PWV) and IMT. In PWA, administration of salbutamol and nitroglycerine was used to assess endothelium-dependent (EDV) and endothelium-independent vasodilation, respectively. In univariate analysis, ADMA was correlated with EDV (r = -0.26; p = 0.02) and IMT (r = 0.32; p = 0.007). In multiple regression analysis, ADMA was independently associated with the female gender, EDV, IMT and total cholesterol (R(2) = 0.30; p < 0.001). No correlation was detected between ADMA and augmentation index, central/brachial blood pressure or aortic PWV. In hypertension patients, ADMA is independently correlated with IMT and EDV. Thus, ADMA is a marker of endothelial dysfunction and intima-media thickening in patients with hypertension.     

Platelet sodium-proton exchange is increased in essential hypertension

Transmembrane sodium-hydrogen (Na+-H+) exchange was measured indirectly in human platelets as the amiloride-sensitive change in volume during incubation in isosmotic sodium propionate. After first establishing the reproducibility of the assay, we measured propionate-activated volume increases in platelets from 24 male essential hypertensive patients and 20 male normotensives. For the entire group, platelet Na+-H+ exchange was significantly (P less than 0.006) higher in hypertensives compared with normotensives. Unlike red blood cell (RDC) cation transport markers of hypertension, platelet Na+-H+ exchange was elevated in both black and white hypertensives. Na+-H+ exchange was significantly positively correlated with diastolic blood pressure and did not correlate significantly with age, body weight or body mass index. In addition, platelet Na+-H+ exchange did not correlate significantly with red blood cell lithium-sodium countertransport activity. Platelet Na+-H+ exchange deserves further study as a marker for pathophysiological abnormalities in human hypertension.     

Plasma endothelin is increased in early essential hypertension

Local vascular generation of endothelin-1 (ET-1) may contribute to elevated peripheral resistance in hypertension. We tested the hypothesis that immunoreactive ET production in the forearm circulation is increased in early essential hypertensive subjects. Ten young, previously untreated male patients with mild essential hypertension and no signs of target organ damage were compared with matched normotensive subjects in an outpatient setting. Arterial and venous samples were obtained from indwelling catheters in the brachial artery and the medial cubital vein, respectively. Samples were collected at baseline and after induction of endothelium-dependent (acetylcholine) vasodilation. Immunoreactive ET (ET) was measured after column extraction by a sensitive radioimmunoassay employing a C-terminal ET-1 antibody with negligible cross-reaction to big-ET. Individual recovery rates were determined for each sample.Basal ET was significantly higher in hypertensive than in normotensive subjects, both in venous and arterial samples (P < .01). This difference was also present after correction for recovery (P < .01). There was no significant difference between venous and arterial ET concentrations. Local vasodilation did not change arterial or venous ET levels. In conclusion, plasma ET is increased in young, untreated, essential hypertensive subjects with no signs of target organ damage. The increased circulating immunoreactive ET may point to a role for the peptide early in the development of high blood pressure.     

Asymmetric dimethylarginine is associated with carotid atherosclerosis in patients with essential hypertension

Abstract

This study was to assess the relationship between asymmetric dimethylarginine (ADMA) and carotid atherosclerosis in patients with essential hypertension. A total of 182 individuals with never-treated essential hypertension and 182 age-matched healthy controls were studied. Plasma ADMA levels, mean intima-media thickness (IMT) and plaque score were significantly greater in hypertensive patients than normotensive controls. ADMA was positively correlated with mean IMT. On multiple logistic regression analysis, ADMA was a crucial independent predictor of carotid plaque formation (plaque score ≥1.1). Our results suggest that increased levels of ADMA are associated with the development of carotid atherosclerosis in hypertensive patients.     

高血压病不同左室构型患者血清hs-CRP、ADMA水平变化及意义

目的 研究高血压病患者在不同左室构型组血清中高敏C反应蛋白(hs-CRP)及非对称性二甲基精氨酸(ADMA)水平,并探讨hs-CRP及ADMA在高血压病和高血压左室重构中的作用.方法 选取体检健康人员30例为对照组及轻中度高血压患者131例,根据左室质量指数(LVMI)和相对室壁厚度(RWT)将其分为4组:左室构型正常组、向心性重构组、向心性肥厚组、离心性肥厚组.应用乳胶增强免疫比浊法测定各组血清中hs-CRP水平,反相高效液相色谱法测定ADMA水平.结果 与对照组比较,高血压病组血清hs-CRP、ADMA升高(P ＜0.01);hsCRP水平随左室构型严重程度的增加而升高,而ADMA则无此规律.hs-CRP与LVMI及RWT呈正相关,ADMA与二者均不相关.结论 hs-CRP和ADMA均参与了高血压病的发生与发展,但只有hs-CRP参与了高血压左室构型的发生与发展.     

肾素-血管紧张素系统基因多态性与原发性高血压左心室肥厚关系的探讨

目的　探讨肾素 血管紧张素系统 (RAS)基因多态性与原发性高血压左心室肥厚 (EH LVH)的相关性以及在EH LVH产生中的多基因协同作用。方法　对 10 9例原发性高血压病 (EH)患者 ,采用聚合酶链反应 (PCR)以及聚合酶链反应 限制性片段长度多态性方法检测血液白细胞染色体DNA中血管紧张素转换酶 [ACE(I D) ]、血管紧张素原 [AGT(M2 35T) ]和血管紧张素Ⅱ 1型受体 [AT1 R(A116 6C) ]基因多态性 ;利用超声心动图检测左心室质量 (LVM)并计算左心室质量指数 (LVMI)。结果　ACE(I D)基因多态性D等位基因频率在EH LVH组中明显增高 (χ2 =4 .6 9,P=0 .0 30 ) ,男性EH患者中 ,ACE(I D)基因型构成比与LVH有关联 (χ2 =9.5 5 ,P =0 .0 0 8)。协同存在AGT TT型时 ,ACE(I D)基因多态性与EH LVH有关 (χ2 =6 .2 2 ,P =0 .0 4 4 ) ,且D等位基因在EH LVH明显增高 (χ2 =6 .91,P =0 .0 0 9) ,该类EH患者发生LVH的相对危险度增高 (OR :2 .5 0 ,95 %CI:1.2 5～ 5 .0 0 )。结论　ACE(I D)基因多态性D等位基因可能是LVH的独立危险因子。ACE基因多态性与AGT基因多态性之间的协同效应表明 ,同时携带AGT TT型时 ,具有ACE(I D)基因多态性D等位基因的EH患者更易发生LVH。     

Renin-angiotensin system blockade improves endothelial dysfunction in hypertension

Angiotensin-converting enzyme (ACE) inhibitor improves the impaired hyperpolarization and relaxation to acetylcholine (ACh) via endothelium-derived hyperpolarizing factor (EDHF) in arteries of spontaneously hypertensive rats (SHR). We tested whether the angiotensin type 1 (AT(1)) receptor antagonist also improves EDHF-mediated responses and whether the combined AT(1) receptor blockade and ACE inhibition exert any additional effects. SHR were treated with either AT(1) receptor antagonist TCV-116 (5 mg. kg(-1). d(-1)) (SHR-T), enalapril (40 mg. kg(-1). d(-1)) (SHR-E), or their combination (SHR-T&E) from 8 to 11 months of age. Age-matched, untreated SHR (SHR-C) and Wistar Kyoto (WKY) rats served as controls (n=8 to 12 in each group). Three treatments lowered blood pressure comparably. EDHF-mediated hyperpolarization to ACh in mesenteric arteries in the absence or presence of norepinephrine was significantly improved in all treated SHR. In addition, the hyperpolarization in the presence of norepinephrine was significantly greater in SHR-T&E than in SHR-E (ACh 10(-5) mol/L with norepinephrine: SHR-C -7; SHR-T -19; SHR-E -15; SHR-T&E -22; WKY -14 mV). EDHF-mediated relaxation, assessed in the presence of indomethacin and N:(G)-nitro-L-arginine, was markedly improved in all treated SHR. Hyperpolarization and relaxation to levcromakalim, a direct opener of ATP-sensitive K(+)-channel, were similar in all groups. These findings suggest that AT(1) receptor antagonists are as effective as ACE inhibitors in improving EDHF-mediated responses in SHR. The beneficial effects of the combined AT(1) receptor blockade and ACE inhibition appears to be for the most part similar to those of each intervention.     

Melatonin prevents increased asymmetric dimethylarginine in young rats with bile duct ligation

Abstract: Identifying and treating kidney injury in cirrhosis is important. Bile duct ligation (BDL) is a commonly used cholestatic liver disease model. We hypothesized that asymmetric dimethylarginine (ADMA) is involved in BDL‐induced oxidative stress and kidney injury, which can be prevented by melatonin. We also intended to elucidate whether increased ADMA is due to increased protein arginine methyltransferase‐1 (PRMT1, ADMA‐synthesizing enzyme) and/or decreased dimethylarginine dimethylaminohydrolase (DDAH, ADMA‐metabolizing enzyme). Three groups of young rats were studied, sham (N = 7), untreated BDL rats (N = 9), and melatonin‐treated BDL rats (N = 6, BDL + M). Melatonin‐treated BDL rats received daily melatonin 1 mg/kg/day via intraperitoneal injection. One‐third of the young BDL rats died compared with none in the BDL + M group. All surviving rats were killed 14 days after surgery. BDL rats had higher plasma aspartate aminotransferase, alanine aminotransferase, direct and total bilirubin, and ammonia levels than shams. They also had kidney injury characterized by increased tubulointerstitial injury scores and plasma creatinine and symmetric dimethylarginine levels, which melatonin prevented. Plasma ADMA levels were elevated in BDL rats, combined with increased hepatic PRMT1 and decreased renal DDAH activity. In addition, melatonin increased hepatic DDAH2 expression, increased DDAH activity and concomitantly decreased ADMA contents in both the liver and kidney. In conclusion, melatonin therapy decreased mortality and prevented kidney injury induced by BDL via reduction of ADMA (by increasing DDAH activity) and oxidative stress.     

Mild-to-moderate hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentrations of asymmetric dimethylarginine.

OBJECTIVES: The aim of this study was to investigate endothelial function and common carotid intima-media thickness (IMT) in healthy young men with mild-to-moderate hypertriglyceridemia. Plasma asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, was measured to further elucidate the mechanisms involved. BACKGROUND: Hypertriglyceridemia is a risk factor for coronary heart disease although the mechanisms behind the increased risk remain to be defined. Acute elevation of plasma triglycerides induced by an intravenous fat load is associated with impaired endothelial function. The results of studies examining acute effects induced by a high-fat meal or effects of chronic hypertriglyceridemia on endothelial function are more inconsistent. METHODS: Flow-mediated vasodilation and nitroglycerin-induced vasodilation of the brachial artery and common carotid IMT were measured noninvasively by ultrasound technique in 15 hypertriglyceridemic (HTG) subjects and 15 matched controls, mean age 34 years. Plasma concentrations of ADMA were measured by high-performance liquid chromatography. RESULTS: Flow-mediated vasodilation was decreased in the HTG group (p < 0.0001), whereas nitroglycerin-induced vasodilation and carotid IMT did not differ significantly. Asymmetric dimethylarginine concentrations were higher in the HTG group (p < 0.05). CONCLUSIONS: Hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentration of ADMA but not with increased IMT of the common carotid artery. The corollary is that chronic hypertriglyceridemia results in endothelial dysfunction, possibly due to increased ADMA concentration, and that endothelial dysfunction might precede increased IMT among the early manifestations of atherosclerosis.     

Increased serum ferritin is common in men with essential hypertension

OBJECTIVES : Insulin-resistance-associated hepatic iron overload syndrome (IRHIO) is characterized by high serum ferritin and presence of metabolic alterations that are part of insulin-resistance syndrome (IRS). Thus, clinical conditions characterized by a high prevalence of IRS may also be characterized by a high prevalence of IRHIO. DESIGN AND METHODS : We studied 88 consecutive patients with essential hypertension, 62 patients with IRHIO and 102 healthy normotensive controls. Hemochromatosis, other conditions able to induce secondary iron overload or serum ferritin increase unrelated to body iron stores were excluded. Iron indices, metabolic profiles and hepatic tests in hypertensive with or without increased serum ferritin and in IRHIO with and without hypertension were studied. Metabolic variables, serum iron indices, liver function tests and hepatic ultrasound data were analysed. Data were compared by non-parametric tests. RESULTS : In men with hypertension, increased serum ferritin was more frequent than in controls (21 versus 0%, P = 0.001). Hypertensive men with increased serum ferritin had more frequent and pronounced metabolic alterations than those with normal serum ferritin, the metabolic abnormalities and serum ferritin being frequently positively correlated. In hypertensive men with increased serum ferritin, metabolic and iron data were similar to those of IRHIO patients with hypertension. CONCLUSIONS : In males, hypertension is characterized by a higher prevalence of increased iron stores and metabolic abnormalities that are part of the IRHIO syndrome. This finding may have clinical implications due to the increased risk of IRHIO patients to develop hepatic cirrhosis and also for the role of iron in early atherogenesis.     

Effects of asymmetric dimethylarginine on renal arteries in portal hypertension and cirrhosis

AIM To evaluate the effects of asymmetric dimethylarginine(ADMA) in renal arteries from portal hypertensive and cirrhotic rats.METHODS Rat renal arteries from Sham(n = 15), pre-hepatic portal hypertension(PPVL; n = 15) and bile duct ligation and excision-induced cirrhosis(BDL; n = 15) were precontracted with norepinephrine, and additional contractions were induced with ADMA(10-6-10-3 mol/L), an endogenous inhibitor of nitric oxide(NO) synthase. Concentration-response curves to acetylcholine(1 × 10-9~(-3) × 10~(-6) mol/L) were determined in precontractedrenal artery segments with norepinephrine in the absence and in the presence of ADMA. Kidneys were collected to determine the protein expression and activity of dimethylarginine dimethylaminohydrolase(DDAH), an enzyme that catabolizes ADMA. RESULTS In renal arteries precontracted with norepinephrine, ADMA caused endothelium-dependent contractions. The pD 2 values to ADMA were similar in the Sham and PPVL groups(4.20 ± 0.08 and 4.11 ± 0.09, P 0.05, respectively), but were lower than those of the BDL group(4.79 ± 0.16, P 0.05). Acetylcholine-induced endothelium-dependent relaxation that did not differ, in terms of p D2 and maximal relaxation, among the 3 groups studied. Treatment with ADMA(3 × 10~(-4) mol/L) inhibited acetylcholine-induced relaxation in the 3 groups, but the inhibition was higher(P 0.05) in the BDL group compared with that for the Sham and PPVL groups. The m RNA and protein expression of DDAH-1 were similar in kidneys from the three groups. Conversely, DDAH-2 expression was increased(P 0.05) in PPVL and further enhanced(P 0.05) in the BDL group. However, renal DDAH activity was significantly decreased in the BDL group. CONCLUSION Cirrhosis increased the inhibitory effect of ADMA on basal- and induced-release of NO in renal arteries, and decreased DDAH activity in the kidney.