Oral L-arginine improves endothelial function in healthy individuals older than 70 years

Ageing is associated with progressive endothelial dysfunction in normal humans. Flow-mediated dilation (FMD) of the brachial artery is impaired in elderly individuals with cardiovascular disease and vascular nitric oxide (NO) bioavailability is reduced. We investigated whether oral L-arginine, the substrate for NO synthesis, can improve impaired FMD in healthy very old people. In a prospective, double-blind, randomized crossover trial, 12 healthy old subjects (age 73.8 +/- 2.7 years) took L-arginine (8 g p.o. two times daily) or placebo for 14 days each, separated by a wash-out period of 14 days. FMD was determined by high-resolution ultrasound in the brachial artery during reactive hyperaemia. Baseline artery diameter was 3.88 +/- 0.18 mm. L-Arginine significantly improved FMD (to 5.7 +/- 1.2%, p < 0.0001), whereas placebo had no effect (-0.25 +/- 0.7%; n.s.). After L-arginine, plasma levels of L-arginine increased significantly (114.9 +/- 11.6 versus 57.4 +/- 5.0 micromol/l), but placebo had no effect. As NO synthesis can be antagonized by its endogenous inhibitor asymmetric dimethyl L-arginine (ADMA), we determined ADMA plasma concentrations, which were elevated at baseline in comparison to healthy middle-aged individuals (3.9 +/- 0.2 versus 1.0 +/- 0.1 micromol/l; p < 0.0001). ADMA remained unchanged during treatment, but L-arginine supplementation normalized the L-arginine/ADMA ratio (p < 0.05). We conclude that in healthy very old age endothelial function is impaired and may be improved by oral L-arginine supplementation, probably due to normalization of the L-arginine/ADMA ratio.     

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.

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 RESULTS: In 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, but the plasma ADMA concentration decreased inversely to %FMD and NOx. A negative correlation between %FMD and plasma ADMA concentration, and a positive correlation between %FMD and plasma NOx concentrations were observed. CONCLUSION: Nasal CPAP improves endothelial function, in part by the decreasing ADMA concentration, thereby potentiating NO production.     

Effect of rosuvastatin on plasma levels of asymmetric dimethylarginine in patients with hypercholesterolemia

Elevated plasma levels of asymmetric dimethylarginine (ADMA) have been associated with attenuated endothelium-dependent vasodilation in hypercholesterolemic patients. However, whether lowering of plasma cholesterol concentration by hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) can reduce plasma ADMA levels is still not clear. This study was a multicenter, randomized, double-blind, placebo-controlled design including 46 patients with elevated low-density lipoprotein cholesterol levels. Patients were randomized into 2 groups: rosuvastatin 10 mg/day and placebo for 6 weeks. Plasma levels of ADMA, 8-isoprostane (as a marker of oxidative stress), homocysteine, and high-sensitivity C-reactive protein were measured at baseline and 6 weeks later. Endothelial function assessed by flow-mediated vasodilation of the brachial artery was performed in 11 patients in the rosuvastatin group and in 12 in the placebo group. Baseline characteristics of both groups were similar, and the plasma ADMA levels were significantly correlated with 8-isoprostane (r = 0.388, p = 0.008). After 6 weeks of treatment, plasma ADMA levels were significantly reduced in the rosuvastatin group (from 0.60 +/- 0.19 to 0.49 +/- 0.10 micromol/L, p <0.001). Increases in flow-mediated vasodilation were positively correlated with reductions in plasma levels of ADMA (p = 0.017) and low-density lipoprotein cholesterol (p <0.001). Thus, our findings suggest that treatment with rosuvastatin in patients with hypercholesterolemia may lead to a significant reduction in plasma ADMA levels, which appear to be related to the improvement in endothelial function by rosuvastatin.     

Role of asymmetrical dimethylarginine in inflammation-induced endothelial dysfunction in human atherosclerosis

We explored the role of asymmetrical dimethylarginine (ADMA) as a cause of endothelial dysfunction induced by systemic inflammation. In vitro data suggest that ADMA bioavailability is regulated by proinflammatory stimuli, but it is unclear whether ADMA is a link between inflammation and endothelial dysfunction in humans. In study 1 we recruited 351 patients with coronary artery disease (CAD) and 87 healthy controls. In study 2 we recruited 69 CAD, 69 healthy, and 10 patients with rheumatoid arthritis, whereas in study 3, 22 healthy and 70 CAD subjects were randomly assigned to Salmonella typhii vaccination (n=11 healthy and n=60 CAD) or placebo (n=11 healthy and n=10 CAD). Circulating interleukin 6/ADMA and flow-mediated dilation (FMD) were measured at 0 and 8 hours. In study 1, ADMA was inversely correlated with FMD in healthy individuals and CAD patients (P<0.0001 for both). However, interleukin 6 was inversely correlated with FMD (P<0.0001) in healthy subjects but not in CAD patients. The positive correlation between ADMA and interleukin 6 was stronger in healthy (r=0.515; P<0.0001) compared with CAD (r=0.289; P=0.0001) subjects. In study 2, both patients with rheumatoid arthritis and CAD had higher interleukin 6 (P<0.0001) and ADMA (P=0.004) but lower FMD (P=0.001) versus healthy subjects. In study 3, vaccination increased interleukin 6 in healthy (P<0.001) and CAD (P<0.001) subjects. FMD was reduced in healthy subjects (P<0.05), but its reduction in CAD was borderline. Vaccination increased ADMA only in healthy subjects (P<0.001). Systemic, low-grade inflammation leads to increased ADMA that may induce endothelial dysfunction. This study demonstrated that ADMA may be a link between inflammation and endothelial dysfunction in humans.     

雌激素替代治疗对绝经后妇女血管内皮舒张功能的影响

为了探讨雌激素抗动脉粥样硬化和降低冠心病发病危险的机制 ,采用无创性高分辨超声法观察雌激素替代治疗对绝经后妇女血管内皮依赖性舒张功能的影响 ,于治疗前后测量血清雌二醇、一氧化氮和血脂水平。结果发现 ,绝经后妇女较绝经前妇女血清雌二醇和一氧化氮下降 (P <0 .0 0 1) ,肱动脉血流介导的舒张反应较绝经前明显下降 (3.84 %± 2 .18%比 10 .0 5 %± 3.18% ,P <0 .0 0 1) ;短期雌激素替代治疗后雌二醇和一氧化氮水平较治疗前极显著升高 (P <0 .0 0 1) ,肱动脉血流介导的舒张反应也显著改善 (9.16 %± 3.0 2 % ,P <0 .0 0 1) ,而雌激素替代治疗并未使血脂发生明显改善 (P >0 .0 5 )。相关分析发现肱动脉血流介导的舒张反应与雌二醇和一氧化氮呈正相关(r值分别为 0 .5 6 4和 0 .72 9,P <0 .0 0 1) ,与总胆固醇呈负相关 (r为 - 0 .36 9,P <0 .0 5 )。结果提示短期雌激素替代治疗可明显改善绝经后妇女内皮依赖性舒血管功能障碍 ,且与血脂的改善无关 ,可能与雌激素的直接血管保护作用有关。     

Long-term angiotensin-converting enzyme inhibition reduces plasma asymmetric dimethylarginine and improves endothelial nitric oxide bioavailability and coronary microvascular function in patients with syndrome X

Angiotensin-converting enzyme (ACE) inhibition has been shown to improve clinical myocardial ischemia in patients with syndrome X (angina pectoris, positive treadmill exercise test, normal coronary angiograms, and no evidence of coronary spasm). This study was conducted to investigate the effects of long-term ACE inhibitors on endothelial nitric oxide (NO) metabolism and coronary microvascular function in patients with syndrome X. After a 2-week washout period, 20 patients with syndrome X were randomized to receive either enalapril, an ACE inhibitor, 5 mg twice daily (n = 10) or placebo (n = 10) in a double-blind design for 8 weeks. Another 6 age- and gender-matched subjects with negative treadmill exercise tests were also studied as controls. Compared with control subjects, patients with syndrome X had significantly reduced coronary flow reserve, reduced plasma levels of nitrate and nitrite (NOx), and a reduced plasma L-arginine to asymmetric dimethylarginine (ADMA) ratio (an index of systemic NO metabolism), as well as reduced endothelial function. These patients also had increased plasma levels of ADMA, which is an endogenous inhibitor of NO synthase and of von Willebrand factor, a marker of endothelial injury. Baseline characteristics including exercise performance and coronary flow reserve were similar between enalapril and placebo groups. After an 8-week treatment period, exercise duration (p = 0.001) and coronary flow reserve (p = 0.001) significantly improved with enalapril but not with placebo. Enalapril treatment, but not placebo, reduced plasma von Willebrand factor (p = 0.03) and ADMA levels (p = 0.01) and increased NOx levels (p = 0.01) and the ratio of L-arginine to ADMA (p <0.01). In patients with syndrome X, the plasma NOx level was positively and ADMA level inversely correlated with coronary flow reserve before and after the treatment. In conclusion, long-term ACE inhibitor treatment with enalapril improved coronary microvascular function as well as myocardial ischemia in patients with syndrome X. This may be related to the improvement of endothelial NO bioavailability with the reduction of plasma ADMA levels.     

Long-term treatment with probucol improves endothelial function in patients with coronary artery disease.

Recent studies have shown that endothelial function is impaired in patients with coronary artery disease (CAD). Probucol has been recognized to have antioxidant properties as well as lipid-lowering effects, and may improve endothelial function. The aim of this study was to evaluate the effects of probucol on endothelial function in patients with CAD. We evaluated endothelial function, based on flow-mediated vasodilation during reactive hyperemia (FMD), and the intima-media thickness (IMT) of the common carotid artery using high resolution ultrasonography in patients either with (CAD group, n=26) or without CAD (Control group, n=12). We measured the serum cholesterol concentration, including the low-density lipoprotein cholesterol (LDL-cholesterol) concentration, and the plasma concentrations of homocyst(e)ine and asymmetric dimethylarginine (ADMA). Measurements of FMD and serum cholesterol were repeated after 3 months of probucol (500 mg/day, n=9) or placebo (n=9) treatment in patients with CAD. The IMT was significantly greater (p < 0.001) and FMD was significantly lower (p < 0.001) in the CAD group than in the Control group. While the serum cholesterol concentration and plasma ADMA were similar in the two groups, the plasma homocyst(e)ine concentrations were higher in the CAD group than in the Control group (p < 0.01). After probucol therapy, FMD was significantly improved in the CAD group (p < 0.05). The serum LDL-cholesterol concentration did not significantly decrease after probucol treatment. Placebo treatment did not alter FMD or the serum cholesterol concentration. Our findings suggest that long-term treatment with probucol improves endothelial function in patients with CAD, an outcome independent of the LDL-cholesterol-lowering effects of probucol, and that homocyst(e)ine may be a better predictor of atherosclerosis than ADMA.     

Transient endothelial dysfunction following flow-mediated dilation assessment

Flow-mediated dilation (FMD) is a widely used tool to investigate endothelial function. However, FMD assessment may cause mechanical damage to the arterial endothelium. In this study we investigated the effect of FMD assessment on endothelial function. We studied 20 healthy subjects (26 ± 6 years; 12 males). FMD was assessed by measuring brachial artery dilation in response to hyperemia after 5 min of forearm cuff inflation. Subjects were studied on 2 subsequent days. On day 1 they underwent two consecutive FMD measures, with the second test (FMD2) performed 15 min after the first test (FMD1). On day 2, the subjects were randomized to receive either placebo (saline) or intravenous l-arginine (10 g in 20 min). At the end of the infusion, patients underwent two consecutive FMD measures following the same protocol as on day 1. Asymmetric dimethyl-arginine (ADMA) serum levels were assessed on day 2 before FMD1 and FMD2. On day 1, FMD2 was lower than FMD1 in both groups (placebo 6.47 ± 2.1 vs. 7.86 ± 1.8%, P < 0.01; arginine 6.13 ± 2.6 vs. 7.76 ± 2.7%, P < 0.01). On day 2, a significant reduction of FMD was observed during FMD2 compared to FMD1 in the placebo group (5.82 ± 1.7 vs. 7.44 ± 2.2%, P < 0.001), but not in the arginine group (7.19 ± 1.5 vs. 7.27 ± 1.5, P = 0.67). ADMA levels significantly increased compared to baseline after FMD1 (0.59 ± 0.12–0.91 ± 0.64 μmol/l, P = 0.036), with similar changes in the two groups. FMD assessment induces a significant impairment of endothelial function. An increase of endogenous NO synthesis inhibitors seems responsible for the phenomenon that is reversed by l-arginine administration.     

高血压对冠心病患者血管内皮功能影响的研究

目的　探讨高血压对冠心病患者血管内皮功能的影响。方法　通过检测 38例单纯冠心病患者 (A组 )、5 2例冠心病合并高血压病患者 (B组 )、12例健康对照组 (C组 )的肱动脉舒张功能 :反应性充血后血管舒张 (FMD)、含服硝酸甘油后的血管舒张 (NID)及血内皮素 (ET)、一氧化氮 (NO)等指标并进行对比分析。结果　 (1)FMD、ET :A、B组较C组均有显著差异 (均P <0 0 1) ;(2 )NO :B组较C组明显降低 (P >0 0 5 ) ;(3)A、B组间 :FMD、ET、NO均有显著差异 (均P <0 0 5 ) ;(4 )NID在三组间无差异 (P <0 0 5 ) ;(5 )FMD :与NO呈正相关 (r=0 4 3,P <0 0 1) ,与SBP、LDL、ET呈负相关(r =- 0 5 2、- 0 36和 - 0 4 7,均P <0 0 1) ;SBP :与LDL、ET呈正相关 (r =0 2 5和 0 4 2 ,P <0 0 5 ) ,与NO呈负相关 (r<- 0 31,P <0 0 1)。结论　冠心病患者存在显著的内皮依赖性舒张功能障碍 ;高血压病加重冠心病患者的内皮依赖性舒张功能障碍 ;FMD与NO、ET均可作为反映冠心病和高血压病者血管内皮功能的无创指标。     

Effects of chronic cigarette smoking on endothelial function in young men

The aim of this study was to elucidate endothelial dysfunction due to chronic cigarette smoking in young smokers and to determine practical markers of the functional derangement. The subjects were young, healthy, male non-smokers (n=11) and smokers (n=9). Endothelium-dependent and -independent vasodilation was assessed by flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID), respectively, and possible markers of endothelial function were measured. FMD in smokers was significantly lower than in control subjects (5.0 ± 2.6% and 9.5 ± 5.2%, p<0.05). Plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator levels were significantly (p<0.05) higher in smokers (6.7 ± 4.5 ng/ml and 4.3 ± 2.0 ng/ml) compared with control subjects (2.9 ± 1.9 ng/ml and 3.0 ± 0.6 ng/ml). Furthermore, PAI-1 levels correlated inversely with FMD (r=-0.451, p<0.05). No significant differences were observed for NID, or plasma NO(2)(-), NO(X), thrombomodulin, von Willebrand factor, and tissue factor pathway inhibitor levels. Chronic cigarette smoking-induced endothelial dysfunction and the PAI-1 level could be a good marker of endothelial dysfunction in young smokers.     

Increased levels of asymmetric dimethylarginine in populations at risk for atherosclerotic disease. Effects of pravastatin

The aim of the present study was to investigate plasma levels of asymmetric dimethylarginine (ADMA), an important endogenous inhibitor of nitric oxide synthase, in populations at high risk for atherosclerosis as compared to healthy controls, and furthermore to evaluate the effect of cholesterol lowering therapy in individuals with hypercholesterolemia. The present study consisted of 32 men with untreated hypercholesterolemia (HC group), 38 individuals with well-controlled insulin-dependent diabetes mellitus (DM group) and 20 healthy individuals (controls). The HC subjects were randomly allocated into a double blinded, placebo-controlled cross-over designed study with 8 weeks treatment with pravastatin (40 mg/day) or matching placebo. ADMA levels were statistically significantly higher in DM and HC individuals as compared to controls (P<0.001 for both), and the L-arginine/ADMA ratios were significantly lower in both groups (P<0.001 and P<0.005, respectively). Significant reductions in total cholesterol (TC) and LDL-C levels on pravastatin were obtained (P<0.001 for both), whereas no changes were observed in the levels of ADMA or the L-arginine/ADMA ratios. Statistically significant correlations between ADMA and TC and LDL-C were found (r=0.41, P<0.001 for both). In conclusion, significantly elevated ADMA levels and reduced L-arginine/ADMA ratios were found in individuals with diabetes type-1 as well as in hypercholesterolemia. Treatment with pravastatin 40 mg/day for 8 weeks had no effect on the levels of ADMA in hypercholesterolemic men.     

围产期高盐饮食对雄性子代大鼠肠系膜动脉DDAH2/ADMA/eNOS/NO通路的影响

目的探讨围产期高盐饮食对雄性子代大鼠肠系膜动脉二甲基精氨酸二甲胺水解酶2(DDAH2)/非对称性二甲基精氨酸(ADMA)/内皮型一氧化氮合酶(e NOS)/一氧化氮(NO)通路的影响。方法实验大鼠分为2组:正常饮食(NSD)组和高盐饮食(HSD)组,分别在围产期以普通饲料(含1%Na Cl)和高盐饲料(含8%Na Cl)喂养,分娩后雄性子鼠继续相同饲料喂养至16周。测量子鼠血压,检测肠系膜动脉内皮依赖性舒张功能,检测血浆和肠系膜动脉NO含量、e NOS活性、ADMA含量,检测肠系膜动脉DDAH2活性及DDAH1和DDAH2蛋白质表达水平。结果 16周时,HSD组收缩压显著高于NSD组(P0.01)。HSD组大鼠肠系膜血管张力低于NSD组(P0.01);用ADMA孵育血管环后,NSD组血管张力显著减弱,而HSD组未见显著性变化。与NSD组比较,HSD组血浆NO含量降低(P0.05),e NOS活性降低(P0.01),ADMA含量增加(P0.05);HSD组肠系膜动脉NO含量下降(P0.01),e NOS活性下降(P0.01),ADMA含量升高(P0.05)。HSD组DDAH2活性降低(P0.01),DDAH2蛋白质表达显著降低(P0.01);DDAH1蛋白质表达未见显著改变。HSD组肠系膜动脉指标相关性分析:e NOS活性与NO含量呈正相关,ADMA含量与e NOS活性呈负相关,DDAH2活性、DDAH2蛋白质表达与ADMA含量呈负相关。结论母体围产期高盐饮食导致其雄性子代收缩压增高,肠系膜动脉内皮依赖性舒张功能障碍,此与肠系膜动脉DDAH2表达下降、活性降低和DDAH2/ADMA/e NOS/NO通路障碍有关。     

血清非对称性二甲基精氨酸在非酒精性脂肪性肝病大鼠模型肝脏炎症活动进程中的变化

目的利用非酒精性脂肪性肝病(NAFLD)大鼠模型观察血清非对称性二甲基精氨酸(ADMA)在NAFLD炎症进程的变化。方法肝组织标本及血清标本分别来自实验组高脂乳剂灌胃法成功构建的NAFLD模型(M组)及同期生理盐水灌胃替代构建的正常对照组(C组)。分别检测M组4、8、12周(M4、M8、M12)和C组12周(C12)大鼠血清ALT、ADMA水平及肝组织匀浆一氧化氮(NO)水平,同期评估各组肝脂肪炎症进程积分(NAS)。数据服从正态分布且方差齐,多组间比较应用单因素方差分析,进一步两两比较应用LSD-t法;服从正态分布且方差不齐,多组间比较应用Kruskal-Wallis H检验;相关性分析应用Pearson相关法。结果与C12组相比,M12组大鼠血清ALT、ADMA水平及肝组织匀浆NO水平显著升高,差异有统计学意义(P值分别为0.010、0.001、0.001)。血清ADMA与ALT水平无明显相关性(r=0.195,P=0.228),与肝组织匀浆NO水平、大鼠NAS呈正相关(r=0.631,P0.001;r=0.782,P0.001)。结论 NAFLD大鼠血清ADMA水平随肝组织脂肪炎症活动进程的加重而逐渐升高,且与肝组织炎症损伤因子NO水平、NAS呈正相关。ADMA作为一种新的炎症因子用于评估NAFLD肝组织慢性炎症程度值得进一步研究证实。     

Assessment of ADMA,estradiol, and progesterone in severe preeclampsia

Background: Decreased nitrous oxide (NO) levels are crucial factors in severe preeclampsia (sPE), and asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthetase. Steroid hormones are closely related to the vascular endothelium. This study determined the levels of and correlations between ADMA, estradiol (E2), and progesterone (Pg) in sPE to investigate the roles of these factors in this disease. Methods: Sixty-two sPE patients (sPE group) were divided into the sPE1 subgroup (28⁺¹–32⁺⁰ weeks of pregnancy), the sPE2 subgroup (32⁺¹–36⁺⁰ weeks), and the sPE3 subgroup (36⁺¹–40⁺⁰ weeks) and 75 normal pregnant women (NC group) were divided into the NC1 subgroup (28⁺¹–32⁺⁰ weeks of gestation), the NC2 subgroup (32⁺¹–36⁺⁰ weeks), and the NC3 subgroup (36⁺¹–40⁺⁰ weeks). Serum and placental ADMA levels were measured by enzyme-linked immunosorbent assay (ELISA), and serum E2 and Pg concentrations were determined by the chemilumineseent immunoassay (CLIA). Results: ADMA concentrations in both the placenta and the maternal serum were significantly higher in the sPE group (p < 0.05). Higher ADMA contents were observed in the placenta relative to the maternal serum (p < 0.05). Serum E2 levels were significantly lower in the sPE group (p < 0.05). For Pg, the only significant difference was observed between the sPE1 and NC1 subgroups (p < 0.05). The Pg/E2 ratios in the sPE groups were significantly higher, with a significant high positive correlation between Pg/E2 ratios and serum ADMA levels. Conclusion: Increased serum levels of ADMA in sPE may result from increased secretion from the placenta, and the increased Pg/E2 ratio may play a role in the development of sPE by aggravating ADMA.     

Plasma asymmetric dimethylarginine (ADMA) levels and atherosclerotic disease in ankylosing spondylitis: a cross-sectional study

Conclusive data about the prevalence of endothelial dysfunction and atherosclerotic process in ankylosing spondylitis (AS) patients with respect to the general population are lacking. Elevated plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, have been reported in clinical conditions associated with endothelial dysfunction and atherosclerotic disease. We performed a cross-sectional study to evaluate plasma ADMA levels and atherosclerotic disease in AS patients. Seventeen consecutive AS patients free of any cardiovascular disease and 17 healthy controls [strictly matched for sex, age (±5 years) and atherosclerotic risk factors] were recruited. Plasma ADMA levels were assessed by capillary electrophoresis. Common carotid artery intima–media thickness (CCA-IMT), flow-mediated dilatation (FMD) and arterial stiffness (aS) were registered as surrogate markers of atherosclerotic disease. Plasma ADMA levels appeared significantly (p = 0.001) higher in AS patients (0.65 ± 0.10 μmoli/L) than in the control subjects (0.54 ± 0.07 μmoli/L) while no statistically significant differences between AS and controls were demonstrated in CCA-IMT, FMD, and aS. AS patients showed increased plasma ADMA levels with respect to control subjects. On the contrary, we were not able to document a significant difference in atherosclerotic process between patients and controls.     

Phytoestrogens do not influence lipoprotein levels or endothelial function in healthy, postmenopausal women

Plant estrogen or phytoestrogens (PE) are increasingly consumed for the purposes of menopause symptom relief and prevention of cardiovascular and other diseases. The objective of this study was to evaluate the effects of PE on plasma lipids and lipoproteins and on endothelial function. Twenty healthy, postmenopausal women, 50 to 70 years old, and with evidence of endothelial dysfunction, were treated with a soybean PE tablet of 80 mg/day of isoflavones. Endothelial function was assessed noninvasively using brachial ultrasound. A double-blind, placebo-controlled, randomized crossover design was employed. After 3 weeks stabilization on a standard fat-reduced diet, subjects received PE or placebo for 8 weeks in random order, separated by a washout period of 8 weeks. Compared with placebo, there were no significant effects of PE on blood pressure and plasma lipid or lipoprotein concentrations. Flow-mediated endothelium-dependent dilation (FMD) in response to reactive hyperemia was not significantly changed by PE ingestion (3. 3 +/- 0.7% on placebo vs 4.1 +/- 0.7% on PE, p >0.4). Variation in FMD was not correlated with change in plasma isoflavone concentration (r = -0.09, p >0.7). Glyceryl trinitrate endothelium-independent dilation was not significantly changed with PE (15.9 +/- 1.3% vs 13.7 +/- 1.2%, p >0.1). These results fail to show a significant impact of medium-term supplementation with 80 mg/day of isoflavones on lipid and lipoprotein levels or on endothelial function in healthy, postmenopausal women.     

Unchanged plasma levels of dimethylarginines and nitric oxide in chronic hepatitis C

Objective. Previous studies have shown that asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and nitric oxide (NO) play a prominent role in liver dysfunction. The objective of this study was to determine whether plasma levels of ADMA, SDMA and NO are altered in patients with chronic hepatitis C. Material and methods. Plasma levels of ADMA, SDMA and NO (nitrite plus nitrate) were measured in 22 patients with chronic hepatitis C and 24 patients with sustained virologic response after treatment with peginterferon plus ribavirin. Seven healthy volunteers served as controls. Results. Plasma levels of ADMA, SDMA and NO were not significantly different between groups: chronic hepatitis C, ADMA 0.55±0.06, SDMA 0.22±0.03, NO 36.3±5.9 µmol/l; treated patients, ADMA 0.60±0.15, SDMA 0.31±0.05, NO 36.1±5.5 µmol/l; controls, ADMA 0.65±0.08, SDMA 0.28±0.05, NO 40.7±8.9 µmol/l). Conclusions. Our results show that plasma NO, ADMA and SDMA concentrations are not changed in patients with chronic hepatitis C without superimposed signs of acute inflammatory activity. Furthermore, no significant differences in plasma values of NO and dimethylarginines were observed between the group of untreated patients and the group of patients treated with interferon plus ribavirin     

Significance of asymmetric dimethylarginine (ADMA) concentrations during coronary circulation in patients with vasospastic angina.

The basal activity of nitric oxide (NO) is reduced in spastic arteries of patients with vasospastic angina (VSA). Elevated concentrations of ADMA are associated with reduced NO production and impaired endothelium-dependent vasodilatation. The aim of this study was to elucidate the role of ADMA and its relationship to NO end-products (NOx; nitrate + nitrite) during coronary circulation in patients with VSA. The plasma ADMA and NOx concentrations during coronary circulation were evaluated in 16 VSA and 16 control patients. Blood samples were obtained from the coronary sinus (V) and the ostium of the left coronary artery (A), and the (V-A) differences of ADMA and NOx were determined. The coronary sinus plasma ADMA concentration in patients with VSA was higher than that in the control. The coronary sinus - arterial (V-A) difference of NOx was negative in the VSA group and approximately zero in the control group (VSA group =-1.4 micromol/L, control group =-0.1 micromol/L, p=0.0005). Furthermore, in the VSA patients, there was a negative correlation between the (V-A) difference of NOx and the basal coronary artery tone at the site of spasm (r=-0.60, p=0.015). A significant negative correlation between the (V-A) differences of NOx and ADMA was observed in patients with VSA (r=-0.52, p<0.05), but not in those of the control. Higher ADMA concentrations might cause the reduced formation of NO that underlies the pathophysiology of coronary vasospasm.     

Elevated plasma concentration of asymmetric dimethylarginine that is reduced by single dose testosterone administration in idiopathic hypogonadotropic hypogonadism patients

Our aim was to investigate whether plasma l-arginine and asymmetric dimethylarginine (ADMA) concentrations and nitric oxide (NO) production are altered in male idiopathic hypogonadotropic hypogonadism (IHH) patients in the hypogonadal state and after single dose testosterone administration compared with those in control subjects. Eighteen newly diagnosed male patients with IHH and 20 healthy volunteer controls matched by age and body mass index were enrolled in the study. Single dose testosterone was administrated im. Initially, pretreatment blood samples were collected after overnight fasting. Posttreatment blood samples were drawn 10 d after the injection. ADMA, l-arginine, and NO were measured in pre- and posttreatment blood samples. The pretreatment ADMA and l-arginine levels were significantly higher, and plasma nitrite plus nitrate (NOx) levels were lower than those in the control group. After 10 d of treatment, ADMA and l-arginine levels were significantly reduced, and NOx levels were significantly increased. There was a significant positive correlation (P < 0.01) between ADMA and l-arginine and a negative correlation between ADMA and NOx levels in patients and controls. In conclusion, the patients with IHH showed elevated plasma ADMA levels associated with a reduction in NO production. Single dose parenteral T administration lowered ADMA concentrations and increased NO production to the control group values.     

Role of PGI2 in the formation and maintenance of hyperdynamic circulatory state of portal hypertensive rats

AIM: To investigate the role of prostacyclin (PGI2) and nitric oxide (NO) in the development and maintenance of hyperdynamic circulatory state of chronic portal hypertensive rats. METHODS: Ninety male Sprague-Dawley rats were divided into three groups: intrahepatic portal hypertension (IHPH) group by injection of CCI4, prehepatic portal hypertension (PHPH) group by partial stenosis of the portal vein and sham-operation control (SO) group. One week after the models were made, animals in each group were subdivided into 4 groups: saline controlled group (n = 23), Nω-nitro-L-arginine (L-NNA)group (n = 21) group, indomethacin (INDO) group (n = 22) and high-dose heparin group (n = 24). The rats were administrated 1mL of saline, L-NNA (3.3 mg/kg-d) and INDO (5 mg/kg·d) respectively through gastric tubes for one week/then heparin (200 IU/Kg/min) was given to rats by intravenous injection for an hour. Splanchnic and systemic hemodynamics were measured using radioactive microsphere techniques. The serum nitrate/nitrite(NO2-/NO3-) levels as a marker of production of NO were assessed by a colorimetric method, and concentration of 6-keto-PGF1α, a stable hydrolytic product of PGI2, was determined by radioimmunoassay. RESULTS: The concentrations of plasma 6-keto-PGFla (pg/mL) and serum NO2-/NO3- (μmol/L) in IHPH rats (1123.85±153.64, 73.34±4.31) and PHPH rats (891.88±83.11, 75.21±6.89) were significantly higher than those in SO rats (725.53±105.54, 58.79±8.47) (P<0.05). Compared with SO rats, total peripheral vascular resistance (TPR) and spanchnic vascular resistance (SVR) decreased but cardiac index (CI) and portal venous inflow (PVI) increased obviously in IHPH and PHPH rats (P<0.05). L-NNA and indomethacin could decrease the concentrations of plasma 6-keto-PGFla and serum NO2/7NO3-in IHPH and PHPH rats (P<0.05) .Meanwhile, CI, FPP and PVI lowered but MAP, TPR and SVR increased(P<0.05). After deduction of the action of NO, there was no significant correlation between plasma PGI2 level and hemodynamic parameters such as CI, TPR, PVI and SVR. However, after deduction of the action of PGI2, NO still correlated highly with the hemodynamic parameters, indicating that there was a close correlation between NO and the hemodynamic parameters. After administration of high-dose heparin, plasma 6-keto- concentrations in IHPH, PHPH and SO rats were significantly higher than those in rats administrated vehicle (P<0.05). On the contrary, levels of serum NO2-/NO3- in IHPH, PHPH and SO rats were significantly lower than those in rats administrated Vehicle (P<0.05). Compared with those rats administrated vehicle, the hemodynamic parameters of portal hypertensive rats, such as CI and PVI, declined significantly after administration of high-dose heparin (P<0.05), while TPR and SVR increased significantly (P<0.05). CONCLUSION: It is NO rather than PGI2 that is a mediator in the formation and maintenance of hyperdynamic circulatory state of chronic portal hypertensive rats.