Improvement of endothelial function and insulin sensitivity with vitamin C in patients with coronary spastic angina: possible role of reactive oxygen species

OBJECTIVES

This study was designed to examine the effect of antioxidant supplementation on the endothelial function and insulin sensitivity in patients with coronary spastic angina (CSA).

BACKGROUND

Insulin resistance may play a key role in coronary heart disease, and there is a possible link between acetylcholine-induced coronary vasoconstriction and hyperinsulinemia in patients with CSA. Endothelial dysfunction is present in the systemic arteries in CSA patients, and reactive oxygen species may cause inactivation of nitric oxide in these patients.

METHODS

We measured flow-mediated dilation of the brachial artery using ultrasound technique in 22 patients with CSA and 20 control subjects. We also evaluated glucose tolerance using a 75-g oral glucose tolerance test and insulin sensitivity using steady-state plasma glucose (SSPG) methods in the same patients.

RESULTS

The incidence of impaired glucose tolerance was higher in the CSA group than in the control group. Vitamin C infusion augmented flow-mediated dilation and decreased SSPG levels in the CSA group (from 3.27 ± 0.77% to 7.00 ± 0.59% [p < 0.001 by analysis of variance (ANOVA)] and from 177.3 ± 13.3 to 143.1 ± 14.9 mg/dl [p = 0.047 by ANOVA], respectively) but not in the control group (from 6.47 ± 0.66% to 6.80 ± 0.60% and from 119.8 ± 11.7 mg/dl to 118.1 ± 11.3 mg/dl, respectively). The steady-state plasma insulin levels were not affected by vitamin C infusion in either group.

CONCLUSIONS

Vitamin C improves both endothelial function and insulin sensitivity in patients with CSA. Thus, reactive oxygen species and/or decreased nitric oxide bioactivity may play an important role in the genesis of both endothelial dysfunction and insulin resistance in patients with CSA.     

Evidence against a role for NADPH oxidase modulating hepatic vascular tone in cirrhosis

BACKGROUND & AIMS: Increased hepatic vascular resistance in cirrhosis is in part due to reduced nitric oxide (NO) bioavailability. This is related to insufficient NO synthesis from endothelial nitric oxide synthase and to enhanced NO scavenging by superoxide radicals (O(2)(-)). Nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase is an important source of O(2)(-) that increases vascular tone in different cardiovascular disorders. Thus, our aims were to study the molecular and biochemical state of NADPH-oxidase in cirrhotic livers and to investigate its possible role in modulating hepatic vascular tone in cirrhosis. METHODS: NADPH-oxidase expression and enzymatic activity were determined in control (n = 8) and CCl(4)-cirrhotic (n = 8) rat livers. Additional control (n = 6) and CCl(4)-cirrhotic (n = 10) rats were treated with apocynin (a selective NADPH-oxidase inhibitor) or its vehicle. Mean arterial pressure, portal pressure, and superior mesenteric arterial blood flow were measured in vivo. Moreover, hepatic endothelial function was evaluated in isolated and perfused rat livers by dose-response curves to acetylcholine. In addition, in 6 control and 6 cirrhotic human livers NADPH-oxidase activity and expression were evaluated. RESULTS: Rat cirrhotic livers had no increased NADPH-oxidase protein expression or activity in relation to control livers. NADPH-oxidase inhibition did not modify splanchnic or systemic hemodynamics in control or cirrhotic rats and did not improve the impaired endothelial-dependent vasodilatory response to acetylcholine of cirrhotic livers. Human cirrhotic livers also did not exhibit increased NADPH-oxidase expression or activity. CONCLUSIONS: Our study shows that NADPH-oxidase activity is decreased in the cirrhotic livers and therefore cannot explain increased hepatic O(2)(-), endothelial dysfunction, and increased vascular tone in cirrhotic livers.     

Arsenic moiety in gallium arsenide is responsible for neuronal apoptosis and behavioral alterations in rats

Gallium arsenide (GaAs), an intermetallic semiconductor finds widespread applications in high frequency microwave and millimeter wave, and ultra fast supercomputers. Extensive use of GaAs has led to increased exposure to humans working in semiconductor industry. GaAs has the ability to dissociate into its constitutive moieties at physiological pH and might be responsible for the oxidative stress. The present study was aimed at evaluating, the principle moiety (Ga or As) in GaAs to cause neurological dysfunction based on its ability to cause apoptosis, in vivo and in vitro and if this neuronal dysfunction translated to neurobehavioral changes in chronically exposed rats. Result indicated that arsenic moiety in GaAs was mainly responsible for causing oxidative stress via increased reactive oxygen species (ROS) and nitric oxide (NO) generation, both in vitro and in vivo. Increased ROS further caused apoptosis via mitochondrial driven pathway. Effects of oxidative stress were also confirmed based on alterations in antioxidant enzymes, GPx, GST and SOD in rat brain. We noted that ROS induced oxidative stress caused changes in the brain neurotransmitter levels, Acetylcholinesterase and nitric oxide synthase, leading to loss of memory and learning in rats. The study demonstrates for the first time that the slow release of arsenic moiety from GaAs is mainly responsible for oxidative stress induced apoptosis in neuronal cells causing behavioral changes.     

定志小丸对东莨菪碱所致小鼠学习记忆障碍的影响及机制

目的:研究经典古方定志小丸(由石菖蒲、远志、茯苓、人参按2∶2∶3∶3比例组成)对东莨菪碱所致小鼠学习记忆障碍的影响及可能的作用机制.方法:将小鼠随机分为正常组、模型组、阳性对照组(石衫碱甲0.05 mg·kg-1)、定志小丸高、中、低剂量组(700,350,175 mg·kg-1),连续灌胃7d后,腹腔注射东茛菪碱(1.5 mg · kg-1)制备小鼠学习记忆障碍模型,通过Morris水迷宫试验评价各组小鼠的学习记忆功能,并测定各组小鼠全脑中谷氨酸(Glu)、γ-氨基丁酸(GABA)、5-羟色胺(5-HT)、多巴胺(DA)、乙酰胆碱(Ach)含量及乙酰胆碱酯酶(AchE)活性.结果:行为学测试结果表明定志小丸能明显降低模型小鼠在Morris水迷宫定位航行试验中的平均潜伏期,增加空间探索试验中的穿越平台次数、目的象限游泳路程及时间的百分比;增加小鼠脑中Glu,5-HT,DA和Ach含量,降低GABA含量和AchE活性.结论:定志小丸可明显改善东莨菪碱所致小鼠学习记忆障碍,增强小鼠学习记忆的能力,其作用机制可能与调节Glu/GABA系统以及提高脑中Ach和单胺递质含量有关.     

The vagus nerve and nicotinic receptors modulate experimental pancreatitis severity in mice

BACKGROUND & AIMS: The nervous system, through the vagus nerve, controls inflammation by decreasing the release of tumor necrosis factor-alpha from endotoxin stimulated macrophages. This anti-inflammatory effect is mediated by an interaction of acetylcholine, the principal neurotransmitter of the vagus nerve, with macrophage cholinergic nicotinic receptors expressing the alpha7 subunit. METHODS: To determine the role of this "nicotinic anti-inflammatory pathway" in experimental pancreatitis, we induced pancreatitis in mice by 12 hourly intraperitoneal injections of cerulein. Pancreatitis was preceded by unilateral left cervical vagotomy or pretreatment with the nicotinic receptor antagonist mecamylamine or by pretreatment with the selective alpha7 nicotinic receptor agonist 3-(2,4-dimethoxybenzylidene) anabaseine (GTS-21). RESULTS: Vagotomy or pretreatment with mecamylamine resulted in an enhanced severity of pancreatitis, as reflected by histology, edema, plasma hydrolases, and interleukin-6 levels. Furthermore, the number of neutrophils migrated to the pancreas was increased in these mice, as shown by myeloperoxidase content and intrapancreatic staining of neutrophils. Conversely, GTS-21 pretreatment strongly decreased the severity of pancreatitis. Pancreatitis-associated pulmonary inflammation was independent of the integrity of the vagus nerve and nicotinic receptors. CONCLUSIONS: This study provides the first evidence for a therapeutic potential of the vagus nerve and the "nicotinic anti-inflammatory pathway" in attenuating inflammation and injury during experimental pancreatitis.     

复方丹参方对拟血管性痴呆大鼠脑内神经递质的影响

目的 :探讨复方丹参方对拟血管性痴呆大鼠的治疗作用机理。方法 :Wistar雄性大鼠经夹闭双侧颈总动脉 (CCA) ,并腹腔注射硝普钠 (2 .5 mg· kg- 1 )造模。选术后 7d存活的有显著学习记忆障碍的大鼠 4 0只为血管性痴呆模型 ,随机分为 4组。西药组给予喜得镇悬浮液 (0 .5 mg· kg- 1 · d- 1 ) ,复方丹参大小剂量组给予复方丹参方稀释液 (剂量分别为 10 g· kg- 1 ·d- 1、5 g· kg- 1· d- 1 ) ,模型组与正常组均给予等容量生理盐水灌胃。连续 2 1天。结果 :模型组与正常组比较 ,模型组大鼠脑内 Ach、5 - HT含量明显降低 ,Ach E活性明显升高 (P<0 .0 1)。复方丹参方大剂量组能明显升高 Ach含量及 5 - HT含量 ,降低脑内 Ach E活性 (P<0 .0 5 ,0 .0 1) ;复方丹参方小剂量组亦有类似作用 ,但 P>0 .0 5。与西药组比较无显著差异 (P>0 .0 5 )。结论 :复方丹参方大小剂量均能改善胆碱能系统的功能 ,调节脑组织 Ach生理代谢 ,从而改善记忆     

Conotoxins down under.

In the four decades since toxinologists in Australia and elsewhere started to investigate the active constituents of venomous cone snails, a wealth of information has emerged on the various classes of peptides and proteins that make their venoms such potent bioactive cocktails. This article provides an overview of the current state of knowledge of these venom constituents, several of which are of interest as potential human therapeutics as a consequence of their high potency and exquisite target specificity. With the promise of as many as 50,000 venom components across the entire Conus genus, many more interesting peptides can be anticipated.     

Inhibition of nitric oxide/cyclic GMP-mediated relaxation by purified flavonoids, baicalin and baicalein, in rat aortic rings

The dried roots of Scutellaria baicalensis Georgi (Huangqin) are widely used in traditional Chinese medicine. We purified two flavonoids, baicalin and baicalein from S. baicalensis Georgi and examined their effects on isolated rat aortic rings. Baicalin (3-50 microM) inhibited endothelium/nitric oxide (NO)-dependent relaxation induced by acetylcholine (Ach) or cyclopiazonic acid (CPA). Baicalein at 50 microM abolished Ach-induced relaxation and markedly reduced CPA-induced relaxation. Treatment with 1mM L-arginine partially but significantly reversed the effects of baicalin (50 microM) or baicalein (50 microM) on Ach-induced relaxation. In endothelium-denuded rings, treatment with baicalin, baicalein or methylene blue partially inhibited relaxations induced by the NO donors, sodium nitroprusside (SNP) and hydroxylamine. Both flavonoids markedly reduced the increase in cyclic GMP levels stimulated by Ach in endothelium-intact rings and by SNP in endothelium-denuded rings. In contrast, exposure of endothelium-denuded rings to baicalin or baicalein did not affect relaxations induced by pinacidil or NS 1619, putative K+ channel activators. Neither flavonoids affected agonist-induced increase in the endothelial [Ca2+]i. Our results indicate that baicalin and baicalein attenuated NO-mediated aortic relaxation and cyclic GMP increases, likely through inhibition of NO-dependent guanylate cyclase activity.     

慢性缺氧对大鼠肺动脉和主动脉舒缩反应的影响

大鼠经模拟高原5000m缺氧15d后,右肺动脉对Ach所致的舒张反应显著减弱,对5-HT所致的收缩反应显著增强,胸主动脉则无这种变化。结果提示,慢性缺氧对肺血管和体血管血管反应性的不同影响可能是高原缺氧环境下肺动脉压升高、体动脉压下降或不变的重要原因之一。     

草问荆总生物碱对大鼠脑内氨基酸类神经递质含量和纹状体内乙酰胆碱含量的影响

目的 研究草问荆总生物碱(TAEP)对大鼠脑内氨基酸类神经递质含量和纹状体内乙配胆碱、(Ach)含量的影肉，提示其对中枢神经系统抑制作用的作用机制。方法 采用双波长扫描定量法和豚鼠回肠生物测定法观察大鼠脑内氨基酸类神经递质的含量和纹状体内Ach含量。结果 TAEP对大鼠脑内4种氨基酸类神经递质(谷氨酸、甘氨酸、γ—氨基丁酸、天冬氨酸)的含量均无影响，但可显著降低大鼠纹状体内Ach的含量。结论 TAEP对中枢神经系统的抑制作用与脑内4种氨基酸类神经递质(谷氨酸、甘氨酸、γ—氨基丁酸、天冬氨酸)的含量无关，而是通过降低Ach的含量，进而影肉多巴胺—2(DA—2)受体达到的。’