The metabolic, catecholamine and cardiovascular effects of exercise in human sympathetic denervation

The cardiovascular and metabolic responses to supine leg exercise were measured in 9 healthy subjects (controls) and in 19 subjects with two primary forms of autonomic failure (11 with peripheral sympathetic denervation [pure autonomic failure; PAF], 8 with central sympathetic failure [multiple system atrophy; MSA]). With exercise, blood pressure increased in controls and fell markedly in subjects with PAF and MSA. Blood pressure returned to baseline in controls, but remained low in the PAF and MSA groups. With exercise, heart rate increased more in controls than the PAF and MSA groups. Resting plasma noradrenaline concentrations in controls and in subjects with MSA were similar, but were lower in subjects with PAF. With exercise, plasma noradrenaline concentrations increased in controls and were unchanged in subjects with PAF; there was no significant increase in the MSA group. Resting plasma lactate, pyruvate and lactate/pyruvate ratios were similar in all three groups. With exercise, lactate concentrations increased until 2 minutes post exercise in all groups. Pyruvate concentrations after 9 minutes' exercise were higher in controls than in the PAF group but were similar to the MSA group; thereafter, concentrations increased similarly in all groups. The lactate/pyruvate ratio increased until 2 minutes post exercise in all groups. Resting plasma free fatty acids, and -hydroxybutyrate were similar in all groups. Plasma glycerol concentrations in control and MSA subjects were similar; concentrations were lower in PAF subjects. With exercise, plasma free fatty acids and glycerol concentrations remained unchanged in all groups; -hydroxybutyrate concentrations decreased less in control subjects than in PAF and MSA subjects.In conclusion, there were similar concentrations of plasma free fatty acids, glycerol and -hydroxybutyrate in control, PAF and MSA subjects; this could indicate up-regulation of -receptors in AF, or that sympathetic activity plays a smaller role in lipolysis. Plasma lactate and pyruvate concentrations increased similarly in all groups, despite marked differences in BP; this suggested an impairment of production or clearance of lactate in AF. A role for lactate-induced vasodilatation, not compensated for by sympathetic vasoconstriction, remains speculative.     

Reflex sympathetic dystrophy in a patient with peripheral sympathetic denervation

Reflex sympathetic dystrophy (RSD) includes persistent pain in an extremity, associated with features of vasomotor dysfunction and, later, dystrophic changes. Many theories have been proposed to explain these clinical features and include sympathetic dysfunction. We report a unique case of RSD following an upper limb fracture in a patient with established severe peripheral sympathetic denervation as part of idiopathic chronic autonomic failure. This case provides evidence that the clinical features of RSD were not mediated via increased sympathetic nerve activity in the affected limb. Locally released neuropeptides or autocoids therefore may be involved in the pathogenesis of RSD. The term sympathetic in RSD may be inappropriate and require revision.     

Cervical sympathetic trunk transection affects inducible nitric oxide synthase expression in rat hippocampus following focal cerebral ischemia/reperfusion injury

BACKGROUND： The stellate ganglion block （SGB） plays a protective role in focal cerebral ischemia/reperfusion injury. The human SGB can be simulated by transection of the cervical sympathetic trunk （TCST） in rats. OBJECTIVE： To observe the effects of TCST on inducible nitric oxide synthase （iNOS） levels and cerebral infarct volume in the hippocampus of rats with cerebral ischemia/reperfusion injury, and to analyze the mechanism of action. DESIGN, TIME AND SETTING： A completely randomized, controlled, neuropathological experiment was performed at the Institute of Neurological Disease, Taihe Hospital, Yunyang Medical College between March and September 2006. MATERIALS： A total of 93 Wistar rats, aged 1718 weeks, of either gender, were used for this study. 2, 3, 5-triphenyl tetrazolium chloride was purchased from Changsha Hongyuan Biological Reagent Company China. Rabbit iNOS antibody and goat anti-rabbit IgG antibody were the products of Wuhan Boster Biological Reagent Co., Ltd., China. METHODS： Ten rats were randomly selected for the sham-operated group. Cerebral ischemia/reperfusion injury was induced by middle cerebral artery occlusion （MCAO） using the suture method in the remaining rats. Forty successful rat models were randomly and equally divided into the following two groups： （1） TCST group： subsequent to TCST, MCAO was performed for 2 hours, followed by 24 hours reperfusion; （2） model group： rats underwent experimental procedures similar to the TCST group, with the exception of TCST. Rats in the sham-operated group were subjected to experimental procedures similar to the model group; however, the thread was only introduced to a depth of 10 mm. MAIN OUTCOME MEASURES： Following 24 hours of reperfusion, functional neurological deficits were scored. Brain tissue sections from ten rats of each group were used to measure cerebral infarct volume by TTC staining. Hippocampal tissue sections of an additional ten rats from each group were used to detect iNOS levels using the s     

癫痫患儿血清一氧化氮和一氧化氮合酶含量的变化及意义

目的　探讨癫疒间 患儿血清一氧化氮 (NO)、一氧化氮合酶 (NOS)的变化及意义。方法　利用ELISA方法 ,测定 5 8例癫疒间 患儿 (癫疒间 组 )和 2 3名健康儿童 (对照组 )血清中NO、NOS的含量 ,并分组比较不同条件下其含量的变化。结果　癫疒间 组血清NO、NOS的含量分别为 (5 .86± 1.2 1) μmol/ml和 (2 8.2 6± 8.4 9)U/ml,较对照组的 (3.78± 0 .74 ) μmol/ml及 (17.86± 4 .5 8)U/ml明显升高 (P <0 0 1) ;发作近期为 (7.31± 1.2 7)μmol/ml和 (31.2 5± 11.35 )U/ml,明显高于发作间期 (4 .2 7± 0 .6 6 ) μmol/ml和 (2 4 .15± 7.85 )U/ml(P <0 0 1) ;癫疒间 组EEG异常者为 (7.18± 1.35 ) μmol/ml和 (34.4 8± 8.5 6 )U/ml,明显高于EEG正常者 (4 .0 4± 0 .75 ) μmol/ml和 (2 2 .85± 7.4 5 )U/ml(P <0 0 1) ;但与发作类型、病程及是否接受治疗无关 (P >0 0 5 )。结论　癫疒间 发作近期血中NO、NOS生成增加 ,NO作为内源性调质参与癫疒间 发作病理生理过程     

L—NAME加强麻醉大鼠低血压诱发的催产素释放作用

取戊巴比妥麻醉大鼠向侧脑室内分别注射一氧化氮合酶的底物Ｌ－精氨酸和ＮＯ合酶抑制剂Ｎ＾Ｇ－硝基－Ｌ－精氨酸甲酯,用放射免疫法测定血浆中催产素水平。结果：侧脑室内注射Ｌ－精氨酸（１００ｇ／Ｌ,１０μＬ,ｎ＝８）和Ｌ－ＮＡＭＥ（５４．０ｔ／Ｌ,５μＬ,ｎ＝１２）,对Ｏ物基础分泌无明显的影响;侧脑室内注射５μＬ Ｌ－ＮＡＭＥ（剂量（１：２７,ｇ／Ｌ,ｎ＝９;剂量２：５４。０ｇ／Ｌｎ＝９）可进一步增强静脉输     

L-NAME加强麻醉大鼠低血压诱发的催产素释放作用

取戊巴比妥麻醉大鼠向侧脑室内分别注射一氧化氮(NO)合酶的底物L-精氨酸和NO合酶抑制剂NG-硝基-L-精氨酸甲酯(L-NAME),用放射免疫法测定血浆中催产素(OT)水平.结果:侧脑室内注射L-精氨酸(100 g/L,10 霯,n=8)和L-NAME(54.0 g/L,5 霯,n=12),对OT的基础分泌无明显影响;侧脑室内注射5 霯 L-NAME(剂量1:27.0 g/L,n=9;剂量2:54.0 g/L,n=8),可进一步增强静脉输注硝普钠引起低血压所诱导的OT分泌升高反应.结果表明L-NAME能加强低血压诱发的OT反射性释放作用,提示NO可能是OT反射性释放的抑制因子.     

一氧化氮／一氧化氮合酶与神经创伤

一氧化氮是一种简单的气体分子,可在哺乳类神经细胞内经一氧化氮合酶作用产生。ＮＯ在神经创伤修复中的多重作用近年来已受到越来越多的重视。本文对ＮＯ／ＮＯＳ与神经创伤和再生之间的关系作一综述。     

Lowered cardiac sympathetic nerve performance in response to exercise in Parkinson's disease

We examined whether cardiac sympathetic denervation influences the cardiovascular response to exercise in Parkinson's disease (PD). Sixteen patients with PD were divided into two groups, according to their cardiac uptake of ¹²³I‐metaiodobenzylguanidine (denervated group, 10 patients with heart to mediastinum (H/M) ratio < 1.7; innervated group, six patients with H/M ratio > 1.7) and compared changes in blood pressure (BP), heart rate (HR), and cardiac contractility with 13 control subjects during ergometric exercise stress. Velocity index (VI), an indicator of cardiac contractility, was measured using impedance cardiography and recorded every minute. Exercise began at a power output of 20 W for the first 2 min and increased 10 W every 2 min to a maximal intensity of 60 W. All control subjects accomplished the procedure while six patients with PD could not continue after the first minute of 50 W loading. There were no significant differences in BP or HR change between the three groups. However, a significant reduction in VI was observed from the first minute of the 30 W workload in the denervated group compared to the control group. This lowered response continued till 50 W loading and was significantly different to the innervated group at 50 W loading. No significant VI changes were observed between the control and innervated groups throughout the exercise test. Patients with PD with reduced MIBG uptake had a lowered cardiac contractility than innervated subjects during exercise, suggesting that this response represents theimpaired exercise capacity of patients with PD with cardiac sympathetic denervation. © 2010 Movement Disorder Society     

The effect of nitric oxide donors on nitric oxide synthase-expressing myenteric neurones in culture.

Previously, we demonstrated that intestinal inflammation leads to a postinflammatory loss of nitric oxide synthase (NOS)-expressing myenteric neurones and motility disturbances. Here, we investigated whether high NO concentrations could be responsible for the decrease in NOS neurones. Myenteric neurone cultures, prepared from guinea-pig small intestine, were incubated with NO donors [sodium nitroprusside (SNP) and 3-morpholinosydnonimine (SIN-1)]. After fixation, NOS neurones were identified by NADPH diaphorase staining and neurone-specific enolase (NSE)-positive neuronal content was assessed with an enzyme-linked immunosorbent assay (ELISA)-based method. Twenty-four hours incubation with SIN-1 (10(-3) mol L(-1)) or SNP (10(-4) mol L(-1) or higher) reduced the number of NADPH diaphorase-positive neurones. SNP incubation did not affect the NSE-positive neuronal content. Shorter incubations (SNP: 4 and 12 h) had no significant effect. The SNP-induced reduction was reversed by glutathione (GSH), but not by NO- or O-scavengers, whereas GSH depletion enhanced the decrease. The NO-dependent guanylate cyclase-blocker 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) did not affect the SNP effect. This reduction can be explained by either specific apoptosis of NOS neurones or downregulation of NOS activity. However, TdT-mediated X-dUTP nick end labelling (TUNEL stainings argue in favour of the latter. In conclusion, the NO donor SNP decreases the number of NOS-expressing myenteric neurones time and concentration dependently, without affecting the amount of neuronal material. Glutathione plays an important protective role.     

Involvement of nitric oxide and nitric oxide synthase activity in anticonvulsive action

The anticonvulsant drug Diazepam (DIA-2 mg/kg b. wt), the nitric oxide (NO) donor L-Arginine (L-Arg-2000 mg/kg b. wt) and the putative nitric oxide synthase (NOS) inhibitor N(G)-Nitro-L-Arginine methyl ester (L-NAME-50 mg/kg b. wt) were used to determine the role of endogenous NO on convulsions induced by picrotoxin (PCT-5 mg/kg b. wt) in rats. Rats given a convulsant dose of PCT (5 mg/kg b. wt) had convulsion and it suppresses the NOS activity and NO concentration in brain regions. The anticonvulsant L-Arg alone significantly increases the NO concentration and NOS activity in brain regions, but not diazepam. Whereas DIA, along with L-Arg, enhances the NO and NOS activity when compared to L-Arg alone. The combination of both OIA and L-Arg completely suppressed the convulsions. L-NAME alone had no effect to produce convulsions but it completely decreased NO concentration and NOS activity and potentiated the PCT convulsions. This was reverted by pre- and post treatment of DIA plus L-Arg indicating, the increased NO concentration and NOS activity in brain regions suppresses convulsions.     

首发偏执型精神分裂症血清NO/NOS水平的研究

目的探讨首发偏执型精神分裂症血清一氧化氮/一氧化氮合成酶（NO/NOS）水平及与精神症状的关系。方法共收集首发偏执型精神分裂症患者26例（研究组）,健康对照者30例（对照组）,采用阳性与阴性症状量表（PANSS）评定患者的精神症状,同时检测血清NO/NOS水平。结果首发偏执型精神分裂症血清NO/NOS水平均显著高于健康对照组（t=2.08,P〈0.05;t=2.72,P〈0.05）,血清NO/NOS水平与精神症状无显著相关性（P〉0.05）;血清NO水平与血清NOS水平两者存在显著正相关（r=0.41,P〈0.05）。结论首发偏执型精神分裂症患者存在血清NO/NOS水平病理性增高。     

青白散对慢性软组织损伤模型大鼠骨骼肌一氧化氮合酶系统和一氧化氮的影响*☆

背景：对慢性软组织损伤后一氧化氮合酶系统和一氧化氮的研究目前较少。 目的：观察青白散对大鼠慢性软组织损伤模型骨骼肌中一氧化氮合酶系统和一氧化氮的影响。 方法：雄性 SD 大鼠随机分为对照组、模型组、氨基胍组、青白散组。后3组采用机械损伤法制备慢性骨骼肌损伤动物模型,分别予以生理盐水 10 mL/kg,0.10 g/kg氨基胍,0.54 g/kg青白散,1次/d,连续 14 d。于给药后1,2,3周,分别检测大鼠肌组织一氧化氮含量、总一氧化氮合酶和诱导型一氧化氮合酶的活性。 结果与结论：骨骼肌损伤修复过程中,模型组大鼠骨骼肌中一氧化氮含量、总一氧化氮合酶和诱导型一氧化氮合酶的活性较对照组显著增高;而青白散组和氨基胍组大鼠骨骼肌中一氧化氮含量、总一氧化氮合酶和诱导型一氧化氮合酶的活性均较模型组显著降低。说明青白散可能通过阻抑诱导型一氧化氮合酶诱导过量一氧化氮的产生,为慢性软组织损伤的修复创造了有利条件。     

Inducible nitric oxide synthase and nitric oxide production by oligodendrocytes

It has been previously demonstrated that microglia and astrocytes produce micromolar amounts of nitric oxide in vitro. In this study, we demonstrate that primary rat oligodendrocytes can be stimulated to produce iNOS mRNA as detected by Northern blot and in situ hybridization analysis and a 131-kDa iNOS protein by Western blot analysis; protein was also detected in cells by single- and double-label immunohistochemistry for iNOS and the oligodendrocyte-specific marker CNPase. NO/NOS are produced as a consequence of activation of the gene encoding the inducible nitric oxide synthase as determined by inhibition with actinomycin D and cyclohexamide. The iNOS is functional, leading to calcium/calmodulin-independent NO production in these in vitro cultures. J. Neurosci. Res. 48:372–384, 1997. © 1997 Wiley-Liss, Inc.     

一氧化氮合酶活性与抑郁症的相关性

目的通过对抑郁症患者一氧化氮合酶（NOS）活性进行检测，从而研究和探讨一氧化氮合酶、一氧化氮（NO）与抑郁症之间的关系。方法采用分光光度法检测抑郁症患者治疗前后的一氧化氮合酶NOS及其亚型（结构型cNOS、诱导型iNOS）的活性，并与正常对照组比较。结果抑郁症组的NOS、cNOS活性显著低于正常对照组；治疗组的NOS、cNOS活性高于抑郁症（无显著性），但治疗后缓解组的NOS、cNOS活性均显著高于治疗前。各组iNOS的活性无显著差异。结论抑郁症病人的NOS活性下降，而且主要是结构型cNOS活性下降，经治疗缓解后有所提高。因此，NOS和NO很有可能在抑郁症的发病过程中起着重要作用。     

Correlation with superior cervical sympathetic ganglion and sympathetic nerve innervation of intracranial artery-electron microscopical studies

When the superior cervical ganglion was resected in dogs, nerve degeneration in arterial walls began after about 28 h and marked degenerative substance was shown after 40–48 h; after 4 days the small cored vesicles of adrenergic axons disappeared. The same condition was seen after 3 months, but after 6 months the small cored vesicles were again visible. When the middle cerebral artery was examined by separating it into the perforating artery near to the internal carotid artery and the peripheral portion of the middle cerebral artery, degeneration of the nerve fibers of the arterial walls occurred earlier in the more proximal portion.The distribution of adrenergic nerve fibers from the superior cervical ganglion is bilateral in the anterior cerebral artery from the anterior communicating artery to the peripheral region, basilar artery, and vertebral artery, but ipsilateral only in the anterior cerebral artery as far as the anterior communicating artery, middle cerebral artery, posterior communicating artery, posterior cerebral artery and superior cerebellar artery.Degeneration of nerve fibers of the walls of these cerebral arteries was not seen ever after stellate ganglionectomy in both sides.     

Cardiac sympathetic denervation in early stages of amyotrophic lateral sclerosis demonstrated by 123I-MIBG-SPECT

Involvement of the autonomic cardiac nervous system in early stages of amyotrophic lateral sclerosis (ALS) was evaluated in 40 patients. I-123-metaiodobenzylguanidine-single photon emission computed tomography (MIBG-SPECT) and heart rate variability (HRV) yielded information about sympathetic and parasympathetic innervation of the heart. MIBG-SPECT is a sensitive diagnostic method for demonstration of early cardiac sympathetic denervation. Both sympathetic and parasympathetic dysfunction was observed in 16 (40%) out of 40 patients. Mean cardiac MIBG uptake as demonstrated by the heart/mediastinum ratio was significantly reduced in all ALS patients in comparison with controls (P<0.01). The global MIBG-SPECT score was clearly abnormal in 29% and slightly abnormal in 22% of patients. HRV was diminished in 6 of 38 patients, 4 of whom having an abnormal MIBG-SPECT score as well. The presented results indicate that ALS patients with mild to moderate impairment may have evidence of postganglionic sympathetic adrenergic cardiac or cardiovagal denervation. To our knowledge, this is the first study indicating possible postganglionic sympathetic denervation in ALS. The original concept of ALS as an isolated degeneration of motor neurons seems to extend to a more widespread understanding of the disease which possibly represents different entities.     

Possible role for nitric oxide dysregulation in critical illness myopathy

Muscle fiber inexcitability and myosin loss underlie weakness in critical illness myopathy (CIM). Nitric oxide (NO) takes part in the maintenance of muscle fiber resting potential and, in pathological conditions accompanied by oxidative stress, may damage proteins through peroxynitrite generation. Sepsis and other conditions associated with CIM may differentially affect expression of NO synthases (NOSs), so that both downregulation and upregulation with excessive peroxynitrite production can be hypothesized. In six patients with CIM we studied NOS1, NOS2, and NOS3 protein expression by immunohistochemistry and Western blot. To investigate peroxynitrite production, we performed immunohistochemistry for nitrotyrosine and measured nitrotyrosine levels by enzyme-linked immunosorbent assay. In three patients, sarcolemmal staining for NOS1 was selectively absent. In the others, it was absent in atrophic fibers and absent or reduced in non-atrophic fibers. Total NOS1 protein content was reduced by 41% in patients compared to controls, whereas no significant changes were found in levels and localization of NOS2, NOS3, and nitrotyrosine. Further studies are warranted to determine whether NOS1 loss plays a role in the pathophysiology of CIM, possibly reducing the release of NO at the sarcolemma and affecting muscle fiber excitability.     

神经源型一氧化氮合酶C276T基因多态性与抑郁症相关分析

目的测定抑郁症患者抗抑郁剂治疗前后血浆一氧化氮（NO）水平变化,旨在探讨神经源型一氧化氮合酶（nNOS）基因C276T多态性与血浆NO浓度及抑郁症发病相关性。方法采用硝酸盐还原酶法测定正常对照组及抑郁症患者治疗前后血浆NO水平;全部受试者取全血标本提取基因组DNA,并采用PCR-RFLP方法对nNOS基因C276T多态性进行基因分型。结果患者组疗前血浆NO水平为（76.8±31.6）μmol/L显著高于疗后[（66.9±25.7）μmol/L,P=0.044]及正常对照组[（64.2±33.3）μmol/L,P=0.02],两组疗后血浆NO水平相比差异无显著性（P=0.588）;根据PCR-RFLP结果,nNOS基因可见两种等位基因条带C、T,组成三种基因型CC、CT、TT,两组等位基因及基因型分布频率差异无显著性（均P〉0.05）,且携带不同基因型者之间血浆NO水平差异亦无显著性（均P〉0.05）。结论血浆NO浓度增高可能是抑郁症发病的影响因素;nNOS基因C276T多态性可能不直接影响血浆NO浓度,也不是抑郁症发病的主要基因因素。     

In vitro and in vivo effects of nitric oxide synthase inhibitors and nitric oxide inactivators on the South American opossum ileocolonic junction*

The potential role of nitrergic nerves in the regulation of the South American (SA) opossum ileocolonic junction (ICJ) function was investigated. In vitro, the effects of nitric oxide (NO) synthase inhibitors and NO inactivators on the non-adrenergic non-cholinergic (NANC) nerve-mediated relaxations of the circular muscle of the SA opossum ICJ were determined by employing isolated strips. Electrical field stimulation (0.2–8.0 Hz) caused frequency-dependent NANC relaxations. Nicotine and ATP also induced concentration dependent NANC relaxations that were abolished by tetrodotoxin (TTX). The relaxation response induced by NANC nerve activation was reduced in a dose dependent manner by NO synthase inhibitors while vasoactive intestinal peptide (VIP) and sodium nitroprusside (SNP) induced relaxations were uninfluenced by these drugs. In vivo, the NO synthase inhibitor, L -NAME, administered into the local artery caused a raise in intraluminal pressure of the ICJ in anaesthetized SA opossums in a L -arginine-preventable manner. Hydroquinone and pyrogallol, while being able to reduce, in a superoxide dimutase (SOD) reversible manner, the relaxations induced by exogenous NO failed to affect the NANC nerve-induced relaxations. Finally, neurones and nerve fibres in the myenteric plexus as well as varicose nerve fibres on the circular smooth layer were positive for NADPH-diaphorase activity. These findings indicate that nitrergic nerves inhibit ICJ circular smooth muscle in vitro and in vivo but cast doubts on the neuromediator being the NO radical.