内源性硫化氢、同型半胱氨酸与阿尔茨海默病的相关性研究进展

本文对内源性硫化氢、同型半胱氨酸与阿尔茨海默病的相关性研究进展作一综述。     

ATP敏感性钾通道对缺血性脑损伤的保护机制

一、ATP敏感性钾通道1.概述ATP敏感性钾通道(ATP-sensitive K channels,KATP通道)是电压非依赖性的、配体门控通道,由Noma于1983年首先在豚鼠的心肌细胞上发现。随后的研究证实,在心肌以外的多种组织如胰腺β细胞、脑神经元、垂体、骨骼肌、肾脏上皮细胞和平滑肌细胞以及线粒体     

脑梗死患者血浆中内源性硫化氢含量的变化

目的探讨脑梗死患者血浆中内源性硫化氢(H2S)含量的变化及其病理生理意义。方法采用分光光度法测定56例脑梗死患者及50名健康对照组血浆H2S含量,并分析脑梗死患者不同临床亚组间血浆H2S含量的差异、血浆H2S含量与缺血性脑血管疾病危险因素的关系。结果脑梗死患者血浆H2S含量(27.32±14.56)μmol/L明显低于对照组(53.78±18.37)μmol/L,(P0.01);脑梗死患者中,大体积脑梗死[(16.98±7.62)μmol/L]与中体积脑梗死血浆H2S含量[(22.50±13.79)μmol/L],均显著低于小体积脑梗死[(35.72±14.63)μmol/L,P0.01];伴有颈动脉斑块形成者血浆H2S含量,远低于无颈动脉斑块形成者[(18.24±10.55)μmol/Lvs(28.76±14.75)μmol/L,P0.01];脑梗死患者中,高血压病者血浆H2S明显低于无高血压病者[(21.24±8.96)μmol/Lvs(34.61±14.95)μmol/L,P0.01],糖尿病者明显低于无糖尿病者[(19.46±9.73)μmol/Lvs(30.51±15.69)μmol/L,P0.01],并且血浆H2S水平与血糖水平呈强负相关(r=-0.5147,P=0.0057),与性别、年龄、胆固醇、甘油三酯、低密度脂蛋白、高密度脂蛋白等无相关关系。结论血浆中H2S水平降低可能与脑梗死临床病情严重性及脑动脉血管病变程度相关。血浆H2S含量的减少可能与缺血性脑血管疾病危险因素高血压、高血糖相关。     

重度缺氧中海马神经元KATP通道的表达改变

目的 探讨重度缺氧状态中ATP敏感性钾通道(KATP)通道在海马神经元上的表达变化. 方法 取培养1周的新生大鼠海马神经元分为4组:第1组为正常对照组,在正常氧状态中(5%CO_2、95%空气)孵育8 h;第2组为处理组,在模拟的缺氧状态(5% CO_2、95%N_2)孵育8h(单纯缺氧组);第3组为二氮嗪+缺氧组,在缺氧处理的同时添加KATP通道激动剂二氮嗪(100μmo1/L1,处理时间为8 h;第4组为甲糖宁+缺氧组,在缺氧处理的同时添加KATP通道阻断剂甲糖宁(100 μmol/L),处理时间为8h.利用MTT、免疫印迹及RT-PCR技术,比较4组细胞存活情况以及缺氧状态中神经元上KATP通道的表达改变. 结果 缺氧8h后,二氮嗪能明显降低细胞的凋亡数量,甲糖宁使细胞的凋亡数量增加,与正常对照组比较,差异均有统计学意义(P<0.05).缺氧状态中KATP通道的SUR1亚基的表达明显增加,而Kir6.2亚基表达量则无明显改变,与正常对照组比较,差异均有统计学意义(P<0.05). 结论 KATP通道的活性及表达改变,对缺氧中的海马神经元的保护起到重要作用.     

急性颈髓损伤对心血管系统影响的临床分析

目的探讨急性颈髓损伤(CSCI)后出现的心血管系统异常情况及其发病机制。方法回顾性对比分析30例CSCI患者与30例非CSCI患者的血压、心率。结果CSCI患者血压、心率明显降低(P均<0.05);颈4以上比颈4以下损伤患者的血压、心率下降更为明显(P均<0.05)。结论急性颈髓损伤后出现心血管系统功能明显异常,血压、心率下降,且其严重度与损伤平面有关。其机制可能为急性颈髓损伤时抑制了体内交感神经系统。     

神经系统中内源性硫化氢相关生物学功能的研究进展

气体信号分子是生物体及细胞内存在的一种具有独特生物学作用的信号途径,具有连续产生、传播和弥散迅速等特点。该命题是随着20世纪80年代中期发现内源性气体分子一氧化氮(NO)通过一氧化氮合酶作用于精氨酸而产生并与细胞内鸟氨酸环化酶结合从而提高胞内环磷酸鸟苷(cGMP)水平并具有舒张血管、抑制血小板聚集和抑制细胞     

帕金森病患者心血管自主神经功能障碍的临床研究

目的研究帕金森病(PD)患者心血管自主神经功能障碍及其相关的影响因素。方法入选PD患者(PD组)51例和健康对照者(对照组)30例,分别进行24 h动态血压和动态ECG监测,对比分析两组的血压变异性(BPV)和心率变异性(HRV)的指标,同时对PD患者进行左旋多巴等效剂量(LED)换算、Hoehn-Yahr分期(H-Y分期)和统一PD评定量表Ⅲ(UPDRSⅢ)评分,探讨BPV和HRV的影响因素。结果 PD组BPV中24h SBPSD、dSBPSD、nSBPSD较对照组明显升高(均P0.05)。PD组HRV中SDNN、RMSSD、HF、LF较对照组明显下降(均P0.05)。PD患者BPV与病程具有正相关(P0.05),HRV与病程、H-Y分期、UPDRSⅢ评分具有负相关(均P0.05)。结论 PD患者存在心血管自主神经功能障碍,且与病程、疾病严重程度及运动症状严重程度有关。     

线粒体KATP通道开放剂对多巴胺能神经细胞的保护作用研究

目的研究线粒体KATP通道的开放对于鱼藤酮诱导的细胞凋亡的保护作用并初步探讨其机制。方法用神经生长因子(NGF)将PC12细胞诱导分化成多巴胺能神经元模型,经鱼藤酮和线粒体KATP通道的开放剂二氮嗪及选择性线粒体KATP通道拮抗剂5-羟葵酸(5-HD)处理,用台盼蓝染色和四甲基偶氮唑盐(MTT)法检测细胞活力,磷脂酰丝氨酸外翻法(Annexin V)检测细胞的凋亡,JC-1检测线粒体膜电位的变化。结果经鱼藤酮处理24h后PC12细胞突起结构消失,细胞体积变小,形态变圆,台盼蓝染色阳性细胞增多,细胞活力下降,可见An-nexin V阳性的早期凋亡细胞,凋亡率为31.1%±2.65%(P<0.01);同时加入二氮嗪能减少PC12细胞的凋亡,凋亡率为17.9%±0.71%(P<0.05);JC-1染色法证实二氮嗪可稳定线粒体膜电位。而同时加入5-HD的PC12细胞活力及线粒体膜电位与鱼藤酮处理组相比无变化。结论鱼藤酮可引起多巴胺神经元的凋亡,线粒体KATP通道的开放剂二氮嗪能够拮抗鱼藤酮的毒性作用,其机制可能是通过在线粒体膜电位降低时稳定线粒体膜电位而起到对多巴胺能细胞的保护作用。     

胞内乳酸对急性分离大鼠新皮层神经元KATP通道的影响

采用膜片钳技术内面向外式记录法,研究了胞内乳酸对急性分离大鼠皮层神经元上ＡＴＰ敏感钾通道（ＫＡＴＰ通道）的影响。结果显示：浴槽液中加入５～２０ ｍ ｍ ｏｌ／Ｌ乳酸,通道电流幅度增大,电导由（２０２±１１）ｐＳ增到大（２５３±１３）ｐＳ;乳酸浓度＞ ２０ ｍ ｍ ｏｌ／Ｌ时,部分通道出现多级开放。当膜超极化时,乳酸可增加通道平均开放时间及开放概率并随其浓度的增大而增加。浴槽液中乳酸浓度为２０ ｍ ｍ ｏｌ／Ｌ时,ＡＴＰ阻断通道电流活动的半数有效浓度（ＩＣ５０）为１ ｍ ｍ ｏｌ／Ｌ,较无乳酸时ＩＣ５０（０．０５ ｍ ｍ ｏｌ／Ｌ）明显增高,即通道对ＡＴＰ敏感性明显降低（Ｐ＜ ０．０１）。上述结果表明：胞内乳酸可通过增大电导、增加开放概率、诱导多通道开放及降低通道的ＡＴＰ敏感性参与调节皮层神经元上ＫＡＴＰ通道。提示：脑在缺氧情况下,胞内无氧代谢所产生的乳酸可先于ＡＴＰ耗竭激活ＫＡＴＰ通道,降低神经元兴奋性,从而起到保护作用。     

谷氨酸受体通道RNA编辑机制与癫痫

由于离子型谷氨酸受体通道亚基A to IRNA编辑机制的异常 ,引起谷氨酸受体通道对的Ca++通透性的改变 ,进而诱发癫痫发作 ,这种机理为原发性癫痫的发生机制提供了新的研究思路。本文介绍国外研究谷氨酸受体通道A to IRNA编辑机制与癫痫的关系的近况。     

Presence of a pet dog and human cardiovascular responses to mild mental stress

The mechanisms underlying the possible cardiovascular benefits of pet ownership have not been established. Using a randomized design, the effect of a friendly dog on cardiovascular and autonomic responses to acute, mild mental stress was investigated. Seventy-two subjects (aged 40±14 y; mean±SD) participated. Rest was alternated with mental stress during four 10-minute periods. An unknown dog was randomly selected to be present during the first or the second half of the study. Blood pressure (BP) and heart rate (HR) were monitored continuously and cardiac autonomic function assessed using spectral analysis of heart period. Heart period variability data were expressed as the ratio of 0.1 Hz to respiratory or high frequency variation (LF/HF). Whereas mental stress significantly increased BP and HR in the absence of the dog (from 125/71 ±3/2 to 133/75±3/2 mm Hg; p<0.001), the presence of the dog had no effect on these variables. Heart period LF/HF ratio was lowest in dog owners in the presence of the dog (dog present 2.8±0.3 versus dog absent 3.4±0.4; p<0.001) and in non-dog owners in the absence of the dog (dog present 3.4±0.4 versus dog absent 2.8±0.3; p<0.001). In conclusion, a friendly but unfamiliar dog does not influence BP or HR either at rest or during mild mental stress. Cardiac autonomic profile was most favorable in the presence of the dog for dog owners and in the absence of the dog for non-owners. This work was supported by Petcare Information and Advisory Service, Victoria, Australia.     

The effects of exposure to moderate altitude on cardiovascular autonomic function in normal subjects

Cardiovascular responses to altitude have been studied on well-trained young subjects, generally at high altitudes (>4000 m). Less known are the effects of exposure to lower altitudes, easily reached by the general population. The aim of the study was to evaluate the effects of exposure to a moderate altitude (2950 m) on heart rate (HR), blood pressure (BP) profile, and cardiovascular autonomic function, and their correlation with hemoglobin oxygen saturation (HbO2S), in untrained subjects of a wide age range. Twenty-seven healthy normotensive subjects (age range 6–83; 8 children, 9 adults, and 10 elderly subjects) underwent a battery of noninvasive cardiovascular reflex tests and 24-h ambulatory BP monitoring. Corrected QT interval was also calculated. HbO₂S was measured with a transcutaneous oxymeter. All measurements were performed at about 200 m (s.l.) and repeated at 2950 m. 24-h HR and systolic/diastolic BP mean values increased at 2950 m in children (% change respectively: 6.4±6.4, p<0.05; 6.5±4.0/13.5±6.9, p<0.05), adults (4.9±8.1, NS; 6.0±5.1/8.1±5.8, p<0.05), and elderly subjects (7.2±4.8, p<0.05; 5.1±2.3/2.8±4.1, p<0.05 for systolic BP only). Standard deviation of BP mean values increased during night-time in the adult group (p<0.05). All subjects scored normal cardiovascular test results and no differences were observed after exposure to 2950m, at both 1 hour and 24 hours from arrival. After exposure to altitude, HbO₂S decreased significantly in the three groups, both on arrival and after 24 hours. No correlation was found between changes in HbO₂S and BP/HR responses, and cardiovascular test results. In conclusion, exposure to moderate altitudes, easily and often reached by the general population, causes a small but significant increase in BP and HR in healthy untrained subjects of a wide age range (6–83 years). Some physiological factors (eg, lower environmental temperature and lifestyle modification) together with hypoxia, possibly more than altered cardiovascular reactivity, seem responsible for this cardiovascular change. In terms of end-organ damage, the clinical relevance of this increase in BP and BP variability for repeated exposure is not known.     

Central nervous system effects of bombesin on the cardiovascular response to cold exposure

The effects of cold exposure on mean arterial pressure (MAP), heart rate (HR) and oxygen consumption (VO₂) were examined in conscious, unrestrained rats receiving intracerebroventricular (i.c.v.) injections of bombesin or appropriate control solutions. Cold exposure elicited significant elevations of MAP, HR and VO₂ in control-treated rats. I.c.v. administration of bombesin produced dose-related suppressions of cold-induced elevations of HR and VO₂, but not MAP. The central nervous system (CNS)-selective somatostasin analog, ODT8-SS, injected i.c.v., reversed the effects of bombesin on HR and VO₂ during cold exposure. Intravenous administration of atropine methyl nitrate did not antagonize the effects of bombesin on HR and VO₂ during cold exposure. HR and VO₂ were strongly correlated in bombesin-treated rats suggesting that this peptide may prevent cold-induced elevations of VO₂ through a CNS action on cardiac function.     

Acute effects of ECT on cardiovascular functioning: relations to patient and treatment variables

In 34 patients with primary, major depressive disorder, randomly assigned to bilateral or right unilateral ECT, heart rate (HR) and blood pressure (BP) were assessed prior and following seizure induction at every treatment. In contrast to prior reports, no cumulative pattern was observed in HR or BP changes as a function of treatment number. Generally, treatment variables, including ECT modality (bilateral vs. unilateral), anesthetic agent (methohexital vs. pentothal), and prior subconvulsive stimulation in a session, had no effects on the magnitude of peak postictal increases in HR or BP. The peak changes were also unrelated to the history of cardiac illness, remission of depressive symptomatology, patient seizure threshold and patient seizure duration. Pre-treatment HR was strongly predictive of peak postictal change in both HR and BP, while pretreatment BP was not. Patients with high pre-ECT HR had smaller peak postictal HR and BP increases. The findings suggested that low dosage, titrated ECT has HR and BP effects similar to traditional high dosage techniques, and that pre-treatment HR is the best predictor of these effects.     

Central Oxytocin Mediates Stress-Induced Tachycardia

To address the role of oxytocin in the control of cardiovascular reactivity, we examined the effect of central injection of oxytocin, vasopressin and mixed base antisense oligodeoxynucleotides on stress-induced cardiovascular and endocrine changes. Antisense oligomers were injected into the paraventricular nucleus (PVN), 4 h prior to the stress test. The oxytocin antisense abolished the tachycardia produced by 5 min of shaker stress. The blood pressure and plasma oxytocin responses were not different between the groups. PVN levels of OT were reduced in the oxytocin antisense-treated group while brain stem levels were increased. These results demonstrate the importance of a specific peptide system, the PVN/oxytocin axis, in stress-induced tachycardia. Further, the data illustrate the effectiveness of short-term treatment with antisense oligomers on physiological responses.     

Long-term cardiovascular safety of psychostimulants in children with attention deficit hyperactivity disorder

Objective: Side effects are a concern during psychostimulant treatment. Unfortunately, many previous studies only investigated short-term effects of psychostimulants in laboratory settings which lack clinical daily routines.

Methods: We examined 1042 patient records of patients with attention deficit hyperactivity disorder (ADHD) who were referred to a pediatric-psychiatry practice over 12?years. Data analysis was based on 466 children with ADHD who were newly treated with psychostimulants and who were not in treatment for elevated blood pressure. We analysed blood pressure percentiles, heart rate and BMI percentiles.

Results: There was a decrease in systolic and diastolic blood pressure percentiles. Heart rate was not affected. BMI slightly declined in girls.

Conclusions: In general psychostimulants were safe. To further elucidate negative effects of psychostimulants, long-term controlled and randomized studies in naturalistic settings are of interest.     

Melanocortin-4 receptor activation stimulates hypothalamic brain-derived neurotrophic factor release to regulate food intake, body temperature and cardiovascular function

In the present study, we aimed to investigate the neuromodulatory role played by hypothalamic brain-derived neurotrophic factor (BDNF) in the regulation of acute cardiovascular and feeding responses to melanocortin-4 receptor (MC4R) activation. In vitro, a selective MC4R agonist, MK1, stimulated BDNF release from isolated rat hypothalami and this effect was blocked by preincubation with the MC3/4R antagonist SHU-9119. In vivo, peripheral administration of MK1 decreased food intake in rats and this effect was blocked by pretreatment with an anti-BDNF antibody administered into the third ventricle. When anorexia was induced with the cannabinoid-1 receptor (CB1R) antagonist AM251, the anti-BDNF antibody did not prevent the reduction in food intake. Peripheral administration of MK1 also increased mean arterial pressure, heart rate and body temperature. These effects were prevented by pretreatment with the anti-BDNF antibody whereas the intracerebroventricular administration of BDNF caused changes similar to those of MK1. These findings demonstrate for the first time that activation of MC4R leads to an acute release of BDNF in the hypothalamus. This release is a prerequisite for MC4R-induced effects on appetite, body temperature and cardiovascular function. By contrast, CB1R antagonist-mediated anorexia is independent of the MC4R/BDNF pathway. Overall, these results show that BDNF is an important downstream mediator of the MC4R pathway.     

Arginine-vasopressin inhibits centrally induced pressor responses by involving hippocampal mechanisms

Administration of arginine-vasopressin (AVP) or prolyl-leucyl-glycinamide (PLG) into a lateral cerebral ventricle reduced the magnitude of systolic blood pressure increase (pressor response) induced by electrical stimulation of the mesencephalic reticular formation (MRF) in urethane-anesthetized rats. Bilateral destruction of the dorsal hippocampus prevented the action of AVP on the pressor response. However, the effect of PLG was only slightly reduced by hippocampal lesion. Microinjection of AVP in the dentate area of the dorsal hippocampus mimicked the action of intracerebroventricularly administered peptides. The effect of a single injection of AVP lasted at least for 60 min. Neither hippocampal damage nor peptide administrations resulted in changes in mean arterial blood pressure (basal BP). Bradycardiac response accompanied the BP increase during MRF stimulation. Hippocampal damage or intracerebroventricular administration of AVP and PLG failed to affect the cardiac response. Injection of AVP into the hippocampus tended to reduce the magnitude of cardiac responses caused by MRF stimulation. It is suggested that the inhibition by AVP of a pressor response produced by MRF stimulation involves the dorsal hippocampus. The action of PLG or related peptides seems to be, at least in part, through mechanisms not involving the hippocampus.     

Assessment of cardiovascular autonomic dysfunction in multiple system atrophy

Because heart rate is controlled mainly by the autonomic nervous system, cardiovascular autonimic dysfunction may contribute to the prognosis of patients with multiple system atrophy (MSA). To clarify cardiovascular autonomic dysfunctions in MSA, the authors investigated the relation between blood pressure (BP) and pulse rate (PR), and assessed a power spectral analysis of heart rate variability (HRV) during the clinical course using ambulatory BP and a heart rate monitor for 24 hours. The authors studied seven patients with MSA (five men and two women, aged 61.0±5.8 years) and seven healthy volunteers (four men and three women, aged 58.0±6.6 years) without hypertension, heart disease, or intracranial lesions. The MSA group showed abnormal circadian variations of BP and PR and a significantly decreased correlation coefficient between BP and PR. A significant decrease and altered circadian variation also existed in the number of changes in successive R-R intervals greater than 50 msec (RR50) and in the power of the high- and low-frequency component of HRV. The authors observed a significant negative correlation between the duration of illness and the number of changes in successive R-R intervals greater than 50 msec. The characteristic dysautonomia in MSA was a decrease in sympathetic and parasympathetic activity, with an abnormal circadian rhythm of BP and HRV. The balance between sympathetic and parasympathetic activity was also impaired. The parasympathetic modulation represented by RR50 worsened according to the development of the illness. Those autonomic dysfunctions may have affected the cardiovascular systems, which may indicate a poor prognosis in patients with MSA. An analysis of HRV and the circadian rhythm of BP and HRV are useful in evaluating cardiac autonomic dysfunctions in MSA.