吸入麻醉药后处理心肌保护作用的研究进展

吸入麻醉药可模拟缺血后处理发挥心肌保护效应,因为能够在心肌缺血后早期再灌注时实施而有着广泛的临床应用前景。吸入麻醉药后处理产生的心肌保护作用与抑制钙超载、增强一氧化氮的保护作用、激活再灌注损伤补救激酶途径、开放三磷酸腺苷敏感性钾通道和抑制线粒体通透性转换孔开放等机制有关,现就吸入麻醉药后处理对心肌缺血-再灌注损伤的保护作用及其机制做一综述。     

缺血后处理对心肌缺血再灌注的保护机制研究进展

缺血后处理(ischemic postconditioning)是在长时间缺血后再灌注早期,对心脏进行数次短暂的再灌注/缺血处理的方法。研究表明,缺血后处理与预处理一样能减轻再灌注心肌的损伤。其保护心肌的作用可能与抑制自由基生成、减轻钙超载、激活蛋白激酶、内源性生成物(如腺苷、阿片肽、一氧化氮等)激活、线粒体的ATP敏感性钾通道开放和线粒体通道转换孔关闭有关。现就后处理对心肌缺血再灌注的保护作用及其机制作一简要综述。     

缺血后处理抑制TLR2信号通路对大鼠缺血再灌注脑损伤的保护作用

目的研究缺血后处理对局灶性缺血和再灌注所造成脑损伤和神经炎症的影响。方法将成年雄性Wistar大鼠随进分为假手术组、局灶性缺血组、缺血后处理组。通过大脑中动脉闭塞术制备局灶性缺血,缺血后处理即在缺血后2 h进行3次30 s/30 s的再灌注/再阻塞。对脑梗死体积、神经系统功能、肿瘤坏死因子(TNF)-α和白细胞介素(IL)-1β的转录水平、TNF-α、IL-1β和TLR2的表达水平进行检查。结果缺血后处理组的脑梗死体积显著小于局灶性缺血组,神经系统功能也得到显著改善。此外,缺血后处理组抑制了TNF-α和IL-1β的转录,及TNF-α、IL-1β和TLR2的表达。结论缺血后处理组可以保护由局灶性缺血/再灌注造成的脑损伤并改善其神经系统功能,这与TNF-α和IL-1β转录的弱化,及TNF-α、IL-1β、TLR2表达的抑制有关。     

AMPK与心肌缺血-再灌注损伤

心肌缺血-再灌注损伤是急性心肌梗死后溶栓疗法、经皮冠状动脉介入治疗、冠状动脉旁路移植术后心肌损伤的重要机制之一。单磷酸腺苷激活的蛋白激酶(AMPK)不仅是细胞内能量代谢的重要调控因子,而且能通过抗氧化应激、内质网应激、抑制凋亡、调节自噬、抗炎、参与缺血预处理或缺血后处理等心肌保护效应减轻心肌缺血-再灌注损伤。因此,AMPK对防治心肌缺血-再灌注损伤有潜在的临床意义。     

一氧化氮与肢体缺血再灌注后肺损伤

一氧化氮（NO）参与了肢体缺血再灌注后肺损伤，一方面内皮型NO减少参与了肺动脉高压的形成、引起器官的灌注量不足、促进“无复流”现象的发生，另一方面诱导型NO升 高则可能通过降低血管的反应性维持器官的灌注，抗血小板和白细胞聚集，参与中性粒细胞的呼吸爆发，发挥非特异性的免疫功能、清除氧自由基、抑制脂质过氧化等而起代偿性的保护作用。NO生成过多或不足也会对机体产生不利的影响。     

Nrf2及其信号通路在肝缺血再灌注损伤中作用的研究进展

肝缺血再灌注损伤是临床上常见的一种肝脏损伤类型.核因子红细胞2相关因子2(Nrf2)可以通过抑制氧化应激、抗炎、抑制细胞凋亡等多种作用来减轻肝脏缺血再灌注损伤.在肝缺血再灌注损伤中起作用的Nrf2相关信号通路主要有KEAP-Nrf2-ARE通路、DOR-PKC-Nrf2通路、Sirt1-Nrf2信号通路、PI3K-AK...     

中风Ⅱ号干预缺血性中风损伤级联反应的实验研究

目的：探讨中药中风Ⅱ号干预缺血性中风损伤的效果及机制,方法：采用单侧结扎沙土鼠颈总动脉的方法制成局灶性缺血性中风动物模型。将45只沙土鼠随机分成3组,即模型组,生理盐水组,中风Ⅱ号组,结果：（1）中风Ⅱ号在3小时内无明显抑制谷氨酸（Glu)效果,而在6小时内则明显抑制Glu释放;（2）中风Ⅱ号能显抑制由缺血缺氧造成的神经细胞及脑间质性水肿,及迟发性神经细胞凋亡。结论：中风Ⅱ号可增强脑组织缺血,缺氧的耐受性,减轻其缺氧损害,有临床应用价值。     

一氧化氮与缺血缺氧性脑损伤时的神经元凋亡

一氧化氮与缺血缺氧性神经元凋亡有着密切联系，缺血性脑损伤时，一氧化氮的过量合成可介导谷氨酸兴奋性毒性，氧化应激，直接损伤DNA影响基因表达及线粒体功能和能量代谢，细胞内Ca^2 上调等途径诱导，促进神经元凋亡，同时，也可通过bcl-2,cGMP依赖途径及抑制细胞色素C释放，降低caspase活性等抑制神经元凋亡。     

RNA干扰在缺血损伤中的研究现状

RNA干扰(RNAi)是一种转录、转录后、翻译不同水平的基因沉默机制,其可能通过诱导靶基因的染色质结构改变,使靶基因的转录受阻或者抑制靶mRNA的翻译,令靶蛋白表达受阻,从而达到高效特异地阻断基因表达的目的.     

缺血半暗带缺血瀑布及其干预

近年来，缺血半暗带（Ischemicpenumbra，IP）和缺血损伤的链式反应-缺血瀑布（Ischermccascade，IC）已成为缺血性中风的研究热点之一，它有可能成为中风治疗的突破点。本文对其研究方法、损伤机理和可干预这些病理过程的神经保护药物综述如下。一、IP的病理生理过程IP是一个围绕缺血核心、脑血流界于严重的缺血核心和正常脑组织之间的区域［1］。目前有学者提出IP的新概念：“潜在的可挽救的脑缺血组织”［2］。这个新概念拓展了IP的内涵，可根据不同特征将IP分类为：电生理IP（自发电活动受抑制而离子稳态和膜电位正常）；血流IP…     

Activation of G i -coupled receptors releases a tonic state of inhibited platelet aggregation

Single-receptor pharmacology does not satisfactorily explain the physiology of the ADP-induced platelet aggregation response. It has been shown that, in addition to G q -coupled receptor activation, one G i -coupled receptor, either the ADP P or the f -adrenoceptor, is required for elicitation of aggregation. The underlying mechanism of this action, however, has not been elucidated. By systematically assaying the entire time course of the aggregation and its fade using two methods of aggregometry, we have investigated the role of graded activation of these two G i -coupled receptors. We demonstrate that constant activation of either of two G q coupled receptors, the ADP P2Y 1 or the 5-HT 2A , and incremental activation of either of the two G i -coupled receptors, tightly regulates the aggregation response in vitro , through the apparent release of a tonic inhibition of platelet aggregation. This tightly regulated release of inhibition, which appears analogous to the phenomena of disinhibition observed in the central nervous system, may be instrumental for the continuous adaptation of the aggregation response to variable physiological conditions.     

β3肾上腺素受体介导的脂解作用与缺血性心衰的关系（英文）

β3肾上腺素受体（β3AR）是新发现的受体,主要参与脂肪组织甘油三酯的降解,产生能量;心衰时心脏中β3AR上调;心肌缺血缺氧时,内源性脂解作用可维持心肌的收缩性;为了维持心功能慢性缺血性心衰代偿期很可能存在能量代谢重建:在神经内分泌激活的同时,以外源性游离脂肪酸（FFA）为主要能量底物,心脏缺血缺氧进一步加重时,β3AR代偿性上调并介导心肌细胞的内源性脂解供能,葡萄糖经由3-磷酸甘油参与合成内源性三酰甘油再脂解而间接供能,葡萄糖的氧化被抑制,此时心肌细胞兼有类似脂肪细胞的功能。心衰时β3AR上调是能量代谢代偿的结果。但上调的β3AR长期过度激活有可能引起心肌组织继发性肉碱缺乏,导致ATP生成障碍使心衰失代偿,因而在心衰失代偿期β3AR阻滞剂可能有利于缓解心衰。而（β3AR激动药最终表现为正性肌力作用还是负性肌力作用,要看在具体的作用部位它对β3AR的直接效应与其对胰岛素的继发效应二者的力量对比）。从理论上讲,β3AR激动药用于慢性缺血性心衰代偿期,既可改善心肌的能量代谢,产生正性肌力作用,又可降低动脉血压,降低心脏的前负荷,从而改善心功能;β3AR激动药还可改善与心衰并存的胰岛素抵抗。心脏能量代谢的缺陷越来越被认为在心衰的进展中起着重要的决定性作用,心脏的代谢适应和适应不良是很有前景的药物治疗新靶点。     

硝酸甘油及线粒体乙醛脱氢酶对心肌保护作用的研究进展

缺血预处理是预防心脏缺血再灌注损伤有效的方法之一,近来发现:药物预处理也能够模拟缺血预处理的机制,减轻心肌缺血再灌注损伤。硝酸甘油预处理能保护心肌,减轻缺血再灌注损伤;其机制与预处理保护机制中线粒体内信号通路有关。线粒体乙醛脱氢酶是硝酸甘油的主要代谢酶,其本身活性的增高也能减轻心肌缺血再灌注损伤。     

The Problem of Persistent Platelet Activation in Acute Coronary Syndromes and Following Percutaneous Coronary Intervention

Platelets play a central role in the atherosclerotic inflammatory response, thrombotic vascular occlusion, microembolization, vasoconstriction, and plaque progression. Persistent platelet activation poses a serious problem among patients with acute coronary syndromes (ACS) and those who have undergone percutaneous coronary intervention (PCI), placing them at risk for ischemic events and subacute stent thrombosis. Patients undergoing PCI are at risk for further ischemic events because of procedure‐related platelet activation as well as the inherent persistent platelet hyperreactivity and enhanced thrombin generation associated with ACS. Persistent platelet activation following an acute coronary event and/or PCI supports incorporating antiplatelet strategies into the standard medical management of such patients. In this clinical setting, antiplatelet therapies are capable of improving outcomes. Aspirin, thienopyridines, and glycoprotein IIb/IIIa inhibitors, the 3 major pharmacologic approaches to persistent platelet activation, target various levels of the hemostatic pathways and thrombus formation. Copyright © 2008 Wiley Periodicals, Inc.     

Role of extracellular matrix metalloproteinases in cardiac remodelling

The latent collagenolytic system is an intrinsic part of normal myocardium. Controlled activation of this system becomes necessary in ventricular chamber remodeling following inflammation and injury, such as dilated cardiomyopathy and myocardial infarction. Evidence exists to indicate activation of collagenolytic enzymes in patients with congestive heart failure and dilated, dysfunctional ventricles due to cardiomyopathy and ischemic heart disease.     

Slow Wall Motion Rather Than Electrical Conduction Delay Underlies Mechanical Dyssynchrony in Postinfarction Patients With Narrow QRS Complex

Post-MI Narrow QRS Dyssynchrony.   Introduction: The mechanism of mechanical dyssynchrony in postinfarction patients with a narrow QRS complex is not defined but essential for cardiac resynchronization therapy (CRT).
Methods and Results: Left ventricular electrical activation and subsequent wall motion were recorded for 16 patients with ischemic cardiomyopathy during intrinsic rhythm using a modified NOGA electromechanical mapping system. Ten patients presented mechanical dyssynchrony on tissue Doppler imaging, while 6 patients served as control subjects. The local activation time (LAT) was set by the maximum downslope of the unipolar electrogram. Local wall motion time (LMT) was defined as the time needed for the catheter tip to traverse half of its maximum inward deflection during systole. LAT and LMT were measured relative to the onset of the QRS complex. Electrical activation showed a septal-to-lateral pattern in all patients with a mean endocardial activation time of 65 ± 13 ms. Control subjects exhibited 97.5% of all LMTs <290 ± 17 ms. Delayed motion areas (cut-off LMT > 300 ms) showed no slowing of conduction. Wall motion time corrected for differences in electrical activation (LMT-LAT) was significantly longer in delayed (289 ± 34 ms) than in regular (204 ± 24 ms) motion areas (P = 0.002). Delayed motion segments were hypokinetic on echocardiography and presented a lower maximum inward motion (9.9 ± 1.1 mm) compared to regular segments (10.9 ± 1.2 mm) on electromechanical maps (P = 0.004). Viability, however, was preserved with unipolar and bipolar voltage amplitude >7 mV and >1.5 mV for 79% of all delayed motion areas.
Conclusion: Dyssynchronous segments of an ischemic myocardium show unimpaired local activation but slow wall motion, thereby limiting the benefit of ventricular preexcitation via CRT. (J Cardiovasc Electrophysiol, Vol. 21, pp. 70–77, January 2010)     

Redox signaling at reperfusion is required for protection from ischemic preconditioning but not from a direct PKC activator

Redox signaling prior to a lethal ischemic insult is an important step in triggering the protected state in ischemic preconditioning. When the preconditioned heart is reperfused a second sequence of signal transduction events, the mediator pathway, occurs which is believed to inhibit mitochondrial permeability transition pore formation that normally destroys mitochondria in much of the reperfused tissue. Prominent among the mediator pathway’s events is activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase. Recently it was found that both activation of PKC and generation of reactive oxygen species (ROS) at the time of reperfusion are required for protection in preconditioned hearts. To establish their relative order we tested whether ROS formation at reperfusion is required in hearts protected by direct activation of PKC at reperfusion. Isolated rabbit hearts were exposed to 30 min of regional ischemia and 2 h of reperfusion. Preconditioned hearts received 5 min of global ischemia and 10 min of reperfusion prior to the index ischemia. Another group of preconditioned hearts was exposed to 300 μM of the ROS scavenger N-(2-mercaptopropionyl) glycine (MPG) for 20 min starting 5 min prior to reperfusion. Infarct size was measured by triphenyltetrazolium staining. Preconditioning reduced infarct size from 36% ± 2% of the ischemic zone in control hearts to only 18 ± 2%. MPG during early reperfusion completely blocked preconditioning’s protection (33 ± 3% infarction). MPG given in the same dose and schedule to non-preconditioned hearts had no effect on infarct size. In the last group phorbol 12-myristate 13-acetate (PMA) (0.05 nM) was given to non-preconditioned hearts from 1 min before to 5 min after reperfusion in addition to MPG administered as in the other groups. MPG did not block protection from an infusion of PMA as infarct size was only 9 ± 2% of the risk zone. We conclude that while redox signaling during the first few minutes of reperfusion is an essential component of preconditioning’s protective mechanism, this step occurs upstream of PKC activation. Returned for 1. revision: 29 August 20071. Revision received: 19 September 2007     

Ischemic preconditioning blocks BAD translocation, Bcl-xL cleavage, and large channel activity in mitochondria of postischemic hippocampal neurons

Transient forebrain or global ischemia induces delayed neuronal death in vulnerable CA1 pyramidal cells with many features of apoptosis. A brief period of ischemia, i.e., ischemic preconditioning, affords robust protection of CA1 neurons against a subsequent more prolonged ischemic challenge. Here we show that preconditioning acts via PI3K/Akt signaling to block the ischemia-induced cascade involving mitochondrial translocation of Bad, assembly of Bad with Bcl-x(L), cleavage of Bcl-x(L) to form its prodeath fragment, DeltaN-Bcl-x(L), activation of large-conductance channels in the mitochondrial outer membrane, mitochondrial release of cytochrome c and Smac/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI), caspase activation, and neuronal death. These findings show how preconditioning acts to prevent the release of cytochrome c and Smac/DIABLO from mitochondria and to preserve the integrity of the mitochondrial membrane. The specific PI3K inhibitor LY294002 administered in vivo 1 h before or immediately after ischemia or up to 120 h later significantly reverses preconditioning-induced protection, indicating a requirement for sustained PI3K signaling in ischemic tolerance. These findings implicate PI3K/Akt signaling in maintenance of the integrity of the mitochondrial outer membrane.     

Update on ischemic colitis: from etiopathology to treatment including patients of intensive care unit

Ischemic colitis is the result of colonic hypoperfusion and is regarded as a relatively rare condition. It can be roughly classified as occlusive and non-occlusive. Pathogenesis includes a usually transient compromise in the colonic vasculature, with a parallel activation of an inflammatory cascade caused primarily by reperfusion. Diagnosis of ischemic colitis remains often difficult and requires a combination of diagnostic techniques, whereas clinical signs are occasionally only seen late as complications. Gold standard is considered to be colonoscopy. Clinical presentation and treatment of ischemic colitis vary widely depending on the degree of ischemia. Patients of intensive care unit (ICU) with ischemic colitis are often under-diagnosed, since the parallel co-morbidities and the nonspecific nature of symptoms that mimic almost any abdominal pathology, can mislead the doctor. Moreover, sedated or ventilated patients can mask many of the characteristic features of ischemic colitis and make the diagnosis challenging. Bedside colonoscopy and diagnostic laparoscopy in ICUs are two options, which seem lately to be reliable and promising in diagnosing ischemic colitis in critically ill patients.