埃他卡林对压力超负荷大鼠心室重构和血浆中PGI2的影响

目的：观察埃他卡林（IPT）对压力超负荷大鼠心室重构的影响,探讨其保护作用与血浆中前列环素（PGI2）的关系。方法：SD大鼠经腹主动脉缩窄6周后诱导压力超负荷高血压模型,随机分为5组（n=9）：①假手术组;②模型组;③IPT 3mg／kg组（IPT 3）;④吲哚美辛2mg/kg（Indo2）组;⑤IPT 3mg／kg＋吲哚美辛2mg／kg（IPT 3＋Indo2）组。RM-6000八导生理记录仪记录血流动力学改变,称量计算心脏重量指数,HE染色和iassort’s染色观察心肌组织病理学改变,比色法检测心肌组织羟脯氨酸含量,放免法检测血浆中PGI2含量。结果：腹主动脉缩窄6周后,与假手术组相比,模型组大鼠出现了明显的高血流动力学状态和心室重构,血浆中PGI2含量也明显降低。而IPT 3mg／kg实验治疗6周可明显改善上述变化。单用吲哚美辛可进一步恶化大鼠的高血流动力学状态和心室重构,合用肼可明显改善高血流动力学状态和心肌纤维化,明显抑制血浆中PGI2含量的降低。结论：IPT可明显逆转腹主动脉缩窄／压力超负荷大鼠的心室重构,其机制可能与胛作用于内皮细胞上的KATP通道,恢复内皮细胞的分泌功能增加PGI2的合成和分泌密切相关。     

埃他卡林对低氧暴露大鼠脑和肺微动脉选择性扩张作用

目的:研究低氧暴露对大鼠脑和肺微动脉内皮功能的影响以及埃他卡林(Ipt)对以上微动脉的扩张作用特征。方法:将雄性SD大鼠随机分为2组,常压常氧组(control)和低氧暴露组(hypoxic),后者置于常压低氧暴露舱内(O27.8%)8 h。分离大鼠管径为(204±5)μm的脑基底动脉、肺微动脉组织,利用DMT微血管张力测定仪在6nmol/L内皮素-1(ET-1)致血管预收缩条件下,利用乙酰胆碱(ACh)考察微动脉内皮功能及观察不同浓度Ipt对脑和肺微动脉张力变化的影响。结果:与常压常氧组对比,10-5 mol/L乙酰胆碱(ACh)对低氧暴露脑肺微动脉扩张率显著降低(P0.05);新型ATP敏感性钾通道开放剂Ipt在(10-11~10-3)mol/L对低氧暴露肺微动脉呈剂量依赖性扩张作用,明显强于对常压常氧组(P0.01),在(10-11~10-3)mol/L对低氧暴露脑微动脉呈剂量依赖性扩张作用,但与常压常氧组相比无显著差异。结论:低氧暴露可导致脑基底动脉和肺微动脉内皮功能受损,Ipt具有选择性增强扩张低氧暴露肺微动脉的作用,但不影响以上条件低氧暴露后脑基底动脉的扩张作用,提示该药可应用于改善低氧暴露所致的肺微血管收缩,为Ipt发展为新型治疗肺动脉高压的药物提供理论基础。     

新型钾通道开放剂对心血管ATP-敏感性钾通道基因表达的调节作用

目的：研究脂肪胺类的新型钾通道开放剂（KCO）埃他卡林（Ipt）和氰胍类的KCO吡那地尔（Pin）对大鼠心血管ATP-敏感性钾通道（KATP）的亚基SUR1、SUR2、Kir6．1和Kir6．2等在mRNA水平的调节作用。方法：SD大鼠给药1周后处死并取组织,提取总RNA,利用反转录-聚合酶链式反应（RT-PCR）研究以上基因在mRNA水平的改变。结果：与正常对照相比,心脏组织中,Ipt和Pin对KATP的4个亚基在mRNA水平均无显著影响;主动脉平滑肌上,Ipt对4个亚基的mRNA表达无显著影响,但Pin可显著上调SUR2的mRNA表达;尾动脉平滑肌上,Ipt对Kit6．1／Kit6．2、Pin对SUR2／Kir6．1均有显著下调的作用。结论：心肌、大动脉平滑肌和小动脉平滑肌KATP基因表达的调控不同,Ipt选择性调节小动脉平滑肌Kit6．1／Kit6．2;Ipt对心血管KATP基因表达的调节作用不同于Pin。     

ATP-sensitive potassium channel opener iptakalim protected against the cytotoxicity of MPP+ on SH-SY5Y cells by decreasing extracellular glutamate level

Mounting evidence reveals that ATP-sensitive potassium (K(ATP)) channel openers (KCOs) exert significant neuroprotection in vivo and in vitro in several models of Parkinson's disease (PD). However, the mechanisms are not well understood. In this study, we demonstrated that SH-SY5Y cells expressed mRNA and proteins for Kir6.1, Kir6.2, SUR1 and SUR2 subunits of K(ATP) channels. Moreover, our results showed that 1-methyl-4-phenyl-pyridinium ion (MPP+) induced up-regulation of mRNA for the Kir6.2 subunit and down-regulation of SUR1. It was further found that pretreatment with iptakalim, a novel K(ATP) channel opener, could attenuate increased extracellular glutamate level and decreased cell survival in SH-SY5Y cell culture after exposure to MPP+. Trans-pyrrolidine-2, 4-dicarboxylic acid (t-PDC), a glutamate transporter inhibitor, partially blocked the effect of iptakalim decreasing extracellular glutamate level. Additionally, iptakalim prevented MPP+-induced inhibition of glutamate uptake in primary cultured astrocytes. The beneficial effects of iptakalim on glutamate uptake of astrocytes were abolished by selective mitochondrial K(ATP) (mitoK(ATP)) channel blocker 5-HD. These results suggest (i) K(ATP) channel dysfunction may be involved in the mechanisms of MPP+-induced cytotoxicity and (ii) iptakalim may modulate glutamate transporters and subsequently alleviate the increase of extracellular glutamate levels induced by MPP+ through opening mitoK(ATP) channels, thereby protecting SH-SY5Y cells against MPP+-induced cytotoxicity.     

ATP-sensitive potassium channel opener iptakalim protects against MPP-induced astrocytic apoptosis via mitochondria and mitogen-activated protein kinase signal pathways

Inhibition of astrocytic apoptosis has been regarded as a novel prospective strategy for treating neurodegenerative disorders such as Parkinson's disease. In the present study, we demonstrated that iptakalim (IPT), an ATP-sensitive potassium channel (K(ATP) channel) opener, exerted protective effect on MPP(+)-induced astrocytic apoptosis, which was reversed by selective mitochondrial K(ATP) channel blocker 5-hydroxydecanoate. Further study revealed that IPT inhibited glutathione (GSH) depletion, mitochondrial membrane potential loss and subsequent release of pro-apoptotic factors (cytochrome c and apoptosis-inducing factor (AIF), and c-Jun NH(2)-terminal kinase/mitogen-activated protein kinases (MAPK) phosphorylation induced by MPP(+). Meanwhile, extracellular signal-regulated kinase (ERK) 1/2 inhibitor PD98059 inhibited the protective effect of IPT on MPP(+)-induced astrocytic apoptosis. Furthermore, IPT could also activate ERK/MAPK and maintain increased phospho-ERK1/2 level after MPP(+) exposure. Taken together, these findings reveal for the first time that IPT protects against MPP(+)-induced astrocytic apoptosis via inhibition of mitochondria apoptotic pathway and regulating the MAPK signal transduction pathways by opening mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels in astrocytes. And targeting K(ATP) channels expressed in astrocytes may provide a novel therapeutic strategy for neurodegenerative disorders.     

Activation of ATP‐sensitive potassium channels facilitates the function of human endothelial colony‐forming cells via Ca2+/Akt/eNOS pathway

Accumulating data, including those from our laboratory, have shown that the opening of ATP‐sensitive potassium channels (K_ATP) plays a protective role in pulmonary vascular diseases (PVD). As maintainers of the endothelial framework, endothelial colony‐forming cells (ECFCs) are considered excellent candidates for vascular regeneration in cases of PVD. Although K_ATP openers (KCOs) have been demonstrated to have beneficial effects on endothelial cells, the impact of K_ATP on ECFC function remains unclear. Herein, this study investigated whether there is a distribution of K_ATP in ECFCs and what role K_ATP play in ECFC modulation. By human ECFCs isolated from adult peripheral blood, K_ATP were confirmed for the first time to express in ECFCs, comprised subunits of Kir (Kir6.1, Kir6.2) and SUR2b. KCOs such as the classical agent nicorandil (Nico) and the novel agent iptakalim (Ipt) notably improved the function of ECFCs, promoting cell proliferation, migration and angiogenesis, which were abolished by a non‐selective K_ATP blocker glibenclamide (Gli). To determine the underlying mechanisms, we investigated the impacts of KCOs on CaMKII, Akt and endothelial nitric oxide synthase pathways. Enhanced levels were detected by western blotting, which were abrogated by Gli. This suggested an involvement of Ca²⁺ signalling in the regulation of ECFCs by K_ATP. Our findings demonstrated for the first time that there is a distribution of K_ATP in ECFCs and K_ATP play a vital role in ECFC function. The present work highlighted a novel profile of K_ATP as a potential target for ECFC modulation, which may hold the key to the treatment of PVD.     

Therapeutic intervention against deacclimatization to high altitude

The incidence of deacclimatization to high altitude syndrome （DAHAS） prevailed up to 80% in highland troops, and 100% in manual workers, and severe DAHAS could significantly affects patients＇ health, work and life. So it is imperative to develop effective prevention and treatment measures for DAHAS. The present review analyzes effective prophylactic and therapeutic measures against DAHAS, implemented at our hospital.