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diazoxide preconditioning plus subsequent hypothermia increased resistance of rat cultured hippocampal neurons against hypoxia-reoxygenation injury

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Chinese Medical Journal 2006年第11期119卷 887-893页

作者： LIU Rong-guo WANG Wei-jian S0NG Na CHEN Yan-qing LI Li-huan Department of Anesthesiology Fujian Provincial Hospital Fuzhou 350001 China Department of Anesthesiology First Affiliated Hospital of Wenzhou Medical College Wenzhou 325000China Department of Anesthesiology Cardiovascular Institute Fuwai Hospital Peking Union Medical college and Chinese Academy of Medical Sciences Beijing 100037 China

Background Cerebral ischemia-reperfusion/hypoxia-reoxygenation insult triggers lots of pathophysiological and biochemical events that separately affect the evolution of cerebral damage. Accordingly, all known effective neuroprotective measures should be taken to get the optimal efficacy of therapy. This study was undertaken to investigate whether diazoxide （DZ） preconditioning combined with the following hypothermia could contribute to synergistic neuroprotection compared with either hypothermia or DZ preconditioning alone. Methods Cultured for 9-10 days in vitro, the hippocampal neurons of SD rats were preconditioned with DZ 0 pmol/L or DZ 250 pmol/L for 1 hour per day and this treatment lasted for 3 days. Subsequently, neurons were subjected to deprivation of oxygen for 4 hours at 37°0, 34°C, 30℃ and 22℃, respectively. This experiment consisted of 8 groups （4 temperature groups and 4 combination groups） and each group contained 12-well or 2-dish cells. Survival rate, expression of Bcl-2, fluorescence magnitude of intracellular calcium, and concentration of malondialdehyde （MDA） were determined at 24 hours after reoxygenation. Results The survival rate and expression of Bcl-2 were both increased in individually hypothermic conditions compared with those at 370G （P〈0.05）, whereas intracellular calcium and MDA did the opposite exhibition simultaneously （P〈0.05）. 22℃ contributed to a higher survival rate and greater expression of Bcl-2 in comparison with other hypothermia （P〈0.05）. Preceding administration of 250 pmol/L DZ took the similar effects on the neurons like hypothermia. Moreover, compared with individual hypothermia or DZ preconditioning, the neuronal survival rate and expression of Bcl-2 in the combination group were increased significantly （P〈0.05）, whereas the calcium fluorescence density and concentration of MDA were reduced further （P〈0.05）. 250 Iamol/L DZ preconditioning combined with 22℃ provided a maximal neuroprotection. Conclusions Compared with ei

关键词： diazoxide hypothermia proto-oncogene protein c-bcl-2 calcium malondialdehyde

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diazoxide preconditioning antagonizes cytotoxicity induced by epileptic seizures

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Neural Regeneration Research 2013年第11期8卷 1000-1006页

作者： Qingxi Fu Zhiqing Sun Jinling Zhang Naiyong Gao Faying Qi Fengyuan Che Guozhao Ma Department of Neurology Linyi People's Hospital Department of Neurology Shandong Provincial Hospital Shandong University

diazoxide, an activator of mitochondrial ATP-sensitive potassium channels, can protect neurons and astrocytes against oxidative stress and apoptosis. In this study, we established a cellular mode of epilepsy by culturing hippocampal neurons in magnesium-free medium, and used this to investigate effects of diazoxide preconditioning on the expression of inwardly rectifying potassium channel （Kir） subunits of the ATP-sensitive potassium. We found that neuronal viability was significantly reduced in the epileptic cells, whereas it was enhanced by diazoxide preconditioning. Double immunofluorescence and western blot showed a significant increase in the expression of Kir6.1 and Kir6.2 in epileptic cells, especially at 72 hours after seizures. diazoxide pretreatment completely reversed this effect at 24 hours after seizures. In addition, Kir6.1 expression was significantly upregulated compared with Kir6.2 in hippocampal neurons after seizures. These findings indicate that diazoxide pretreatment may counteract epileptiform discharge-induced cytotoxicity by suppressing the expression of Kir subunits.

关键词： neural regeneration ATP-sensitive potassium channel activator of mitochondrial ATP-sensitivepotassium channel epilepsy diazoxide inwardly recti^ing potassium channel subunit hippocampal neuron cytotoxicity neuroprotection grants-supported paper neuroregeneration

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Neuroprotective effects of a mitochondrial K^+-ATP channel opener (diazoxide) are mediated by Bcl-2 expression upregulation

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Neural Regeneration Research 2011年第12期6卷 956-960页

作者： Majid Katebi Mansooreh Soleimani Mehdi Mehdizadeh Department of Anatomy School of MedicineHormozgan University of Medical Sciences Cellular and Molecular Research Center Tehran University of Medical Sciences Department of Anatomy School of MedicineTehran University of Medical Sciences Research Institute for Islamic & Complementary Medicine Tehran University of Medical Sciences

Mitochondrial K＋-ATP （mito-KATP） channels play an important role in cellular function and survival following ischemic stress. The present results revealed that intervention with diazoxide, a mito-KATP channel opener, led to an increase in Bcl-2 expression in the cerebral cortex of rats subjected to cerebral ischemia reperfusion injury. In addition, the intervention also led to clear improvements in neuronal mitochondrial morphology and consciousness post-injury. Glibenclamide a mito-KATP channel blocker, exhibited the converse effects. Both diazoxide and glibenclamide exerted dose-dependent effects （in particular, at 18 mg/kg diazoxide and 25 mg/kg glibenclamide）. These findings suggest that diazoxide exerts a neuroprotective effect on cerebral ischemia reperfusion injury by opening mito-KATP channels and upregulating Bcl-2 expression.

关键词： K-ATP channel Bcl-2 cerebral ischemia reperfusion injury diazoxide

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Effects of diazoxide Treatments on Electrophysiologyic Properties in Guinea Pig Papillary Muscles Undergoing Ischemia/Reperfusion

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2005年第3期25卷 257-259页

作者：杨运海韩召敏胡志伟张凯伦 Department of Cardiovascular Surgery Union Hospital Tongji Medical College Huazhong University of Science and Technology Department of Pharmacy Union Hospital Tongji Medical College Huazhong University of Science and Technology

The effects of diazoxide treatments on electrophysiologyic properties in guinea pig papillary muscles undergoing ischemia/reperfusion was studied using intracellular microelectrode technique. Twenty-four guinea pigs were randomly divided into three groups (n=8 in each group). In control group, *** solution was given. In experimental group, *** solution with diazoxide (100 mol/L) was given. In pretreatment group, the muscle was treated with diazoxide 20 min before arrested with *** cardioplegia. The results showed that the APD_50 and APD_90 in experimental and pretreatment groups were significantly shorter after 5 and 10 min reperfusion (Pdiazoxide is better than that of pretreatment with diazoxide or *** solution alone.

关键词： diazoxide cardioplegia electrophysiology cardioprotection

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Cardioprotective Effects of diazoxide on Myocardial Ischemia/Reperfusion Injury in Rats

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2006年第6期26卷 690-692页

作者：张凯伦赵静杨运海胡志伟 Department of Cardiovascular Surgery Union Hospital Tongji Medical College Huazhong University of Science and Technology

In order to study the cardioprotective effects of diazoxide on the myocardial ischemia/reperfusion injury of rats and mechanisms, the healthy SD rats were randomly divided into 2 groups： the rats in the experimental group were injected with diazoxide for preconditioning with the dosage of 12.5 mg/kg through the right femoral vein and those in the control group was only administered with the equal volume of media. After 10 rain, a left thoracotomy was performed and the left anterior descending branch was occluded for 2 h. Two h later, the left anterior descending branch was reperfused for 2 h and then the heart was quickly excised to be used for measurement of MDA, SOD and the infarct size, in situ cell apoptosis detection and observation of the cell ultrastructure by electron microscopy. The results showed that as compared with the control group, MDA, the infarct size and cell apoptosis in the experimental group were greatly reduced （P〈0.05）. And the cell ultrastructure was obviously improved, But the activity of SOD had no change （P〉0.05）. It was concluded that diazoxide could protect the rats from myocardial ischemia/reperfusion injury, which might be contributed to the reduction of lipid peroxidation and cell apoptosis.

关键词： diazoxide cardioprotection ischemia/reperfusion injury apoptosis rat

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Mechanism of diazoxide-mediated Cardioprotection

Mechanism of Diazoxide-mediated Cardioprotection

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第十五届国际药理学大会

作者： Mehta Neeraj arg Vivek Division of Pharmacology College of PharmacyOhio State University Columbus OHU.S.A. Division of Pharmacology College of PharmacyOhio State University Columbus OHU.S.A.

＜正＞ Ischemic preconditioning （IPC） can be mimicked by K+ channel openers such as diazoxide. diazoxide has multiple ATP-sensitive K+ channel （KATP）-indepen-dent actions, and the mechanism underlying diazoxidemediated cardioprotection remains inconclusive. Giving that the KATP pore-forming subunit Kir6.2-knock-out mice have shown no cardioprotection of IPC, we tested the hypothesis that diazoxide protects the heart by promoting import of Kir6.2-containing KATP into mitochondria from cytosol where they are synthesized. The effect of diazoxide on mitochondrial localization of Kir6.2 was examined in KATP deficient COS-7 cells transfected with HA tagged Kir6.2 and SUR2A by laser confocal microscopy. We found that the percentage of cells showing mitochondrial localization of Kir6.2 was significantly higher in diazoxide （100 micro M）-treated group than that in control group （68.0% vs. 11.0%）. The effect was almost completely prevented by the KATP channel inhibitors 5-hydroxydecanoate or glibenclamide, or a selective protein kinase C （PKC） inhibitor chelerythrine. We conclude that diazoxide increases Kir6.2-containing KATP channels in mitochondria by activation of PKC.

关键词： preconditioning diazoxide PKC

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氯苯甲噻二嗪(diazoxide)的评价

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国外医学参考资料.药学分册 1974年第5期 305-307页

作者：张楠森

恶性（即急进型）高血压的特征为舒张压突然升高并持续在130毫米汞柱以上,3～4级眼底病变,视神经乳头水肿,肾功能损害及脑病常见发生。氯苯甲噻二嗪为治疗恶性高血压及脑病的药物,快速静脉注射后可迅速减低舒张压。其化学结构式为: 氯... 详细信息

恶性（即急进型）高血压的特征为舒张压突然升高并持续在130毫米汞柱以上,3～4级眼底病变,视神经乳头水肿,肾功能损害及脑病常见发生。氯苯甲噻二嗪为治疗恶性高血压及脑病的药物,快速静脉注射后可迅速减低舒张压。其化学结构式为: 氯苯甲噻二嗪的化学结构虽与噻嗪类和尿药相似,但无利尿作用。本品的分子式为C8H7ClN2O2S,分子量230.67,熔点325℃。其性状为白色结晶、无嗅,略溶于水及碱性氢氧化物溶液,其水溶液可用氢氧化钠调节pH至11.6,澄明无色,在室温避光条件下可稳定二年,如变色失效,不可应用。作用原理

关键词：恶性高血压氯苯氯代烃降压效应血浆半衰期 diazoxide 快速静脉注射降压幅度舒张压高血糖

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diazoxide对乳鼠窦房结细胞模拟缺血-再灌注时的保护作用研究

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介入放射学杂志 2003年第S1期12卷 136-页

作者：仝识非宋治远钟理第三军医大学附属西南医院心内科重庆市介入心脏病学研究所重庆400038

目的　为探讨KATP通道开放剂diazoxide对模拟缺血再灌注时培养乳鼠窦房结细胞的保护作用及其可能机制。方法　分离乳鼠窦房结细胞 ,纯化培养 2d后进行实验。随机分为对照组、模拟缺血再灌注组 (I/R)、KATP通道开放剂diazoxide干预组... 详细信息

目的　为探讨KATP通道开放剂diazoxide对模拟缺血再灌注时培养乳鼠窦房结细胞的保护作用及其可能机制。方法　分离乳鼠窦房结细胞 ,纯化培养 2d后进行实验。随机分为对照组、模拟缺血再灌注组 (I/R)、KATP通道开放剂diazoxide干预组 (D +I/R)及KATP通道阻断剂 5 HD干预组 (5 HD +D +I/R及 5 HD +I/R)。以流式细胞计检测各组窦房结细胞存活率 ;用激光共聚焦显微镜测定各组窦房结细胞内钙。并采用全细胞膜片钳技术测定各组细胞L型钙 (L ICa)电流密度。结果　①D +I/R组窦房结细胞存活率 6 1.4 3%± 5 .14 %较I/R组显著增加 ;而 5 HD +D +I/R组 5 2 .35 %± 4 .94 %及 5 HD +I/R组 5 3.16 %±5 .35 %均较D +I/R组明显降低。②D +I/R组窦房结细胞相对荧光值较I/R显著降低 ;5 HD +D +I/R及5 HD +I/R两组均较D +I/R组显著增高。③D +I/R组窦房结细胞L ICa密度较I/R组显著增加。 5 HD +D +I/R组与 5 HD +I/R组的L ICa密度较D +I/R组明显减低。结论　KATP通道开放剂diazoxide降低窦房结细胞内钙负荷 ,对模拟缺血再灌注时的窦房结细胞有保护作用 ,并可对抗模拟缺血再灌注对窦房结细胞L型钙电流的影响。

关键词：再灌注模拟缺血窦房结心脏传导系统乳鼠 diazoxide 细胞

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Application of dezocine patient-controlled epidural analgesia in postoperative analgesia in patients with total myomectomy

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World Journal of Clinical Cases 2024年第20期12卷 4265-4271页

作者： Feng-Feng Ning Ting-Ting Yao Xiao-Xia Wang Department of Anesthesiology Gansu Provincial Maternity and Child-care HospitalLanzhou 730050Gansu ProvinceChina Department of Gynecology Gansu Provincial Maternity and Child-Care HospitalLanzhou 730050Gansu ProvinceChina

BACKGROUND Uterine fibroids are common benign gynecological *** who experience excessive menstruation,anemia,and pressure symptoms should be administered medication,and severe cases require a total *** procedure is invasive and causes severe postoperative pain,which can affect the patient’s postoperative sleep quality and,thus,the recovery *** To evaluate use of dezocine in patient-controlled epidural analgesia(PCEA)for postoperative pain management in patients undergoing total *** We selected 100 patients undergoing total abdominal hysterectomy for uterine fibroids and randomized them into two groups:A control group receiving 0.2%ropivacaine plus 0.06 mg/mL of morphine and an observation group receiving 0.2%ropivacaine plus 0.3 mg/mL of diazoxide in their *** assessed included pain levels,sedation,recovery indices,PCEA usage,stress factors,and sleep *** The observation group showed lower visual analog scale scores,shorter postoperative recovery indices,fewer mean PCEA compressions,lower cortisol and blood glucose levels,and better polysomnographic parameters compared to the control group(P<0.05).The cumulative incidence of adverse reactions was lower in the observation group than in the control group(P<0.05).CONCLUSION Dezocine PCEA can effectively control the pain associated with total myomectomy,reduce the negative impact of stress factors,and have less impact on patients’sleep,consequently resulting in fewer adverse effects.

关键词： diazoxide Patient-controlled epidural analgesia Total hysterectomy Sleep impacts Adverse effects

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Beneficial effects of adenosine triphosphate-sensitive K^+ channel opener on liver ischemia/reperfusion injury

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World Journal of Gastroenterology 2014年第41期20卷 15319-15326页

作者： Mateus Antunes Nogueira Ana Maria Mendona Coelho Sandra Nassa Sampietre Rosely Antunes Patzina Fabiano Pinheiro da Silva Luiz Augusto Carneiro D'Albuquerque Marcel Cerqueira Cesar Machado Department of Gastroenterology (LIM/37) Medical SchoolUniversity of Sao Paulo Department of Clinical Emergency (LIM/51) Medical SchoolUniversity of Sao Paulo

AIM:To investigate the effect of diazoxide administration on liver ischemia/reperfusion ***:Wistar male rats underwent partial liver ischemia performed by clamping the pedicle from the medium and left anterior lateral segments for 1 h under mechanical *** were divided into 3 groups:Control Group,rats submitted to liver manipulation,Saline Group,rats received saline,and diazoxide Group,rats received intravenous injection diazoxide(3.5 mg/kg) 15 min before liver reperfusion.4 h and 24 h after reperfusion,blood was collected for determination of aspartate transaminase(AST),alanine transaminase(ALT),tumor necrosis factor(TNF-α),interleukin-6(IL-6),interleukin-10(IL-10),nitrite/nitrate,creatinine and tumor growth factor-β1(TGF-β1).Liver tissues were assembled for mitochondrial oxidation and phosphorylation,malondialdehyde(MDA) content,and histologic *** vascular permeability and myeloperoxidase(MPO) were also ***:Four hours after reperfusion the diazoxide group presented with significant reduction of AST(2009 ± 257 U/L vs 3523 ± 424 U/L,P = 0.005); ALT(1794 ± 295 U/L vs 3316 ± 413 U/L,P = 0.005); TNF-α(17 ± 9 pg/mL vs 152 ± 43 pg/mL,P = 0.013; IL-6(62 ± 18 pg/mL vs 281 ± 92 pg/mL); IL-10(40 ± 9 pg/mL vs 78 ± 10 pg/mL P = 0.03),and nitrite/nitrate(3.8 ± 0.9 μmol/L vs 10.2 ± 2.4 μmol/L,P = 0.025) when compared to the saline group.A significant reduction in liver mitochondrial dysfunction was observed in the diazoxide group compared to the saline group(P diazoxide group showed a reduction of AST(495 ± 78 U/L vs 978 ± 192 U/L,P = 0.032); ALT(335 ± 59 U/L vs 742 ± 182 U/L,P = 0.048),and TGF-β1(11 ± 1 ng/mL vs 17 ± 0.5 ng/mL,P = 0.004) serum levels when compared to the saline *** control group did not present alterations when compared to the

关键词： Liver ischemia/reperfusion diazoxide K+ channel op

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