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Protective effects of iptakalim,a novel ATP-sensitive potassium channel opener,on global cerebral ischemia-evoked insult in gerbils

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Acta Pharmacologica Sinica 2006年第6期27卷 665-672页

作者： Hua CHEN~(2,4)Yong YANG~(2,4)Hong-hong YAO~2 Xing-chun TANG~2 Jian-hua DING~2 Hai WANG~3 Gang HU~(2,5)2 Laboratory of Neuropharmacology,department of Anatomy,Histology and pharmacology,Nanjing Medical University,Nanjing 210029,china 3 department of cardiovascular pharmacology,beijing institute of pharmacology and toxicology,beijing 100850,china department of Anatomy Laboratory of Neuropharmacology Histology and Pharmacology Nanjing Medical University Nanjing China department of cardiovascular pharmacology Beijing Institute of Pharmacology and Toxicology Beijing China

Aim:To investigate the protective role of iptakalim,a novel ATP sensitive potas-sium channel opener,on global cerebral ischemia-evoked insult in gerbils andglutamate-induced PC 12 cell ***:Global cerebral ischemia was in-duced by occluding the bilateral common carotid arteries in gerbils for 5 *** field maze and T-maze were employed to investigate the experimental thera-peutic value of iptakalim on ischemic brain insult（n=8）.The pyramidal cells in thehippocampal CA1 regions were counted to assess the protective effects *** released from the gerbil hippocampus and PC12 cells weredetermined by *** calcium was measured by Fluo-3 AM with ABio-Rad Radiance 2100TM confocal system in conjunction with a Nikon *** glutamate uptake measurements were determined by liq-uid scintillation ***:Iptakalim（0.5-4.0 mg/kg per day,ip）couldreduce the high locomotor activity evoked by ischemia and improve global cere-bral ischemia-induced working memory *** studies revealedthat iptakalim could increase the survival neuron in the hippocampus CA1 zone ina dose-dependent ***,iptakalim could reverse ischemia-evokedincreases of glutamate in the hippocampus of *** an in vitro study,iptakalimprotected PC12 cells against glutamate-induced excitotoxicity,reduced the[Ca2+]iincreases,and enhanced the glutamate uptake activity of primary ***:Iptakalim plays a key role in preventing global cerebralischemia-evoked insults in gerbils and glutamate-induced PC12 cell injury by *** might be a promising novel candidate for the preventionand/or treatment of stroke.

关键词： ATP-sensitive potassium channel opener iptakalim global cerebral ischemia neuroprotection excitotoxicity

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Detection and quantitation of PS20, a phosphorothioate oligodeoxynucleotides in monkey plasma

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Acta Pharmacologica Sinica 2004年第6期25卷 99-104页

作者： Ming-mei SHANG, Hai-feng SONG2, Xiu-wen LIU, Zhong-ming TANG department of pharmacology and toxicology, the institute of Radiation Medicine, Academy of Military Medical Sciences, beijing 100850, china department of pharmacology and toxicology the Institute of Radiation Medicine Academy of Military Medical Sciences 北京 100850

AIM: To establish the method for quantitation of the phosphorothioate oligodeoxynucleotides (S-ODNs) in plasma. METHODS: Two solid-phase extraction columns combined with a strong anion-exchange column were utilized to remove proteins and lipids in plasma, and the salts were removed by a reverse-phase column followed by dialysis with a 2500 Da-cutoff membrane. The concentration of the tested S-ODNs, PS20, and its metabolites extracted from the plasma were determined by the method of non-gel sieving capillary electrophoresis (NGCE) with diode array detection in the presence of internal standard (IS). RESULTS: The method was with good base number specificity. Relative standard deviation % of both intra and inter assay were all less than 10 %, and the total mean recovery was about 91 %. The methodology was successfully used to determine the PK behavior of an anti-tumor antisense S-ODNs in monkeys and identify the metabolites with single base difference. CONCLUSION: The combined method of solid-phase extraction and NGCE could be used to study the pharmacokinetics of S-ODNs, and the main parameters of the methodology met the requirement of PK study.

关键词： antisense oligodeoxyribonucleotides thionucleotides rhesus monkey plasma solid-phase extraction capillary electrophoresis non-gel sieving internal standard

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Proteomic response analysis of endothelial cells of human coronary artery to stimulation with carbachol

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Acta Pharmacologica Sinica 2004年第9期 22-28页

作者： Min YU, Dong-mei CHEN, Gang HU, Hai WANGbeijing institute of pharmacology and toxicology, beijing 100850, china department of pharmacology and Neurobiology, Nanjing Medical University, Nanjing 210029,china

AIM: To identify the molecular basis of the endothelial target for acetylcholine (ETA). METHODS: Proteomic methods were used to monitor changes in protein expression in the first 10 h following the stimulation of human coronary endothelial cells with carbachol 100 μmol/L. Thirty proteins showing the largest changes were identified by mass spectrometry. RESULTS: Based on analysis with Image Master 2-D

关键词： endothelium carbachol human coronary artery endothelial cells proteome two-dimensional gel electrophoresis protein identification

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C16,a novel advanced glycation endproduct breaker,restores cardiovascular dysfunction in experimental diabetic rats

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Acta Pharmacologica Sinica 2005年第12期26卷 1460-1466页

作者： Gang CHENG~3 Li-li WANG~(2,4) Wen-sheng QU~2 Long LONG~2 Hao CUI~2 Hong-ying LIU~2 Ying-lin CAO~3 Song LI~2 2 beijing institute of pharmacology and toxicology,beijing 100850,china 3 Shenyang Pharmaceutical University,Shenyang 110016,china Shenyang Pharmaceutical University Shenyang China beijing institute of pharmacology and toxicology Beijing China

Aim:Advanced glycation endproducts（AGE）have been implicated in the patho-genesis of diabetic complications,including diabetic cardiovascular dysfunction.3-[2-（4-Bromo-phenyl）-1-methyl-2-oxo-ethyl]-4,5,6,7-tetrahydro-benzothiazol-3-iumbromide（C16）,a novel AGE breaker,was investigated for its effects on the deve-lopment of cardiovascular disease in diabetic ***:Rats that hadstreptozotocin-induced diabetes for 12 weeks were divided into groups receivingC 16 or vehicle by ***:In hemodynamic studies of the left ventricle,C16 treatment（25 or 50 mg/kg）for 4 weeks resulted in a significant increase in leftventricular systolic pressure,+dp/dtmax,and-dp/dtmaxas compared with vehicle-treated diabetic ***,in hemodynamic studies of the cardiovascularsystem,C16（12.5,25,or 50 mg/kg）treatment for 4 weeks resulted in a dose-dependent and significant increase in cardiac output,a reduction of total periph-eral resistance,and an increase in systemic arterial compliance when comparedwith vehicle-treated diabetic *** studies showed that C16 treatmentalso resulted in a significant decrease in immunoglobulin G-red blood cell surfacecrosslink content and an increase in collagen *** and im-munohistochemical examinations indicated that C 16 was able to prevent increasesof the collagen type Ⅲ/Ⅰ ratio in the aorta and decrease the accumulation of AGEin the ***:C16 has the ability to reduce AGE accumulation intissues in vivo,and can restore diabetes-associated cardiovascular disorders *** provides a potential therapeutic approach for cardiovascular diseaseassociated with diabetes and aging in humans.

关键词： C16 advanced glycation endproduct cardiovascular dysfunction hemodynamics diabetes collagen

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Moclobemide up-regulates proliferation of hippocarnpal progenitor cells in chronically stressed mice

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Acta Pharmacologica Sinica 2004年第11期 24-28页

作者： Yun-feng LI, You-zhi ZHANG, Yan-qin LIU, Heng-lin WANG, Li YUAN, Zhi-pu LUObeijing institute of pharmacology and toxicology, beijing 100850 department of Anesthesiology, 309 Hospital of beijing, beijing 100091, china

AIM: To explore the action mechanism of antidepressants. METHODS: The PC12 cell proliferation was detected by flow cytometry,. The proliferation of hippocampal progenitor cells and level of brain-derived neurotrophic factor (BDNF) were measured by immunohistochemistry. RESULTS: Treatment with N-methylaspartate (NMDA) 600μmol/L for 3 d significantly decreased the percentage of S-phase in PC12 cells, while in the presence of classical antidepressant, moclobemide (MOC) 2 and 10μmol/L, the percentage in S-phase increased. Furthermore, the proliferation of progenitor cells in hippocampal dentate gyrus (subgranular zone), as well as the level of BDNF in hippocampus significantly decreased in chronically stressed mice, while chronic administration with MOC 40 mg/kg (ip) up-regulated the progenitor cell proliferation and BDNF level in the same time course. CONLUSION: Up-regulation of the proliferation of hippocampal progenitor cells is one of the action mechanisms for MOC, which may be closely related to the e

关键词： antidepressants moclobemide neurogenesis stress brain-derived neurotrophic factor N-methylaspartate

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Targeting at SUR2B/Kir6.1 subtype of ATP-sensitive potassium channel opener natakalim improves pressure overload-induced heart failure

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沈阳药科大学学报 2008年第S1期25卷 96-97页

作者： TANG Yuan1,2,LONG Chao-liang2,WANG Hai2(1.institute of Materia Medica,College of Pharmacy,Third Military Medical University,Chongqing 400038,china 2.department of cardiovascular pharmacology,beijing institute of pharmacology and toxicology,beijing 100850,china)

Objective To explore the new stratigies targeting at SUR2B/Kir6.1 subtype against pressure overload-induced heart *** Pressure overload-induced heart failure was induced in Wistar rat by abdominal aortic banding(AAB).The effects of natakalim(1,3,9 mg·kg-1·d-1,10 weeks)were assessed on myocardial hypertrophy and heart failure,cardiac histology,vasoactive compounds,and gene *** working heart and isolated tail artery helical strips were used to examine the influence of natakalim on heart and resistant *** Ten weeks after the onset of pressure overload,natakalim therapy potently inhibited cardiac hypertrophy and prevented heart *** inhibited the changes of left ventricular haemodynamic parameters,reversed the increase of heart mass index,left ventricular weight index and lung weight index *** examination demonstrated that there were no significant hypertrophy and fibrosis in hearts of pressure overload rat treated with *** examination of heart revealed well-organized myofibrils with mitochondria grouped along the periphery of longitudinally oriented fibers in natakalim group *** content of serum NO and plasma PGI2 was increased,while that of plasma ET-1 and cardiac tissue hydroxyproline,ANP and BNP mRNA was down-regulated in natakalim-treated *** at concentrations ranging from 0.01-100 μM had no effects on isolated working heart derived from Wistar rats;however,natakalim had endothelium-dependent vasodilation effects on the isolated tail artery helical strips precontracted with *** These results indicate that natakalim improves heart failure due to pressure overload by activating KATP channel SUR2B/Kir6.1 subtype and reversing endothelial dysfunction.

关键词： natakalim pressure overload KATP channel SUR2B/Kir6.1

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Taurine inhibits ischemia/reperfusion-induced compartment syndrome in rabbits

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Acta Pharmacologica Sinica 2005年第7期26卷 821-827页

作者： Ji-xian WANG~(2,3) Yan LI~2 Li-ke ZHANG~4 Jing ZHAO~5 Yong-zheng PANG~(2,3) Chao-shu TANG~(3,5) Jing ZHANG~(2,3,6) 1 institute of cardiovascular Disease Research,The First Hospital of Peking University,beijing 100034,china 3 Key Laboratory of Molecular cardiovascular Science,Ministry of Education,beijing 100083,china 4 department of Pathophysiology,Capital institute of Medicine,beijing 100054,china 5 department of Physiology Health Center of Medical Sciences,Peking University,beijing 100083,china institute of cardiovascular Disease Research The First Hospital of Peking University Beijing China Key Laboratory of Molecular cardiovascular Science Ministry of Education Beijing China department of Pathophysiology Capital Institute of Medicine Beijing China department of Physiology Health Center of Medical Sciences Peking University Beijing China

Aim:To investigate effects of taurine on ischemia/reperfusion(I/R)-induced com-partment syndrome in rabbit hind ***:Rabbits underwent femoralartery occlusion after ligation of branches from terminal aorta to femoral *** a 7-h ischemia,reperfusion was established with the use of heparinizedpolyethylene *** received taurine(1 g/kg)or normal saline(control)by iv infusion 10 min before shunt *** reperfusion,anterior com-partment pressure(ACP)was monitored continuously in the left lower *** muscle triphenyltetrazolium chloride(TTC)level,taurine contentand myeloperoxidase activity were *** stress was induced in thein vitro gastrocnemius muscle slices by free radical generating systems(FRGS),and the malondialdehyde content was measured in presence or absence of ***:After 7 h of ischemia,none of the parameters that we measured weredifferent from those before ischemia,except that TTC reduction decreased by80%.In the control group,after 2 h of reperfusion,ACP increased 4.5-fold,andgastrocnemius muscle taurine content was reduced by 33%.In taurine-treatedanimals,at 2 h reperfusion,the mean arterial blood pressure and heart rate wereincreased,by 6% and 10%.ACP decreased by 39%,muscle edema decreased by16%,TTC reduction increased by 150%,and lactate dehydrogenase decreased by36% compared to control *** and muscle taurine content increased by70% and 88%,*** the taurine-treated group,at 2 h repeffusion,plasmamalondialdehyde and conjugated diene content were decreased by 38% and 23%,respectively,and muscle malondialdehyde and conjugated diene content decreasedby 22% and 30%,respectively compared to the control *** 2 h reperfusion,myeloperoxidase activity was increased 3.5-fold in control *** the in vitrostudy,taurine decreased malondialdehyde content in muscle slices incubatedwith hypochlorous acid in a dose-dependent manner,but there was no changewhen incubated

关键词： taurine compartment syndromes reperfu sion injury

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Role of inositol 1,4,5-trisphosphate receptors in α1-adrenergic receptorinduced cardiomyocyte hypertrophy

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Acta Pharmacologica Sinica 2006年第7期27卷 895-900页

作者： Da-li LUO~(2,3,5) Jian GAO~2 Xiao-mei LAN~3 Gang WANG~4 Sheng WEI~4 Rui-ping XIAO~4 Qi-de HAN~32 department of pharmacology,School of Chemical Biology & Pharmaceutical Sciences,Capital University of Medical Sciences,beijing 100069,china 3 institute of cardiovascular Science at Health Science Center,Peking University beijing 100083,china 4 institute of Molecular Medicine and College of Life Science,Peking University,beijing 100871,china department of pharmacology School of Chemical Biology & Pharmaceutical Sciences Capital University of Medical Sciences Beijing China institute of cardiovascular Science at Health Science Center Peking University Beijing China institute of Molecular Medicine and College of Life Science Peking University Beijing China

Aim:Intracellular Ca2+plays pivotal roles in diverse cellular functions,includinggene transcription that underlies cardiac remodeling during stress ***,the role of inositol 1,4,5-trisphosphate receptors（IP3Rs）in the media-tion of cardiac intracellular Ca2+and hypertrophic growth remains *** with neonatal rat ventricular myocytes suggests that activation of IP3Rsmay be linked to α1adrenergic receptor（α1AR）increased stereotyped Ca2+sparkoccurrence and global Ca2+***,we hypothesized that Ca2+releasethrough IP3Rs was necessary for α1AR-stimulated cardiac ***:We used myoinositol 1,4,5-trisphosphate hexakis（butyryloxymethyl）ester（IP3BM）,a membrane-permeant ester of IP3,to activate IP3Rs directly,and Fluo 4/AM tomeasure intracellular Ca2+***:IP3BM(10μmol·L-1)mimicked theeffects of phenylephrine,a selective agonist of α1AR,in increments in local Ca2+spark release（especially in the perinuclear area）and global Ca2+*** importantly,IP3R inhibitors,2-aminoethoxydiphenyl borateand Xestospongin C,abolished the IP3BM-induced Ca2+responses,and signifi-cantly suppressed α1AR-induced cardiomyocyte hypertrophy assayed by cellsize,[3H]leucine incorporation and atrial natriuretic factor gene expression,dur-ing sustained（48 h）phenylephrine ***:These results,therefore,provide cellular mechanisms that link IP3R signaling to α1AR-stimulatedgene expression and cardiomyocyte hypertrophy.

关键词： inositol 1,4,5-trisphosphate receptors Ca2+sparks α1 adrenergic stimulation cardiac hypertrophy

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Structure-efficacy relationships of immunostimulatory activity of CpG-containing oligodeoxynucleotides on mouse spleen cells

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Acta Pharmacologica Sinica 2007年第10期28卷 1637-1644页

作者： Hai-yan DU~3,Shao-you XIA~4,Hai-feng SONG~(2,5),Na LI~2,Ming-mei SHANG~2,Jia ZOU~2,Qing-qing WANG~2,Lun OU~2,XiaoSUN~2,Ai-guo JI~3,Zhong-ming TANG~2~2 department of pharmacology and toxicology,beijing institute of Radiation Medicine,beijing 100850,china ~3 institute of Biochemical andBiotech Drugs,School of Pharmacy,Shandong University,Ji-nan 250012,china ~4 department of General Surgery,General Hospital of PLA,beijing100853,china department of pharmacology and toxicology Beijing Institute of Radiation Medicine Beijing 100850 China. songhf@***.

Aim:To study the relationship between primary structures of oligodeoxynucleo-tides （ODN） containing unmethylated deoxycytidyl-deoxyguanosine （CpG）dinucleotide motifs and their immunostimulatory activities in mouse spleen ***:A series of CpG ODN with different primary structures were *** capabilities to stimulate mouse spleen cell proliferation were determined by[3H]thymidine incorporation *** （interleukin [IL]-6,IL-12,and IFN-α）secretion spectra induced by CpG ODN were assessed by *** ability ofCpG ODN to activate natural killer cells was evaluated by standard 4 *** cytometry was utilized to examine the expressions of various lympho-cyte surface molecules on diverse *** effective CpG ODN for murine,ODN1826,was set as the template of modification and the positive ***:The immunostimulatory activities of CpG ODN with different sequencesand compositions varied markedly,both in character and in *** was uselessfor improving the immunostimulatory activity of ODN1826 by simply increasingthe functional hexameric CpG motif number,modifying the site of CpG motifs,orchanging the distance between multi-CpG ***,an addition of a self-complementary palindrome structure at the 3'-end,but not the 5'-end of CpG ODN,aroused marked improvement in its *** designed ODN had superiorcomprehensive immunostimulatory properties compared to ODN ***:The immunostimulatory activity of a CpG ODN was relevant to its primary *** was useless for promoting immunostimulatory activity to simply change CpGmotif number,space,or *** 3'-end palindrome structure of CpG ODN isassociated with enhanced immunostimulatory activity.

关键词： CpG oligodeoxynucleotides immunostimulation structure-activity relationship

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Effects of I-tetrahydropalmatine on locomotor sensitization to oxycodone in mice

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Acta Pharmacologica Sinica 2005年第5期 533-538页

作者： Yan-li LIU~(1,2),Jian-hui LIANG~3,Ling-di YAN~1,Rui-bin SU~1,Chun-fu WU~2,Ze-hui GONG~(1,4) ~1beijing institute of pharmacology and toxicology,beijing 100850,china ~2department of pharmacology,Shenyang Pharmaceutical University,Shenyang 110016,china ~3department of Neuropharmacology,National institute on Drug Dependence,Peking University, beijing 100083,china

Aim:Recent studies have shown that 1-tetrahydropalmatine(l-THP),an activecomponent of Corydolis yanhusuo,can inhibit the development of the condi-tional place preference induced by opioid receptor agonists,but the effects of l-THP on locomotor sensitivity induced by opioid receptor agonists have not *** the present study,the effects of l-THP on locomotor sensitizationto oxycodone,which is an opioid receptor agonist,were ***:Micetreated daily for 7 d with 5 mg/kg oxycodone and challenged with the same doseafter 5 days of washout showed locomotor *** order to study theeffects of l-THP on locomotor sensitization induced by oxycodone,l-THP wasadministered at doses of 6.25,12.5,and 18.75 mg/kg,40 min prior to treatment ***:l-THP per se did not affect the locomotor activity at thedoses of 6.25,12.5,and 18.75 mg/kg,but could antagonize the hyperactivity in-duced by oxycodone(5mg/kg).Co-administration of l-THP(18.75 mg/kg),40 minprior to oxycodone,could inhibit the development of sensitization to *** addition,l-THP(6.25,12.5,and 18.75 mg/kg,ig)dose-dependently preventedthe expression of oxycodone ***:These results suggestedthat l-THP could attenuate the locomotor-stimulating effects of oxycodone andinhibit the development and expression of oxycodone behavioral sensitization.

关键词： l-tetrahydropalmatine oxycodone locomotor sensitization

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