跳到主要內容

臺灣博碩士論文加值系統

(44.201.97.0) 您好!臺灣時間:2024/04/13 12:17
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:陳筱婷
研究生(外文):Shiau-Ting Chen
論文名稱:TM-1在正常及糖尿病小鼠之心血管及降血糖作用評估
論文名稱(外文):Evaluation of the Chronic Cardioprotective and Hypoglycemic Effects of TM-1 in Normal and Diabetic Mice
指導教授:蘇銘嘉
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:69
中文關鍵詞:心肌缺血再灌流損傷心肌壞死TM-1eNOSNO
外文關鍵詞:Myocardial ischemia/reperfusion injuryMyocardium necrosisTM-1eNOSNO
相關次數:
  • 被引用被引用:0
  • 點閱點閱:154
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
背景:TM-1為aporphine生物鹼類的衍生物,是thaliporphine的新衍生物。之前本實驗室研究發現,單次靜脈注射TM-1在麻醉大鼠和兔子的開胸缺血再灌流實驗具有心臟保護作用。本篇實驗主要研究長期口服TM-1對於心臟冠狀動脈阻塞後再灌流所造成的損傷,是否具有保護的作用,並探討其可能的機轉。

方法:正常ICR小鼠於禁食後口服給予TM-1 20mg//kg,觀察小鼠血糖和胰島素變化。正常、高油飲食引發的第二型、STZ引發的第一型糖尿病ICR小鼠口服兩週的TM-1之後,觀察其水、食物攝取量及體重變化。取其心臟使用Langendorff離體心臟灌流模式,讓全心臟缺血30分鐘,之後再灌流2小時。觀察缺血再灌流後,冠狀動脈血流、心跳速率、心臟梗塞面積以及灌流液中LDH、NO含量的變化。並利用西方點墨法及NOS inhibitor,更進一步探討TM-1的作用機轉。給予離體小鼠心臟組織isoproterenol,觀察心臟收縮力變化。

結果:實驗結果發現正常小鼠口服TM-1之後,可明顯減緩血糖升高,並且能促進胰島素的分泌。另一方面,發現正常及糖尿病小鼠長期口服TM-1之後,不會影響老鼠的食物、水攝取量及體重。心臟經離體缺血再灌流後,發現TM-1能減少正常、第二型、第一型糖尿病老鼠心肌的梗塞面積,並且能讓正常老鼠心臟的LDH釋放量減少。於離體小鼠心房及心室實驗,發現TM-1不會影響其對isoproterenol的反應。此外,長期口服TM-1能阻止缺血再灌流後心臟eNOS表現量減少,在心臟缺血再灌流前給予NOS inhibitor L-NAME,發現老鼠心肌的梗塞面積和LDH釋放量有增加的趨勢。

結論:TM-1對於心臟冠狀動脈缺血再灌流損傷具有保護作用,可能的機轉是透過維持心臟eNOS表現量達到心臟保護作用,減少心肌細胞壞死途徑,來降低心臟再灌流損傷。
口試委員審定書……………………………………… I
誌謝…………………………………………………… II
縮寫表………………………………………………… III
中文摘要……………………………………………… V
英文摘要……………………………………………… VII
第一章 緒論……………………………………… 1
Tab.1-1………………………………………………… 1
Fig.1-1………………………………………………… 3
Fig.1-2………………………………………………… 5
Fig.1-3………………………………………………… 6
Fig.1-4………………………………………………… 7
Fig.1-5………………………………………………… 8
Fig.1-6………………………………………………… 9
Fig.1-7………………………………………………… 10
Fig.1-8………………………………………………… 11
Fig.1-9………………………………………………… 13
Fig.1-10…………………………………………………14
文獻回顧…………………………………………………14
動機及研究目的…………………………………………15
Fig.1-11…………………………………………………16
第二章 實驗材料與方法………………………………17
Fig.2-1………………………………………………… 21
第三章 實驗結果…………………………………… 29
Tab.3-1………………………………………………… 35
Fig.3-1………………………………………………… 36
Fig.3-2………………………………………………… 37
Fig.3-3………………………………………………… 38
Fig.3-4………………………………………………… 40
Fig.3-5………………………………………………… 42
Fig.3-6………………………………………………… 44
Fig.3-7………………………………………………… 46
Fig.3-8………………………………………………… 47
Fig.3-9………………………………………………… 48
第四章 討論………………………………………… 50
Fig.4-1………………………………………………… 56
Tab.4-2………………………………………………… 57
第五章 結論………………………………………… 58
參考文獻……………………………………………… 59
Balakumar P, Rohilla A, Singh M. Pre-conditioning and postconditioning to limit ischemia-reperfusion-induced myocardial injury: what could be the next footstep? Pharmacol Res 2008;57:403–12.

Beckman JS. Ischemic injury mediator. Nature 1990;345:27–8.

Bolli R. Cardioprotective function of inducible nitric oxide synthase and role of nitric oxide in myocardial ischemia and preconditioning: an overview of a decade of research. J Mol Cell Cardiol 2001;33:1897-918.

Buja LM. Myocardial ischemia and reperfusion injury. Cardiovasc Pathol 2005; 14:170-5.

Chang WL, Chung CH, Wu YC, Su MJ. The vascular and cardioprotective effects of liriodenine in ischemia–reperfusion injury via NO-dependent pathway. Nitric Oxide 2004;11:307–15.

Chi TC, Lee SS, Su MJ. Antihyperglycemic effect of aporphines and their derivatives in normal and diabetic rats. Planta Med 2006;72:1175–80.

Chiao CW, Lee SS, Wu CC, Su MJ. Thaliporphine increases survival rate and attenuates multiple organ injury in LPS-induced endotoxaemia. Naunyn Schmiedebergs Arch Pharmacol 2005;371:34–43.

Cohen MV, Yang XM, Downey JM. The pH hypothesis of postconditioning. Staccato reperfusion reintroduces oxygen and perpetuates myocardial acidosis. Circulation 2007;115:1895–903.

Collard CD, Gelman S. Pathophysiology, clinical manifestations, and prevention of ischemia–reperfusion injury. Anesthesiology 2001;94:1133–8.

Curtis MJ, Hearse DJ. Ischaemia-induced and reperfusion-induced arrhythmias differ in their sensitivity to potassium: implications for mechanisms of initiation and maintenance of ventricular fibrillation. J Mol Cell Cardiol 1989;21:21–40.

Di Lisa F, Bernardi P. Mitochondria and ischemia-reperfusion injury of the heart: Fixing a hole. Cardiovasc Res 2006;70:199–209.

Di Napoli P, Taccardi AA, De Caterina R, Barsotti A. Pathophysiology of ischemia–reperfusion injury: experimental data. Ital Heart J 2002;3:24S–8S.

Ganz W. Direct demonstration in dogs of the absence of lethal reperfusion injury. J Thrombos Thromboly 1997;4:105–7.

Gateau-Roesch O, Argaud L, Ovize M. Mitochondrial permeability transition pore and postconditioning. Cardiovasc Res 2006;70:264–73.

Go LO, Murry CE, Richard VJ, Weischedel GR, Jennings RB, Reimer KA. Myocardial neutrophil accumulation during reperfusion after reversible or irreversible injury. Am J Physiol 1988;255:H1188–98.
Goto M, Liu Y, Yang X-M, Ardell JL, Cohen MV, Downey JM. Role of bradykinin in protection of ischemic preconditioning in rabbit hearts. Circ Res 1995;77:611–21.

Gross ER, Gross GJ. Ischemic preconditioning and myocardial infarction: an update and perspective. Drug Discov Today Dis Mech 2007;4:165–74.

Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion – a target for cardioprotection. Cardiovascular Research. 2004; 61:372–85.

Hampton CR, Shimamoto A, Rothnie CL, Griscavage-Ennis J, Chong A, Dix DJ, et al. HSP70.1 and 70.3 are required for late-phase protection induced by ischemic preconditioning of mouse hearts. Am J Physiol Heart Circ Physiol 2003;285:H866–74.

Hare JM, Colucci WS. Role of nitric oxide in the regulation of myocardial function. Prog Cardiovasc Dis 1995;38:155–66.

Hausenloy DJ, Maddock HL, Baxter GF, Yellon DM. Inhibiting mitochondrial permeability transition pore opening: a newparadigm inmyocardial preconditioning. Cardiovasc Res 2002;55:534–43.

Hung LM, Lee SS, Chen JK, Huang SS, Su MJ. Thaliporphine protects ischemic and ischemic-reperfused rat hearts via an NO-dependent mechanism. Drug Dev Research 2001;52:446–453.

Hung LM, Lee SS, Su MJ. Cardioprotective effect of thaliporphine on ischemic and ischemic reperfusion rat heart. The eighth Southeast Asian-Western Pacific Regional Meeting of Pharmacologist 1999. Abstract No P005.

Javadov S, Lim K, Kerr P, Suleiman M, Angelini G, Halestrap AP. Protection of hearts from reperfusion injury by propofol is associated with inhibition of the mitochondrial permeability transition. Cardiovasc Res 2000;45:360–9.

Kaeffer N, Richard V, Francoise A, Lallemand F, Henry JP, Thuillez C. Preconditioning prevents chronic reperfusion-induced coronary endothelial dysfunction in rats. Am J Physiol 1996;271:H842–9.

Kitakaze M, Node K, Minamino T, Kosaka H, Shinozaki Y, Mori H, Inoue M, Hori M, Kamada T. Role of nitric oxide in regulation of coronary blood flow during myocardial ischemia in dogs. J Am Coll Cardiol 1996;27:1804–12.

Krieg T, Qin Q, Philipp S, Alexeyev MF, Cohen MV, Downey JM. Acetylcholine and bradykinin trigger preconditioning in the heart through a pathway that includes Akt and NOS. Am J Physiol Heart Circ Physiol 2004;287:H2606–11.

Kudo M, Wang Y, Xu M, Ayub A, Ashraf M. Adenosine A(1) receptor mediates late preconditioning via activation of PKC-delta signaling pathway. Am J Physiol Heart Circ Physiol 2002;283:H296–301.

Laude K, Favre J, Thuillez C, Richard V. NO produced by endothelial NO synthase is a mediator of delayed preconditioning-induced endothelial protection. Am J Physiol Heart Circ Physiol 2003;284:H2053–60.

Lee SS, Yang HC. Isoquinoline alkaloids from Neolitsea Konishii. Chin Chem Soc 1992;39:189.

Libby P, Thersoux P. Pathophysiology of coronary artery disease. Circulation 2005;111:3481–8.

Maddaford TG, Pierce GN. Myocardial dysfunction is associated with activation of Na+/H+ exchange immediately during reperfusion. Am J Physiol 1997;273:H2232–9.

Martinou JC, Green DR. Breaking the mitochondrial barrier. Nat Rev Mol Cell Biol 2001;2:63–7.

Maxwell SRJ, Lip GYH. Reperfusion injury: a review of the pathophysiology, clinical manifestations and therapeutic options. Int J Cardiol 1997;58:95–117.

McCord JM. Oxygen derived free radicals in post-ischemic tissue injury. N Engl J Med 1985;312:159–63.

Miles AM, Chen Y, Owens MW, et al. Fluorometric determination of nitric oxide. Methods 1995;7:40–7.

Misko TP, Schilling RJ, Salvemini D, et al. A Fluorometric assay for the measurement of nitrite in biological samples. Anal Biochem1993;214:11–6.

Moens AL, Claeys MJ, Timmermans JP, Vrints CJ. Myocardial ischemia/reperfusion-injury, a clinical view on a complex pathophysiological process. Int J Cardiol 2005;100:179–90.

Monassier JP. Reperfusion injury in acute myocardial infarction. From bench to cath lab. Part I: Basic considerations. Arch Cardiovasc Dis 2008;101:491–500.

Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124–36.

Murry CE, Richard VJ, Jennings RB, Reimer KA. Myocardial protection is lost before contractile function recovers from ischemic preconditioning. Am J Physiol 1991;260:H796–804.

Nayler WG, Panagiotopoulos S, Elz JS, Daly MJ. Calcium-mediated damage during post-ischaemic reperfusion. J Mol Cell Cardiol 1988; 20:41–54.

O’Neill PG, Charlat ML, Michael LH, Roberts R, Bolli R. Influence of neutrophil depletion on myocardial function and flow after reversible ischemia. Am J Physiol 1989;256:H341–51.

Opie LH. Myocardial infarct size. Part I. Basic Condiderations. Am Heart J 1980;100:355–72.
Opie LH. The heart: physiology and metabolism. 2nd edition. Raven Press; 1991.

Pabla R, Buda AJ, Flynn DM, Salzberg DB, Lefer DJ. Intracoronary nitric oxide improves postischemic coronary blood flow and myocardial contractile function. Am J Physiol 1995;269:H1113–21.

Park JL, Lucchesi BR. Mechanisms of myocardial reperfusion injury. Ann Thorac Surg 1999;68:1905–12.

Parker JC, Andrews KM, Allen MR, Stock JL, McNeish JD. Glycemic control in mice with targeted disruption of the glucagon receptor gene. Biochem Biophys Res Commun 2002;290:839–43.

Penna C, Mognetti B, Tullio F, gattullo D, Mancardi D, Pagliaro P, et al. The platelet activating factor triggers preconditioning-like cardioprotective effect via mitochondrialK-ATP channels and redox-sensible signaling. J Physiol Pharmacol 2008;59:47–54.

Pepine CJ, Nichols WW. The pathophysiology of chronic ischemic heart disease. Clin Cardiol 2007;30:I-4–9.

Piper HM, Garcia-Dorado D, Ovize M. A fresh look at reperfusion injury. Cardiovasc Res 1998;38:291–300.

Piper HM, Garcia-Dorado D. Prime causes of rapid cardiomyocyte death during reperfusion. Ann Thorac Surg 1999;68:1913–9.

Piper HM, Meuter K, Schäfer C. Cellular mechanisms of ischemia-reperfusion injury. Ann Thorac Surg 2003;75:S644–8.

Powers SK, Murlasits Z, Wu M, Kavazis AN. Ischemia-reperfusion-induced cardiac injury: a brief review. Med Sci Sports Exerc 2007;39:1529–36.

Richard V, Kaeffer N, Tron C, Thuillez C. Ischemic preconditioning protects against coronary endothelial dysfunction induced by ischemia and reperfusion. Circulation 1994;89:1254–61.

Schaper W, Schaper J. Reperfusion injury: an opinionated view. J Thrombos Thromboly 1997;4:113–6.

Serrano CV Jr, Mikhail EA, Wang P, Noble B, Kuppusamy P, Zweier JL. Superoxide and hydrogen peroxide induce CD18-mediated adhesion in the postischemic heart. Biochim Biophys Acta 1996;1316:191–202.

Shandelya SM, Kuppusamy P, Weisfeldt ML, Zweier JL. Evaluation of the role of polymorphonuclear leukocytes on contractile function in myocardial reperfusion injury. Evidence for plasma-mediated leukocyte activation. Circulation 1993;87:536–46.

Silverman HM, Stern MD. Ionic basis of ischemic cardiac injury: insights from celluar studies. Cardiovasic Res 1994;28:581–97.

Smith EF 3rd, Egan JW, Bugelski PJ, Hillegass LM,Hill DE, Griswold DE. Temporal relation between neutrophil accumulation and myocardial reperfusion injury. Am J Physiol 1988;255:H1060–8.

Steenbergen C, Perlman ME, London RE, Murphy E. Mechanism of preconditioning: ionic alterations. Circ Res 1993;72:112–25.

Su MJ, Chang YM, Chi JF, Lee SS. Thaliporphine, a positive inotrophic agent with a negative chronotrophic action. Eur J Pharmacol 1994;254:141–50.

Tarpey MM, Wink DA, Grisham MB. Methods for detection of reactive metabolites of oxygen and nitrogen: in vitro and in vivo considerations. Am J Physiol Regul Integr Comp Physiol 2004;286:R431–44.

Thompson-Gorman SL, Zweier JL. Evaluation of the role of xanthine oxidase in myocardial reperfusion injury. J Biol Chem 1990;265:6656–63.

Vinten-Johansen J. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury. Cardiovasc Res 2004;61:481–97.

Warltier DC, Zyvoloski MG, Gross GJ, Hardman HF, Brooks HL. Determination of experimental myocardial infarct size. J Pharmacol Methods 1981;6:199–210.

Wenxia C, Mehrotra S, Danser AH, Schoemaker RG. The role of calcitonin generelated peptide (CGRP) in ischemic preconditioning in isolated rat hearts. Eur J Pharmacol 2006;531:246–53.
Williams FM. Neutrophils and myocardial reperfusion injury. Pharmacol Ther 1996;72:1–12.

Xia Y, Khatchikian G, Zweier JL. Adenosine deaminase inhibition prevents free radical mediated injury in the postischemic heart. J Biol Chem 1996;271:10096–102.

Xie YW, Wolin MS. Role of nitric oxide and its interaction with superoxide in the suppression of cardiac muscle mitochondrial respiration. Involvement in response to hypoxia/reoxygenation. Circulation 1995;94:2580-6.

Yasojima K, Kilgore KS, Washington RA, Lucchesi BR, McGeer PL. Complement gene expression by rabbit heart: upregulation by ischemia and reperfusion. Circ Res 1998;82:1224–30.

Yellon DM, Downey JM. Preconditioning themyocardium: fromcellular physiology to clinical cardiology. Physiol Rev 2003;83:1113–51.

Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007;357:1121–35.

Zhang J, Ping P, Vondriska TM, Tang XL,Wang GW, Cardwell EM, et al. Cardioprotection involves activation of NF-kappa B via PKC-dependent tyrosine and serine phosphorylation of 1 kappa B-alpha. Am J Physiol Heart Circ Physiol 2003;285:H1753–8.

Zhao ZQ, Vinten-Johansen J. Myocardial apoptosis and ischemic preconditioning. Cardiovasc Res 2002;55:438–55.

Zweier JL, Flaherty JT, Weisfeldt ML. Direct measurement of free radical generation following reperfusion of ischemic myocardium. Proc Natl Acad Sci USA 1987;84:1404–7.

Zweier JL, Talukder MA. The role of oxidants and free radicals in reperfusion injury. Cardiovasc Res 2006;70:181–90.

行政院衛生署(2009)中華民國九十六年台灣地區死因統計結果摘要。行政院衛生署衛生統計資訊網。
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top