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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳志成 | |
dc.contributor.author | I-Lun Chen | en |
dc.contributor.author | 陳依綸 | zh_TW |
dc.date.accessioned | 2021-06-13T15:19:55Z | - |
dc.date.available | 2013-07-26 | |
dc.date.copyright | 2008-07-26 | |
dc.date.issued | 2008 | |
dc.date.submitted | 2008-07-22 | |
dc.identifier.citation | Willius FA: Angina pectoris and surgical conditions of the abdomen. Annals of
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Current medicinal chemistry 2004;11:3185-3202. 14 Pan HL, Khan GM, Alloway KD, Chen SR: Resiniferatoxin induces paradoxical changes in thermal and mechanical sensitivities in rats: Mechanism of action. J Neurosci 2003;23:2911-2919. 15 Karai L, Brown DC, Mannes AJ, Connelly ST, Brown J, Gandal M, Wellisch OM, Neubert JK, Olah Z, Iadarola MJ: Deletion of vanilloid receptor 1-expressing primary afferent neurons for pain control. The Journal of clinical investigation 2004;113:1344-1352. 16 Pan HL, Chen SR: Sensing tissue ischemia: Another new function for capsaicin receptors? Circulation 2004;110:1826-1831. 17 Lingueglia E: Acid-sensing ion channels in sensory perception. The Journal of biological chemistry 2007;282:17325-17329. 18 Naves LA, McCleskey EW: An acid-sensing ion channel that detects ischemic pain. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica [et al 2005;38:1561-1569. 19 Sutherland SP, Benson CJ, Adelman JP, McCleskey EW: Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons. Proceedings of the National Academy of Sciences of the United States of America 2001;98:711-716. 20 Immke DC, McCleskey EW: Lactate enhances the acid-sensing na+ channel on ischemia-sensing neurons. Nature neuroscience 2001;4:869-870. 48 21 Molliver DC, Immke DC, Fierro L, Pare M, Rice FL, McCleskey EW: Asic3, an acid-sensing ion channel, is expressed in metaboreceptive sensory neurons. Molecular pain 2005;1:35. 22 Yagi J, Wenk HN, Naves LA, McCleskey EW: Sustained currents through asic3 ion channels at the modest ph changes that occur during myocardial ischemia. 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Am J Physiol Heart Circ Physiol 2005;289:H30-36. 33 Kurata M, Iidaka T, Sasayama Y, Fukushima T, Sakimura M, Shirai N: Correlation among clinicopathological parameters of myocardial damage in rats treated with isoproterenol. Experimental animals / Japanese Association for Laboratory Animal Science 2007;56:57-62. 34 Zhang J, Knapton A, Lipshultz SE, Weaver JL, Herman EH: Isoproterenol-induced cardiotoxicity in sprague-dawley rats: Correlation of reversible and irreversible myocardial injury with release of cardiac troponin t and roles of inos in myocardial injury. Toxicologic pathology 2008;36:277-278. 35 Manfrini O, Pizzi C, Trere D, Fontana F, Bugiardini R: Parasympathetic failure and risk of subsequent coronary events in unstable angina and non-st-segment elevation myocardial infarction. European heart journal 2003;24:1560-1566. 36 Hsieh YL, Chiang H, Tseng TJ, Hsieh ST: Enhancement of cutaneous nerve regeneration by 4-methylcatechol in resiniferatoxin-induced neuropathy. Journal of neuropathology and experimental neurology 2008;67:93-104. 37 Ugawa S, Ueda T, Yamamura H, Shimada S: In situ hybridization evidence for the coexistence of asic and trpv1 within rat single sensory neurons. Brain research 2005;136:125-133. 38 McMahon SB, Jones NG: Plasticity of pain signaling: Role of neurotrophic factors exemplified by acid-induced pain. Journal of neurobiology 2004;61:72-87. 49 39 Downey JM, Davis AM, Cohen MV: Signaling pathways in ischemic preconditioning. Heart failure reviews 2007;12:181-188. 40 Oldenburg O, Qin Q, Sharma AR, Cohen MV, Downey JM, Benoit JN: Acetylcholine leads to free radical production dependent on k(atp) channels, g(i) proteins, phosphatidylinositol 3-kinase and tyrosine kinase. Cardiovascular research 2002;55:544-552. 41 Oberhauser V, Schwertfeger E, Rutz T, Beyersdorf F, Rump LC: Acetylcholine release in human heart atrium: Influence of muscarinic autoreceptors, diabetes, and age. Circulation 2001;103:1638-1643. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/37139 | - |
dc.description.abstract | 心臟局部血液供應不足而造成的心肌缺血與局部酸化,臨床上常會導致胸
痛甚至是死亡。然而感受疼痛抑或是動物體對此現象的反應機制尚待探索。第 三型酸敏性離子通道分布在傳遞心臟感覺的神經束上,且能接受氫離子的刺激 活化而傳遞神經衝動,因此有極大可能參與心肌缺血後的調控。本研究使用心 電圖無線遙測系統,觀察由Isoproterenol 所引發ASIC3 剔除小鼠心肌缺血的 表現。 Isoproterenol 能夠有效的造成小鼠心跳加速,並且產生ST 波不正常的降 低。除了在組織缺氧的實驗中,證明此藥確實能造成局部缺氧,更進一步由心 肌纖維化的病理染色中,得到Isoproterenol 造成心肌損害的證據。在ASIC3 剔除小鼠的實驗裡,我們觀察到心跳加速以及ST 波不正常降低的表現時間都較 野生型小鼠延長,且有較嚴重的心肌纖維化現象。在ST 波恢復正常之前,我們 發現野生型小鼠表現了較高的副交感神經活性。 為了進一步研究調控原理,我們在Isoproterenol 所引發的心肌缺血模型 中,利用阿托品抑制副交感神經的活性,發現阿托品僅會影響野生型小鼠在心 跳加速與ST 波不正常降低等症狀的恢復情形,而ASIC3 剔除小鼠則不受其影 響。相反的,阿托品並不會影響野生型小鼠在心肌纖維化上的表現,卻能降低 心肌纖維化在ASIC3 剔除小鼠中的表現。此外,我們使用resiniferatoxin (RTX) 除去另一種酸敏性通道TRPV1 的影響,並且發現TRPV1 並未參與調控此較輕微 的心肌缺血現象。然而RTX 會造成神經受損,因此引發許多不預期的反應。 此報告中,我們建立了一個由Isoproterenol 所誘發的小鼠心肌缺血模 型,更進一步用來解釋,ASIC3 極有可能扮演察覺此現象的角色,並引發自律 神經的調節。而TRPV1 並未參與在此調控中 | zh_TW |
dc.description.abstract | Cardiac ischemia (angina pectoris), the situation when heart receives insufficient blood supply,
always causes clinical problems such as chest pain or even death. However, how cardiac sensory neurons respond to ischemia and cause pain sensation is still unknown. Acid-sensing ion channel 3 (ASIC3) is the possible candidate expressed on cardiac sensory afferents to sense protons and solicit some regulations. Here, we used radio-telemetry electrocardiography to examine Isoproterenol (Iso)-induced cardiac ischemia in mice lacking ASIC3. Iso-treated mice increased heart rate (tachycardia) and showed ST-depression in electrocardiogram indicating an episode of cardiac ischemia. These results were further proofed by positive labeling of Hypoxyprobe, which reacts with proteins in hypoxic tissues, and pathological consequences of cardiac fibrosis. ASIC3-/- mice performed longer duration of Iso-induced tachycardia and ST-depression as well as more severe cardiac fibrosis than ASIC3+/+ mice. Furthermore, ASIC3+/+ mice showed higher parasympathetic tones than ASIC3-/- mice just before ST-depression vanished based on heart rate variability analyses. To further resolve the underlying mechanism, we used atropine to block parasympathetic neuron activity in Iso-induced cardiac ischemia and found atropine altered the recovery phases of ST-depression and tachycardia only in ASIC3+/+ but not ASIC3-/- mice. In contrast, atropine didn’t affect Iso-induced cardiac fibrosis in ASIC3+/+ mice, whereas atropine reduced Iso-induced cardiac fibrosis in ASIC3-/- mice. Besides, we used resiniferatoxin (RTX) to rule out contribution of TRPV1 (another acid sensor) and found TRPV1 is not involved in this milder cardiac ischemia. However, unexpected neuropathic effects were generated. In conclusion, we developed an animal model for cardiac ischemia induced by Isoproterenol and demonstrated that ASIC3 is involved in detection and triggering ischemia-induced autonomic regulation. TRPV1 is not involved in this condition. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T15:19:55Z (GMT). No. of bitstreams: 1 ntu-97-R95b41001-1.pdf: 15287456 bytes, checksum: 804e93a0c533feffd015247e0ccde21f (MD5) Previous issue date: 2008 | en |
dc.description.tableofcontents | 口試委員會審定書…………………………………………………………………………………...i
誌謝…………………………………………………………………………………..........................ii 中文摘要…………………………………………………………………………….........................iii Abstract………………………………………………………………………………………………iv Contents……………………………………………………………………………............................v List of Figures………………………………………………………………………………………..ix List of Tables…………………………………………………………………………………………x Chapter 1: Introduction1…………………………………………………………………………...1 1.1 Angina pectoris and cardiac nociception……………………………………………………2 1.2 Myocardial ischemia and ischemia pain…………………………………………………….2 1.3 Induction of myocardial ischemia…………………………………………………………...3 1.3.1 Isoproterenol (Iso)……………………………………………………………………..4 1.3.2 β-adrenergic receptors………………………………………………………………...4 1.4 Regulation of cardiac ischemia……………………………………………………………...5 1.4.1 Myocadio-neuronal reception…………………………………………………………5 1.4.1.1 Acidosis and proton-sensing………………………………………………...6 1.4.1.1.1 Vanilloid receptor 1 (VR1 or TRPV1)……………………………7 1.4.1.1.2 Acid-sensing ion channel 3 (ASIC3)……………………………...7 1.4.2 Autonomic nervous system……………………………………………………………8 1.4.2.1 From heart rate variability to neural activity………………………………9 1.4.2.2 Parasympathetic neuron…………………………………………………..10 1.4.2.3 Muscarinic Receptors and atropine………………………………………10 1.5 Cardiac fibrosis……………………………………………………………………………11 1.6 Subjects in this study………………………………………………………………………11 Chapter 2: Material and Methods………………………………………………………………..12 2.1 Animal……………………………………………………………………………………..13 2.2 Radio-telemetry electrocardiogram (ECG) recording……………………………………..14 2.2.1 Animals preparation………………………………………………………..14 2.2.2 Radio-telemetry setup………………………………………………………14 2.2.2.1 Preference setting for analysis……………………………………..15 2.2.2.2 Criteria of data selection…………………………………………...15 2.2.3 Electrocardiogram tracing procedure………………………………………...16 2.2.4 Heart rate variability in frequency domain…………………………………..16 2.3 Induction of cardiac ischemia……………………………………………………………...17 2.3.1 Isoproterenol preparation…………………………………………………….17 2.3.2 Hypoxyprobe-1 plus kit……………………………………………………...17 2.3.3 Systematic lactate concentration test………………………………………...18 2.4 Approach to the Signaling pathway in vivo………………………………………………..19 2.4.1 Inhibition of parasympathetic neuron activity……………………………….19 2.4.2 Blocking TRPV1 channels…………………………………………………..19 2.5 Pathology…………………………………………………………………………………..20 2.5.1 Collagen stain for cardiac fibrosis…………………………………………...20 2.5.2 Fibrosis quantification……………………………………………………….21 2.6 c-fos and pERK staining…………………………………………………………………...21 2.6.1 Tissue preparation……………………………………………………………21 2.6.2 immunostaining……………………………………………………………...22 2.7 Statistics…………………………………………………………………………………....23 Chapter 3: Results…………………………………………………………………………………24 3.1 Isoproterenol-induced cardiac ischemia…………………………………………………...25 3.1.1 Isoproterenol indeed induced cardiac ischemia in mice……………………..25 3.1.2 Lactate concentration was rising after Iso-injection…………………………26 3.1.3 Length of cardiac ischemia duration…………………………………………26 3.1.3.1 Cardiac ischemia duration is longer in ASIC3-/- mice than in ASIC3+/+ mice after Iso-treatment…………………...27 3.1.4 Tachycardia…………………………………………………………………..27 3.1.4.1 Iso and atropine-induced tachycardia have different recovery curve.28 3.1.4.2 Blunt response to Iso-induced tachycardia in ASIC3-/ - mice..............28 3.1.5 Heart rate variability (HRV)…………………………………………………29 3.1.5.1 ASIC3-/-mice showed lower parasympathetic tone than ASIC3+/+ mice when ST-depression recovered………………...29 3.1.6 Pathology examination………………………………………………………29 3.1.6.1 ASIC3-/-mice have more severe cardiac fibrosis than ASIC3+/+ mice 7 days after Iso treatment……………………………30 3.2 Atropine Effect…………………………………………………………………………….31 3.2.1 Co-injection of Iso and atropine prolonged cardiac ischemia duration in ASIC3+/+ mice……………………………………………………31 3.2.2 Co-injection of atropine altered the recovery phases of Iso-induced tachycardia ASIC3+/+ mice……………………………………....31 3.2.3 Co-injection of atropine had no effect on autonomic activity of Iso-treated mice……………………………………………………………32 3.2.4 ASIC3+/+and ASIC3-/- mice have similar affected area 7 days after co-injection of Iso and atropine…………………………………………32 3.3 RTX effects………………………………………………………………………………...33 3.3.1 Mice change thermal sensitivity after RTX treatment………………………….33 3.3.2 TRPV1 receptors are diminished after RTX treatment………………………...34 3.3.3 Evident bradycardia was observed in mice after RTXtreatment……………….34 3.3.4 Prolong ischemia duration was found in RTX-pretreated ASIC3+/+ mice……...35 3.4.5 Iso-induced tachycardia had different recovery pattern in RTX-pretreated mice35 3.4.6 RTX-pretreated ASIC3-/-mice have higher parasympathetic tone than RTX-pretreated ASIC3+/+ mice when ST-depression recovers with time..36 3.4.7 RTX-pretreated ASIC3+/+and ASIC3-/- mice have similar affected area 7 days after Iso-injection…………………………..……………...36 3.4 c-fos and pERK staining………………………………………………………………….37 3.4.1 c-fos presented in spinal cord dorsal horn after Iso-injection but no significant different among genotypes………………………………………...37 3.4.2 pERK presented in mice DRG neuron in 5 minute after Iso-treatment but no significant different among genotypes.…………...................................................38 Chapter 4: Discussion……………………………………………………………………………...39 4.1 Isoproterenol-induced cardiac ischemia……………...……………………………………40 4.2 Atropine effect……………………………………………………………………………..42 4.3 RTX effect…………………………………………………………………………………42 4.4 Pathology after cardiac ischemia…………………………………………………………..44 4.5 The signaling pathway involved in sensing cardiac ischemia……………………………..46 4.6 Conclusion………………………………………………………………………………....46 Reference……………………………………………………………………………………………47 Appendix……………………………………………………………………………………………77 | |
dc.language.iso | en | |
dc.title | 第三型酸敏性離子通道調控由乙型交感神經作用劑所引發之心肌缺血 | zh_TW |
dc.title | The Role of ASIC3 in Isoproterenol-induced Cardiac ischemia | en |
dc.type | Thesis | |
dc.date.schoolyear | 96-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 郭博昭,鄭敬楓,蘇俊魁,孫維欣 | |
dc.subject.keyword | 心絞痛,心肌缺血,局部酸化,酸敏性離子通道,自律神經系統, | zh_TW |
dc.subject.keyword | ASIC3,cardaic ischemia,Isoproterenol,chest pain,autonomic nerves system, | en |
dc.relation.page | 77 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2008-07-24 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 動物學研究所 | zh_TW |
顯示於系所單位: | 動物學研究所 |
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