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研究生:蔡佩靜
研究生(外文):Pei-Jing Tsai
論文名稱:萊克多巴胺對心血管疾病大鼠之急性循環生理研究
論文名稱(外文):Acute hemodynamic changes in cardiovascular disease rat models exposed to Ractopamine.
指導教授:鄭尊仁鄭尊仁引用關係
指導教授(外文):Tsun-Jen Cheng
口試委員:吳焜裕王雋之林敏雄
口試日期:2014-06-26
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:職業醫學與工業衛生研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文出版年:2014
畢業學年度:102
語文別:中文
論文頁數:77
中文關鍵詞:萊克多巴胺心血管毒性動脈硬化高血壓血行動力學
外文關鍵詞:ractopamine hydrochloridecardiovascular toxicityatherosclerosishypertensionhemodynamics
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  萊克多巴胺為動物飼料添加物,除了可增加瘦肉比率外,藥理學上其亦具有乙型受體促進作用,因此經由食入可能引起心血管的不良健康效應,多種瘦肉精中又以萊克多巴胺毒性最低、代謝最快,所以在坊間使用率最高,但相關的毒性研究卻最少。在過去動物實驗中發現,健康動物暴露到萊克多巴胺後,對心血管系統、生殖系統、免疫系統等都有負面健康效應,但目前並無對易感受族群的相關研究,因此本研究欲探討萊克多巴胺對於心血管疾病大鼠與健康大鼠之急性血行動力學的效應是否有差異。
  本研究使用健康大鼠(WKY)、自發性高血壓大鼠(SHR),以及WKY培養的動脈硬化大鼠模式大鼠(Atherosclerosis WKY, AW),每組24隻以隨機分派方式分成4個劑量組(0、3、9、27 mg/Kg BW),以胃管灌食方式給予萊克多巴胺後,利用生理資料連續量測系統收集暴露前5分鐘及暴露後1小時之生理資料,並進行血液採集,以探討心血管疾病大鼠與健康大鼠在血行動力學上之差異。
  本研究發現,各品系大鼠在暴露最高劑量的萊克多巴胺後,皆產生心跳上升、心輸出量增加及周邊血管阻力下降的現象,符合其藥理作用,並且發現在易感受族群的生理變化會較為顯著,在自發性高血壓大鼠暴露到高劑量萊克多巴胺後,會產生血壓降低的現象,而在動脈硬化模式大鼠暴露到中劑量之萊克多巴胺後,則會產生血壓升高的現象,因此本研究結果顯示,在急性循環生理上,萊克多巴胺會導致易感受族群有較顯著的血壓變化。


  Ractopamine hydrochloride (RAC) is authorized for use in feed destined for specific poultry and livestock in some countries to improve feed efficiency, weight gain and carcass leanness, increase in muscle mass and decrease in body fat. Although RAC is not for use in humans, people may be exposed to it through the consumption of meat and internal organs containing RAC residues. The dose-dependent effects of RAC in specific organs and systems were studied in a limited number of studies in healthy animals and human volunteer subjects. And the recently-adopted maximum residue limits (MRLs) for RAC are based on the results of above studies. Pharmacologically, RAC is a β-adrenergic agonist, as it could activate both β1- and β2-adrenergic receptors. Although compared to other β-adrenergic agonists, RAC is lower in toxicity and can be rapidly metabolized; its CV toxicity for the consumers is still a concern. Since patients with underlying cardiovascular diseases are often more susceptible to agents with CV toxicity, more studies should be conducted to determine whether or no more stringent MRLs of residual RAC in meats should be recommended. Therefore, we aim to investigate the acute hemodynamic effects of RAC in rats between 12-13 weeks of age with underlying cardiovascular disease (CVD).
  Forty-eight male Wistar Kyoto (WKY) rats were randomizedly divided into atherosclerotic (AW) group and control group. Additional twenty-four spontaneously hypertensive rats (SHRs) were selected as an animal model of primary hypertension. Early AS lesions were induced by chronic administration of N omega-nitro-L-arginine methyl ester in drinking water and feeding a high-cholesterol (1%) diet. Dose-response relationships between RAC exposure and acute hemodynamic changes of rats were investigated following oral administration at different dosage levels of 0, 3, 9 and 27 mg/kg bw of RAC by gastric intubation. Hemodynamic parameters in rats with different disease model and dosage were measured using a high-fidelity pressure-volume catheter positioned in the chamber of left ventricle, and two high-fidelity pressure transducers at the left carotid and femoral arteries of each rat. Continuous recordings were collected beginning 5 minutes (min) before exposure until 60 min after exposure. The data were analyzed on a beat-to-beat basis and reported as 2- or 5- min periods.
  Our results revealed that three rat groups showed different dose-response relationship and time course with respect to RAC exposure. As expected, these findings are more prominent in rats with underlying CVD. Increasing heart rate (HR), increasing cardiac output (CO) and decreasing peripheral vascular resistance (TPR) were observed in all highest-dose subgroups. A significant decrease of blood pressure was observed in SHRs exposed to the highest-dose of RAC. Relative to this finding, a significant elevation of SBP was observed in AW rats exposed to 9 mg/kg bw of RAC. Based on our findings, more studied should be conducted to confirm the cardiovascular toxicity of RAC in susceptible populations and make reference to safety limits of residual RAC for meats.


致謝..............................................I
目錄..............................................III
表目錄.............................................V
圖目錄.............................................VI
中文摘要...........................................1
Abstract.........................................2
第一章 前言與研究目的................................4
第二章 文獻回顧.....................................5
2.1瘦肉精種類與毒性.................................5
2.1.1瘦肉精簡介....................................5
2.1.2瘦肉精對心血管效應的機轉.........................5
2.2萊克多巴胺的健康效應..............................6
2.2.1萊克多巴胺的健康效應............................6
2.2.2萊克多巴胺的心血管研究..........................6
2.2.3萊克多巴胺的動物實驗研究.........................7
2.3血行動力學指標...................................7
2.4易感動物模式之病生理..............................9
2.4.1自發性高血壓大鼠...............................9
2.4.2動脈粥狀硬化大鼠...............................9
第三章 材料與方法..................................11
3.1研究設計......................................11
3.2動物飼養及動物模式..............................11
3.3建立動脈硬化大鼠模式.............................12
3.4暴露方式及劑量選擇..............................12
3.5實驗方法......................................13
3.6資料處理與統計分析..............................13
第四章 結果.......................................15
4.1實驗動物基本特性................................15
4.2動脈硬化組的組織病理切片.........................15
4.3萊克多巴胺對血行動力學的急性效應...................15
第五章 討論......................................18
5.1萊克多巴胺對健康大鼠之心血管作用...................18
5.2萊克多巴胺對自發性高血壓大鼠之心血管作用.............20
5.3萊克多巴胺對動脈硬化模式大鼠之心血管作用.............21
5.4萊克多巴胺對健康組與心血管疾病組的急性生理變化之差異...22
5.5研究優點與限制..................................23
第六章 結論與建議...................................24
第七章 參考文獻....................................25
第八章 附錄.......................................30




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