https://scholars.lib.ntu.edu.tw/handle/123456789/194394
Title: | CARVEDILOL心臟之直接藥理作用:正常與鐵質負荷心臟之保護作用機轉 | Authors: | 吳美環 | Issue Date: | 1999 | Publisher: | 臺北市:國立臺灣大學醫學院小兒科 | Abstract: | 地中海貧血症病兒因需反覆輸血 易導致鐵質堆積,近年雖有排鐵劑治療 之引進,但鐵質沉積於心臟造成的心肌 症及心律不整仍是地中海貧血症病兒之 重要死因(63%)。地中海貧血症病兒之 心肌症,初期雖以舒張功能受損為主, 末期則合併收縮功能不良而導致心臟衰 竭,傳統心衰竭藥物(包括毛地黃、利 尿劑及ACE拮抗劑等)效果並不理想。 Carvedilol為第二代之β拮抗 劑,其接受器之拮抗作用依序為β1>α 1>β2。由於對α接受器亦有拮抗作用 可降低血管阻力,可於心衰竭時投以。 此外,Carvedilol亦有明顯之抗氧化能 力。已有許多臨床報告證實carvedilol 對慢性心衰竭的療效並通過認證。 因為鐵質沉積造成之心肌症其機 轉與鐵質可能誘發free radical產生有 關,因此我們推想carvedilol由於有抗 氧化作用,且有改善心衰竭之作用應有 助於鐵沉積心肌症之症狀緩解。我們的 初步經驗相當令人振奮。初例為20歲地 中海症女孩,因反覆輸血已有心肌功能 受損,但於接受carvedilol治療後,心 肌功能有大幅改善。由於此病人臨床上 並無心跳加速等交感神經亢奮之現象, carvedilol直接對心臟的影響是很可能 存在的。 本實驗利用確立的離體心臟模式來探討 傳導系統之電生理特性之變化及再灌流 不整脈之誘發。結果顯示Carvedilol確 能直接改變心電生理特性,可縮短房室 結之傳導及心室組織之抑阻期。對於再 灌流不整脈之誘發概率亦能略減少 (100%降到81%)。此外並能停止再灌流 不整脈,但最多只有50%效力(1.5μM與 5.4μM皆然)。至於細胞內鐵質負荷後 所導致的心電生理變化為心週期延長及 房室間傳導性與心室組織抑阻期之縮 短,而carvedilol之添加並無法顯著更 改其鐵質負荷導致之變化。而細胞外鐵 質負荷後,其心週期亦延長,而房室傳 導也延長。由以上之結果我們可推論 carvedilol除其原本之強β弱α抗拮劑 之作用外,亦有直接之電生理效應,急 性鐵質負荷可能改變心電生理特性,但 carvedilol並無效改變急性鐵質負荷所 導致之改變。 Background. Myocardial iron storage along with the secondary cardiomyopathy is an unavoidable problem in thalassemia patients and remains the most common cause of death. Conventional treatment for the heart failure is helpful but still unsatisfactory. Carvedilol, a "third generation" ß blocking agent that at † 八十六年度及以前的一般 國科會專題計畫(不含產學 合作研究計畫)亦可選擇適 用,惟較特殊的計畫如國科 會規劃案等,請先洽得國科 會各學術處同意。 therapeutic doses blocks all three adrenergic receptors, with a rank order of potency of ß1> a1 > ß2. Because of its a-blocking effect, carvedilol is a moderate vasodilator on acute administration and therefore has a good initial tolerability in patients with heart failure. Besides, carvedilol has been shown as a strong antioxidant. Since increased levels of redox-active iron with free radical production may be the mechanism of tissue damage in thalassemia patients, we hypothesize that carvedilol will be helpful for the thalassemia patients, by the attenuation of enhanced sympathetic activity as well as the attenuation of free radical damage in iron-loaded hearts. Methods. The direct modification by various interventions on cardiac conduction system was performed by intracardiac recording and stimulation in isolated, Langendorff perfused hearts. The and proarrhythmic potential was assessed by the incidence of ischemia/reperfusion arrhythmias after various interventions. Results. Carvedilol may directly shorten progressively the conduction through the AV node as well as the ventricular refractory period (1.5 and 4.5 mM). However, theses changes were irreversible. As to the conduction through the atrial, His-Purkinje system and their refractoriness were not significantly modified by carvedilol Intracellular iron-load by co-addition with pyrithione 10 mM might significantly prolong the basic cycle length, shorten the wenckebach cycle length and the ventricular effective refractory period. Furthermore, the addition of carvedilol failed to convert these changes. Extracellular iron-load induced by co-addition of the ADP and Fe might prolong the basic cycle length and the conduction through the AV node (AH interval). Carvedilol can modestly convert the ventricular tachyarrhythmias induced by ischemia-reperfusion. At 1.5 mM and 4.5 mM, carvedilol could covert half of the reperfusion arrhythmias. Pretreatment by carvedilol (1.5 or 4.5 mM) could decrease the incidence of reperfusion arrhythmias from 100% (5/5) to 81% (9/11). Conclusions. Direct electropgysiological effects of carvedilol and the potential of ameliorating ischemia-reperfusion arrhythmias had been documented. Acute iron-load may alos alter the elctrophysiological properties of the heart. However, carvedilol could not convert these changes. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/22828 | Other Identifiers: | 882314B002135 | Rights: | 國立臺灣大學醫學院小兒科 |
Appears in Collections: | 醫學系 |
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