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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

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行政院國家科學委員會專題研究計畫成果報告

Pr epar ation of NSC Pr oject Repor ts

計畫編號:NSC 88-2314-B-002-135

執行期限:87 年 8 月 1 日至 88 年 7 月 31 日

主持人:吳美環 台大醫學院小兒科

一、中文摘要 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。 二、ABSTRACT

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。

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therapeutic doses blocks all three adrenergic receptors, with a rank order of potency of ß1>

α1 > ß2. Because of its α-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 µM). 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 µM 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 µM and 4.5 µM, carvedilol could covert half of the reperfusion

arrhythmias. Pretreatment by carvedilol (1.5 or 4.5 µM) 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.

三、緣由與目的

The fate of thalassemia major patients has substantially been improved during the past 15 years following the introduction of high-controlled regimens of blood transfusion and chelation therapy.1 However, myocardial iron storage is still unavoidable and remains the most common cause of death (63%).2-3 At the end stage, patients are usually die of intractable heart failure and sudden (arrhythmic) death. Such thalassemia-related cardiomyopathy heart is characterized by predominant diastolic dysfunction in the early stage and by systolic dysfunction in the late stage.4-6 Our previous study has found that prognostic values of the left ventricular diastolic index.6 Furthermore, the coexistence of pulmonary bed alteration may lead to right ventricle surcharge and aggravate the heart failure. Conventional treatment for the heart failure in thalassemia-related cardiomyopathy include: digoxin, diuretics, and angiotensin converting enzyme inhibitor. However, the result is still unsatisfactory.1

Carvedilol, a "third generation" ß-blocking agent that at therapeutic doses blocks all three adrenergic receptors, with a rank order of potency of ß1> α1 > ß2.7 Because of its α-blocking effect, carvedilol is a moderate vasodilator on acute administration and therefore has a good initial tolerability in patients with heart failure. Besides, carvedilol

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3 has been shown as a strong antioxidant.8 Clinical benefits have been well documented in patients with chronic heart failure from several multicenter clinical trials and hence carvedilol had been approved for the treatment of heart failure.9-12

Our previous observation in thalassemia patients has indicated the prognostic values of echocardiography, including the diastolic and systolic parameters.6 The heart failure may be improved by conventional medications, but the heart failure progressed. Since increased levels of redox-active iron with free radical production may be the mechanism of tissue damage in thalassemia patients, we propose that carvedilol will be helpful for the thalassemia patients, not only by the attenuation of enhanced sympathetic activity but also the attenuation of free radical damage in iron-loaded hearts.

四、結果

1. Direct electrophysiological effects A). Carvedilol:

Carvedilol can cause progressively shortening of the conduction through the AV node. The ventricular refractory period was also significantly shortened (1.5 and 4.5 µM). However, theses changes were irreversible. (Table 1) As to the conduction through the atrial, His-Purkinje system and their refractoriness were not significantly modified by carvedilol

B). Intracellular iron-load: Intracellular iron-load by co-addition with pyrithione 10 µM had been shown that the intracellular Fe load may 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.

C). Extracellular iron-load: Extracellular

iron-load was induced by co-addition of the ADP and Fe. The results showed that the extracellular iron-load may significantly prolong the basic cycle length and the conduction through the AV node (AH interval).

2. Antiarrhythmic effects (Ischemia-reperfusion model)

A). Carvediolol: Carvedilol can modestly convert the ventricular tachyarrhythmias induced by ischemia-reperfusion. Carvedilol at 0.5 µM failed to convert the tachyarrhythmias , at 1.5

µM, carvedilol converted one out of two induced tacharrhythmias and at 4.5 µM carvedilol could only convert 3 out of 6 induced ventricular tachyarrhythmias. B). Pretreatment by carvedilol (1.5 or 4.5 µM) could decrease the incidence of reperfusion arrhythmias from 100% (5/5) to 81% (9/11) (No statistical significance).

五、討論

Direct electrophysiological effects had been well shown in this study. However, the antiarrhythmic efficacy was only fair. Pretreatment with carvedilol provided the hearts only weakly against the development of ischemia-reperfusion arrhythmia. Acute cellular iron load mal alter the elctrophysiological properties of the hearts. However, carvediolol failed to modify these changes. These data suggested a modest weak direct antiarrhythmia efficacy of carvedilol other than its beta-blocking activities. The effects of acute iron load could not be prevented by carvedilol. Whether carvedilol may protect the hearts from chronic iron load remained unanswered. Further investigation is mandatory.

六、參考文獻

1. Vecchio C, Derchi G: Management of cardiac complications is patients with

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thalassemia major. Seminars in Hematology 1995;32:288-296.

2. Borgna-Pignatti C, Zurlo MG, De Stefano P, et al: Mortality and causes of death in thalassemia major. 5th international conference on thalassemias and the haemoglobinopathies. March 29 April 3 1993, Nicosia, Cyprus.

3. Wolfe L, Olivieri N, Sallan D, et al: Prevention of cardiac disease by subcutaneous deferoxamine in patients with thalassemia major. N Engl J Med 1985;312:1600-1603.

4. Ehlers K, Levin A, Markenson A, et al: Longitudinal study of cardiac function in thalassemia major. Ann NY Acad Sci 1980;344:397-404.

5. Engle M, Erlandson M, Smith C: Late cardiac complications of chronic, severe, refractory anemia with hemochromatosis. Circulation 1984;30:698-705.

6. Hou JW, Wu MH, Lin KH, Lue HC: Prognostic significance of left ventricular diastolic indexes in ß-thalassemia major. Arch Pediat Adol Med 1994;148-862-866.

7. Ruffulo RR, Gelai M, Heible JP, Willette RN, Nichols AJ. The pharmacology of carvedilol. Eur J Clin Pharmacol 1990;38:S82-S88.

8. Yue T-L, Cheng H-Y, Lysko PG, McKenna PJ, Feuerstein R, Gu JL, Lysko KA, Davis LL, Feuerstein G. Carvedilol, a new vasodilator and beta-adrenoceptor antagonist, is and antioxidant and free radical scavenger. J Pharmacol Exp Ther 1992;263:92-98.

9. Colucci WS, Packer M, Bristow MR, Gilbert EM, Cohn JN, Gowler MB, Krueger SK, Hershberger R, Uretsky BF, Bowers JA, Sackner-Bernstein JD, Young ST, Holcslaw TL, Lukas MA: Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. Circulation 1996;94:2800-2806.

10. Packer M, Bristow MR, Cohn JN, Colucci

WS, Fowler MB, Gilbert EM, Shusterman NH: The effect of carvedilol on morbidity and mortality in patients with chronic heart falure. N Engl J Med 1996;334:1349-1355.

11. Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Hershberger RE, Kubo SH, Narahara KA, Ingersoll H, Krueger S,Young S, Shusterman N: Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation 1996;94:2807- 2816. 12. Australia/New Zealand heart failure research collaborative group. Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet 1997;349:375-380.

13. Lesnefsky EJ, Ye J, Exogenous intracellular, but not extracellular, iron augments myocardial reperfustion injury. Am J Physiol 1994;266:H384-H392. 14. Hoque AN, Karmazyn M: Effect of sodium-hydrogen exchange inhibition on functional and metabolic impairment produced by oxidative stress in the isolated rat heart. Canadian J Physiology & Pharmacology 1997;75:(4)326-334.

15. Wu MH, Su MJ, Lue HC: Age-related quinidine effects on ionic currents of rabbit cardiac myocytes. J Mol Cell Cardiol 1994;26:1167-1177.

參考文獻

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