乙醯左旋肉鹼（Acetyl-L-Carnitine）與羥苯甘胺酸（Oxfenicine）對鏈佐黴素（Streptozotocin）所引發之糖尿病鼠心臟力學之影響

Effects of Acetyl-L-Carnitine and Oxfenicine on the Cardiac Pumping Mechanics in Streptozotocin-Induced Diabetic Rats

王植賢(Chih-Hsien Wang)

指導教授 ： 張國柱

國立臺灣大學/醫學院/生理學研究所/博士(2014年)

https://doi.org/10.6342/NTU.2014.02512

摘要

研究背景：
對於糖尿病所引起的左心室心肌功能病變的治療方式，改變心肌細胞能量來源的代謝方式是其中一種方法。由於脂質代謝佔心肌能量來源的大部分，在這個研究裡，我們以肉鹼 (carnitine) 的衍生物乙醯左旋肉鹼 (acetyl-L-carnitine，ALC) 及羥苯甘胺酸 (oxfenicine，OXF) (一種carnitine palmitoyltransferase-1抑制劑) 來影響脂質進入粒腺體的代謝途徑，治療以鏈佐黴素 (streptozotocin) 所引發的糖尿病Wistar-Kyoto鼠，並利用測量左心室壓力與主動脈血流量以得知心臟的收縮功能與內部阻力，比較兩種不同治療方式對於心臟泵浦功能的影響。
研究方法：
以鏈佐黴素 (55mg/kg) 注入兩個月大Wistar-kyoto大鼠尾靜脈誘發糖尿病，之後分別每天餵與乙醯左旋肉鹼 (1 g/L於飲用水) 或是羥苯甘胺酸 (150 mg/kg經口灌食)，治療八週後分別與年紀相同之正常組與糖尿病未治療組作比較。在麻醉開胸後測量左心室壓力與升主動脈之血流，以計算最大收縮彈性 (maximal systolic elastance, Emax) 與理論最大血流 (theoretical maximum flow, Qmax)。生理上，Emax可以反映一個完整心臟的心肌收縮功能 (contractility)，而Qmax則是與左心室內部阻力有反比關係。

研究結果：
相較于正常組之Wistar-kyoto大鼠，糖尿病鼠的Emax下降，但Qmax不變，顯示心臟的收縮功能下降。不論是以乙醯左旋肉鹼或是羥苯甘胺酸治療糖尿病鼠，Emax均可以增加，顯示兩者均可以改善因糖尿病所引起的心臟收縮力下降。然而，僅有乙醯左旋肉鹼可以降低心肌細胞的丙二醇(malondialdehyde, MDA) 含量，減少脂質的過氧化產物產生。另一方面，以羥苯甘胺酸治療糖尿病鼠會增加週邊血管總阻力，減少Qmax，顯示在以羥苯甘胺酸治療後，心室內部阻力反而增加。
研究結論：
相對於羥苯甘胺酸，乙醯左旋肉鹼對於因糖尿病所引起的心臟泵浦功能不良的治療結果更為適當。因為乙醯左旋肉鹼不但可以增加心肌的收縮功能 (Emax)，且不會增加週邊血管總阻力，不至於增加心臟的內部阻力。

關鍵字

肉鹼棕櫚醯轉移酶-1 ； 彈性-阻力模型 ； dP/dtmax ； dP/dtmin ； 理論最大血流量 ； 硫巴比妥鹽檢測法

並列摘要

Introduction:
In the treatment of patients with diabetes, one objective is an improvement of cardiac metabolism to alleviate the left ventricular (LV function. For this study, we compared the effects of acetyl-L-carnitine (one of the carnitine derivatives) and of oxfenicine (a carnitine palmitoyltransferase-1 inhibitor) on cardiac pumping mechanics in streptozotocin-induced diabetes in male Wistar rats, with a particular focus on the pressure-flow-volume relationship.
Methods:
Diabetes was induced by a single tail vein injection of 55 mg kg-1 streptozotocin. The diabetic animals were treated on a daily basis with either acetyl-L-carnitine (1 g L-1 in drinking water) or oxfenicine (150 mg kg-1 by oral gavage) for 8 wk. They were also compared with untreated age-matched diabetic controls. LV pressure and ascending aortic flow signals were recorded to calculate the maximal systolic elastance (Emax) and the theoretical maximum flow (Qmax). Physically, Emax reflects the contractility of the myocardium as an intact heart, whereas Qmax has an inverse relationship with the LV internal resistance.
Results:
When comparing the diabetic rats with their age-matched controls, the cardiodynamic condition was characterized by a decline in Emax associated with the unaltered Qmax. Acetyl-L-carnitine (but not oxfenicine) had reduced cardiac levels of malondialdehyde in these insulin-deficient animals. However, treating with acetyl-L-carnitine or oxfenicine resulted in an increase in Emax, which suggests that these 2 drugs may protect the contractile status from deteriorating in the diabetic heart. By contrast, Qmax showed a significant fall after administration of oxfenicine, but not with acetyl-L-carnitine. The decrease in Qmax corresponded to an increase in total vascular resistance when treated with oxfenicine.
Conclusions:
Acetyl-L-carnitine, but not oxfencine, optimizes the integrative nature of cardiac pumping mechanics by preventing the diabetes-induced deterioration in myocardial intrinsic contractility associated with unaltered LV internal resistance.

並列關鍵字

Carnitine palmitoyltransferase-1 ； Elastance-Resistance Model ； dP/dtmax ； dP/dtmin ； Theoretical maximum flow ； MDA/TBARS assay

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