Fenofibrate對streptozotocin所誘發糖尿病鼠之動脈系統物理性質的影響

Abstract

研究背景與目的：糖尿病人調節醣類及脂肪代謝的功能出現異常，增加心臟對脂肪酸的利用作為能量來源。長期處於如高三酸甘油酯血症這樣的代謝改變會加劇糖尿病人心肌缺血的病徵並降低心肌功能。Peroxisome Proliferator–Activated Receptors (PPARs)被認為可能可用以治療糖尿病、高血脂及動脈硬化等代謝疾病，其中PPARα特別具有改善因代謝異常或糖尿病所引起的高血脂症狀，然而在治療糖尿病心臟功能的作用上，PPARα卻表現出物種特異性的情形。Fenofibrate (Feno)是一種PPARα的致效劑，目前已證實可改善高血脂，另外在血管方面亦具有抑制發炎反應及預防動脈硬化的作用。本篇將利用主動脈輸入阻抗頻譜分析方法，評估Feno在streptozotocin (STZ)誘發之糖尿病大鼠身上，對其動脈管物理特性所造成之影響。 研究方法：隨機將兩個月大之Wistar-Kyoto大鼠分成四組：(i)正常組(NC)；(ii)正常組餵食Feno (NC+Feno)；(iii)STZ誘發之糖尿病組(DM)；(iv)糖尿病餵食Feno組(DM +Feno)。以尾靜脈注射STZ(55mg kg-1)誘發大鼠產生糖尿病，待其出現高血糖症狀，給予餵食組大鼠每日灌食Feno(100mg kg-1)，連續給藥8週並與同齡未給藥之糖尿病控制組做對照，同步記錄大鼠主動脈血壓及血流訊號，以動脈系統的阻抗頻譜分析，接著利用主動脈輸入阻抗頻譜脈衝分析技術取得動脈波反射的相關數據。實驗後採集血液樣本進行血漿中三酸甘油酯、游離脂肪酸、總膽固醇的含量分析，並以硫代巴比妥酸反應物質進行丙二醛的含量分析。 研究結果：與糖尿病控制組相較之下，長期餵食糖尿病鼠Feno在血壓參數、心跳速率、心輸出量及周邊總阻力皆無顯著差異。另外，Feno會增加糖尿病鼠主動脈的特徵阻抗，然而對主動脈容積度並無影響。而在波反射現象方面，Feno會降低因糖尿病所上升的波反射係數達32.4%( p<0.001)，意味著長期餵食糖尿病鼠Feno可延遲脈波反射返回的現象，此結果亦可從波傳輸時間上升了21.1%(p<0.001)得到驗證。而由波傳輸時間的顯著上升及波反射係數的顯著下降的結果顯示，Feno可能可以減輕因糖尿病所導致的左心室收縮負荷的惡化，並藉由減輕糖尿病所引起的收縮負荷來預防心臟肥厚的現象，此可由左心室重量對體重的比值有顯著下降的結果證實。另外亦觀察到給予糖尿病鼠Feno可降低血漿中的三酸甘油酯及游離脂肪酸，以及降低血漿與主動脈中的丙二醛含量。 結論：長期給予Feno治療以STZ誘發之糖尿病大鼠，可減輕其主動脈收縮負荷及改善心臟肥厚的現象，可能與降低血漿中的三酸甘油酯及游離脂肪酸，並降低血漿中及主動脈中的脂質氧化物丙二醛有關。

Background and purpose：Patients with diabetes have disturbances in the regulation of carbohydrate and fat metabolism, leading to an impaired cardiac glucose oxidation and a greater uptake and utilization of free fatty acids. These metabolic changes by prolonged hyperglycemia are responsible for both the increased susceptibility of the diabetic heart to myocardial ischemia and greater decrease of myocardial performance. Peroxisome proliferator–activated receptors (PPARs) are promising targets for the development of new drugs, which treat metabolic disorders such as diabetes, dyslipidemia and atherosclerosis. Although activation of the nuclear receptor, PPAR-α, exerts species-specific activities in the diabetic heart, PPAR-α activators appear to be particularly indicated to treat dyslipidemia of the metabolic syndrome and diabetes mellitus. Fenofibrate (Feno), a PPAR-α agonist, has been demonstrated to improve dyslipidemia, inhibiting proinflammatory and proatherogenic responses in the vasculature. The present study focused on investigating the effects of Feno on the physical properties of the arterial system in streptozotocin (STZ)-induced diabetic in rats, using aortic input impedance analysis. Methods：Male Wistar rats at two months were randomly divided into four groups as follows：(i) normal control (NC)；(ii) NC treated with Feno (NC+Feno)；(iii) STZ-induced diabetic rats (DM)；(iv) DM treated with Feno (DM+Feno). Diabetes was induced in animals by a single tail vein injection with 55mg kg-1 STZ. After development of hyperglycemia, rats were treated for 8 weeks with Fenofibrate (100 mg kg-1) by oral gavage and compared with the age-matched untreated diabetic controls. Pulsatile aortic pressure and flow signals were measured to perform the vascular impedance analysis. Arterial wave reflection was derived using the impulse response function of the filtered aortic input impedance spectra. At the end of catheterization, blood samples from the animals studied were collected for determination of plasma levels of triglyceride (TG), free fatty acid (FFA), and total cholesterol. Thiobarbituric acid reactive substances (TBARS) measurement was used to estimate malondialdehyde (MDA) content. Results：Feno produced no significant changes in pressure parameters, basal heart rate, cardiac output and total peripheral resistance in the DM. On the other hand, aortic characteristic impedance but not systemic arterial compliance was increased in response to treatment of the STZ-diabetic rats with Feno. As for wave reflection phenomena, Feno attenuated the diabetes-related augmentation in wave reflection factor by 32.4%( p<0.001). Long-term administration of Feno to the STZ-diabetic animals also resulted in a delay return of the pulse wave reflection, as evidenced by the increase of 21.1% in wave transit time( p<0.001). A significant increase in wave transit time and a decrease in wave reflection factor suggested that Feno may alleviate the diabetes-induced deterioration in systolic loading condition for the left ventricle (LV). The decline in systolic load by Feno treatment could be responsible for the prevention of cardiac hypertrophy in the DM, as manifested by the fall of LV weight-body weight ratio. This was in parallel with its lowering of TG and FFA levels in plasma and MDA/TBARS content in plasma and aortic walls in diabetes. Conclusion：Long-term treatment of the STZ-diabetic rats with Feno attenuates aortic systolic load and cardiac hypertrophy, possibly through its decrease of TG and FFA levels in plasma and lipid oxidation-derived MDA/TBARS content in plasma and aortic walls.