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

Abstract

背景與目的：過氧化物增殖激活物受體 (Peroxisome Proliferator-Activated Receptors, PPARs) 是一種位於細胞核內之受體活化型因子 (ligand-activated nuclear factor) ，與其配體 (ligand) 結合後，可促進基因轉錄活化，調控脂肪代謝 (lipid metabolism)、能量平衡(energy balance)、抑制發炎反應 (inflammation) 以及防止動脈粥狀硬化 (atherosclerosis) 發生。PPARs 家族一共包含三個成員，分別為 PPAR-α、 PPAR-γ與 PPAR-β/δ。其中 PPARγ 具有增進血管功能與調節血壓的能力。 Thiazolidinediones (TZDs) 是一類具有 PPARγ高度專一性的人工合成配體， Rosiglitazone (Rosi) 為該類藥物之一員，在臨床上被用於治療第二型糖尿病患者胰島素阻抗問題。我們將利用主動脈輸入阻抗頻譜分析方法來評估 Rosi 是否能改善 Streptozotocin (STZ) 誘發糖尿病鼠所衍生出的動脈系統物理性惡化。 方法：我們使用 Rosi 對糖尿病鼠進行胃管灌食，將兩個月大之雄性 Wistar 大鼠隨機分成四組，分組如：第一組、正常組（NC）；第二組、正常餵食 Rosi 組（NC＋Rosi）；第三組、糖尿病組（DM）；第四組、糖尿病餵食 Rosi 組（DM＋Rosi）。糖尿病鼠施予尾靜脈注射 STZ (55 mg．kg-1) 誘發大鼠產生糖尿病，待其出現高血糖後，餵藥組，每天灌食 rosiglitazone (10 mg．kg-1) ，四組同步進行八周。將大鼠麻醉後，進行右側頸動脈插管 (catheterization) 至升主動脈處，以記錄主動脈血壓波與血流訊號，將進行主動脈頻譜分析。動脈波反射現象，以主動脈輸入阻抗頻譜分析利用逆傅立葉級數轉換後，經由脈衝分析法得之。插管結束，收集血液樣本，將大鼠犧牲並摘除心臟與主動脈，進行三酸甘油酯、游離脂肪酸、總膽固醇含量分析。使用硫代巴比妥酸反應物質 (thiobarbituric acid reactive substances, TBARS) 分析方法，測定血漿與組織中丙二醛 (malondialdehyde, MDA) 含量。 結果：Rosi 不會改善 STZ 所誘發糖尿病鼠的心跳速率降低現象；也不會影響心輸出量、心搏量以及周邊血管總阻力。另外一方面，Rosi 會增加糖尿病鼠主動脈特徵阻抗，對於主動脈容積度並沒有影響。Rosi 能降低糖尿病鼠的波反射係數（wave reflection factor, Rf）放大現象，降低幅度達到 20.0% (P<0.05)；還能延緩 17.9% (P<0.05) 的波傳輸時間（wave transit time, τ）。長期施予 Rosi 治療能改善糖尿病鼠波反射現象，藉由降低波反射係數以及增加波反射時間，能降低糖尿病鼠左心室收縮負荷力。另外 Rosi 能有效降低糖尿病鼠血漿三酸甘油脂（triglyceride）、游離脂肪酸（free fatty acid）與脂肪過氧化物丙二醛（malondialdehyde）。主動脈壁的丙二醛含量也有達到顯著下降。經由左心室重對體重標準化的數值降低，證實 Rosi 治療下的糖尿病鼠，能改善左心室肥厚之現象。 結論：Rosi 能有效降低糖尿病鼠血漿中三酸甘油酯、游離脂肪酸與主動脈壁的丙二醛，並且能改善左心室收縮負荷以及心室肥厚之現象。

Background Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear factors involved in the transcriptional regulation of lipid metabolism, energy balance, inflammation and atherosclerosis. The PPAR family comprises three members: α, γ and β/δ. Increasing evidence suggests that PPAR-γ is involved in the regulation of vascular function and blood pressure in addition to its well recognized role in metabolism. Thiazolidinediones (TZDs) are high affinity synthetic PPAR-γ ligands that have been used to treat patients with insulin resistance and type 2 diabetes. Herein, the aim of the study was to determine whether rosiglitazone (Rosi), one of the chemical compounds of TZDs, prevents the diabetes-related deterioration in physical properties of the arterial system in streptozotocin-induced diabetes in rats, using aortic input impedance. Method Male Wistar rats at 2 months were randomly divided into four groups as follow: ( i ) normal control rats (NC); (ii) NC treated with Rosi (NC+Rosi); (iii) STZ-induced diabetic rats (DM); (iv) DM treated with Rosi (DM+Rosi). Diabetes was induced in animals by single tail vein injection with 55 mg．kg-1 STZ. After induction of hyperglycemia, rats were treated with Rosi 10 mg．kg -1 by oral gavage for 8 weeks and compared with the age-matched untreated diabetic rats. Pulsatile pressure and flow signals were measured in the ascending aorta and were subjected to further 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. The blood samples were collected and conserved after experiment. Result The low basal heart rat in the STZ-diabetic rats did not change in response to Rosi treatment. After exposure to Rosi, the diabetic animals did not differ in cardiac output, stroke volume and total peripheral resistance from the untreated diabetic controls. On the other hand, aortic characteristic impedance but not systemic arterial compliance was increased in response to treatment of the STZ-diabetic rats with Rosi. As for arterial wave reflection phenomena, Rosi attenuated the diabetes-related augmentation in wave reflection factor by 20.0% (P<0.05). Long-term administration of Rosi to the STZ-diabetic animals also resulted in a delay return of the pulse wave reflection, as evidenced by the increase of 17.9% in wave transit time (P<0.05). A significant increase in wave transit time and a decrease in wave reflection factor suggested that Rosi may alleviate the diabetes-induced deterioration in systolic loading condition for the left ventricle (LV). This was in parallel with its lowering of FFA and TG levels in plasma and MDA/TBARS content in plasma and aortic walls in diabetes. The decline in systolic load by Rosi treatment could be responsible for the prevention of cardiac hypertrophy in the DM, as manifested by the fall of LV weight-body weight ratio. Conclusion Rosi attenuates the diabetes-induced augmentation in LV systolic load and cardiac hypertrophy, which parallelled with its decrease of FFA and TG levels in plasma and lipid oxidation-derived MDA/TBARS content in plasma and aortic walls.