Olmesartan ameliorates arterial stiffening and cardiac hypertrophy in fructose-fed rats

背景：大量增加果糖攝取量會導致高血壓、胰島素阻抗及脂質異常，這三者對於心血管疾病皆為已確立的危險因子。果糖亦可能造成醣化最終產物 (advanced glycation end-product，AGE) 形成，影響某些動脈系統的物理特性。Olmesartan (OLM) 為一種血管收縮素受體阻斷劑，在離體研究中發現能抑制AGE形成。本篇的研究目標主要是評估OLM在動物體內，是否能藉由抑制不正常的代謝病徵及病態的主動脈膠原蛋白醣化現象，而改善果糖所引發動脈系統物理特性的改變。 方法：雄性Wistar大鼠於兩個月大時，開始將10%濃度的果糖摻入其飲用水中，給予自由飲取。在餵食果糖為期六週的倒數21天開始，每日以灌食方式給予大鼠每公斤體重10毫克的OLM作治療，並與年齡匹配的果糖餵食 (fructose-fed，FF) 大鼠作為對照組別。藉由實驗當中記錄到的脈態升主動脈血壓及血流訊號，作為描述動脈系統物理特性及脈波反射現象的依據。 結果：與FF組別相較，經由OLM治療後的FF組顯示，無論在心輸出量 (cardiac output)、心搏量 (stroke volume) 及主動脈收縮壓 (systolic aortic pressure)，皆有明顯的改善。OLM亦能改善果糖對於阻力型血管物理特性上所產生的不良影響，降低19.2% (P<0.005) 的總周邊阻力 (total peripheral resistance)。在動脈血流的脈態性質方面，OLM減緩了因果糖飲食所誘發的動脈延展度 (distensibility) 下降，在主動脈特徵阻抗 (aortic characteristic impedance) 上降低了23.9% (P<0.005)，在主動脈平均壓所對應之主動脈容積度 (aortic compliance at mean aortic pressure) 上增進了40.2% (P<0.05)。經OLM治療後的FF組別，波傳輸時間 (wave transit time) 明顯增加29.1% (P<0.005)，且波反射係數 (wave reflection factor) 降低13.6% (P<0.05)，顯示OLM能改善果糖飲食所造成左心室收縮負荷 (systolic load) 的增加。此外，心室重量以體重校正後之比值 (左心室比率，為心室肥厚的指標) 亦可經由OLM的投予而減少，顯示果糖飲食所導致的心室肥厚可因OLM降低了主動脈硬化而獲得改善。由生化物質分析中發現，OLM能夠降低因果糖餵食而升高的三酸甘油酯 (triglyceride)、胰島素 (insulin) 及丙二醛 (malondialdehyde) 血中濃度。另外，果糖飲食會促進動脈管壁中AGE的含量增加，此現象亦可經由OLM的治療得到改善。 結論：OLM能改善果糖所引起之動脈硬化及左心室肥厚，可能是由於OLM減緩了果糖引發的代謝性病徵並抑制主動脈膠原蛋白的不正常醣化現象。Objective：Fructose loading may cause hypertension, insulin resistance and dyslipidaemia, a triad of established risk factors for cardiovascular diseases. It also helps in the formation of advanced glycation end-products (AGEs) that could contribute to certain physical changes of the arterial system. Olmesartan (OLM), an angiotensin Ⅱ receptor blocker, has been reported to inhibit in vitro the production of AGEs. Herein, we determined whether OLM prevents the fructose-induced deterioration in physical properties of the arterial system, through targeting the abnormal metabolic profiles as well as the pathogenic glycation on aortic collagen in intact animals. Methods：Male Wistar rats at 2 months were given 10% fructose in drinking water for 6 weeks. Meanwhile, the fructose-fed (FF) animals received daily treatment with OLM (10 mg kg-1) by oral gavage for the last 21 days of the 6-week period and compared with the untreated FF group. Pulsatile aortic pressure and flow signals were measured to describe the physical properties of the arterial system along with the pulse wave reflection phenomena. Results：After exposure to OLM, the FF rats exhibited a significant improvement in cardiac output, stroke volume and systolic aortic pressure. OLM also prevented the fructose-derived deterioration in physical properties of the resistance vessels, as evidenced by the reduction of 19.2% in total peripheral resistance (P<0.005). As for the pulsatile nature of blood flows in arteries, OLM retarded the fructose-induced decline in aortic distensibility, as reflected in the fall of 23.9% in aortic characteristic impedance (P<0.005) and the rise of 40.2% in systemic arterial compliance (P<0.05). Treatment of the FF animals with OLM also resulted in an essential increase of 29.1% in wave transit time (P<0.005) and a decrease of 13.6% in wave reflection factor (P<0.05). These suggest that OLM may attenuate the fructose-derived augmentation in systolic vascular load imposed on the heart. Meanwhile, the diminished ratio of the left ventricular weight to body weight suggests that prevention of the fructose-related cardiac hypertrophy by OLM may correspond to the drug-induced decline in aortic stiffening. In addition, OLM therapy lowered plasma triglyceride, insulin, and malondialdehyde levels induced by fructose loading. Glycation-derived modification on aortic collagen was also found to be enhanced in the FF rats and the advanced glycation process was retarded by OLM treatment. Conclusion：OLM administration to the FF rats prevents arterial stiffening and cardiac hypertrophy, possibly through improvement of the fructose-derived metabolic profiles and inhibition of the pathogenic glycation on aortic collagen.目次……………………………………………………………………i次……………………………………………………………………iv次……………………………………………………………………v寫表…………………………………………………………………vi文摘要………………………………………………………………ix文摘要………………………………………………………………xi獻回顧二型糖尿病…………………………………………………………1脈硬化………………………………………………………………2糖……………………………………………………………………4管收縮素與血管收縮素受體阻斷劑olmesartan…………………15脈物理性質之量化…………………………………………………20動脈輸入阻抗頻譜的特性及功能…………………………………21究目標………………………………………………………………24料與方法驗動物製備…………………………………………………………25驗動物分組…………………………………………………………25液中葡萄糖濃度測定………………………………………………26壓波及血流波之測量………………………………………………27術流程………………………………………………………………28料轉換與分析方法…………………………………………………30心室比率……………………………………………………………37動脈管壁中單一醣化最終產物之萃取……………………………37體電泳………………………………………………………………38化物質分析…………………………………………………………39計……………………………………………………………………40果本資料………………………………………………………………41動脈輸入阻抗頻譜…………………………………………………42態基本血行力學參數………………………………………………42態血行力學參數……………………………………………………43化物質分析…………………………………………………………43動脈單一醣化最終產物之膠體電泳結果…………………………44論 糖飲水及OLM劑量投予………………………………………………45糖餵食及OLM對心血管動脈物理特性之影響………………………45糖餵食及OLM對生化物質之影響……………………………………51LM對果糖餵食大鼠之主動脈管壁組成成分的影響…………………53結……………………………………………………………………54 考文獻………………………………………………………………6