臺灣博碩士論文加值系統

背景和目的：由國民健康局的資料顯示近年來國人的十大死因趨向於以心臟血管等疾病為主，而高血壓為其主要的危險因子之一。高血壓的情形下，血管內皮功能會有受損的情形。此外，氧化壓力上升對於血管功能失調和高血壓的發病機制，扮演一個重要的角色。原兒茶酸 (protocatechuic acid, PCA) 屬多酚類化合物，且為天然的抗氧化物，先前研究指出原兒茶酸具有很強的抗氧化能力。目前已知運動訓練可以有效改善心血管功能，然而尚無研究去探討和比較原兒茶酸和運動訓練對於高血壓心血管功能的影響，因此本研究目的是探討和比較長期原兒茶酸和運動介入對於高血壓心血管功能的影響，並探究其生理調控機制。方法：本研究以動物實驗模式進行，將六周大之高血壓大鼠隨機分成高血壓組 (不做任何介入) (spontaneously hypertensive rat, SHR)、高血壓餵食原兒茶酸組 (SHR+PCA) 和高血壓運動訓練組 (SHR+EX)，並以周齡相符之正常血壓之大鼠 (Wistar-Kyoto rat, WKY) 作為對照組，實驗共分為四組。高血壓餵食原兒茶酸組為每天每公斤體重給予200毫克的原兒茶酸添加於飲用水中，餵食八週；而高血壓運動訓練組則是每天規律進行跑步機運動訓練六十分鐘，每週五天，為期八週。於八週介入期間和結束後，分別測量四組血壓、心跳、和血管舒張功能等參數，並檢測血液抗氧化酵素的活性與脂質氧化傷害的程度，最後亦分析血管內皮功能相關蛋白質的表現量。結果：本研究發現於八週原兒茶酸和運動介入後，與不作任何介入之高血壓組相較下，結果顯示：(1) 顯著降低血壓 (2) 增加由乙醯膽鹼、胰島素和類胰島素生長因子-1 所調節之血管舒張功能 (3) 降低胰島素阻抗 (4) 增加一氧化氮生成量 (5) 增加血管中一氧化氮合成酶、胰島素受器和類胰島素生長因子-1 受器蛋白質表現量 (6) 增加抗氧化能力。結論：本研究顯示原兒茶酸和運動介入皆可有效改善部分之高血壓心血管功能，建議未來可作為高血壓族群之臨床介入方式。

Background and purpose：Oxidative stress elevation plays an important role in the pathogenesis of endothelial dysfunction and hypertension. Previous studies have indicated that the Protocatechuic acid (PCA) has strong antioxidant capacity. Moreover, exercise has been known to improve cardiovascular function. However, few research explored and compared the effects of PCA and exercise intervention on cardiovascular function in hypertension. Thus, the purpose of this study was to investigate the effects of long-term PCA and exercise intervention on cardiovascular function in hypertension, and explore its physiological mechanisms. Methods：Six-week-old male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were used in this study. The SHR were randomly divided into sedentary control (SHR), SHR with PCA feeding (SHR+PCA), and SHR with exercise training (SHR+EX) groups. The SHR+PCA group was feeded with, the PCA solution (0.2 g/kg body weight per day), adjusted from the daily water consumption, for a total of 8 weeks. In addition, the SHR+EX group was trained by the treadmill at moderate intensity for 5 days/week, 8 weeks. At the end of experiments, the cardiovascular responses were measured and compared among four groups. The serum levels of antioxidants and oxidants were examined, and the related vascular protein expression was also evaluated. Results：We found that, compared with the sedentary control SHR, the PCA and exercise intervention significantly could：(1) lower blood pressure; (2) increase acetylcholine-, insulin-, and IGF-1-induced vasodilation responses in aortas; (3) reduce insulin resistance; (4) increase nitric oxide production; (5) increase the protein expression of aortic eNOS, IR, and IGF-1R (6) increase the antioxidant activities. Conclusion：Either PCA or exercise training could significantly improve parts of cardiovascular function in hypertension, which may be applied in hypertensive population clinically.

中文摘要………………………………………………………………iv
英文摘要………………………………………………………………vi
謝誌……………………………………………………………………viii
目錄……………………………………………………………………ix
表目錄…………………………………………………………………xiv
圖目錄…………………………………………………………………xv

第壹章 緒論………………………………………………………………1
第一節 研究背景……………………………………………………1
第二節 研究目的……………………………………………………2
第三節 研究問題……………………………………………………2
第四節 研究假設……………………………………………………3
第貳章 文獻探討…………………………………………………………4
第一節 高血壓………………………………………………………4
第二節 自由基與體內抗氧化防禦系統……………………………6
一、 自由基……………………………………………………6
二、 體內抗氧化防禦系統………………………………………9
第三節 高血壓與氧化壓力………………………………………11
第四節 多酚與高血壓……………………………………………12
第五節 原兒茶酸 (protocatechuic acid, PCA)……………………14
第六節 胰島素與類胰島素生長因子……………………………16
第七節 運動與高血壓……………………………………………18
第参章 材料與方法……………………………………………………20
第一節 實驗動物來源與飼養……………………………………20
第二節 長期運動訓練計畫………………………………………21
第三節 休息時心搏率與血壓測量之方法………………………22
第四節 胰島素阻抗指標………………………………………23
一、 血糖偵測…………………………………………………23
二、 胰島素含量………………………………………………23
三、 Homeostasis model assessment for insulin resistance (HOMA-IR) ……………………………………………23
第五節 血管舒張反應之量測……………………………………24
一、 血清的製備………………………………………………24
二、 血管段的製備……………………………………………24
三、 血管段活性測試…………………………………………25
四、 內皮依賴性血管舒張反應………………………………26
五、 非內皮依賴性血管舒張反應……………………………26
六、 一氧化氮合成酶和 PI3-kinase 的作用…………………26
第六節 一氧化氮含量分析………………………………………27
第七節 檸檬酸合成酶之活性分析………………………………28
第八節 西方墨點法………………………………………………29
一、 組織樣本前處理…………………………………………29
二、 蛋白質定量………………………………………………29
三、 蛋白質變性………………………………………………30
四、 SDS-PAGE 配置…………………………………………30
五、 跑電泳膠片………………………………………………31
六、 電泳膠片的轉漬 (membrane transfer) 及 blotting………31
七、 接上一級抗體與二級抗體………………………………31
第九節 脂質過氧化分析和抗氧化酵素之活性分析……………32
一、 脂質過氧化丙二醛含量分析……………………………32
二、 過氧化氫酶之活性分析…………………………………33
第十節 統計分析………………………………………………34
第肆章 結果……………………………………………………………35
第一節 基本生理參數……………………………………………35
第二節 胰島素阻抗指標…………………………………………36
第三節 血管舒張反應之量測……………………………………36
一、 乙醯膽鹼所調節之血管舒張反應………………………36
二、 胰島素所調節之血管舒張反應…………………………37
三、 類胰島素生長因子所調節之血管舒張反應……………38
四、 SNP所調節之血管舒張反應……………………………38
五、 L-NAME和 Wortmannin 抑制劑對於乙醯膽鹼所調節之血管舒張反應………………………………………………39
六、 L-NAME和Wortmannin 抑制劑對於胰島素所調節之血管舒張反應……………………………………………………40
七、 L-NAME和Wortmannin 抑制劑對於類胰島素生長因子所調節之血管舒張反應……………………………………40
第四節 一氧化氮含量分析………………………………………41
第五節 檸檬酸合成酶之活性……………………………………42
第六節 血管功能相關之蛋白質表現量…………………………42
一、 內皮細胞一氧化氮合成酶之蛋白質表現量 ……………42
二、 胰島素受器之蛋白質表現量…………………………43
三、 類胰島素生長因子之蛋白質表現量…………………43
第七節 脂質過氧化物含量分析和抗氧化酵素之活性分析……43
一、 脂質過氧化丙二醛含量分析……………………………43
二、 抗氧化酵素之活性分析…………………………………44
第伍章 討論與結論…………………………………………………45
參考文獻…………………………………………………………………58
















表目錄

表1、八週原兒茶酸和運動介入後之體重、休息時心跳和血壓參數…82
表2、八週原兒茶酸和運動介入後之空腹血糖值、胰島素含量和 Homeostasis model assessment for insulin resistance (HOMA-IR) ………………………………………………………83
表3、八週原兒茶酸和運動介入後之比目魚肌檸檬酸合成酶活性……84












圖目錄

圖1、經八週原兒茶酸和運動介入後，累積劑量之乙醯膽鹼對於大鼠胸主動脈血管所調節血管舒張反應曲圖…………………………85
圖2、經八週原兒茶酸和運動介入後，累積劑量之胰島素對於大鼠胸主動脈血管所調節血管舒張反應曲線圖…………………………86
圖3、經八週原兒茶酸和運動介入後，累積劑量之類胰島素生長因子-1對於大鼠胸主動脈血管所調節血管舒張反應曲線圖…………87
圖4、經八週原兒茶酸和運動介入後，累積劑量之劑量 SNP 對於大鼠胸主動脈血管所調節血管舒張反應曲線圖……………………88
圖5、經八週原兒茶酸和運動介入後，在L-NAME (10-6M)抑制劑作用下，乙醯膽鹼對於大鼠胸主動脈血管所調節之血管舒張反應結果…………………………………………………………………89
圖6、經八週原兒茶酸和運動介入後，在wortmannin (3×10-7M) 抑制劑作用下，乙醯膽鹼對於大鼠胸主動脈血管所調節之血管舒張反應結果………………………………………………………………90
圖7、經八週原兒茶酸和運動介入後，在L-NAME (10-6M)抑制劑作用下，胰島素對於大鼠胸主動脈血管所調節之血管舒張反應結果…………………………………………………………………91
圖8、經八週原兒茶酸和運動介入後，在wortmannin (3×10-7M) 抑制劑作用下，胰島素對於大鼠胸主動脈血管所調節之血管舒張反應結果…………………………………………………………………92
圖9、經八週原兒茶酸和運動介入後，在L-NAME (10-6M)抑制劑作用下，類胰島素生長因子-1對於大鼠胸主動脈血管所調節之血管舒張反應結果………………………………………………………93
圖10、經八週原兒茶酸和運動介入後，在wortmannin (3×10-7M) 抑制劑作用下，類胰島素生長因子-1對於大鼠胸主動脈血管所調節之血管舒張反應結果……………………………………………94
圖11、 八週原兒茶酸和運動介入後之一氧化氮 (Nitrate+Nitrite) 含量分析結果………………………………………………………95
圖12、 八週原兒茶酸和運動介入後之內皮細胞一氧化氮合成酶蛋白質表現量變化…………………………………………………96
圖13、八週原兒茶酸和運動介入後之胰島素受器蛋白質表現量變化………………………………………………………………97
圖14、 八週原兒茶酸和運動介入後之類胰島素生長因子-1受器蛋白質表現量變化…………………………………………………98
圖15、 八週原兒茶酸和運動介入後之丙二醛濃度變化……………99
圖16、 八週原兒茶酸和運動介入後過氧化氫酶酵素活性變……100

Abraham, P., Saumet, J. L., & Chevalier, J. M. (1997). External iliac artery endofibrosis in athletes. Sports Medicine (Auckland, NZ), 24(4), 221-226.
Adegunloye, B., Omoniyi, J., Owolabi, O., Ajagbonna, O., Sofola, O., & Coker, H. (1996). Mechanisms of the blood pressure lowering effect of the calyx extract of Hibiscus sabdariffa in rats. African Journal of Medicine and Medical Sciences, 25(3), 235-238.
Ahmad, S. (1995). Oxidative stress and antioxidant defenses in biology: Kluwer Academic Pub.
Aldini, G., Carini, M., Piccoli, A., Rossoni, G., & Facino, R. M. (2003). Procyanidins from grape seeds protect endothelial cells from peroxynitrite damage and enhance endothelium-dependent relaxation in human artery: new evidences for cardio-protection. Life Sciences, 73(22), 2883-2898.
Allen, C., & Bayraktutan, U. (2009). Oxidative stress and its role in the pathogenesis of ischaemic stroke. International Journal of Stroke, 4(6), 461-470.
Ariga, T., & HAMANO, M. (1990). Radical scavenging action and its mode in procyanidins B-1 and B-3 from Azuki Beans to peroxyl radicals (Food & Nutrition). Agricultural and Biological Chemistry, 54(10), 2499-2504.
Arvola, P., Wu, X., Kähönen, M., Mäkynen, H., Riutta, A., Mucha, I., . . . Pörsti, I. (1999). Exercise enhances vasorelaxation in experimental obesity associated hypertension. Cardiovascular Research, 43(4), 992-1002.
Ausiello, D. A., Benos, D. J., Abboud, F., Koopman, W., & Epstein, P. (2003). Pathogenesis of hypertension. Annals of Internal Medicine, 139, 761-776.
Bagchi, D., Bagchi, M., Stohs, S. J., Ray, S. D., Sen, C. K., & Preuss, H. G. (2002). Cellular protection with proanthocyanidins derived from grape seeds. Annals of the New York Academy of Sciences, 957(1), 260-270.
Bakris, G. L., Standley, P. R., Palant, C. E., Walsh, M. F., & Sowers, J. R. (1996). Analogy between endothelial/mesangial cell and endothelial/vascular smooth muscle cell interactions. Endocrinology of the Vasculature, 1, 341-355.
Baron, A. D., & Clark, M. G. (1997). Role of blood flow in the regulation of muscle glucose uptake. Annual review of nutrition, 17(1), 487-499.
Bergendi, L., Benes, L., Durackova, Z., & Ferencik, M. (1999). Chemistry, physiology and pathology of free radicals. Life Sciences, 65(18-19), 1865-1874.
Block, G. (1992). The data support a role for antioxidants in reducing cancer risk. Nutrition Reviews, 50(7), 207-213.
Block, G., & Langseth, L. (1994). Antioxidant vitamins and disease prevention. Food Technology, 48(7), 80-84.
Blum, W. F., & Schweizer, R. (2003). Insulin-like growth factors and their binding proteins. Diagnostics of Endocrine Function in Children and Adolescents. Basel, Karger, 166-199.
Breimer, L. H. (1990). Molecular mechanisms of oxygen radical carcinogenesis and mutagenesis: the role of DNA base damage. Molecular Carcinogenesis, 3(4), 188-197.
Brown, M. D., Dengel, D. R., Hogikyan, R. V., & Supiano, M. A. (2002). Sympathetic activity and the heterogenous blood pressure response to exercise training in hypertensives. Journal of Applied Physiology, 92(4), 1434-1442.
Brum, P. C., Da Silva, G. J. J., Moreira, E. D., Ida, F., Negrão, C. E., & Krieger, E. M. (2000). Exercise training increases baroreceptor gain sensitivity in normal and hypertensive rats. Hypertension, 36(6), 1018-1022.
Burton, G. W., & Ingold, K. (1984). Beta-carotene: an unusual type of lipid antioxidant. Science, 224(4649), 569-573.
Cai, H., & Harrison, D. G. (2000). Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circulation Research, 87(10), 840-844.
Cameron, J. D., & Dart, A. M. (1994). Exercise training increases total systemic arterial compliance in humans. American Journal of Physiology-Heart and Circulatory Physiology, 266(2), H693-H701.
Cao, Y., Zhang, L., Ma, C., Chang, B., Chen, Y. C., Tang, Y., & Liu, X. (2009). Metabolism of protocatechuic acid influences fatty acid oxidation in rat heart: new anti-angina mechanism implication. Biochemical Pharmacology, 77(6), 1096-1104.
Carretero, O. A., & Oparil, S. (2000). Essential hypertension: Part I: definition and etiology. Circulation, 101(3), 329-335.
Chen, H., & Chiang, I. P. (1996). Chronic exercise decreases adrenergic agonist-induced vasoconstriction in spontaneously hypertensive rats. American Journal of Physiology-Heart and Circulatory Physiology, 271(3), H977-H983.
Chen, H., Chiang, I. P., & Jen, C. J. (1996). Exercise training increases acetylcholine-stimulated endothelium-derived nitric oxide release in spontaneously hypertensive rats. Journal of Biomedical Science, 3(6), 454-460.
Chen, X., Touyz, R. M., Park, J. B., & Schiffrin, E. L. (2001). Antioxidant effects of vitamins C and E are associated with altered activation of vascular NADPH oxidase and superoxide dismutase in stroke-prone SHR. Hypertension, 38(3), 606-611.
Chobanian, A. V., Bakris, G. L., Black, H. R., Cushman, W. C., Green, L. A., Izzo Jr, J. L., . . . Wright Jr, J. T. (2003). The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. The Journal of the American Medical Association, 289(19), 2560-2572.
Chowdhary, S., & Townend, J. (2001). Nitric oxide and hypertension: not just an endothelium derived relaxing factor! Journal of Human Hypertension, 15(4), 219-217.
Collett-Solberg, P. F., & Cohen, P. (1996). The role of the insulin-like growth factor binding proteins and the IGFBP proteases in modulating IGF action. Endocrinology &Metabolism Clinics of North America, 25(3), 591-614.
Cornelissen, V. A., & Fagard, R. H. (2005). Effects of endurance training on blood pressure, blood pressure–regulating mechanisms, and cardiovascular risk factors. Hypertension, 46(4), 667-675.
Coyle, J. T., & Puttfarcken, P. (1993). Oxidative stress, glutamate, and neurodegenerative disorders. Science, 262(5134), 689-695.
Croft, K. D. (1998). The chemistry and biological effects of flavonoids and phenolic acidsa. Annals of the New York Academy of Sciences, 854(1), 435-442.
Davies, K. J. A., Quintanilha, A. T., Brooks, G. A., & Packer, L. (1982). Free radicals and tissue damage produced by exercise. Biochemical and Biophysical Research Communications, 107(4), 1198-1205.
Dinenno, F. A., Tanaka, H., Monahan, K. D., Clevenger, C. M., Eskurza, I., DeSouza, C. A., & Seals, D. R. (2001). Regular endurance exercise induces expansive arterial remodelling in the trained limbs of healthy men. The Journal of Physiology, 534(1), 287-295.
Dominguez, L. J., Peuler, J. D., & Sowers, J. R. (1996). Endocrine regulation of vascular smooth muscle intermediary metabolism. Endocrinology of the Vasculature, 1, 325-339.
Drexler, H., & Hornig, B. (1999). Endothelial dysfunction in human disease. Journal of Molecular and Cellular Cardiology, 31(1), 51-60.
Dunbar, C. (1992). The antihypertensive effects of exercise training. New York State Journal of Medicine, 92(6), 250-255.
Dunsford, C., Sweeney, M., & Gottschall-Pass, K. (2003). Lowbush blueberry consumption reduces atherosclerotic plaque size in hypercholesterolemic rabbits.
Epstein, F. H., & Ross, R. (1999). Atherosclerosis—an inflammatory disease. New England Journal of Medicine, 340(2), 115-126.
Esterbauer, H., Gebicki, J., Puhl, H., & Jurgens, G. (1992). The role of lipid peroxidation and antioxidants in oxidative modification of LDL. Free Radical Biology and Medicine, 13(4), 341-390.
Facchini, F. S., & Saylor, K. L. (2003). A low-iron-available, polyphenol-enriched, carbohydrate-restricted diet to slow progression of diabetic nephropathy. Diabetes, 52(5), 1204-1209.
Fagard, R., Grauwels, R., Groeseneken, D., Lijnen, P., Staessen, J., Vanhees, L., & Amery, A. (1985). Plasma levels of renin, angiotensin II, and 6-ketoprostaglandin F1 alpha in endurance athletes. Journal of Applied Physiology, 59(3), 947-952.
FAGARD, R. H. (2001). Exercise characteristics and the blood pressure response to dynamic physical training. Medicine & Science in Sports & Exercise, 33(6), S493-494.
Fagard, R. H. (2011). Exercise therapy in hypertensive cardiovascular disease. Progress in Cardiovascular Diseases, 53(6), 404-411.
Fregly, M. J. (1984). Effect of an exercise regimen on development of hypertension in rats. Journal of Applied Physiology, 56(2), 381-387.
Frei, B. (1994). Natural antioxidants in human health and disease: Academic Pr.
Fridovich, I. (1995). Superoxide radical and superoxide dismutases. Annual Review of Biochemistry, 64(1), 97-112.
Fukai, T., & Ushio-Fukai, M. (2011). Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxidants & Redox Signaling, 15(6), 1583-1606.
Gimbrone, M. A. (1995). Vascular endothelium: an integrator of pathophysiologic stimuli in atherosclerosis. The American Journal of Cardiology, 75(6), 67B-70B.
Glaze, W. H. (1986). Reaction products of ozone: a review. Environmental Health Perspectives, 69, 151-157.
Goto, C., Higashi, Y., Kimura, M., Noma, K., Hara, K., Nakagawa, K., . . . Nara, I. (2003). Effect of different intensities of exercise on endothelium-dependent vasodilation in humans. Circulation, 108(5), 530-535.
Goto, C., Nishioka, K., Umemura, T., Jitsuiki, D., Sakagutchi, A., Kawamura, M., . . . Higashi, Y. (2007). Acute moderate-intensity exercise induces vasodilation through an increase in nitric oxide bioavailiability in humans&ast. American Journal of Hypertension, 20(8), 825-830.
Grazioli, V., Schiavo, R., Casari, E., Marzatico, F., Rodriguez y Baena, R., & Gaetani, P. (1998). Antioxidant enzymatic activities and lipid peroxidation in cultured human chondrocytes from vertebral plate cartilage. FEBS Letters, 431(2), 149-153.
Green, D. J., Maiorana, A., O'Driscoll, G., & Taylor, R. (2004). Effect of exercise training on endothelium‐derived nitric oxide function in humans. The Journal of Physiology, 561(1), 1-25.
Group, I. C.-o. R. (1988). Sodium, potassium, body mass, alcohol and blood pressure: the INTERSALT study. Journal of hypertension. Supplement: Official Journal of the International Society of Hypertension, 6(4), S584-S586.
Gruner, S., Volk, H. D., & Baehr, R. V. (1986). The influence of phagocytic stimuli on the expression of HLA‐DR antigens; role of reactive oxygen intermediates. European Journal of Immunology, 16(2), 212-215.
Halliwell, B. (1991). Reactive oxygen species in living systems: source, biochemistry, and role in human disease. The American Journal of Medicine, 91(3), S14-S22.
Halliwell, B. (1993). Cigarette smoking and health: a radical view. The Journal of the Royal Society for the Promotion of Health, 113(2), 91-96.
Halliwell, B., & Aruoma, O. I. (1993). DNA and free radicals: Ellis Horwood New York, London.
Halliwell, B., & Chirico, S. (1993). Lipid peroxidation: its mechanism, measurement, and significance. The American Journal of Clinical Nutrition, 57(5), 715S-724S.
Halliwell, B., & Cross, C. E. (1994). Oxygen-derived species: their relation to human disease and environmental stress. Environmental Health Perspectives, 102(Suppl 10), 5-12.
Halliwell, B., & Gutteridge, J. (1985). Oxygen radicals and the nervous system. Trends in Neurosciences, 8, 22-26.
Hansson, H. A., Jennische, E., & Skottner, A. (1987). Regenerating endothelial cells express insulin-like growth factor-I immunoreactivity after arterial injury. Cell and Tissue Research, 250(3), 499-505.
Hermansen, K. (2000). Diet, blood pressure and hypertension. British Journal Nutrition, 83 Suppl 1, S113-119. doi: S0007114500001045 [pii]
Hertog, M. G. L., Feskens, E. J. M., Kromhout, D., Hollman, P., & Katan, M. (1993). Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. The Lancet, 342(8878), 1007-1011.
Hirose, Y., Tanaka, T., Kawamori, T., Olnishi, M., Makita, H., Mori, H., . . . Hara, A. (1995). Chemoprevention of urinary bladder carcinogenesis by the natural phenolic compound protocatechuic acid in rats. Carcinogenesis, 16(10), 2337-2342.
Imai, H., Narashima, K., Arai, M., Sakamoto, H., Chiba, N., & Nakagawa, Y. (1998). Suppression of leukotriene formation in RBL-2H3 cells that overexpressed phospholipid hydroperoxide glutathione peroxidase. Journal of Biological Chemistry, 273(4), 1990-1997.
Isenovic, E. R., Meng, Y., Divald, A., Milivojevic, N., & Sowers, J. R. (2002). Role of phosphatidylinositol 3-kinase/Akt pathway in angiotensin II and insulin-like growth factor-1 modulation of nitric oxide synthase in vascular smooth muscle cells. Endocrine, 19(3), 287-291.
Jennings, G., Nelson, L., Nestel, P., Esler, M., Korner, P., Burton, D., & Bazelmans, J. (1986). The effects of changes in physical activity on major cardiovascular risk factors, hemodynamics, sympathetic function, and glucose utilization in man: a controlled study of four levels of activity. Circulation, 73(1), 30-40.
Kühnau, J. (1976). The flavonoids. A class of semi-essential food components: their role in human nutrition. World Review of Nutrition and Dietetics, 24, 117-191.
Kahn, A. M., & Song, T. (1996). Effects of insulin on vascular smooth muscle contraction. Endocrinology of the Vasculature, 1, 215-223.
Karim, M., McCormick, K., & Kappagoda, C. T. (2000). Effects of cocoa extracts on endothelium-dependent relaxation. The Journal of Nutrition, 130(8), 2105S-2108S.
Kawamori, T., Tanaka, T., Kojima, T., Suzui, M., Ohnishi, M., & Mori, H. (1994). Suppression of azoxymethane‐induced rat colon aberrant crypt foci by dietary protocatechuic acid. Cancer Science, 85(7), 686-691.
Kern, P., Svoboda, M., Eckel, R., & Van Wyk, J. (1989). Insulinlike growth factor action and production in adipocytes and endothelial cells from human adipose tissue. Diabetes, 38(6), 710-717.
Khan, N. Q., Lees, D. M., Douthwaite, J. A., Carrier, M. J., & Corder, R. (2002). Comparison of red wine extract and polyphenol constituents on endothelin-1 synthesis by cultured endothelial cells. Clinical Science, 103(48), 72-75.
Khorsandi, M., Fagin, J. A., Fishbein, M. C., Forrester, J. S., & Cercek, B. (1992). Effects of hypophysectomy on vascular insulin-like growth factor-I gene expression after balloon denudation in rats. Atherosclerosis, 93(1-2), 115-122.
Khorsandi, M. J., Fagin, J. A., Giannella-Neto, D., Forrester, J. S., & Cercek, B. (1992). Regulation of insulin-like growth factor-I and its receptor in rat aorta after balloon denudation. Evidence for local bioactivity. Journal of Clinical Investigation, 90(5), 1926-1931.
Kim, J., Montagnani, M., Koh, K. K., & Quon, M. J. (2006). Reciprocal relationships between insulin resistance and endothelial dysfunction. Circulation, 113(15), 1888-1904.
Kim, S. H., Kang, K. W., Kim, K. W., & Kim, N. D. (2000). Procyanidins in crataegus extract evoke endothelium-dependent vasorelaxation in rat aorta. Life Sciences, 67(2), 121-131.
KINGWELL, B. A. (2000). Nitric oxide-mediated metabolic regulation during exercise: effects of training in health and cardiovascular disease. The FASEB Journal, 14(12), 1685-1696.
Kokkinos, P. F., Narayan, P., Colleran, J. A., Pittaras, A., Notargiacomo, A., Reda, D., & Papademetriou, V. (1995). Effects of regular exercise on blood pressure and left ventricular hypertrophy in African-American men with severe hypertension. New England Journal of Medicine, 333(22), 1462-1467.
Kuru, O., Şentürk, Ü., Demir, N., Yeşilkaya, A., Ergüler, G., & Erkılıc, M. (2002). Effect of exercise on blood pressure in rats with chronic NOS inhibition. European Journal of Applied Physiology, 87(2), 134-140.
Kwan, C. Y., Zhang, W. B., Deyama, T., & Nishibe, S. (2004). Endothelium-dependent vascular relaxation induced by Eucommia ulmoides Oliv. bark extract is mediated by NO and EDHF in small vessels. Naunyn-Schmiedeberg's Archives of Pharmacology, 369(2), 206-211.
López-Sepúlveda, R., Jiménez, R., Romero, M., Zarzuelo, M. J., Sánchez, M., Gómez-Guzmán, M., . . . Pérez-Vizcaíno, F. (2008). Wine polyphenols improve endothelial function in large vessels of female spontaneously hypertensive rats. Hypertension, 51(4), 1088-1095.
Lüscher, T. F., & Vanhoutte, P. M. (1990). The endothelium: modulator of cardiovascular function: CRC.
Laughlin, M. H., Schrage, W. G., McAllister, R. M., Garverick, H., & Jones, A. (2001). Interaction of gender and exercise training: vasomotor reactivity of porcine skeletal muscle arteries. Journal of Applied Physiology, 90(1), 216-227.
Lawes, C. M. M., Hoorn, S. V., & Rodgers, A. (2008). Global burden of blood-pressure-related disease, 2001. The Lancet, 371(9623), 1513-1518.
Levine, G. N., Frei, B., Koulouris, S. N., Gerhard, M. D., Keaney, J. F., & Vita, J. A. (1996). Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation, 93(6), 1107-1113.
Lin, W. L., Hsieh, Y. J., Chou, F. P., Wang, C. J., Cheng, M. T., & Tseng, T. H. (2003). Hibiscus protocatechuic acid inhibits lipopolysaccharide-induced rat hepatic damage. Archives of Toxicology, 77(1), 42-47.
Lorenz, M., Wessler, S., Follmann, E., Michaelis, W., Düsterhöft, T., Baumann, G., . . . Stangl, V. (2004). A constituent of green tea, epigallocatechin-3-gallate, activates endothelial nitric oxide synthase by a phosphatidylinositol-3-OH-kinase-, cAMP-dependent protein kinase-, and Akt-dependent pathway and leads to endothelial-dependent vasorelaxation. Journal of Biological Chemistry, 279(7), 6190-6195.
Maeda, S., Miyauchi, T., Kakiyama, T., Sugawara, J., Iemitsu, M., Irukayama-Tomobe, Y., . . . Matsuda, M. (2001). Effects of exercise training of 8 weeks and detraining on plasma levels of endothelium-derived factors, endothelin-1 and nitric oxide, in healthy young humans. Life Sciences, 69(9), 1005-1016.
Mark, A. (1996). The sympathetic nervous system in hypertension: a potential long-term regulator of arterial pressure. Journal of Hypertension. Supplement: Official Journal of The International Society of Hypertension, 14(5), S159-165.
Matchett, M. D., MacKinnon, S. L., Sweeney, M. I., Gottschall-Pass, K. T., & Hurta, R. A. R. (2005). Blueberry flavonoids inhibit matrix metalloproteinase activity in DU145 human prostate cancer cells. Biochemistry and Cell Biology, 83(5), 637-643.
Matchett, M. D., MacKinnon, S. L., Sweeney, M. I., Gottschall-Pass, K. T., & Hurta, R. A. R. (2006). Inhibition of matrix metalloproteinase activity in DU145 human prostate cancer cells by flavonoids from lowbush blueberry (Vaccinium angustifolium): possible roles for protein kinase C and mitogen-activated protein-kinase-mediated events. The Journal of Nutritional Biochemistry, 17(2), 117-125.
MatÉs, J. É. M., Pérez-Gómez, C., & De Castro, I. N. (1999). Antioxidant enzymes and human diseases. Clinical Biochemistry, 32(8), 595-603.
Matsumoto, A., Hirata, Y., Momomura, S., Fujita, H., Yao, A., Sata, M., & Serizawa, T. (1994). Increased nitric oxide production during exercise. Lancet, 343(8901), 849-850.
Mendes, A., Desgranges, C., Chèze, C., Vercauteren, J., & Freslon, J. L. (2003). Vasorelaxant effects of grape polyphenols in rat isolated aorta. Possible involvement of a purinergic pathway. Fundamental & Clinical Pharmacology, 17(6), 673-681.
Mizugaki, M., Ishizawa, F., Yamazaki, T., & Hishinuma, T. (2000). Epigallocatechin gallate increase the prostacyclin production of bovine aortic endothelial cells. Prostaglandins &Other Lipid Mediators, 62(2), 157-164.
Mukai, Y., & Sato, S. (2011). Polyphenol-containing azuki bean (Vigna angularis) seed coats attenuate vascular oxidative stress and inflammation in spontaneously hypertensive rats. The Journal of Nutritional Biochemistry, 22(1), 16-21.
Ndiaye, M., Chataigneau, M., Lobysheva, I., Chataigneau, T., & Schini-Kerth, V. B. (2005). Red wine polyphenol-induced, endothelium-dependent NO-mediated relaxation is due to the redox-sensitive PI3-kinase/Akt-dependent phosphorylation of endothelial NO-synthase in the isolated porcine coronary artery. The FASEB Journal, 19(3), 455-457.
Ndiaye, M., Chataigneau, T., Andriantsitohaina, R., Stoclet, J. C., & Schini-Kerth, V. B. (2003). Red wine polyphenols cause endothelium-dependent EDHF-mediated relaxations in porcine coronary arteries via a redox-sensitive mechanism. Biochemical and Biophysical Research Communications, 310(2), 371-377.
Negishi, H., Xu, J. W., Ikeda, K., Njelekela, M., Nara, Y., & Yamori, Y. (2004). Black and green tea polyphenols attenuate blood pressure increases in stroke-prone spontaneously hypertensive rats. The Journal of Nutrition, 134(1), 38-42.
Neto, C. C. (2007). Cranberry and blueberry: evidence for protective effects against cancer and vascular diseases. Molecular Nutrition & Food Research, 51(6), 652-664.
Norton, C., Kalea, A. Z., Harris, P. D., & Klimis-Zacas, D. J. (2005). Wild blueberry-rich diets affect the contractile machinery of the vascular smooth muscle in the Sprague-Dawley rat. Journal of Medicinal Food, 8(1), 8-13.
Panza, J. A., Quyyumi, A. A., Brush Jr, J. E., & Epstein, S. E. (1990). Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. New England Journal of Medicine, 323(1), 22-27.
Parkinson, A. (2001). Biotransformation of xenobiotics: McGraw-Hill New York.
Pataki, T., Bak, I., Kovacs, P., Bagchi, D., Das, D. K., & Tosaki, A. (2002). Grape seed proanthocyanidins improved cardiac recovery during reperfusion after ischemia in isolated rat hearts. The American Journal of Clinical Nutrition, 75(5), 894-899.
Peng, N., Prasain, J. K., Dai, Y., Moore, R., Arabshahi, A., Barnes, S., . . . Wyss, J. M. (2009). Chronic dietary kudzu isoflavones improve components of metabolic syndrome in stroke-prone spontaneously hypertensive rats. Journal of Agricultural and Food Chemistry, 57(16), 7268-7273.
Perrini, S., Henriksson, J., Zierath, J. R., & Widegren, U. (2004). Exercise-induced protein kinase C isoform-specific activation in human skeletal muscle. Diabetes, 53(1), 21-24.
Pescatello, L. S., Franklin, B. A., Fagard, R., Farquhar, W. B., Kelley, G. A., & Ray, C. A. (2004). Exercise and hypertension. Medicine & Science in Sports & Exercise, 36(3), 533-553.
Potenza, M. A., Marasciulo, F. L., Tarquinio, M., Tiravanti, E., Colantuono, G., Federici, A., . . . Montagnani, M. (2007). EGCG, a green tea polyphenol, improves endothelial function and insulin sensitivity, reduces blood pressure, and protects against myocardial I/R injury in SHR. American Journal of Physiology-Endocrinology and Metabolism, 292(5), E1378-E1387.
Pou, S., Pou, W., Bredt, D., Snyder, S., & Rosen, G. (1992). Generation of superoxide by purified brain nitric oxide synthase. Journal of Biological Chemistry, 267(34), 24173-24176.
Prior, R. L., Cao, G., Martin, A., Sofic, E., McEwen, J., O'Brien, C., . . . Krewer, G. (1998). Antioxidant capacity as influenced by total phenolic and anthocyanin content, maturity, and variety of vaccinium species. Journal of Agricultural and Food Chemistry, 46 (7), 0021-8561.
Pryor, W. A., & Stone, K. (1993). Oxidants in cigarette smoke radicals, hydrogen peroxide, peroxynitrate, and peroxynitritea. Annals of the New York Academy of Sciences, 686(1), 12-27.
Rikans, L. E., & Hornbrook, K. R. (1997). Lipid peroxidation, antioxidant protection and aging. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1362(2-3), 116-127.
Rizzoni, D. (2002). Endothelial dysfunction in hypertension: fact or fantasy? Journal of Hypertension, 20(8), 1479-1481.
Sandalio, L. M., López-Huertas, E., Bueno, P., & Del Río, L. A. (1997). Immunocytochemical localization of copper, zinc superoxide dismutase in peroxisomes from watermelon (Citrullus vulgaris Schrad.) cotyledons. Free Radical Research, 26(3), 187-194.
Sandström, J., Nilsson, P., Karlsson, K., & Marklund, S. L. (1994). 10-fold increase in human plasma extracellular superoxide dismutase content caused by a mutation in heparin-binding domain. Journal of Biological Chemistry, 269(29), 19163-19166.
Sato, S., Mukai, Y., Yamate, J., Kato, J., Kurasaki, M., Hatai, A., & Sagai, M. (2008). Effect of polyphenol‐containing azuki bean (VignaI angularis) extract on blood pressure elevation and macrophage infiltration in the heart and kidney of spontaneously hypertensive rats Clinical and Experimental Pharmacology and Physiology, 35(1), 43-49.
Sever, P. S., & Poulter, N. R. (1989). A hypothesis for the pathogenesis of essential hypertension: the initiating factors. Journal of Hypertension, 7, S9-12.
Shi, G. F., An, L. J., Jiang, B., Guan, S., & Bao, Y. M. (2006a). Alpini protocatechuic acid protects against oxidative damage in vitro and reduces oxidative stress in vivo. Neuroscience Letters, 403(3), 206-210.
Shi, G. F., An, L. J., Jiang, B., Guan, S., & Bao, Y. M. (2006b). Alpinia protocatechuic acid protects against oxidative damage in vitro and reduces oxidative stress in vivo. Neuroscience Letters, 403(3), 206-210.
Shimokawa, H., Flavahan, N. A., & Vanhoutte, P. M. (1991). Loss of endothelial pertussis toxin-sensitive G protein function in atherosclerotic porcine coronary arteries. Circulation, 83(2), 652-660.
Shoemaker, J. K., & Bonen, A. (1995). Vascular actions of insulin in health and disease. Canadian Journal of Applied Physiology, 20(2), 127-154.
Sies, H. (1996). Antioxidants in disease mechanisms and therapy (Vol. 38): Academic Pr.
Sigalov, A. B., & Stern, L. J. (1998). Enzymatic repair of oxidative damage to human apolipoprotein AI. FEBS Letters, 433(3), 196-200.
Solzbach, U., Hornig, B., Jeserich, M., & Just, H. (1997). Vitamin C improves endothelial dysfunction of epicardial coronary arteries in hypertensive patients. Circulation, 96(5), 1513-1519.
Sowers, J. R. (1996). Effects of insulin and IGF-I on vascular smooth muscle glucose and cation metabolism. Diabetes, 45, S47-S51.
Sowers, J. R. (1997). Insulin and insulin-like growth factor in normal and pathological cardiovascular physiology. Hypertension, 29(3), 691-699.
Spanos, G. A., & Wrolstad, R. E. (1992). Phenolics of apple, pear, and white grape juices and their changes with processing and storage. A review. Journal of Agricultural and Food Chemistry, 40(9), 1478-1487.
Stadtman, E. R., & Oliver, C. (1991). Metal-catalyzed oxidation of proteins. Physiological consequences. The Journal of Biological Chemistry, 266(4), 2005-2008.
Stamler, J. S., Simon, D. I., Osborne, J. A., Mullins, M. E., Jaraki, O., Michel, T., . . . Loscalzo, J. (1992). S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds. Proceedings of the National Academy of Sciences, 89(1), 444-448.
Steinberg, H., Brechtel, G., Johnson, A., Fineberg, N., & Baron, A. (1994). Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. Journal of Clinical Investigation, 94(3), 1172-1179.
Stoclet, J. C., Chataigneau, T., Ndiaye, M., Oak, M. H., El Bedoui, J., Chataigneau, M., & Schini-Kerth, V. B. (2004). Vascular protection by dietary polyphenols. European Journal of Pharmacology, 500(1), 299-313.
Sun, E., Xu, H., Liu, Q., Zhou, J., Zuo, P., & Wang, J. (1995). The mechanism for the effect of selenium supplementation on immunity. Biological Trace Element Research, 48(3), 231-238.
Sweeney, M., Kalt, W., MacKinnon, S., Ashby, J., & Gottschall-Pass, K. (2002). Feeding rats diets enriched in lowbush blueberries for six weeks decreases ischemia-induced brain damage. Nutritional Neuroscience, 5(6), 427-431.
Taddei, S., Virdis, A., Ghiadoni, L., Sudano, I., Notari, M., & Salvetti, A. (1999). Vasoconstriction to endogenous endothelin-1 is increased in the peripheral circulation of patients with essential hypertension. Circulation, 100(16), 1680-1683.
Tanaka, T., Kawamori, T., Ohnishi, M., Okamoto, K., Mori, H., & Hara, A. (1994). Chemoprevention of 4-nitroquinoline 1-oxide-induced oral carcinogenesis by dietary protocatechuic acid during initiation and postinitiation phases. Cancer Research, 54(9), 2359-2365.
Tanaka, T., Kojima, T., Kawamori, T., & Mori, H. (1995). Chemoprevention of digestive organs carcinogenesis by natural product protocatechuic acid. Cancer, 75(S6), 1433-1439.
Tanaka, T., Kojima, T., Kawamori, T., Yoshimi, N., & Mori, H. (1993). Chemoprevention of diethylnitrosamine-induced hepatocarcinogenesis by a simple phenolic acid protocatechuic acid in rats. Cancer Research, 53(12), 2775-2779.
Teixeira, H. D., Schumacher, R. I., & Meneghini, R. (1998). Lower intracellular hydrogen peroxide levels in cells overexpressing CuZn-superoxide dismutase. Proceedings of the National Academy of Sciences, 95(14), 7872-7875.
Ting, H. H., Timimi, F. K., Boles, K. S., Creager, S. J., Ganz, P., & Creager, M. A. (1996). Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. Journal of Clinical Investigation, 97(1), 22-28.
Tipton, C. M. (1991). Exercise, training and hypertension: an update. Exercise and Sport Sciences Reviews, 19, 447-505.
Tipton, C. M., Matthes, R. D., Marcus, K. D., Rowlett, K. A., & Leininger, J. (1983). Influences of exercise intensity, age, and medication on resting systolic blood pressure of SHR populations. Journal of Applied Physiology, 55(4), 1305-1310.
Tseng, T. H., Hsu, J. D., Lo, M. H., Chu, C. Y., Chou, F. P., Huang, C. L., & Wang, C. J. (1998). Inhibitory effect of Hibiscus protocatechuic acid on tumor promotion in mouse skin. Cancer Letters, 126(2), 199-207.
Tseng, T. H., Kao, T. W., Chu, C. Y., Chou, F. P., Lin, W. L., & Wang, C. J. (2000). Induction of apoptosis by hibiscus protocatechuic acid in human leukemia cells via reduction of retinoblastoma (RB) phosphorylation and Bcl-2 expression. Biochemical Pharmacology, 60(3), 307-315.
Tseng, T. H., Wang, C. J., & Kao, E. S. (1996). Hibiscus protocatechuic acid protects against oxidative damage induced by tert-butylhydroperoxide in rat primary hepatocytes. Chemico-Biological Interactions, 101(2), 137-148.
Uchida, S., Ozaki, M., Akashi, T., Yamashita, K., Niwa, M., & Taniyama, K. (1995). Effects of (‐)‐epigallocatechin‐3‐O‐gallate (green tea tannin) on the life span of stroke‐prone spontaneously hypertensive rats Clinical and Experimental Pharmacology and Physiology, 22, S302-S303.
Urata, H., Tanabe, Y., Kiyonaga, A., Ikeda, M., Tanaka, H., Shindo, M., & Arakawa, K. (1987). Antihypertensive and volume-depleting effects of mild exercise on essential hypertension. Hypertension, 9(3), 245-252.
von Schantz, T., Bensch, S., Grahn, M., Hasselquist, D., & Wittzell, H. (1999). Good genes, oxidative stress and condition–dependent sexual signals. Proceedings of the Royal Society of London. Series B: Biological Sciences, 266(1414), 1-12.
von Sonntag, C. (1987). The chemical basis of radiation biology: Taylor & Francis London.
Wallerath, T., Deckert, G., Ternes, T., Anderson, H., Li, H., Witte, K., & Förstermann, U. (2002). Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation, 106(13), 1652-1658.
Wallerath, T., Poleo, D., Li, H., & Förstermann, U. (2003). Red wine increases the expression of human endothelial nitric oxide synthase: a mechanism that may contribute to its beneficial cardiovascular effects. Journal of the American College of Cardiology, 41(3), 471-478.
Walsh, M., Barazi, M., Pete, G., Muniyappa, R., Dunbar, J., & Sowers, J. (1996). Insulin-like growth factor I diminishes in vivo and in vitro vascular contractility: role of vascular nitric oxide. Endocrinology, 137(5), 1798-1803.
Wang, S. Y., & Jiao, H. (2000). Scavenging capacity of berry crops on superoxide radicals, hydrogen peroxide, hydroxyl radicals, and singlet oxygen. Journal of Agricultural and Food Chemistry, 48(11), 5677-5684.
Whitworth, J. A., & Chalmers, J. (2004). World health organisation-international society of hypertension (WHO/ISH) hypertension guidelines. Clinical and Experimental Hypertension (New York, NY: 1993), 26(7-8), 747-752.
Wilcox, J. N., Subramanian, R. R., Sundell, C. L., Tracey, W. R., Pollock, J. S., Harrison, D. G., & Marsden, P. A. (1997). Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Arteriosclerosis, Thrombosis, and Vascular Biology, 17(11), 2479-2488.
Wu, H., Jeng, Y., Yue, C. J., Chyu, K., Hsueh, W., & Chan, T. (1994). Endothelial-dependent vascular effects of insulin and insulin-like growth factor I in the perfused rat mesenteric artery and aortic ring. Diabetes, 43(8), 1027-1032.
Wu, X., Pittman III, H. E., Hager, T., Hager, A., Howard, L., & Prior, R. L. (2009). Phenolic acids in black raspberry and in the gastrointestinal tract of pigs following ingestion of black raspberry. Molecular Nutrition & Food Research, 53(S1), 76-84.
Yoshida, K., Kondo, T., & Ito, M. (2005). Analysis of polyphenols in water extract of red Adzuki Bean, Vigna angularis. Ite Letters on Batteries New Technologies and Medicine, 6(3), 226-231.
Zeng, G., & Quon, M. J. (1996). Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. Journal of Clinical Investigation, 98(4), 894-898.
Zhao, X., Gu, Z., Attele, A. S., & Yuan, C. S. (1999). Effects of quercetin on the release of endothelin, prostacyclin and tissue plasminogen activator from human endothelial cells in culture. Journal of Ethnopharmacology, 67(3), 279-285.