近幾年在動物實驗中發現，攝取高果糖可能會引發高血壓。氧化壓力在高血壓發展成為重要的致病因子。據報研究指出，餵養果糖大鼠增加過氧化物的產生可能是經由NAD（P）H氧化酶介導的。超氧化物歧化酶（SOD）是抗氧化最重要的酶之一。然而，果糖誘導高血壓的信號傳導機制仍不清楚。孤立束核在中樞神經系統中扮演著重要的調控血壓的角色，不僅接收來自周邊感壓接受器傳來的訊息以進行整合，而孤立束核本身也會受到其他物質的調控。我們先前的研究發現，在孤立束核中累積的過氧化物可能會誘發高血壓。作為重要的抗氧化劑，白藜蘆醇可於紅葡萄酒中提煉出並有助於預防心血管疾病。在藥理劑量，白藜蘆醇可增加血管中一氧化氮的濃度，並在動物模式中發現可提高一氧化氮的生物利用度。在神經細胞株、初級神經細胞以及腦內都發現，白藜蘆醇是AMPK的活化劑，最近的報導中，metformin可以透過AMPK的活化，進而促進神經性一氧化氮合成酶(nNOS)以及內皮性一氧化氮合成酶(eNOS)的活性。因此, 我們提出一個假設，在孤立束核中，白藜蘆醇可藉由調控一氧化氮及過氧化物的生成，改善果糖攝食所引起的高血壓。針對此一假說，我們提出下列三個研究方向： 1. 探討在孤立束核，果糖攝食引起高血壓是否因為過氧化物的增加所造成。2. 探討果糖攝食引起高血壓可能的致病機轉。3. 探討餵與白藜蘆醇是否可預防及治療果糖攝食引起高血壓及可能的機轉。
我們將WKY大鼠分為二組：1.控制組(C)；2.餵食10%果糖水(F) 並利用尾動脈壓量測法持續觀察期間的血壓變化，發現持續一周之後實驗組有顯著的血壓上升，同時在孤立束核中以及延腦鼻端腹外側核的過氧化物有顯著的增加而一氧化氮產量也有顯著性地減少。最後取出腦幹中的孤立束核組織進行逆轉錄聚合酶鏈式反應以及西方墨點分析法等技術來探討訊息傳遞分子之間的關係，我們進一步觀察到NAD（P）H氧化酶的子單位p22-phox 以及 p67-phox 還有RAGE 的活性在孤立束核中有顯著的增加，另外SOD2的活性則是顯著性的下降。根據上述的結果，我們將WKY大鼠分為五組：1.控制組(C)；2.餵食10%果糖水(F)；3.利用管餵白藜蘆醇(R)；4.同時餵食10%果糖水和管餵白藜蘆醇(FR)四周；5.先餵食10%果糖水2周後再同時管餵白藜蘆醇(F2R)，並利用尾動脈壓量測法持續觀察期間的血壓變化，持續二周後，F組以及F2R組的血壓明顯上升，而R組與FR組的血壓與C組相同。此外，當F2R組管餵白藜蘆醇之後，發現可以改善果糖攝食引致高血壓。果糖攝食引致高血壓可能透過活化NAD（P）H氧化酶和超氧化物歧化酶活性降低，增加過氧化物並且抑制一氧化碳的生成有關。當給予白藜蘆醇之後，可能透過活化AMPK進而活化一氧化氮合成酶的活性，使一氧化氮增加，改善果糖攝食引致高血壓的症狀。綜合以上結果，在孤立束核中，經由增加 NAD（P）H氧化酶活性和超氧化物歧化酶活性降低，可能是果糖攝食引致高血壓的致病機轉原因之一，白藜蘆醇可以預防以及改善果糖攝食引起的高血壓。

Recent studies demonstrated that fructose intake can increase blood pressure in experimental animals. Oxidative stress has emerged as an important pathogenic factor in the development of hypertension. It has been reported that increased superoxide production in fructose-fed rat mediated through nicotinamide adenine dinucleotide phosphate NAD(P)H oxidase. Superoxide dismutase (SOD) is one of the most important enzymes against oxidative stress. However, the signaling mechanisms of fructose which induce hypertension through superoxide remain unclear. Nucleus tractus solitarii (NTS) is the integrative center for baroreflex. Our previous study had revealed that accumulation of superoxide in the NTS can induce hypertension. As an important antioxidant in red wine, resveratrol is likely to contribute to the potential of red wine to prevent cardiovascular disease. At pharmacological doses, resveratrol increases vascular nitric oxide (NO) levels and improves NO bioavailability in animal models. Resveratrol is a potent activator of AMPK in neuronal cell lines, primary neurons, and the brain. Recent reports have indicated that metformin targets AMPK which activates nNOS and eNOS. Therefore, we hypothesized that resveratrol causes blood pressure decrease through regulating nitric oxide and superoxide production in the NTS of fructose-fed rats. There were three specific aims: 1. To investigate whether fructose induce superoxide production and causes hypertension in the NTS. 2. To investigate which signaling pathway is involved in fructose-induced hypertension. 3. To investigate which signaling pathway is involved in resveratrol modulates blood pressure.
Male Wistar Kyoto rats (WKY) were divided into two groups: control group and fed with 10% fructose water group for 1 week. After one-week treatment, the systolic blood pressure and superoxide production increased significantly and the nitrate level in the NTS was significantly decreased. Immunoblotting showed that administration of fructose significantly increased NADPH oxidase subunits p22-phox, p67-phox activity, RAGE activity and reduce SOD2 activity in the NTS. Based on our previous studies, male Wistar-Kyoto rats (WKY) were divided into five groups: Group I: Control group; Group II: fructose-fed rats (FFR) fed with 10% fructose for 4 weeks; Group III: Control + resveratrol (R) rats received a gavage of resveratrol; Group IV: FFR+ resveratrol (FR) fed with 10% fructose and resveratrol ; Group V: FFR + 2weeks resveratrol (F2R) fed with 10% fructose and received a gavage of resveratrol 2 weeks. We found that systolic blood pressure measured by tail-cuff method in F group rats and F2R group rats revealed a significantly increased than C group rats continuously through week 0 to week 2 but R group rats and FR group rats were no difference with C group. However, received a gavage of resveratrol (10 mg/kg/d) 2 weeks, F2R group revealed a significantly decrease in SBP than the F group continuously through week 2 to week 4. Fructose-induced hypertension increased NADPH oxidase activity and SOD2 activity related to inhibit the production of NO in the regulation of blood pressure. These results suggest that in the NTS, intake of fructose induces NADPH oxidase activity and reduces SOD2 activity to increase blood pressure. Resveratrol can not only reverse fructose-induced hypertension but also prevent fructose-induced hypertension.

Chinese Abstract……………………………………………………………I
English Abstract…………………………………………………………..III
Abbreviation………………………………………………………………VI
Contents…………………………………………………………………VIII
1. Introduction…………………………..…………………….…………..1
1.1 Fructose and hypertension………………………………………1
1.2 Oxidative stress…………………………………………….........2
1.3 Angiotensin II and its receptors……………………………........3
1.4 The receptor for advanced glycation end-products (RAGE)……4
1.5 NADPH oxidase………………………………………………...6
1.6 Superoxide dismutase (SOD)…………………………………...7
1.7 Resveratrol……………………………………………………..10
1.8 AMP-activated protein kinase (AMPK)……………………….12
1.9 Nitric oxide signaling and central cardiovascular regulation in
brainstem nuclei…….....................................................................14
2. Specific Aims………………………………………………………....17
3. Materials and Methods……………………………………………….18
3.1 Animals…………………………………………………………...18
3.2 Blood pressure measurement……………………………………..19
3.3 Determination of NO in NTS……………………………….……19
3.4 ROS production in the NTS……………………………………...20
3.5 Real-time reverse transcriptase-polymerase chain reaction……....21
3.6 Western blot analysis……………………………………………..22
3.7 Rac1 activation assay…………………………………………….23
3.8 Statistical analysis………………………………………………..24
4. Results……………………………………….……………………….25
4.1 The cardiovascular changes of the studied rars…………….…….25
4.2 NO production significantly reduced in NTS of F group rats……25
4.3 Significantly generated ROS in NTS of F group rats......................26
4.4 Effects of fructose on the mRNA Expression for NADPH Oxidase Subunits p22-phox in the NTS of studied rats…………….……...26
4.5 Effects of fructose on the p22-phox protein expression in the NTS of studied rats…………………………………………….………26
4.6 Effects of fructose on the mRNA Expression for NADPH Oxidase Subunits p67-phox in the NTS of studied rats……………………27
4.7 Effects of fructose on the p67-phox protein expression in the NTS of studied rats………………………………………..…….……...27
4.8 Effects of fructose on the mRNA Expression for NADPH Oxidase Subunits p47-phox in the NTS of studied rats……………………28
4.9 Effects of fructose on the SOD2 mRNA expression in the NTS of studied rats……...............................................................................28
4.10 Effects of fructose on the SOD2 protein expression in the NTS of studied rats………………………………………………….……29
4.11 Effects of fructose on the SOD1 mRNA expression in the NTS of studied rats…………………………………….…………………29
4.12 Effects of fructose on the SOD1 protein expression in the NTS of studied rats…………………………….…………………………30
4.13 Effects of fructose on the SOD3 mRNA expression in the NTS of studied rats……………………………………………..............................30
4.14 No difference of Rac1 activation in NTS of studied rats………..31
4.15 Effects of fructose on the RAGE protein expression in the NTS of studied rats…………………………………..............................................31
4.16 Effects of fructose on the AT1R protein expression in the NTS of studied rats……………………………………………………………….32
4.17 The cardiovascular changes of the studied rats………….............32
4.18 Effects of resveratrol on the AMPKT172 phosphorylation in the NTS of studied rats……………………………………………………....33
4.19 Effects of resveratrol on the nNOSs1416 phosphorylation in the NTS of studied rats…………......................................................................34
4.20 Effects of resveratrol on the eNOSs633 phosphorylation in the NTS of studied rats……….........................................................................34
4.21 Effects of resveratrol on the eNOSs1177 phosphorylation in the NTS of studied rats…………......................................................................35
5. Discussion……………………………………………………………..36
6. Conclusion………………………………………………………….…45
7. Future Perspectives……………………………………….…………...46
8. References………………………………………………………….….47
9. Figures and Figure Legends……………………………………….…..65
10. Supplemental Figures and Figure Legends……………………………98

Araki, T., Sasaki, Y., and Milbrandt, J. (2004). Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science 305, 1010-1013.
Barra, D., Schinina, M.E., Simmaco, M., Bannister, J.V., Bannister, W.H., Rotilio, G., and Bossa, F. (1984). The primary structure of human liver manganese superoxide dismutase. J Biol Chem 259, 12595-12601.
Barraco, R.A., Ergene, E., Dunbar, J.C., and el-Ridi, M.R. (1990). Cardiorespiratory response patterns elicited by microinjections of neuropeptide Y in the nucleus tractus solitarius. Brain Res Bull 24, 465-485.
Baur, J.A., and Sinclair, D.A. (2006). Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5, 493-506.
Bendall, J.K., Rinze, R., Adlam, D., Tatham, A.L., de Bono, J., Wilson, N., Volpi, E., and Channon, K.M. (2007). Endothelial Nox2 overexpression potentiates vascular oxidative stress and hemodynamic response to angiotensin II: studies in endothelial-targeted Nox2 transgenic mice. Circ Res 100, 1016-1025.
Bhatt, S.R., Lokhandwala, M.F., and Banday, A.A. (2011). Resveratrol prevents endothelial nitric oxide synthase uncoupling and attenuates development of hypertension in spontaneously hypertensive rats. Eur J Pharmacol 667, 258-264.
Bray, G.A., Nielsen, S.J., and Popkin, B.M. (2004). Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr 79, 537-543.
Bredt, D.S., and Snyder, S.H. (1990). Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci U S A 87, 682-685.
Canto, C., Gerhart-Hines, Z., Feige, J.N., Lagouge, M., Noriega, L., Milne, J.C., Elliott, P.J., Puigserver, P., and Auwerx, J. (2009). AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056-1060.
Carlsson, L.M., Jonsson, J., Edlund, T., and Marklund, S.L. (1995). Mice lacking extracellular superoxide dismutase are more sensitive to hyperoxia. Proc Natl Acad Sci U S A 92, 6264-6268.
Chan, S.H., Hsu, K.S., Huang, C.C., Wang, L.L., Ou, C.C., and Chan, J.Y. (2005). NADPH oxidase-derived superoxide anion mediates angiotensin II-induced pressor effect via activation of p38 mitogen-activated protein kinase in the rostral ventrolateral medulla. Circ Res 97, 772-780.
Chen, Z., Peng, I.C., Sun, W., Su, M.I., Hsu, P.H., Fu, Y., Zhu, Y., DeFea, K., Pan, S., Tsai, M.D., Shyy, J.Y. (2009). AMP-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase Ser633. Circ Res 104, 496-505.
Cheng, T.H., Liu, J.C., Lin, H., Shih, N.L., Chen, Y.L., Huang, M.T., Chan, P., Cheng, C.F., and Chen, J.J. (2004). Inhibitory effect of resveratrol on angiotensin II-induced cardiomyocyte hypertrophy. Naunyn Schmiedebergs Arch Pharmacol 369, 239-244.
Cordova, A.C., Jackson, L.S., Berke-Schlessel, D.W., and Sumpio, B.E. (2005). The cardiovascular protective effect of red wine. J Am Coll Surg 200, 428-439.
Crapo, J.D., Oury, T., Rabouille, C., Slot, J.W., and Chang, L.Y. (1992). Copper,zinc superoxide dismutase is primarily a cytosolic protein in human cells. Proc Natl Acad Sci U S A 89, 10405-10409.
Cuzzocrea, S., Mazzon, E., Dugo, L., Di Paola, R., Caputi, A.P., and Salvemini, D. (2004). Superoxide: a key player in hypertension. FASEB J 18, 94-101.
Dasgupta, B., and Milbrandt, J. (2007). Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci U S A 104, 7217-7222.
Delbosc, S., Paizanis, E., Magous, R., Araiz, C., Dimo, T., Cristol, J.P., Cros, G., and Azay, J. (2005). Involvement of oxidative stress and NADPH oxidase activation in the development of cardiovascular complications in a model of insulin resistance, the fructose-fed rat. Atherosclerosis 179, 43-49.
Dimo, T., Rakotonirina, S.V., Tan, P.V., Azay, J., Dongo, E., and Cros, G. (2002). Leaf methanol extract of Bidens pilosa prevents and attenuates the hypertension induced by high-fructose diet in Wistar rats. J Ethnopharmacol 83, 183-191.
Evans, J.L., Goldfine, I.D., Maddux, B.A., and Grodsky, G.M. (2002). Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev 23, 599-622.
Folz, R.J., and Crapo, J.D. (1994). Extracellular superoxide dismutase (SOD3): tissue-specific expression, genomic characterization, and computer-assisted sequence analysis of the human EC SOD gene. Genomics 22, 162-171.
Fryer, L.G., Hajduch, E., Rencurel, F., Salt, I.P., Hundal, H.S., Hardie, D.G., and Carling, D. (2000). Activation of glucose transport by AMP-activated protein kinase via stimulation of nitric oxide synthase. Diabetes 49, 1978-1985.
Fukui, T., Ishizaka, N., Rajagopalan, S., Laursen, J.B., Capers, Q.t., Taylor, W.R., Harrison, D.G., de Leon, H., Wilcox, J.N., and Griendling, K.K. (1997). p22phox mRNA expression and NADPH oxidase activity are increased in aortas from hypertensive rats. Circ Res 80, 45-51.
Fulton, D., Gratton, J.P., McCabe, T.J., Fontana, J., Fujio, Y., Walsh, K., Franke, T.F., Papapetropoulos, A., and Sessa, W.C. (1999). Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399, 597-601.
Gao, L., Wang, W., Li, Y.L., Schultz, H.D., Liu, D., Cornish, K.G., and Zucker, I.H. (2005). Sympathoexcitation by central ANG II: roles for AT1 receptor upregulation and NAD(P)H oxidase in RVLM. Am J Physiol Heart Circ Physiol 288, H2271-2279.
Geroldi, D., Falcone, C., and Emanuele, E. (2006). Soluble receptor for advanced glycation end products: from disease marker to potential therapeutic target. Curr Med Chem 13, 1971-1978.
Geroldi, D., Falcone, C., Emanuele, E., D'Angelo, A., Calcagnino, M., Buzzi, M.P., Scioli, G.A., and Fogari, R. (2005). Decreased plasma levels of soluble receptor for advanced glycation end-products in patients with essential hypertension. J Hypertens 23, 1725-1729.
Griendling, K.K., Minieri, C.A., Ollerenshaw, J.D., and Alexander, R.W. (1994). Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 74, 1141-1148.
Guyenet, P.G., Darnall, R.A., and Riley, T.A. (1990). Rostral ventrolateral medulla and sympathorespiratory integration in rats. Am J Physiol 259, R1063-1074.
Han, Y.S., Zheng, W.H., Bastianetto, S., Chabot, J.G., and Quirion, R. (2004). Neuroprotective effects of resveratrol against beta-amyloid-induced neurotoxicity in rat hippocampal neurons: involvement of protein kinase C. Br J Pharmacol 141, 997-1005.
Hardie, D.G., Salt, I.P., Hawley, S.A., and Davies, S.P. (1999). AMP-activated protein kinase: an ultrasensitive system for monitoring cellular energy charge. Biochem J 338 ( Pt 3), 717-722.
Hardie, D.G., Scott, J.W., Pan, D.A., and Hudson, E.R. (2003). Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett 546, 113-120.
Hart, P.J., Balbirnie, M.M., Ogihara, N.L., Nersissian, A.M., Weiss, M.S., Valentine, J.S., and Eisenberg, D. (1999). A structure-based mechanism for copper-zinc superoxide dismutase. Biochemistry 38, 2167-2178.
Hattori, R., Otani, H., Maulik, N., and Das, D.K. (2002). Pharmacological preconditioning with resveratrol: role of nitric oxide. Am J Physiol Heart Circ Physiol 282, H1988-1995.
Hawley, S.A., Gadalla, A.E., Olsen, G.S., and Hardie, D.G. (2002). The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes 51, 2420-2425.
Hawley, S.A., Pan, D.A., Mustard, K.J., Ross, L., Bain, J., Edelman, A.M., Frenguelli, B.G., and Hardie, D.G. (2005). Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2, 9-19.
Hirooka, Y. (2008). Role of reactive oxygen species in brainstem in neural mechanisms of hypertension. Auton Neurosci 142, 20-24.
Hofmann, M.A., Drury, S., Fu, C., Qu, W., Taguchi, A., Lu, Y., Avila, C., Kambham, N., Bierhaus, A., Nawroth, P., Neurath M.F., Slattery, T., Beach, D., McClary, J., Nagashima, M., Morser, J., Stern, D. and Schmidt, A.M. (1999). RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97, 889-901.
Hori, O., Brett, J., Slattery, T., Cao, R., Zhang, J., Chen, J.X., Nagashima, M., Lundh, E.R., Vijay, S., Nitecki, D., Morser, J., Stern, D. and Schmidt, A.M. (1995). The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem 270, 25752-25761.

Hudson, B.I., Carter, A.M., Harja, E., Kalea, A.Z., Arriero, M., Yang, H., Grant, P.J., and Schmidt, A.M. (2008). Identification, classification, and expression of RAGE gene splice variants. FASEB J 22, 1572-1580.
Huttunen, H.J., Fages, C., and Rauvala, H. (1999). Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J Biol Chem 274, 19919-19924.
Hwang, I.S., Ho, H., Hoffman, B.B., and Reaven, G.M. (1987). Fructose-induced insulin resistance and hypertension in rats. Hypertension 10, 512-516.
Hwang, J.T., Kwon, D.Y., Park, O.J., and Kim, M.S. (2008). Resveratrol protects ROS-induced cell death by activating AMPK in H9c2 cardiac muscle cells. Genes Nutr 2, 323-326.
Ignarro, L.J., Buga, G.M., Wood, K.S., Byrns, R.E., and Chaudhuri, G. (1987a). Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A 84, 9265-9269.
Ignarro, L.J., Byrns, R.E., Buga, G.M., and Wood, K.S. (1987b). Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. Circ Res 61, 866-879.
Infanger, D.W., Sharma, R.V., and Davisson, R.L. (2006). NADPH oxidases of the brain: distribution, regulation, and function. Antioxid Redox Signal 8, 1583-1596.
Kantzides, A., and Badoer, E. (2005). nNOS-containing neurons in the hypothalamus and medulla project to the RVLM. Brain Res 1037, 25-34.
Kim, H.T., Kim, Y.H., Nam, J.W., Lee, H.J., Rho, H.M., and Jung, G. (1994). Study of 5'-flanking region of human Cu/Zn superoxide dismutase. Biochem Biophys Res Commun 201, 1526-1533.
Kim, M.J., Shin, K.S., Chung, Y.B., Jung, K.W., Cha, C.I., and Shin, D.H. (2005). Immunohistochemical study of p47Phox and gp91Phox distributions in rat brain. Brain Res 1040, 178-186.
Kishi, T., Hirooka, Y., Kimura, Y., Ito, K., Shimokawa, H., and Takeshita, A. (2004). Increased reactive oxygen species in rostral ventrolateral medulla contribute to neural mechanisms of hypertension in stroke-prone spontaneously hypertensive rats. Circulation 109, 2357-2362.
Kislinger, T., Fu, C., Huber, B., Qu, W., Taguchi, A., Du Yan, S., Hofmann, M., Yan, S.F., Pischetsrieder, M., Stern, D., et al. (1999). N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. J Biol Chem 274, 31740-31749.
Kukidome, D., Nishikawa, T., Sonoda, K., Imoto, K., Fujisawa, K., Yano, M., Motoshima, H., Taguchi, T., Matsumura, T., and Araki, E. (2006). Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes 55, 120-127.
Lambeth, J.D. (2004). NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4, 181-189.
Langcake P, P.R. (1976). The production of resveratrol by Vitis vinifera and other members of the Vitaceae as a response to infection or injury. Physiol Plant Pathol,. 9, 77-86.
Laursen, J.B., Rajagopalan, S., Galis, Z., Tarpey, M., Freeman, B.A., and Harrison, D.G. (1997). Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension. Circulation 95, 588-593.
Leslie, R.A. (1985). Neuroactive substances in the dorsal vagal complex of the medulla oblongata: nucleus of the tractus solitarius, area postrema and dorsal motor nucleus of the vagus. Neurochem Int 7, 191-212.
Levanon, D., Lieman-Hurwitz, J., Dafni, N., Wigderson, M., Sherman, L., Bernstein, Y., Laver-Rudich, Z., Danciger, E., Stein, O., and Groner, Y. (1985). Architecture and anatomy of the chromosomal locus in human chromosome 21 encoding the Cu/Zn superoxide dismutase. EMBO J 4, 77-84.
Li, J.M., and Shah, A.M. (2004). Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 287, R1014-1030.
Lin, L.H., and Talman, W.T. (2005). Soluble guanylate cyclase and neuronal nitric oxide synthase colocalize in rat nucleus tractus solitarii. J Chem Neuroanat 29, 127-136.
Liu, Z., Song, Y., Zhang, X., Zhang, W., Mao, W., Wang, W., Cui, W., Jia, X., Li, N., Han, C., et al. (2005). Effects of trans-resveratrol on hypertension-induced cardiac hypertrophy using the partially nephrectomized rat model. Clin Exp Pharmacol Physiol 32, 1049-1054.
Lo, W.C., Jan, C.R., Chiang, H.T., and Tseng, C.J. (2000). Modulatory effects of carbon monoxide on baroreflex activation in nucleus tractus solitarii of rats. Hypertension 35, 1253-1257.
Loewy, A.D. (1990). Central regulation of autonomic functions. (New York, Oxford Univ. Press).
Makino, A., Skelton, M.M., Zou, A.P., and Cowley, A.W., Jr. (2003). Increased renal medullary H2O2 leads to hypertension. Hypertension 42, 25-30.
Marklund, S.L. (1982). Human copper-containing superoxide dismutase of high molecular weight. Proc Natl Acad Sci U S A 79, 7634-7638.
Marklund, S.L., Holme, E., and Hellner, L. (1982). Superoxide dismutase in extracellular fluids. Clin Chim Acta 126, 41-51.
Matsumura, K., Averill, D.B., and Ferrario, C.M. (1998). Angiotensin II acts at AT1 receptors in the nucleus of the solitary tract to attenuate the baroreceptor reflex. Am J Physiol 275, R1611-1619.
McCord, J.M., and Fridovich, I. (1969a). Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem 244, 6049-6055.
McCord, J.M., and Fridovich, I. (1969b). The utility of superoxide dismutase in studying free radical reactions. I. Radicals generated by the interaction of sulfite, dimethyl sulfoxide, and oxygen. J Biol Chem 244, 6056-6063.
Miatello, R., Cruzado, M., and Risler, N. (2004). Mechanisms of cardiovascular changes in an experimental model of syndrome X and pharmacological intervention on the renin-angiotensin-system. Curr Vasc Pharmacol 2, 371-377.
Miatello, R., Risler, N., Castro, C., Gonzalez, S., Ruttler, M., and Cruzado, M. (2001). Aortic smooth muscle cell proliferation and endothelial nitric oxide synthase activity in fructose-fed rats. Am J Hypertens 14, 1135-1141.
Miatello, R., Vazquez, M., Renna, N., Cruzado, M., Zumino, A.P., and Risler, N. (2005). Chronic administration of resveratrol prevents biochemical cardiovascular changes in fructose-fed rats. Am J Hypertens 18, 864-870.
Morbidelli, L., Donnini, S., and Ziche, M. (2003). Role of nitric oxide in the modulation of angiogenesis. Curr Pharm Des 9, 521-530.
Mosqueda-Garcia, R., Tseng, C., Appalsamy, M., Beck, C., and Robertson, D. (1991). Cardiovascular excitatory effects of adenosine in the nucleus of the solitary tract. Hypertension 18, 494-502.
Mosqueda-Garcia, R., Tseng, C.J., Appalsamy, M., and Robertson, D. (1990). Cardiovascular effects of microinjection of angiotensin II in the brainstem of renal hypertensive rats. J Pharmacol Exp Ther 255, 374-381.
Murphy, B.A., Fakira, K.A., Song, Z., Beuve, A., and Routh, V.H. (2009). AMP-activated protein kinase and nitric oxide regulate the glucose sensitivity of ventromedial hypothalamic glucose-inhibited neurons. Am J Physiol Cell Physiol 297, C750-758.
Murray, C.J., and Lopez, A.D. (1997). Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet 349, 1436-1442.
Nakazono, K., Watanabe, N., Matsuno, K., Sasaki, J., Sato, T., and Inoue, M. (1991). Does superoxide underlie the pathogenesis of hypertension? Proc Natl Acad Sci U S A 88, 10045-10048.
Neeper, M., Schmidt, A.M., Brett, J., Yan, S.D., Wang, F., Pan, Y.C., Elliston, K., Stern, D., and Shaw, A. (1992). Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem 267, 14998-15004.
Nicholson, S.K., Tucker, G.A., and Brameld, J.M. (2008). Effects of dietary polyphenols on gene expression in human vascular endothelial cells. Proc Nutr Soc 67, 42-47.
Nozoe, M., Hirooka, Y., Koga, Y., Sagara, Y., Kishi, T., Engelhardt, J.F., and Sunagawa, K. (2007). Inhibition of Rac1-derived reactive oxygen species in nucleus tractus solitarius decreases blood pressure and heart rate in stroke-prone spontaneously hypertensive rats. Hypertension 50, 62-68.
Pagano, P.J., Chanock, S.J., Siwik, D.A., Colucci, W.S., and Clark, J.K. (1998). Angiotensin II induces p67phox mRNA expression and NADPH oxidase superoxide generation in rabbit aortic adventitial fibroblasts. Hypertension 32, 331-337.
Paravicini, T.M., and Touyz, R.M. (2006). Redox signaling in hypertension. Cardiovasc Res 71, 247-258.
Pelaez, L.I., Manriquez, M.C., Nath, K.A., Romero, J.C., and Juncos, L.A. (2003). Low-dose angiotensin II enhances pressor responses without causing sustained hypertension. Hypertension 42, 798-801.
Raucci, A., Cugusi, S., Antonelli, A., Barabino, S.M., Monti, L., Bierhaus, A., Reiss, K., Saftig, P., and Bianchi, M.E. (2008). A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10). FASEB J 22, 3716-3727.
Rees, D., Palmer, R., Schulz, R., Hodson, H., and Moncada, S. (1990a). Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo. Br J Pharmacol 101, 746-752.
Rees, D.D., Palmer, R.M., Schulz, R., Hodson, H.F., and Moncada, S. (1990b). Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo. Br J Pharmacol 101, 746-752.
Richard, J.L. (1987). [Coronary risk factors. The French paradox]. Arch Mal Coeur Vaiss 80 Spec No, 17-21.
Richter, C., Park, J.W., and Ames, B.N. (1988). Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci U S A 85, 6465-6467.
Rodrigo, R., Prat, H., Passalacqua, W., Araya, J., Guichard, C., and Bachler, J.P. (2007). Relationship between oxidative stress and essential hypertension. Hypertens Res 30, 1159-1167.
Ruggiero, D.A., Mtui, E.P., Otake, K., and Anwar, M. (1996). Central and primary visceral afferents to nucleus tractus solitarii may generate nitric oxide as a membrane-permeant neuronal messenger. J Comp Neurol 364, 51-67.
Ruster, C., Bondeva, T., Franke, S., Tanaka, N., Yamamoto, H., and Wolf, G. (2009). Angiotensin II upregulates RAGE expression on podocytes: role of AT2 receptors. Am J Nephrol 29, 538-550.
Schmidt, A.M., Hori, O., Brett, J., Yan, S.D., Wautier, J.L., and Stern, D. (1994). Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. Arterioscler Thromb 14, 1521-1528.
Schnackenberg, C.G., Welch, W.J., and Wilcox, C.S. (1998). Normalization of blood pressure and renal vascular resistance in SHR with a membrane-permeable superoxide dismutase mimetic: role of nitric oxide. Hypertension 32, 59-64.
Schumacker, P.T. (2002). Angiotensin II signaling in the brain: compartmentalization of redox signaling? Circ Res 91, 982-984.
Serrano, F., Kolluri, N.S., Wientjes, F.B., Card, J.P., and Klann, E. (2003). NADPH oxidase immunoreactivity in the mouse brain. Brain Res 988, 193-198.
Shin, D.S., Didonato, M., Barondeau, D.P., Hura, G.L., Hitomi, C., Berglund, J.A., Getzoff, E.D., Cary, S.C., and Tainer, J.A. (2009). Superoxide dismutase from the eukaryotic thermophile Alvinella pompejana: structures, stability, mechanism, and insights into amyotrophic lateral sclerosis. J Mol Biol 385, 1534-1555.
Siemann EH, C.L. (1992). Concentration of the phytoalexin resveratrol in wine. Am J Enol Vitic, 43, 49—52
Smith, R.M., Connor, J.A., Chen, L.M., and Babior, B.M. (1996). The cytosolic subunit p67phox contains an NADPH-binding site that participates in catalysis by the leukocyte NADPH oxidase. J Clin Invest 98, 977-983.
Spyer, K.M., Mifflin, S.W., and Withington-Wray, D.J. (1987). Organization of the autonomic nervous system: control and peripheral mechanisms. (New York, Alan R. Lisps).
Stapleton, D., Mitchelhill, K.I., Gao, G., Widmer, J., Michell, B.J., Teh, T., House, C.M., Fernandez, C.S., Cox, T., Witters, L.A., et al. (1996). Mammalian AMP-activated protein kinase subfamily. J Biol Chem 271, 611-614.
Tagawa, T., Fontes, M.A., Potts, P.D., Allen, A.M., and Dampney, R.A. (2000). The physiological role of AT1 receptors in the ventrolateral medulla. Braz J Med Biol Res 33, 643-652.
Thandapilly, S.J., Louis, X.L., Yang, T., Stringer, D.M., Yu, L., Zhang, S., Wigle, J., Kardami, E., Zahradka, P., Taylor, C., Anderson, H.D. and Netticadan, T. (2011). Resveratrol prevents norepinephrine induced hypertrophy in adult rat cardiomyocytes, by activating NO-AMPK pathway. Eur J Pharmacol 668, 217-224.
Tran, L.T., Yuen, V.G., and McNeill, J.H. (2009). The fructose-fed rat: a review on the mechanisms of fructose-induced insulin resistance and hypertension. Mol Cell Biochem 332, 145-159.
Tseng, C., Biaggioni, I., Appalsamy, M., and Robertson, D. (1988). Purinergic receptors in the brainstem mediate hypotension and bradycardia. Hypertension 11, 191-197.
Tseng, C.J., Appalsamy, M., Robertson, D., and Mosqueda-Garcia, R. (1993). Effects of nicotine on brain stem mechanisms of cardiovascular control. J Pharmacol Exp Ther 265, 1511-1518.
Tseng, C.J., Chou, L.L., Ger, L.P., and Tung, C.S. (1994). Cardiovascular effects of angiotensin III in brainstem nuclei of normotensive and hypertensive rats. J Pharmacol Exp Ther 268, 558-564.
Tseng, C.J., Ger, L.P., and Tung, C.S. (1991). Interrelation between alpha 2-adrenoreceptor system and neuropeptide Y in rat nucleus tractus solitarii. Proc Natl Sci Counc Repub China B 15, 86-91.
Tseng, C.J., Liu, H.Y., Lin, H.C., Ger, L.P., Tung, C.S., and Yen, M.H. (1996). Cardiovascular effects of nitric oxide in the brain stem nuclei of rats. Hypertension 27, 36-42.
Tseng, C.J., Mosqueda-Garcia, R., Appalsamy, M., and Robertson, D. (1989). Cardiovascular effects of neuropeptide Y in rat brainstem nuclei. Circ Res 64, 55-61.
Vincent, S., and Kimura, H. (1992). Histochemical mapping of nitric oxide synthase in the rat brain. Neuroscience 46, 755-784.
Wan, X.S., Devalaraja, M.N., and St Clair, D.K. (1994). Molecular structure and organization of the human manganese superoxide dismutase gene. DNA Cell Biol 13, 1127-1136.
Wang, G., Anrather, J., Glass, M.J., Tarsitano, M.J., Zhou, P., Frys, K.A., Pickel, V.M., and Iadecola, C. (2006). Nox2, Ca2+, and protein kinase C play a role in angiotensin II-induced free radical production in nucleus tractus solitarius. Hypertension 48, 482-489.
Wang, G., Anrather, J., Huang, J., Speth, R.C., Pickel, V.M., and Iadecola, C. (2004). NADPH oxidase contributes to angiotensin II signaling in the nucleus tractus solitarius. J Neurosci 24, 5516-5524.
Wang, Q., Xu, J., Rottinghaus, G.E., Simonyi, A., Lubahn, D., Sun, G.Y., and Sun, A.Y. (2002). Resveratrol protects against global cerebral ischemic injury in gerbils. Brain Res 958, 439-447.
Wautier, M.P., Chappey, O., Corda, S., Stern, D.M., Schmidt, A.M., and Wautier, J.L. (2001). Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am J Physiol Endocrinol Metab 280, E685-694.
Weisiger, R.A., and Fridovich, I. (1973). Mitochondrial superoxide simutase. Site of synthesis and intramitochondrial localization. J Biol Chem 248, 4793-4796.
Xu, Y., Porntadavity, S., and St Clair, D.K. (2002). Transcriptional regulation of the human manganese superoxide dismutase gene: the role of specificity protein 1 (Sp1) and activating protein-2 (AP-2). Biochem J 362, 401-412.
Yeh, C.C., Wan, X.S., and St Clair, D.K. (1998). Transcriptional regulation of the 5' proximal promoter of the human manganese superoxide dismutase gene. DNA Cell Biol 17, 921-930.
Yoo, H.Y., Chang, M.S., and Rho, H.M. (1999). Heavy metal-mediated activation of the rat Cu/Zn superoxide dismutase gene via a metal-responsive element. Mol Gen Genet 262, 310-313.
Zhang, Y., Croft, K.D., Mori, T.A., Schyvens, C.G., McKenzie, K.U., and Whitworth, J.A. (2004). The antioxidant tempol prevents and partially reverses dexamethasone-induced hypertension in the rat. Am J Hypertens 17, 260-265.
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., Musi, N., Hirshman, M.F., Goodyear, L.J. and Moller, D.E. (2001). Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108, 1167-1174.
Zimmerman, M.C., and Davisson, R.L. (2004). Redox signaling in central neural regulation of cardiovascular function. Prog Biophys Mol Biol 84, 125-149.