研究報告指出胰島素阻抗和高胰島素血症可能是造成第二型糖尿病與高血壓的重要致病因素，目前已知胰島素阻抗在週邊組織引起內皮細胞功能失調、血管阻力增加、交感神經系統過度興奮造成血管收縮，進而發展成高血壓。但關於胰島素阻抗引起高血壓在中樞神經系統的機轉則有待進一步瞭解。先前研究報告顯示增加週邊組織超氧陰離子產生，及抑制內皮細胞一氧化氮，與胰島素阻抗、高血壓形成有密切相關性。位於中樞神經系統的孤立束核及延腦鼻端腹外側核是調控感壓接受器輸入與交感神經輸出重要核區。另一方面，過氧化增生活化受體(Peroxisome Proliferator-Activated Receptor, PPAR)致活劑為目前臨床用於治療第二型糖尿病患者之處方藥物，其藥理作用為活化PPARγ，增強週邊組織對胰島素敏感性，繼而促進血糖下降。近期在動物及人體研究中發現，PPARγ致活劑具有降血壓之作用，然而其降血壓機轉並未被詳細探討。因此，我們想進一步研究，在高果糖飼料引發胰島素阻抗和高血壓的動物模式，給予過氧化增生活化受體致活劑rosiglitazone或pioglitazone，產生降血壓作用狀況下，一氧化氮與超氧陰離子在孤立束核和延腦鼻端腹外側核參與之角色。
研究以成熟雄性正常血壓Wistar-Kyoto (WKY) 大鼠為實驗動物，將其分為四組進行，實驗組三組動物給予8週60%高果糖飼料，對照組則給予相同週數正常飼料；實驗組中二組在餵食60%高果糖飼料6週後，連續灌食rosiglitazone或pioglitazone (10 mg/kg/day)持續14天，所有動物每週均測量其尾動脈壓，隔週抽血觀察血糖及胰島素變化，於八週實驗結束時，進行口服葡萄糖耐量測試，並觀察孤立束核與延腦鼻端腹外側核區內超氧陰離子與一氧化氮的變化。實驗結果發現，高果糖飼料可以成功誘導胰島素阻抗、高血壓和高三酸甘油酯血症等代謝症候群徵候；給予rosiglitazone或pioglitazone，可以明顯改善胰島素阻抗並且有降低血壓和三酸甘油酯的情形；於孤立束核與延腦鼻端腹外側核區內超氧陰離子，會因餵食高果糖飼料而增加含量，給予PPARγ致活劑並未改善此二核氧化壓力表現；另一方面，一氧化氮的含量在此二核區同樣顯著增加，處理PPARγ致活劑後顯著降低其含量；在分子層面，實驗結果發現，於孤立束核與延腦鼻端腹外側核區內NADPH氧化酶及超氧化物歧化酶並無明顯變化，但於延腦鼻端腹外側核區內增加nNOS表現並伴隨iNOS表現減少；而PPARγ致活劑會抑制延腦鼻端腹外側核nNOS表現及增加iNOS表現，產生降血壓效果。綜合本研究所得結果，高果糖飼料誘發代謝症候群的過程中，孤立束核和延腦鼻端腹外側核區內，超氧陰離子與一氧化氮的過量產生可能是造成高血壓的原因之一；處理過氧化增生活化受體致活劑rosiglitazone或pioglitazone產生降血壓效果，可能與抑制延腦鼻端腹外側核nNOS表現及增加iNOS表現有關。

Insulin resistacne and hyperinsulinemia are important risk factors for development of type 2 diabetes mellitus and hypertension. Recently, accumulating evidence has shown that endothelial dysfunction, increases in peripheral vessel resistnce and overactivation of the sympathetic neruvous system contribute to the development of insulin resistance-associated hypertension. The signigicance of cardiovascular regulatory center in the brain stem in pathophysiology of the insulin resistance-induced hypertension, however, has not been explored. Previously studies have proved that increases in superoxide anion (O2˙−) production in peripheral tissue and suppression of nitric oxide (NO) expression in the endothial cell are involved in insulin resistance and hypertension. The nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (RVLM) are involved in neural regulation of blood pressure by serving respectively as the primary baroreceptor afferent terminal sites and the location of sympathetic premotor neurons for cardiovascular regulation in the brain stem. Clinically, the peroxisome proliferator-activated receptor (PPAR) agonist is commonly prescribed for the treatment of type 2 diabetes mellitus by activate PPARγ to enhance peripheral tissue insulin sensitizing ability, to maintain blood glucose homeostasis. Intriguingly, both animal and human studies revealed that PPARγ agonist also possesses blood pressure lowering effect, although the underlying mechanism is not clear. We therefore investigated in the present study the role of NO and O2˙− in the NTS and RVLM in the pathophysiology of the high fructose diet-induced insulin resistacne and hypertension, and to evaluate the potential central
antihypertensive effect of PPARγ agonist in rats subjected to high fructose diet.
The normotensive male Wistar Kyoto rats (WKY) were divided into 4 groups, including 3 experimental group that received 60% high fructose diet for 8 weeks and one control group that received regular chow diet for the same period of time. Within the 3 experimental groups, two of them received oral administration of rosiglitazone or pioglitazone (10 mg/kg/day) at the last two weeks (from week 6 to week 8) and the third group received saline ingestion. Systemic blood pressure was measured by tail vein sphygmomanometer very week and venous blood was drawn every other week to measure blood sugar and insulin level. At the end of the experiment, oral glucose tolerance test (OGTT) was tested and O2˙− and NO production in the NTS and RVLM were quantified.
In adult male WKY rats I found that high fructose diet induced insulin resistance, hypertriglycemia and hypertension. Oral administration of rosiglitazone or pioglitazone significantly blunted the hypertension, hypertriglyceridemia, and ameliorated insulin resistance induced by high fructose diet. The high fructose diet also increased tissue level of O2˙− in the NTS and RVLM. PPARγ agonist treatment for two weeks did not affect the induced oxidative stress in these two nuclei. NO production was also increased in the NTS and RVLM after high fructose diet for 6 weeks. Oral treatment of rosiglitazone or pioglitazone significantly attenuated NO production after high fructose diet. At the molecular level, protein expressions of the NADPH oxdase subunits (p40phox, p47phox and gp91phox) and superoxide dismutase (cupper/zinc SOD, mitochondrial SOD, extracellular SOD) were not altered in the NTS or RVLM after high fructose diet alone or in addition with rosiglitazone or pioglitazone treatment. In the RVLM, there was a significant increase in neuronal NO synthase (nNOS) expression with concomitant decrease in inducible NOS (iNOS) expression. Oral treatment of PPARγ agonist for two weeks significantly suppressed the induced nNOS upregulation and attenuated the induced downregulation of iNOS expression in the RVLM.
Together these results suggest that overproduction of O2˙− and NO in the NTS and RVLM may related to the development of insulin resistance-associated hypertension. Oral treatment of PPARγ agonist, including rosiglitazone and pioglitazone, may provide antihypertensive protection by superssing the induced-nNOS expression and increasing the induced-iNOS expression in the RVLM.

正文目錄 Ⅰ
英文縮寫表 Ⅱ
中文摘要 Ⅳ
英文摘要 Ⅶ
第一章 緒論與文獻回顧 1
第二章 研究動機與目的 16
第三章 實驗材料和方法 20
第四章 實驗結果 33
第五章 討論 43
第六章 結論 51
第七章 未來研究方向 53
參考文獻 56
實驗圖表 74

Aicher SA, Milner TA, Pickel VM, Reis DJ. Anatomical substrates for baroreflex sympathoinhibition in the rat. Brain Res Bull. 2000; 51: 107-110.

AI-Khalili L, Forsgren M, Kannisto K, Zierath JR, Lonnqvist F, Krook A. Enhanced insulin-stimulated glycogen synthesis in response to insulin, metformin or rosiglitazone is associated with increased mRNA expression of GLUT4 and peroxisomal proliferator activator receptor γ co-activator 1. Diabetologia. 2005; 48: 1173-1179.

Ambruso DR, Bolscher BG, Stokman PM, Verhoeven AJ, Roos D. Assembly and activation of the NADPH: O2 oxidoreductase in human neutrophils after stimulation with phorbol myristate acetate. J Biol Chem. 1990; 265: 924-930.

Anderson EA, Mark AL. The vasodilator action of insulin. Implication for the insulin hypothesis of hypertension. Hypertension. 1993; 21: 136-141.

Azuma H, Ishikawa M, Sekizaki S. Endothelium-dependent inhibition of platelet aggregation. Br J Pharmacol. 1986; 88: 411-415.

Basciano H, Federico L, Adeli K. Fructose, insulin resistance, and metabolic dyslipidemia. Nutr Metab (Lond). 2005; 2: 5-19.

Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly. Am J Physiol. 1996; 271: C1424-C1437.

Berenguer LM, Garcia-Estan J, Ubeda M, Ortiz AJ, Quesada T. Role of renin-angiotensin system in the impairment of baroreflex control of heart rate in renal hypertension. J Hypertens. 1991; 9: 1127-1133.

Berry C, Brosnan MJ, Fennell J, Hamilton CA, Dominiczak AF. Oxidative stress and vascular damage in hypertension. Curr Opin Nephrol Hypertens. 2001; 10: 247-255.

Berry C, Hamilton CA, Brosnan MJ, Magill FG, Berg GA, McMurray JJ, Dominiczak AF. Investigation into the sources of superoxide in human blood vessels: angiotensin II increases superoxide production in human internal mammary arteries. Circulation. 2000; 101: 2206-2212.

Bissoli NS, Cicilini MA, Vasquez EC, Cabral AM. The diuretic chlorthalidone normalizes baroreceptors and Bezold-Jarisch reflexes in DOCA-salt hypertensive rats. Pharmacol Res. 2000; 41: 483-491.

Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-α, -β, and -γ in the adult rat. Endocrinology. 1996; 137: 354-366.

Bredt DS. Endogenous nitric oxide synthesis: biological functions and pathophysiology. Free Radic Res. 1999; 31: 577-596.

Bredt DS, Snyder SH. Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci USA. 1990; 87: 682-685.

Brodbeck J, Balestra ME, Saunders AM, Roses AD, Mahley RW, Huang Y. Rosiglitazone increases dendritic spine density and rescues spine loss caused by apolipoprotein E4 in primary cortical neurons. Proc Natl Acad Sci USA. 2008; 105: 1343-1346.

Buchanan TA, Meechan WP, Jeng YY, Yang D, Chan TM, Nadler JL, Scott S, Rude RK, Hsueh WA. Blood pressure lowering by pioglitazone. evidence for a direct vascular effect. J Clin Invest. 1995; 96: 354-360.

Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res. 2000; 87: 840-844.

Calaresu FR, Yardley CP. Medullary basal sympathetic tone. Annu Rev Physiol. 1988; 50: 511-524.

Calkin AC, Cooper ME, Jandeleit-Dahm KA. Gemfibrozil decreases atherosclerosis in experimental diabetes in association with a reduction in oxidative stress and inflammation. Diabtologia. 2006; 49: 766-774.

Calkin AC, Forbes JM, Smith CM, Lassila M, Cooper ME, Jandeleit-Dahm KA, Allen TJ. Rosiglitazone attenuates atherosclerosis in a model of insulin insufficiency independent of its metabolic effects. Arterioscler Thromb Vasc Biol. 2005; 25: 1903-1909.

Calkin AC, Thomas MC. PPAR agonists and cardiovascular disease in diabetes. PPAR Res. 2008; 2008: 245410-245421.

Campbell IW. The clinical significance of PPARγ agonism. Curr Mol Med. 2005; 5: 349-363.

Chan JYH, Wang LL, Wu KLH, Chan SHH. Reduced functional expression and molecular synthesis of inducible nitric oxide synthase in rostral ventrolateral medulla of spontaneously hypertensive rats. Circulation. 2001b; 104: 1676-1681.

Chan SHH, Hsu KS, Huang CC, Wang LL, Ou CC, Chan JYH. NADPH oxidase-derived superoxide anion mediates angiotensin II-induced pressor effect via activation of p38 mitogen-activated protein kinase in the rostral ventrolateral medulla. Cir Res. 2005; 97: 772-780.

Chan SHH, Tai MH, Li CY, Chan JYH. Reduction in molecular synthesis or enzyme activity of superoxide dismutase and catalase contributes to oxidative stress and neurogenic hypertension in spontaneously hypertensive rats. Free Radic Bio Med. 2006; 40: 2028-2039.

Chan SHH, Wang LL, Chan JYH. Differential engagements of glutamate and GABA receptors in cardiovascular actions of endogenous nNOS or iNOS at rostral ventrolateral medulla of rats. Br J Pharmacol. 2003; 138: 584-593.

Cotgreave IA, Moldéus P, Orrenius S. Host biochemical defense mechanisms against prooxidants. Annu Rev Pharmacol Toxicol. 1988; 28: 189-212.
Cross AR, Segal AW. The NADPH oxidase of professional phagocytes-prototype of the NOX electron transport chain systems. Biochim Biophys Acta. 2004; 1657: 1-22.
Delbosc S, Paizanis E, Magous R, Araiz C, Dimo T, Cristol JP, Cros G, Azay J. 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. 2005; 179: 43-49.
Dobrian AD, Schriver SD, Khraibi AA, Prewitt RL. Pioglitazone prevents hypertension and reduces oxidative stress in diet-induced obesity. Hypertension. 2004; 43: 48-56.
Donahue JE, Johanson CE. Apolipoprotein E, amyloid-beta, and blood-brain barrier permeability in Alzheimer disease. J Neuropathol Exp Neurol. 2008; 67: 261-270.
Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005; 365: 1415-1428.
Faraci FM, Didion SP. Vascular protection superoxide dismutase isoforms in the vessel wall. Arterioscler Thromb Vasc Biol. 2004; 24: 1367-1373.
Ferrari R, Ceconi C, Curello S, Cargnoni A, Pasini E, De Giuli F, Albertini A. Role of oxygen free radicals in ischemic and reperfused myocardium. Am J Clin Nutr. 1991; 53: 215S-222S.
Ford ES. Risks for all-cause mortality cardiovascular disease, and diabetes associated with the metabolic syndrome. A summary of the evidence. Diabetes care. 2005; 28: 1769-1778.
Füllert S, Schneider F, Haak E, Rau H, Badenhoop K, Lübben G, Usadel KH, Konrad T. Effects of pioglitazone in nondiabetic patients with arterial hypertension: a double-bind, placebo-controlled study. J Clin Endocrinol Metab. 2002; 87: 5503-5506.
Furlong B, Henderson AH, Lewis MJ, Smith JA. Endothelium-derived relaxing factor inhibits in vitro platelet aggregation. Br J Pharmacol. 1987; 90: 687-692.
Gegick CG, Altheimer MD. Thiazolidinediones: comparison of long-term effects on glycemic control and cardiovascular risk factors. Curr Med Res Opin. 2004; 20: 919-930.
Gentile MT, Poulet R, Pardo AD, Cifelli G, Maffei A, Vecchione C, Passarelli F, Landolfi A, Carullo P, Lembo G. Beta-Amyloid deposition in brain is enhanced in mouse models of arterial hypertension. Neurobiol Aging. 2009; 30: 222-228.
Ginsberg HN. Insulin resistance and cardiovascular disease. J Clin Invest. 2000; 106: 453-458.
Goldberg RB, Kendall DM, Deeg MA, Buse JB, Zagar AJ, Pinaire JA, Tan MH, Khan MA, Perez AT, Jacober SJ, GLAI Study Investigators. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2005; 28: 1547-1554.
Green S. PPAR: a mediator of peroxisome proliferator action. Mutation Res. 1995; 333: 101-109.
Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury: Part II: animal and human studies. Circulation. 2003; 108: 2034-2040.
Grossan E. Rosiglitazone reduces blood pressure and urinary albumin excretion in type 2 diabetes: G Bakris et al. J Hum Hypertens. 2003; 17: 5-6.
Grundy SM, Hansen B, Smith SC Jr, Cleeman JI, Kahn RA; American Heart Association; National Heart, Lung, and Blood Institute; American Diabetes Association. Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association conference on scientific issues related to management. Circulation. 2004; 109: 551-556.
Guyenet PG. The sympathetic control of blood pressure. Nat Rev Neurosci. 2006; 7: 335-346.
Hauner H. The mode of action of thiazolidinediones. Diabetes Metab Res Rev. 2002; 18: S10-S15.
Heikkinen S, Auwerx J, Argmann CA. PPARγ in human and mouse physiology. Biochim Biophys Acta. 2007; 1771: 999-1013.
Hirooka Y, Kishi T, Sakai K, Shimokawa H, Takeshitaa A. Effect of overproduction of nitric oxide in the brain stem on the cardiovascular response in conscious rats. J Cadiovasc Pharmacol. 2003a; 41:
S119-S126.
Hirooka Y, Sakai K, Kishi T, Ito K, Shimokawa H, Takeshita A. Enhanced depressor response to endothelial nitric oxide synthase gene transfer into the nucleus tractus solitarii of spontaneously hypertensive rats. Hypertens Res. 2003b; 26: 325-331.
Hsieh PS, Tsai HC, Kuo CH, Chan JYH, Shyu JF, Cheng WT, Liu TT. Selective COX2 inhibition improves whole body and muscular insulin resistance in fructose-fed rats. Eur J Clin Invest. 2008; 38: 812-819.
Hsueh WA, Jackson S, Law RE. Control of vascular cell proliferation and migration by PPARγ : a new approach to the macrovascular complications of diabetes. Diabetes Care. 2001; 24: 392-397.
Huang TH, Razmovski-Naumovski V, Kota BP, Lin DS, Roufogalis BD. The pathophysiological function of peroxisome proliferator-activated receptor-γ in lung-related diseases. Respir Res. 2005; 6: 102-110.
Hwang IS, Ho H, Hoffman BB, Reaven GM. Fructose-induced insulin resistance and hyertension in rats. Hypertension. 1987; 10: 512-516.
Hwang J, Kleinhenz DJ, Rupnow HL, Campbell AG, Thule PM, Sutliff RL, Hart CM. The PPARγ ligand, rosiglitazone, reduces vascular oxidative stress and NADPH oxidase expression in diabetic mice. Vasc Pharmacol. 2007; 46: 456-462.
Ignarro LJ, Byrns RE, Buga GM, Wood KS. Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. Circ Res. 1987; 61: 866-879.
Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990; 347: 645-650.
Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C and IkB-α. Diabetes. 2002; 51: 2005-2011.
Jacob RA. The integrated antioxidant system. Nutr Res. 1995; 15: 755-766.
Jeske I, Morrison SF, Cravo SL, Reis DJ. Identification of baroreceptor reflex interneurons in the caudal ventrolateral medulla. Am J Physiol. 1993; 264: R169-R178.
Ježek P, Hlavatà L. Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism. Int J Biochem Cell Biol. 2005; 37: 2478-2503.
Kishi T, Hirooka Y, Ito K, Sakai K, Shimokawa H, Takeshita A. Cardiovascular effects of overexpression of endothelial nitric oxide synthase in the rostral ventrolateral medulla in stroke-prone spontaneously hypertensive rats. Hypertension. 2002; 39: 264-268.
Kishi T, Hirooka Y, Kimura Y, Ito K, Shimokawa H, Takeshita A. Increased reactive oxygen species in rostral ventrolateral medulla contribute to neural mechanisms of hypertension in stroke-prone spontaneously hypertensive rats. Circulation. 2004; 109: 2357-2362.
Koshinaka K, Oshida Y, Han YQ, Ohsawa I, Sato Y. The effect of nitric oxide synthase inhibitor on improved insulin action by pioglitazone in high-fructose-fed rats. Metabolism. 2004; 53: 22-27.
Kota BP, Huang TH, Roufogalis BD. An overview on biological mechanisms of PPARs. Pharmacol Res. 2005; 51: 85-94.
Lambeth JD. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol. 2004; 4: 181-189.
Lantelme P, Cerutti C, Lo M, Paultre CZ, Ducher M. Mechanisms of spontaneous baroreflex impairment in lyon hypertensive rats. Am J Physiol. 1998; 275: R920-R925.
Lassègue B, Griendling KK. Reactive oxygen species in hypertension; an update. Am J Hypertens. 2004; 17: 852-860.
Lee CH, Chawla A, Urbiztondo N, Liao D, Boisvert WA, Evans RM. Transcriptional repression of atherogenic inflammation: modulation by PPARδ. Science. 2003; 302: 453-457.
Lee JM, Zhai G, Liu Q, Gonzales ER, Yin K, Yan P, Hsu CY, Vo KD, Lin W. Vascular permeability precedes spontaneous intracerebral hemorrhage in stroke-prone spontaneously hypertensive rats. Stroke. 2007; 38: 3289-3291.
Leibovitz E, Schiffrin EL. PPAR activation: a new target for the treatment of hypertension. J Cardiovasc Pharmacol. 2007; 50: 120-125.
Liu IM, Tzeng TF, Liou SS, Lan TW. Myricetin, a naturally occurring flavonol, ameliorates insulin resistance induced by a high-fructose diet in rats. Life Sci. 2007; 81: 1479-1488.
Lo WC, Jan CR, Wu SN, Tseng CJ. Cardiovascular effects of nitric oxide and adenosine in the nucleus tractus solitarii of rats. Hypertension. 1998; 32: 1034-1038.
Loewy, AD. Central autonomic pathways. In: Loewy, AD, and KM Spyer. (Eds.), Central Regulation of Autonomic Funcions.1990; Oxford University Press, New York, pp.88-103.
Maeda M, Hirano H, Kudo H, Doi Y, Higashi K, Fujimoto S. Injection of antisense oligos to nNOS into nucleus tractus solitarii increases blood pressure. Neuroreport. 1999; 10: 1957-1960.
Maeshiba Y, Kiyota Y, Yamashita K, Yoshimura Y, Motohashi M, Tanayama S. Disposition of the new antidiabetic agent pioglitazone in rat, dogs, and monkeys. Arzneimittelforschung. 1997; 47: 29-35.
Malinowski JM, Bolesta S. Rosiglitazone in the treatment of type 2 diabetes mellitus: a critical review. Clin Ther. 2000; 22: 1151-1168.
Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors. Cell. 1995; 83: 841-850.
Matsumoto T, Kobayashi T, Kamata K. Relationships among ET-1, PPARγ oxidative stress and endothelial dysfunction in diabetic animals. J Smooth Muscle Res. 2008; 44: 41-55.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985; 28: 412-419.
McIntyre M, Bohr DF, Dominiczak AF. Endothelial function in hypertension: The role of superoxide anion. Hypertension. 1999; 34: 539-545.
Meerarani P, Badimon JJ, Zias E, Fuster V, Moreno PR. Metabolic syndrome and diabetic atherothrombosis: implications in vascular complications. Curr Mol Med. 2006; 6: 501-514.
Melley DD, Evans TW, Quinlan GJ. Redox regulation of neutrophil apoptosis and the systemic inflammatory response syndrome. Clin Sci (Lond). 2005; 108: 413-424.
Midaoui AE, Wu L, Wang R, Champlain JD. Modulation of cardiac and aortic peroxisome proliferator-activated receptor-γ expression by oxidative stress in chronically glucose-fed rats. Am J Hypertens. 2006; 19: 407-412.
Miyazaki Y, Mahankali A, Matsuda M, Mahankali S, Hardies J, Cusi K, Mandarino LJ, DeFronzo RA. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab. 2002; 87: 2784-2791.
Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, Ouyang X, Feig DI, Block ER, Herrea-Acosta J, Patel JM, Johnson RJ. A causal role for uric acid in fructose induced metabolic syndrome. Am J Physiol Renal Physiol. 2006; 290: 625-631.
Nandhini ATA, Thirunavukkarasu V, Ravichandran MK, Anuradha CV. Effect of taurine on biomarkers of oxidative stress in tissues of fructose-fed insulin-resistant rats. Sigapore Med J. 2005; 46: 82-87.
Nisbet RE, Sutliff RL, Hart CM. The role of peroxisome proliferator-activated receptors in pulmonary vascular disease. PPAR Res. 2007; 2007: 18797-18806.
Nishio K, Sakurai M, Kusuyama T. A randomized comparison of pioglitazone to inhibit restenosis after coronary stenting in patients with type 2 diabetes. Diabetes Care. 2006; 29: 101-106.
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007; 356: 2457-2471.
Oliver WR Jr, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, Lewis MC, Winegar DA, Sznaidman ML, Lambert MH, Xu HE, Sternbach DD, Kliewer SA, Hansen BC, Willson TM. A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport. Proc Natl Acad Sci USA. 2001; 98: 5306-5311.
Ollerstam A, Pittner J, Persson AE, Thorup C. Increased blood pressure in rats after long-term inhibition of the neuronal isoform of nitric oxide synthase. J Clin Invest. 1997; 99: 2212-2218.
Ono A, Kuwaki T, Kumada M, Fujita T. Differential central modulation of baroreflex by salt loading in normotensive and spontaneously hypertensive rats. Hypertension. 1997; 29: 808-814.
Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988; 333: 664-666.
Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987; 327: 524-526.
Pandey NR, Benkirane K, Amiri F, Schiffrin EL. Effects of PPARγ knock-down and hyperglycemia on isulin signaling in vascular smooth 67
muscle cells from hypertensive rats. J Cardiovasc Pharmacol. 2007; 49: 346-354.
Paton JF, Waki H, Abdala AP, Dickinson J, Kasparov S. Vascular-brain signaling in hypertension: role of angiotensin IΙ and nitric oxide. Curr Hypertens Rep. 2007; 9: 242-247.
Peter Harmel AL, Kendall DM, Buse JB, Boyle PJ, Marchetti A, Lau H. Impact of adjunctive thiazolidinedione therapy on blood lipid levels and glycemic control in patients with type 2 diabetes. Curr Med Res Opin. 2004; 20: 215-223.
Pitzalis MV, Passantino A, Massari F, Forleo C, Balducci C, Santoro G, Mastropasqua F, Antonelli G, Rizzon P. Diastolic dysfunction and baroreflex sensitivity in hypertension. Hypertension. 1999; 33: 1141-1145.
Prast H, Philippu A. Nitric oxide as modulator of neuronal function. Prog Neurobiol Med. 2001; 226: 814-824.
Pyner S, Coote JH. Rostroventrolateral medulla neurons preferentially project to target-specified sympathetic preganglionic neurons. Neuroscience. 1998; 83: 617-631.
Raha S, Robinson BH. Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci. 2000; 25: 502-508.
Rapoport RM, Murad F. Agonist-induced endothelium-dependent relaxation in rat thoracic aorta may be mediated through cGMP. Circ Res. 1983; 52: 352-357.
Reaven GM. Banting Lecture 1988: Role of insulin resistance in human disease. Diabetes. 1988; 37: 1595-1607.
Reaven GM. The metabolic syndrome: requiescat in pace. Clin Chem. 2005; 51: 931-938.
Reaven GM, Lithell H, Landsberg L. Hypertension and associated 68
metabolic abnormalities-the role of insulin resistance and the sympathoadrenal system. N Engl J Med. 1996; 334: 374-381.
Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor- γ is a negative regulator of macrophage activation. Nature. 1998; 391: 79-82.
Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM, Zartau-Hind ME, Hosford DA, Roses AD, Rosiglitazone in Alzheimer’s Disease Study Group. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease. Pharmacogenomics J. 2006; 6: 246-254.
Ross CA, Amsstrong DM, Ruggiero DA, Pickel VM, Joh TH, Reis DJ. Adrenaline neurons in the rostral ventrolateral medulla innervate thoracic spinal cord: a combined immunocytochemical and retrograde transport demonstration. Neurosci Lett. 1981; 25: 257-267.
Ross CA, Ruggiero DA, Joh TH, Park DH, Reis DJ. Adrenaline synthesizing neurons in the rostral ventrolateral medulla: a possible role in tonic vasomotor control. Brain Res. 1983; 273: 356-361.
Ruggeri P, Brunori A, Cogo CE, Storace D, Nardo FD, Burattini R. Enhanced sympathetic reactivity associates with insulin resistance in the young Zucker rat. Am J Physiol Regul Intergr Comp Physiol. 2006; 261: R376-R382.
Ryan MJ, Didion SP, Mathur S, Faraci FM, Sigmund CD. PPARγ agonist rosiglitazone improves vascular function and lowers blood pressure in hypertensive transgenic mice. Hypertension. 2004; 43: 661-666.
Sakai K, Hirooka Y, Matsuo I, Eshima K, Shigematsu H, Shimokawa H, Takeshita A. Overexpression of eNOS in NTS causes hypotension and bradycardia in vivo. Hypertension. 2000; 36: 1023-1028.
Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes. 1996; 45: 1661-1669.
Sarafidis PA, Lasaridis AN. Actions of peroxisome proliferator-activated receptors-γ agonists explaining a possible blood pressure-lowering effect. Am J Hypertens. 2006; 19: 646-653.
Schiffrin EL. Peroxisome proliferator-activated receptors and cardiovascular remodeling. Am J Physiol Heart Circ Physiol. 2005; 288: 1037-1043.
Sharabi Y, Oron-Herman M, Kamari Y, Avni I, Peleg E, Shabtay Z, Grossman E, Shamiss A. Effect of PPAR-gamma agonist on adiponectin levels in the metabolic syndrome: lessons from the high fructose fed rat model. Am J Hypertens. 2007; 20: 206-210.
Sheppard FR, Kelher MR, Moore EE, McLaughlin NJ, Banerjee A, Silliman CC. Structural organization of the neutrophil NADPH oxidase: phosphorylation and translocation during priming and activation. J Leukoc Biol. 2005; 78: 1025-1042.
Shinozaki K, Ayajiki K, Nishio Y, Sugaya T, Kashiwagi A, Okamuro T. Evidence for a causal role of the rennin-angiotnsin system in vascular dysfunction associated with insulin resistance. Hypertension. 2004; 43: 255-262.
Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest. 2000; 106: 171-176.
Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes. 1998; 47: 507-514.
Spyer KM. Central nervous mechanisms contributing to cardiovascular control. J Physiol. 1994; 474: 1-19.
Sumimoto H, Miyano K, Takeya R. Molecular composition and regulation of the Nox family NAD(P)H oxidases. Biochem Biophys Res Commun. 2005; 338: 677-686.
Szasz T, Thakali K, Fink GD, Watts SW. A comparison of arteries and veins in oxidative stress: producers, destroyers, function, and disease. Exp Biol Med (Maywood). 2007; 232: 27-37.
Tai MH, Wang LL, Wu KLH, Chan JYH. Increased superoxide anion in rostral ventrolateral medulla contributes to hypertension in spontaneously hypertensive rats via interactions with nitric oxide. Free Radic Biol Med. 2005; 38: 450-462.
Tai MH, Weng WT, Lo WC, Chan JYH, Lin CJ, Lam HC, Tseng CJ. Role of nitric oxide in alpha-melanocyte-stimulating hormone-induced hypotension in the nucleus tractus solitarii of the spontaneously hypertensive rats. J Pharmacol Exp Ther. 2007; 321: 455-461.
Tain YL, Baylis C. Dissecting the causes of oxidative stress in an in vivo model of hypertension. Hypertension. 2006; 48: 828-829.
Takatori S, Zamami Y, Mio M, Kurosaki Y, Kawasaki H. Chronic hyperinsulinemia enhances adrenergic vasoconstriction and decreases calcitonin gene-related peptide-containing nerve-mediated vasoliation in pithed rats. Hypertens Res. 2006; 29: 361-368.
Tanaka T, Yamamoto J, Iwasaki S, Asaba H, Hamura H, Ikeda Y, Watanabe M, Magoori K, Ioka RX, Tachibana K, Watanabe Y, Uchiyama Y, Sumi K, Lguchi H, Ito S, Doi T, Hamakubo T, Naito M, Auwerx J, Yanagisawa M, Kodama T, Sakai J. Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome. Pro Natl Acad Sci USA. 2003; 100: 15924-15929.
Taniyama Y, Griendling KK. Reactive oxygen species in the vasculature: molecular and cellular mechanisms. Hypertension. 2003; 42: 1075-1081.
Tank J, Jordan J, Diedrich A, Stoffels M, Franke G, Faulhaber HD, Luft FC, Busjahn A. Genetic influences on baroreflex function in normal twins. Hypertension. 2001; 37: 907-910.
Titheradge MA. Nitric oxide in septic shock. Biochim Biophys Acta. 1999; 1411: 437-455.
Tran LT, MacLeod KM, McNeill JH. Endothelin-1 modulates angiotensin II in the development of hypertension in fructose-fed rats. Mol Cell Biochem. 2009a; 325: 89-97.
Tran LT, MacLeod KM, McNeill JH. The fructose- fed rat: a review on the mechanisms of fructose-induced insulin resistacne and hypertension.
Mol Cell Biochem. 2009b; 332: 145-159.
Tsai HY, Wu LY, Hwang LS. Effect of a proanthocyanidin-rich extract from longan flower on markers of metabolic syndrome in fructose-fed rats. J Agric Food Chem. 2008; 56: 11018-11024.
Tseng CJ, Liu HY, Lin HC, Ger LP, Tung CS, Yen MH. Cardiovascular effects of nitric oxide in the brain stem nuclei of rats. Hypertension. 1996; 27: 36-42.
Ueno M, Sakamoto H, Tomimoto H, Akiguchi I, Onodera M, Hunang CL, Kanenishi K. Blood-brain barrier is impaired in the hippocampus of young adult spontaneously hypertensive rats. Acta Neuropathol. 2004; 107: 532-538.
Verma S, McNeill JH. Insulin resistance and hypertension: pharmacological and mechanistic studies. Can J Diabetes Care. 2000; 23: 23-42.
Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, Fishel MA, Kulstad JJ, Green PS, Cook DG, Kahn SE, Keeling ML, Craft S. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry. 2005; 13: 950-958.
Wu L, Wang R, De Champlain J, Wilson TW. Beneficial and deleterious effects of rosiglitazone on hypertension development in spontaneously hypertensive rats. Am J Hypertens. 2004; 17: 749-756.
Yki-Jarvinen H. Thiazolidinediones. N Engl J Med. 2004; 351:
1106-1118.
Yosefy C, Magen E, Kiselevich A, Priluk R, London D, Volchek L, Viskoper RJ Jr. Rosiglitazone improves, while Glibenclamide worsens blood pressure control in treated hypertensive diabetic and dyslipidemic subjects via modulation of insulin resistance and sympathetic activity. J Cardiovasc Pharmacol. 2004; 44: 215-222.