• 1
    Endemann DH, Schiffrin EL. Endothelial dysfunction. J Am Soc Nephrol 2004;15:198392.
  • 2
    Schulz E, Anter E, Keaney JF, Jr. Oxidative stress, antioxidants, and endothelial function. Curr Med Chem 2004;11:1093104.
  • 3
    Wrieden WL, Hannah MK, Bolton-Smith C, Tavendale R, Morrison C, Tunstall-Pedoe H. Plasma vitamin C and food choice in the third Glasgow MONICA population survey. J Epidemiol Community Health 2000;54:35560.
  • 4
    Hampl JS, Taylor CA, Johnston CS. Vitamin C deficiency and depletion in the United States: the Third National Health and Nutrition Examination Survey, 1988 to 1994. Am J Public Health 2004;94:8705.
  • 5
    Lykkesfeldt J. Smoking depletes Vitamin C: should smokers be recommended to take supplements. In: HalliwellBB, PoulsenHE, (eds). Cigarette Smoke and Oxidative Stress, Berlin Heidelberg: Springer Verlag, 2006:23760.
  • 6
    Jacob RA. Assessment of human vitamin C status. J Nutr 1990;120 (Suppl 11):14805.
  • 7
    Lykkesfeldt J, Christen S, Wallock LM, Chang HH, Jacob RA, Ames BN. Ascorbate is depleted by smoking and repleted by moderate supplementation: a study in male smokers and nonsmokers with matched dietary antioxidant intakes. Am J Clin Nutr 2000;71:5306.
  • 8
    Siomek A, Gackowski D, Rozalski R, Dziaman T, Szpila A, Guz J et al . Higher leukocyte 8-oxo-7,8-dihydro-2′-deoxyguanosine and lower plasma ascorbate in aging humans? Antioxid Redox Signal 2007;9:14350.
  • 9
    Cunningham JJ, Ellis SL, McVeigh KL, Levine RE, Calles-Escandon J. Reduced mononuclear leukocyte ascorbic acid content in adults with insulin-dependent diabetes mellitus consuming adequate dietary vitamin C. Metabolism 1991;40:1469.
  • 10
    Johnston CS, Beezhold BL, Mostow B, Swan PD. Plasma vitamin C is inversely related to body mass index and waist circumference but not to plasma adiponectin in nonsmoking adults. J Nutr 2007;137:175762.
  • 11
    Ginter E. Chronic vitamin C deficiency increases the risk of cardiovascular diseases. Bratisl Lek Listy 2007;108:41721.
  • 12
    Gey KF, Stahelin HB, Eichholzer M. Poor plasma status of carotene and vitamin C is associated with higher mortality from ischemic heart disease and stroke: Basel Prospective Study. Clin Investig 1993;71:36.
  • 13
    Nyyssonen K, Parviainen MT, Salonen R, Tuomilehto J, Salonen JT. Vitamin C deficiency and risk of myocardial infarction: prospective population study of men from eastern Finland. BMJ 1997;314:6348.
  • 14
    Langlois M, Duprez D, Delanghe J, De BM, Clement DL. Serum vitamin C concentration is low in peripheral arterial disease and is associated with inflammation and severity of atherosclerosis. Circulation 2001;103:18638.
  • 15
    Fidlar E, Sheppard M, McHenry EW. The physiological properties of ascorbic acid: the increase in metabolism of guinea-pigs on a diet deficient in ascorbic acid. Biochem J 1939;33:3446.
  • 16
    Fox FW, Levy LF. Experiments confirming the antiscorbutic activity of dehydroascorbic acid and a study of its storage and that of ascorbic acid by the guinea-pig at different levels of intake. Biochem J 1936;30:2117.
  • 17
    Willis GC. An experimental study of intimal ground substance in atherosclerosis. Can Med Assoc J 1953;69:1722.
  • 18
    Willis GC. The reversibility of atherosclerosis. Can Med Assoc J 1957;77:1068.
  • 19
    Ginter E, Bobek P, Gerbelova M. The effect of acute deficiency and of prolonged low intake of vitamin C on the spectrum of serum lipoproteins in guinea pigs. Bratisl Lek Listy 1965;45:116.
  • 20
    Ginter E, Bilisics L, Cerven J. Cholesterol metabolism under conditions of acute and chronic vitamin C deficiency in guinea-pigs. Physiol Bohemoslov 1965;14:46671.
  • 21
    Ginter E. [Effect of vitamin C on the metabolism of cholesterol and atherogenesis]. Cesk Fysiol 1968;17:42336.
  • 22
    Ginter E, Bobek P, Vargova D. Tissue levels and optimum dosage of vitamin C in guinea pigs. Nutr Metab 1979;23:21726.
  • 23
    Jenkins SA. Vitamin C status, serum cholesterol levels and bile composition in the pregnant guinea-pig. Br J Nutr 1980;43:95100.
  • 24
    Ginter E, Ondreicka R, Bobek P, Simko V. The influence of chronic vitamin C deficiency on fatty acid composition of blood serum, liver triglycerides and cholesterol esters in guinea pigs. J Nutr 1969;99:2616.
  • 25
    Bjorkhem I, Kallner A. Hepatic 7α-hydroxylation of cholesterol in ascorbate-deficient and ascorbate-supplemented guinea pigs. J Lipid Res 1976;17:3605.
  • 26
    Ginter E, Bobek P, Babala J, Barbierikova E. The effect of ascorbic acid on the lipid metabolism of guinea-pigs fed an atherogenic diet. Cor Vasa 1969;11:6573.
  • 27
    Ginter E, Babala J, Cerven J. The effect of chronic hypovitaminosis C on the metabolism of cholesterol and atherogenisis in guinea pigs. J Atheroscler Res 1969;10:34152.
  • 28
    Sulkin NM, Sulkin DF. Tissue changes induced by marginal vitamin C deficiency. Ann N Y Acad Sci 1975;258:31728.
  • 29
    Nambisan B, Kurup PA. Ascorbic acid and glycosaminoglycan and lipid metabolism in guinea pigs fed normal and atherogenic diets. Atherosclerosis 1975;22:44761.
  • 30
    Zloch Z. Changes in the cholesterol content of high-density plasma lipoproteins in guinea pigs in the presence of a raised exogenous cholesterol intake and different degrees of vitamin C saturation. Physiol Bohemoslov 1982;31:55762.
  • 31
    Satinder, Sarkar AK, Majumdar S, Chakravarti RN. Effect of ascorbic acid deficiency on the development of experimental atherosclerosis. Indian J Med Res 1987;86:35160.
  • 32
    Ginter E, Jurcovicova M. Chronic vitamin C deficiency lowers fractional catabolic rate of low-density lipoproteins in guinea pigs. Ann N Y Acad Sci 1987;498:4735.
  • 33
    Kothari LK, Sharma P. Aggravation of cholesterol induced hyperlipidemia by chronic vitamin C deficiency: experimental study in guinea pigs. Acta Biol Hung 1988;39:4957.
  • 34
    Sharma P, Pramod J, Sharma PK, Chaturvedi SK, Kothari LK. Effect of vitamin C administration on serum & aortic lipid profile of guineapigs. Indian J Med Res 1988;87:2839.
  • 35
    Rath M, Pauling L. Immunological evidence for the accumulation of lipoprotein(a) in the atherosclerotic lesion of the hypoascorbemic guinea pig. Proc Natl Acad Sci USA 1990;87:938890.
  • 36
    Sen S, Mukherjee S. Interrelationship of dietary lipids and ascorbic acid with hepatic enzymes of cholesterol metabolic pathway. Indian J Exp Biol 1997;35:425.
  • 37
    Roomi MW. Association between hyperlipidemia and hepatic cytochrome P-450 in guinea pigs. Res Commun Mol Pathol Pharmacol 1997;97:13950.
  • 38
    Fernandez ML, Vega S, Ayala MT, Shen H, Conde K, Vergara-Jimenez M et al . Vitamin C level and dietary fat saturation alter hepatic cholesterol homeostasis and plasma LDL metabolism in guinea pigs. J Nutr Biochem 1997;8:41424.
  • 39
    Montano CE, Fernandez ML, McNamara DJ. Regulation of apolipoprotein B-containing lipoproteins by vitamin C level and dietary fat saturation in guinea pigs. Metabolism 1998;47:88391.
  • 40
    Weinstein M, Babyn P, Zlotkin S. An orange a day keeps the doctor away: scurvy in the year 2000. Pediatrics 2001;108:E55.
  • 41
    Hirschmann JV, Raugi GJ. Adult scurvy. J Am Acad Dermatol 1999;41:895906.
  • 42
    Ginter E. Marginal vitamin C deficiency, lipid metabolism, and atherogenesis. Adv Lipid Res 1978;16:167220.
  • 43
    Fernandez ML, Volek JS. Guinea pigs: A suitable animal model to study lipoprotein metabolism, atherosclerosis and inflammation. Nutr Metab (Lond) 2006;3:17.
  • 44
    West KL, Fernandez ML. Guinea pigs as models to study the hypocholesterolemic effects of drugs. Cardiovasc Drug Rev 2004;22:5570.
  • 45
    Fernandez ML. Guinea pigs as models for cholesterol and lipoprotein metabolism. J Nutr 2001;131:1020.
  • 46
    Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk 1996;3:2139.
  • 47
    Shen BW, Scanu AM, Kezdy FJ. Structure of human serum lipoproteins inferred from compositional analysis. Proc Natl Acad Sci USA 1977;74:83741.
  • 48
    Ooi TC, Ooi DS. The atherogenic significance of an elevated plasma triglyceride level. Crit Rev Clin Lab Sci 1998;35:489516.
  • 49
    Chapman MJ, Mills GL. Characterization of the serum lipoproteins and their apoproteins in hypercholesterolaemic guinea pigs. Biochem J 1977;167:921.
  • 50
    Shaikh M, Wootton R, Nordestgaard BG, Baskerville P, Lumley JS, La Ville AE et al . Quantitative studies of transfer in vivo of low density, Sf 12–60, and Sf 60–400 lipoproteins between plasma and arterial intima in humans. Arterioscler Thromb 1991;11:56977.
  • 51
    Rapp JH, Lespine A, Hamilton RL, Colyvas N, Chaumeton AH, Tweedie-Hardman J et al . Triglyceride-rich lipoproteins isolated by selected-affinity anti-apolipoprotein B immunosorption from human atherosclerotic plaque. Arterioscler Thromb 1994;14:176774.
  • 52
    Dunn WA, Rettura G, Seifter E, Englard S. Carnitine biosynthesis from gamma-butyrobetaine and from exogenous protein-bound 6-N-trimethyl-L-lysine by the perfused guinea pig liver. Effect of ascorbate deficiency on the in situ activity of gamma-butyrobetaine hydroxylase. J Biol Chem 1984;259:1076470.
  • 53
    Nelson PJ, Pruitt RE, Henderson LL, Jenness R, Henderson LM. Effect of ascorbic acid deficiency on the in vivo synthesis of carnitine. Biochim Biophys Acta 1981;672:1237.
  • 54
    Ha TY, Otsuka M, Arakawa N. The effect of graded doses of ascorbic acid on the tissue carnitine and plasma lipid concentrations. J Nutr Sci Vitaminol (Tokyo) 1990;36:22734.
  • 55
    Camps L, Reina M, Llobera M, Gtsson-Olivecrona G, Olivecrona T, Vilaro S. Lipoprotein lipase in lungs, spleen, and liver: synthesis and distribution. J Lipid Res 1991;32:187788.
  • 56
    Vilaro S, Llobera M, Gtsson-Olivecrona G, Olivecrona T. Lipoprotein lipase uptake by the liver: localization, turnover, and metabolic role. Am J Physiol 1988;254:G711G722.
  • 57
    Hasham SN, Pillarisetti S. Vascular lipases, inflammation and atherosclerosis. Clin Chim Acta 2006;372:17983.
  • 58
    Frick M, Weidinger F. Endothelial function: a surrogate endpoint in cardiovascular studies? Curr Pharm Des 2007;13:174150.
  • 59
    Jablonski KL, Seals DR, Eskurza I, Monahan KD, Donato AJ. High-dose ascorbic acid infusion abolishes chronic vasoconstriction and restores resting leg blood flow in healthy older men. J Appl Physiol 2007;103:171521.
  • 60
    Holowatz LA, Thompson CS, Kenney WL. Acute ascorbate supplementation alone or combined with arginase inhibition augments reflex cutaneous vasodilation in aged human skin. Am J Physiol Heart Circ Physiol 2006;291:H2965H2970.
  • 61
    Singh N, Graves J, Taylor PD, MacAllister RJ, Singer DR. Effects of a ‘healthy’ diet and of acute and long-term vitamin C on vascular function in healthy older subjects. Cardiovasc Res 2002;56:11825.
  • 62
    Ting HH, Timimi FK, Boles KS, Creager SJ, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 1996;97:228.
  • 63
    Timimi FK, Ting HH, Haley EA, Roddy MA, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. J Am Coll Cardiol 1998;31:5527.
  • 64
    Hirai N, Kawano H, Hirashima O, Motoyama T, Moriyama Y, Sakamoto T et al . Insulin resistance and endothelial dysfunction in smokers: effects of vitamin C. Am J Physiol Heart Circ Physiol 2000;279:H1172H1178.
  • 65
    Beckman JA, Goldfine AB, Gordon MB, Creager MA. Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans. Circulation 2001;103:161823.
  • 66
    Heitzer T, Finckh B, Albers S, Krohn K, Kohlschutter A, Meinertz T. Beneficial effects of α-lipoic acid and ascorbic acid on endothelium-dependent, nitric oxide-mediated vasodilation in diabetic patients: relation to parameters of oxidative stress. Free Radic Biol Med 2001;31:5361.
  • 67
    Mullan BA, Ennis CN, Fee HJ, Young IS, McCance DR. Pretreatment with intravenous ascorbic acid preserves endothelial function during acute hyperglycaemia (R1). Clin Exp Pharmacol Physiol 2005;32:3405.
  • 68
    Arcaro G, Cretti A, Balzano S, Lechi A, Muggeo M, Bonora E et al . Insulin causes endothelial dysfunction in humans: sites and mechanisms. Circulation 2002;105:57682.
  • 69
    Evans M, Anderson RA, Smith JC, Khan N, Graham JM, Thomas AW et al . Effects of insulin lispro and chronic vitamin C therapy on postprandial lipaemia, oxidative stress and endothelial function in patients with type 2 diabetes mellitus. Eur J Clin Invest 2003;33:2318.
  • 70
    Darko D, Dornhorst A, Kelly FJ, Ritter JM, Chowienczyk PJ. Lack of effect of oral vitamin C on blood pressure, oxidative stress and endothelial function in Type II diabetes. Clin Sci (Lond) 2002;103:33944.
  • 71
    Antoniades C, Tousoulis D, Tountas C, Tentolouris C, Toutouza M, Vasiliadou C et al . Vascular endothelium and inflammatory process, in patients with combined Type 2 diabetes mellitus and coronary atherosclerosis: the effects of vitamin C. Diabet Med 2004;21:5528.
  • 72
    Chen H, Karne RJ, Hall G, Campia U, Panza JA, Cannon RO, III et al . High-dose oral vitamin C partially replenishes vitamin C levels in patients with Type 2 diabetes and low vitamin C levels but does not improve endothelial dysfunction or insulin resistance. Am J Physiol Heart Circ Physiol 2006;290:H137H145.
  • 73
    Tousoulis D, Antoniades C, Vasiliadou C, Kourtellaris P, Koniari K, Marinou K et al . Effects of atorvastatin and vitamin C on forearm hyperaemic blood flow, asymmentrical dimethylarginine levels and the inflammatory process in patients with type 2 diabetes mellitus. Heart 2007;93:2446.
  • 74
    Levine GN, Frei B, Koulouris SN, Gerhard MD, Keaney JF, Jr., Vita JA. Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 1996;93:110713.
  • 75
    Ito K, Akita H, Kanazawa K, Yamada S, Terashima M, Matsuda Y et al . Comparison of effects of ascorbic acid on endothelium-dependent vasodilation in patients with chronic congestive heart failure secondary to idiopathic dilated cardiomyopathy versus patients with effort angina pectoris secondary to coronary artery disease. Am J Cardiol 1998;82:7627.
  • 76
    Gokce N, Keaney JF, Jr, Frei B, Holbrook M, Olesiak M, Zachariah BJ et al . Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 1999;99:323440.
  • 77
    Hamabe A, Takase B, Uehata A, Kurita A, Ohsuzu F, Tamai S. Impaired endothelium-dependent vasodilation in the brachial artery in variant angina pectoris and the effect of intravenous administration of vitamin C. Am J Cardiol 2001;87:11549.
  • 78
    Tousoulis D, Xenakis C, Tentolouris C, Davies G, Antoniades C, Crake T et al . Effects of vitamin C on intracoronary l-arginine dependent coronary vasodilatation in patients with stable angina. Heart 2005;91:131923.
  • 79
    Erbs S, Gielen S, Linke A, Mobius-Winkler S, Adams V, Baither Y et al . Improvement of peripheral endothelial dysfunction by acute vitamin C application: different effects in patients with coronary artery disease, ischemic, and dilated cardiomyopathy. Am Heart J 2003;146:2805.
  • 80
    Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 2001;104:26738.
  • 81
    Hornig B, Landmesser U, Kohler C, Ahlersmann D, Spiekermann S, Christoph A et al . Comparative effect of ace inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: role of superoxide dismutase. Circulation 2001;103:799805.
  • 82
    Landmesser U, Merten R, Spiekermann S, Buttner K, Drexler H, Hornig B. Vascular extracellular superoxide dismutase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation. Circulation 2000;101:226470.
  • 83
    Drossos GE, Toumpoulis IK, Katritsis DG, Ioannidis JP, Kontogiorgi P, Svarna E et al . Is vitamin C superior to diltiazem for radial artery vasodilation in patients awaiting coronary artery bypass grafting? J Thorac Cardiovasc Surg 2003;125:3305.
  • 84
    Ting HH, Timimi FK, Haley EA, Roddy MA, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemia. Circulation 1997;95:261722.
  • 85
    Perticone F, Ceravolo R, Maio R, Cloro C, Candigliota M, Scozzafava A et al . Effects of atorvastatin and vitamin C on endothelial function of hypercholesterolemic patients. Atherosclerosis 2000;152:5118.
  • 86
    John S, Schneider MP, Delles C, Jacobi J, Schmieder RE. Lipid-independent effects of statins on endothelial function and bioavailability of nitric oxide in hypercholesterolemic patients. Am Heart J 2005;149:473.
  • 87
    Virdis A, Pinto S, Versari D, Salvetti G, Bernini G, Fruzzetti F et al . Effect of oral contraceptives on endothelial function in the peripheral microcirculation of healthy women. J Hypertens 2003;21:227580.
  • 88
    Schindler TH, Nitzsche EU, Munzel T, Olschewski M, Brink I, Jeserich M et al . Coronary vasoregulation in patients with various risk factors in response to cold pressor testing: contrasting myocardial blood flow responses to short- and long-term vitamin C administration. J Am Coll Cardiol 2003;42:81422.
  • 89
    Pullin CH, Bonham JR, McDowell IF, Lee PJ, Powers HJ, Wilson JF et al . Vitamin C therapy ameliorates vascular endothelial dysfunction in treated patients with homocystinuria. J Inherit Metab Dis 2002;25:10718.
  • 90
    Kanani PM, Sinkey CA, Browning RL, Allaman M, Knapp HR, Haynes WG. Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans. Circulation 1999;100:11618.
  • 91
    Virdis A, Ghiadoni L, Cardinal H, Favilla S, Duranti P, Birindelli R et al . Mechanisms responsible for endothelial dysfunction induced by fasting hyperhomocystinemia in normotensive subjects and patients with essential hypertension. J Am Coll Cardiol 2001;38:110615.
  • 92
    Chambers JC, McGregor A, Jean-Marie J, Obeid OA, Kooner JS. Demonstration of rapid onset vascular endothelial dysfunction after hyperhomocysteinemia: an effect reversible with vitamin C therapy. Circulation 1999;99:115660.
  • 93
    Hanratty CG, McGrath LT, McAuley DF, Young IS, Johnston DG. The effect on endothelial function of vitamin C during methionine induced hyperhomocysteinaemia. BMC Cardiovasc Disord 2001;1:1.
  • 94
    Labinjoh C, Newby DE, Wilkinson IB, Megson IL, MacCallum H, Melville V et al . Effects of acute methionine loading and vitamin C on endogenous fibrinolysis, endothelium-dependent vasomotion and platelet aggregation. Clin Sci (Lond) 2001;100:12735.
  • 95
    Pleiner J, Schaller G, Mittermayer F, Bayerle-Eder M, Roden M, Wolzt M. FFA-induced endothelial dysfunction can be corrected by vitamin C. J Clin Endocrinol Metab 2002;87:29137.
  • 96
    Steer P, Millgard J, Basu S, Lithell H, Vessby B, Berne C et al . Vitamin C, diclophenac, and l-arginine protect endothelium-dependent vasodilation against elevated circulating fatty acid levels in humans. Atherosclerosis 2003;168:6572.
  • 97
    Bayerle-Eder M, Pleiner J, Mittermayer F, Schaller G, Roden M, Waldhausl W et al . Effect of systemic vitamin C on free fatty acid-induced lipid peroxidation. Diabetes Metab 2004;30:4339.
  • 98
    Watanabe S, Tagawa T, Yamakawa K, Shimabukuro M, Ueda S. Inhibition of the renin-angiotensin system prevents free fatty acid-induced acute endothelial dysfunction in humans. Arterioscler Thromb Vasc Biol 2005;25:237680.
  • 99
    Ling L, Zhao SP, Gao M, Zhou QC, Li YL, Xia B. Vitamin C preserves endothelial function in patients with coronary heart disease after a high-fat meal. Clin Cardiol 2002;25:21924.
  • 100
    Solzbach U, Hornig B, Jeserich M, Just H. Vitamin C improves endothelial dysfunction of epicardial coronary arteries in hypertensive patients. Circulation 1997;96:15139.
  • 101
    Taddei S, Virdis A, Ghiadoni L, Magagna A, Salvetti A. Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation 1998;97:22229.
  • 102
    Natali A, Sironi AM, Toschi E, Camastra S, Sanna G, Perissinotto A et al . Effect of vitamin C on forearm blood flow and glucose metabolism in essential hypertension. Arterioscler Thromb Vasc Biol 2000;20:24016.
  • 103
    Sherman DL, Keaney JF, Jr., Biegelsen ES, Duffy SJ, Coffman JD, Vita JA. Pharmacological concentrations of ascorbic acid are required for the beneficial effect on endothelial vasomotor function in hypertension. Hypertension 2000;35:93641.
  • 104
    On YK, Kim CH, Sohn DW, Oh BH, Lee MM, Park YB et al . Improvement of endothelial function by amlodipine and vitamin C in essential hypertension. Korean J Intern Med 2002;17:1317.
  • 105
    Schneider MP, Delles C, Schmidt BM, Oehmer S, Schwarz TK, Schmieder RE et al . Superoxide scavenging effects of N-acetylcysteine and vitamin C in subjects with essential hypertension. Am J Hypertens 2005;18:11117.
  • 106
    Holowatz LA, Kenney WL. Local ascorbate administration augments NO- and non-NO-dependent reflex cutaneous vasodilation in hypertensive humans. Am J Physiol Heart Circ Physiol 2007;293:H1090H1096.
  • 107
    Taddei S, Virdis A, Ghiadoni L, Salvetti G, Bernini G, Magagna A et al . Age-related reduction of NO availability and oxidative stress in humans. Hypertension 2001;38:2749.
  • 108
    Taddei S, Virdis A, Ghiadoni L, Magagna A, Favilla S, Pompella A et al . Restoration of nitric oxide availability after calcium antagonist treatment in essential hypertension. Hypertension 2001;37:9438.
  • 109
    Taddei S, Virdis A, Ghiadoni L, Versari D, Salvetti G, Magagna A et al . Calcium antagonist treatment by lercanidipine prevents hyperpolarization in essential hypertension. Hypertension 2003;41:9505.
  • 110
    Higashi Y, Sasaki S, Nakagawa K, Matsuura H, Oshima T, Chayama K. Endothelial function and oxidative stress in renovascular hypertension. N Engl J Med 2002;346:195462.
  • 111
    Duffy SJ, Gokce N, Holbrook M, Hunter LM, Biegelsen ES, Huang A et al . Effect of ascorbic acid treatment on conduit vessel endothelial dysfunction in patients with hypertension. Am J Physiol Heart Circ Physiol 2001;280:H528H534.
  • 112
    Ward NC, Hodgson JM, Croft KD, Burke V, Beilin LJ, Puddey IB. The combination of vitamin C and grape-seed polyphenols increases blood pressure: a randomized, double-blind, placebo-controlled trial. J Hypertens 2005;23:42734.
  • 113
    Magen E, Viskoper R, Mishal J, Priluk R, Berezovsky A, Laszt A et al . Resistant arterial hypertension and hyperlipidemia: atorvastatin, not vitamin C, for blood pressure control. Isr Med Assoc J 2004;6:7426.
  • 114
    Ward NC, Hodgson JM, Croft KD, Clarke MW, Burke V, Beilin LJ et al . Effects of vitamin C and grape-seed polyphenols on blood pressure in treated hypertensive individuals: results of a randomised double blind, placebo-controlled trial. Asia Pac J Clin Nutr 2003;12 (Suppl):S18.
  • 115
    Pleiner J, Mittermayer F, Schaller G, MacAllister RJ, Wolzt M. High doses of vitamin C reverse Escherichia coli endotoxin-induced hyporeactivity to acetylcholine in the human forearm. Circulation 2002;106:14604.
  • 116
    Cangemi R, Angelico F, Loffredo L, Del BM, Pignatelli P, Martini A et al . Oxidative stress-mediated arterial dysfunction in patients with metabolic syndrome: Effect of ascorbic acid. Free Radic Biol Med 2007;43:8539.
  • 117
    Tesauro M, Schinzari F, Rovella V, Melina D, Mores N, Barini A et al . Tumor necrosis factor-α antagonism improves vasodilation during hyperinsulinemia in metabolic syndrome. Diabetes Care 2008;31:143941.
  • 118
    Higashi Y, Sasaki S, Nakagawa K, Kimura M, Noma K, Sasaki S et al . Low body mass index is a risk factor for impaired endothelium-dependent vasodilation in humans: role of nitric oxide and oxidative stress. J Am Coll Cardiol 2003;42:25663.
  • 119
    Perticone F, Ceravolo R, Candigliota M, Ventura G, Iacopino S, Sinopoli F et al . Obesity and body fat distribution induce endothelial dysfunction by oxidative stress: protective effect of vitamin C. Diabetes 2001;50:15965.
  • 120
    Hornig B, Arakawa N, Kohler C, Drexler H. Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure. Circulation 1998;97:3638.
  • 121
    Hirashima O, Kawano H, Motoyama T, Hirai N, Ohgushi M, Kugiyama K et al . Improvement of endothelial function and insulin sensitivity with vitamin C in patients with coronary spastic angina: possible role of reactive oxygen species. J Am Coll Cardiol 2000;35:18606.
  • 122
    Ellis GR, Anderson RA, Chirkov YY, Morris-Thurgood J, Jackson SK, Lewis MJ et al . Acute effects of vitamin C on platelet responsiveness to nitric oxide donors and endothelial function in patients with chronic heart failure. J Cardiovasc Pharmacol 2001;37:56470.
  • 123
    Richartz BM, Werner GS, Ferrari M, Figulla HR. Reversibility of coronary endothelial vasomotor dysfunction in idiopathic dilated cardiomyopathy: acute effects of vitamin C. Am J Cardiol 2001;88:10015.
  • 124
    Pleiner J, Schaller G, Mittermayer F, Marsik C, MacAllister RJ, Kapiotis S et al . Intra-arterial vitamin C prevents endothelial dysfunction caused by ischemia-reperfusion. Atherosclerosis 2008;197:38391.
  • 125
    Heitzer T, Baldus S, Von KY, Rudolph V, Meinertz T. Systemic endothelial dysfunction as an early predictor of adverse outcome in heart failure. Arterioscler Thromb Vasc Biol 2005;25:11749.
  • 126
    Ellis GR, Anderson RA, Lang D, Blackman DJ, Morris RH, Morris-Thurgood J et al . Neutrophil superoxide anion–generating capacity, endothelial function and oxidative stress in chronic heart failure: effects of short- and long-term vitamin C therapy. J Am Coll Cardiol 2000;36:147482.
  • 127
    Murchie KJ, Jennings GL, Kingwell BA. Supplemental oxygen does not modulate responses to acetylcholine or ascorbic acid in the forearm of patients with congestive heart failure. Clin Sci (Lond) 2000;99:5763.
  • 128
    Widlansky ME, Biegelsen ES, Hamburg NM, Duffy SJ, Keaney JF, Jr., Vita JA. Coronary endothelial dysfunction is not rapidly reversible with ascorbic acid. Free Radic Biol Med 2004;36:12330.
  • 129
    Cross JM, Donald AE, Nuttall SL, Deanfield JE, Woolfson RG, MacAllister RJ. Vitamin C improves resistance but not conduit artery endothelial function in patients with chronic renal failure. Kidney Int 2003;63:143342.
  • 130
    Ghiadoni L, Cupisti A, Huang Y, Mattei P, Cardinal H, Favilla S et al . Endothelial dysfunction and oxidative stress in chronic renal failure. J Nephrol 2004;17:5129.
  • 131
    Williams MJ, Sutherland WH, McCormick MP, De Jong SA, McDonald JR, Walker RJ. Vitamin C improves endothelial dysfunction in renal allograft recipients. Nephrol Dial Transplant 2001;16:12515.
  • 132
    Eskurza I, Monahan KD, Robinson JA, Seals DR. Effect of acute and chronic ascorbic acid on flow-mediated dilatation with sedentary and physically active human ageing. J Physiol 2004;556:31524.
  • 133
    Galetta F, Franzoni F, Virdis A, Ghiadoni L, Taddei S, Salvetti A et al . Endothelium-dependent vasodilation and carotid artery wall remodeling in athletes and sedentary subjects. Atherosclerosis 2006;186:18492.
  • 134
    Taddei S, Galetta F, Virdis A, Ghiadoni L, Salvetti G, Franzoni F et al . Physical activity prevents age-related impairment in nitric oxide availability in elderly athletes. Circulation 2000;101:2896901.
  • 135
    Heitzer T, Just H, Munzel T. Antioxidant vitamin C improves endothelial dysfunction in chronic smokers. Circulation 1996;94:69.
  • 136
    Motoyama T, Kawano H, Kugiyama K, Hirashima O, Ohgushi M, Yoshimura M et al . Endothelium-dependent vasodilation in the brachial artery is impaired in smokers: effect of vitamin C. Am J Physiol 1997;273:H164450.
  • 137
    Zhang J, Ying X, Lu Q, Kallner A, Xiu RJ, Henriksson P et al . A single high dose of vitamin C counteracts the acute negative effect on microcirculation induced by smoking a cigarette. Microvasc Res 1999;58:30511.
  • 138
    Kaufmann PA, Gnecchi-Ruscone T, Di TM, Schafers KP, Luscher TF, Camici PG. Coronary heart disease in smokers: vitamin C restores coronary microcirculatory function. Circulation 2000;102:12338.
  • 139
    Raitakari OT, Adams MR, McCredie RJ, Griffiths KA, Stocker R, Celermajer DS. Oral vitamin C and endothelial function in smokers: short-term improvement, but no sustained beneficial effect. J Am Coll Cardiol 2000;35:161621.
  • 140
    Stamatelopoulos KS, Lekakis JP, Papamichael CM, Papaioannou TG, Cimboneriou A, Stamatelopoulos SF. Oral administration of ascorbic acid attenuates endothelial dysfunction after short-term cigarette smoking. Int J Vitam Nutr Res 2003;73:41722.
  • 141
    Teramoto K, Daimon M, Hasegawa R, Toyoda T, Sekine T, Kawata T et al . Acute effect of oral vitamin C on coronary circulation in young healthy smokers. Am Heart J 2004;148:3005.
  • 142
    De Sousa MG, Yugar-Toledo JC, Rubira M, Ferreira-Melo SE, Plentz R, Barbieri D et al . Ascorbic acid improves impaired venous and arterial endothelium-dependent dilation in smokers. Acta Pharmacol Sin 2005;26:44752.
  • 143
    Kaehler J, Koeke K, Karstens M, Schneppenheim R, Meinertz T, Heitzer T. Impaired capacity for acute endogenous fibrinolysis in smokers is restored by ascorbic acid. Free Radic Biol Med 2008;44:31521.
  • 144
    Young JM, Shand BI, McGregor PM, Scott RS, Frampton CM. Comparative effects of enzogenol and vitamin C supplementation versus vitamin C alone on endothelial function and biochemical markers of oxidative stress and inflammation in chronic smokers. Free Radic Res 2006;40:8594.
  • 145
    Fennessy FM, Moneley DS, Wang JH, Kelly CJ, Bouchier-Hayes DJ. Taurine and vitamin C modify monocyte and endothelial dysfunction in young smokers. Circulation 2003;107:4105.
  • 146
    Pellegrini MP, Newby DE, Johnston NR, Maxwell S, Webb DJ. Vitamin C has no effect on endothelium-dependent vasomotion and acute endogenous fibrinolysis in healthy smokers. J Cardiovasc Pharmacol 2004;44:11724.
  • 147
    Hirooka Y, Eshima K, Setoguchi S, Kishi T, Egashira K, Takeshita A. Vitamin C improves attenuated angiotensin II-induced endothelium-dependent vasodilation in human forearm vessels. Hypertens Res 2003;26:9539.
  • 148
    Bohm F, Settergren M, Pernow J. Vitamin C blocks vascular dysfunction and release of interleukin-6 induced by endothelin-1 in humans in vivo. Atherosclerosis 2007;190:40815.
  • 149
    Protogerou AD, Lekakis JP, Kontoyanni DD, Stamatelopoulos KS, Tsotsoros ND, Papaioannou TG et al . Effect of ascorbic acid on forearm reactive hyperaemia in patients with hypercholesterolaemia. Eur J Cardiovasc Prev Rehabil 2004;11:14954.
  • 150
    Van Guilder GP, Hoetzer GL, Greiner JJ, Stauffer BL, DeSouza CA. Acute and chronic effects of vitamin C on endothelial fibrinolytic function in overweight and obese adult humans. J Physiol 2008;586:352535.
  • 151
    Landmesser U, Spiekermann S, Dikalov S, Tatge H, Wilke R, Kohler C et al . Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular superoxide dismutase. Circulation 2002;106:30738.
  • 152
    Versari D, Daghini E, Rodriguez-Porcel M, Sattler K, Galili O, Pilarczyk K et al . Chronic antioxidant supplementation impairs coronary endothelial function and myocardial perfusion in normal pigs. Hypertension 2006;47:47581.
  • 153
    Aikawa K, Saitoh S, Muto M, Osugi T, Matsumoto K, Onogi F et al . Effects of antioxidants on coronary microvascular spasm induced by epicardial coronary artery endothelial injury in pigs. Coron Artery Dis 2004;15:2130.
  • 154
    Chade AR, Rodriguez-Porcel M, Herrmann J, Zhu X, Grande JP, Napoli C et al . Antioxidant intervention blunts renal injury in experimental renovascular disease. J Am Soc Nephrol 2004;15:95866.
  • 155
    Chade AR, Krier JD, Rodriguez-Porcel M, Breen JF, McKusick MA, Lerman A et al . Comparison of acute and chronic antioxidant interventions in experimental renovascular disease. Am J Physiol Renal Physiol 2004;286:F1079F1086.
  • 156
    Rodriguez-Porcel M, Herrman J, Chade AR, Krier JD, Breen JF, Lerman A et al . Long-term antioxidant intervention improves myocardial microvascular function in experimental hypertension. Hypertension 2004;43:4938.
  • 157
    De NF, Demontis MP, Rodriguez-Porcel M, Anania V, Lerman LO, Napoli C. Renal blood flow in hypercholesterolemic pigs is increased by chronic antioxidant treatment. J Vet Pharmacol Ther 2003;26:1136.
  • 158
    Rodriguez JA, Grau A, Eguinoa E, Nespereira B, Pérez-Ilzarbe M, Arias R et al . Dietary supplementation with vitamins C and E prevents downregulation of endothelial NOS expression in hypercholesterolemia in vivo and in vitro. Atherosclerosis 2002;165:3340.
  • 159
    Rodriguez-Porcel M, Lerman A, Best PJ, Krier JD, Napoli C, Lerman LO. Hypercholesterolemia impairs myocardial perfusion and permeability: role of oxidative stress and endogenous scavenging activity. J Am Coll Cardiol 2001;37:60815.
  • 160
    Stulak JM, Lerman A, Porcel MR, Caccitolo JA, Romero JC, Scaff HV et al . Renal vascular function in hypercholesterolemia is preserved by chronic antioxidant supplementation. J Am Soc Nephrol 2001;12:188291.
  • 161
    Simova II, Denchev SV, Dimitrov SI, Ivanova R. Endothelial function in patients with and without diabetes mellitus with different degrees of coronary artery stenosis. J Clin Ultrasound 2009;37:359.
  • 162
    Benjamin EJ, Larson MG, Keyes MJ, Mitchell GF, Vasan RS, Keaney JF, Jr. et al . Clinical correlates and heritability of flow-mediated dilation in the community: the Framingham Heart Study. Circulation 2004;109:6139.
  • 163
    Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O, Robinson J et al . Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation 1993;88:214955.
  • 164
    Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev 2007;87:315424.
  • 165
    Buettner GR. The pecking order of free radicals and antioxidants: lipid peroxidation, α-tocopherol, and ascorbate. Arch Biochem Biophys 1993;300:53543.
  • 166
    May JM, Qu ZC. Ascorbic acid efflux and re-uptake in endothelial cells: maintenance of intracellular ascorbate. Mol Cell Biochem 2009;325:7988.
  • 167
    Jackson TS, Xu A, Vita JA, Keaney JF, Jr. Ascorbate prevents the interaction of superoxide and nitric oxide only at very high physiological concentrations. Circ Res 1998;83:91622.
  • 168
    Smith AR, Visioli F, Hagen TM. Vitamin C matters: increased oxidative stress in cultured human aortic endothelial cells without supplemental ascorbic acid. FASEB J 2002;16:11024.
  • 169
    Visioli F, Smith A, Zhang W, Keaney JF, Jr., Hagen T, Frei B. Lipoic acid and vitamin C potentiate nitric oxide synthesis in human aortic endothelial cells independently of cellular glutathione status. Redox Rep 2002;7:2237.
  • 170
    Huang A, Vita JA, Venema RC, Keaney JF, Jr. Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. J Biol Chem 2000;275:17399406.
  • 171
    Schmidt HH, Smith RM, Nakane M, Murad F. Ca2+/calmodulin-dependent NO synthase type I: a biopteroflavoprotein with Ca2+/calmodulin-independent diaphorase and reductase activities. Biochemistry 1992;31:32439.
  • 172
    Andrew PJ, Mayer B. Enzymatic function of nitric oxide synthases. Cardiovasc Res 1999;43:52131.
  • 173
    Baek KJ, Thiel BA, Lucas S, Stuehr DJ. Macrophage nitric oxide synthase subunits. Purification, characterization, and role of prosthetic groups and substrate in regulating their association into a dimeric enzyme. J Biol Chem 1993;268:211209.
  • 174
    Cai S, Khoo J, Mussa S, Alp NJ, Channon KM. Endothelial nitric oxide synthase dysfunction in diabetic mice: importance of tetrahydrobiopterin in eNOS dimerisation. Diabetologia 2005;48:193340.
  • 175
    Schmidt PP, Lange R, Gorren AC, Werner ER, Mayer B, Andersson KK. Formation of a protonated trihydrobiopterin radical cation in the first reaction cycle of neuronal and endothelial nitric oxide synthase detected by electron paramagnetic resonance spectroscopy. J Biol Inorg Chem 2001;6:1518.
  • 176
    Kwon NS, Nathan CF, Stuehr DJ. Reduced biopterin as a cofactor in the generation of nitrogen oxides by murine macrophages. J Biol Chem 1989;264:20496501.
  • 177
    Fukuda Y, Teragawa H, Matsuda K, Yamagata T, Matsuura H, Chayama K. Tetrahydrobiopterin improves coronary endothelial function, but does not prevent coronary spasm in patients with vasospastic angina. Circ J 2002;66:5862.
  • 178
    Fukuda Y, Teragawa H, Matsuda K, Yamagata T, Matsuura H, Chayama K. Tetrahydrobiopterin restores endothelial function of coronary arteries in patients with hypercholesterolaemia. Heart 2002;87:2649.
  • 179
    Laursen JB, Somers M, Kurz S, McCann L, Warnholtz A, Freeman BA et al . Endothelial regulation of vasomotion in apoE-deficient mice: implications for interactions between peroxynitrite and tetrahydrobiopterin. Circulation 2001;103:12828.
  • 180
    Pannirselvam M, Simon V, Verma S, Anderson T, Triggle CR. Chronic oral supplementation with sepiapterin prevents endothelial dysfunction and oxidative stress in small mesenteric arteries from diabetic (db/db) mice. Br J Pharmacol 2003;140:7016.
  • 181
    Tiefenbacher CP, Bleeke T, Vahl C, Amann K, Vogt A, Kubler W. Endothelial dysfunction of coronary resistance arteries is improved by tetrahydrobiopterin in atherosclerosis. Circulation 2000;102:21729.
  • 182
    Ueda S, Matsuoka H, Miyazaki H, Usui M, Okuda S, Imaizumi T. Tetrahydrobiopterin restores endothelial function in long-term smokers. J Am Coll Cardiol 2000;35:715.
  • 183
    Verma S, Lovren F, Dumont AS, Mather KJ, Maitland A, Kieser TM et al . Tetrahydrobiopterin improves endothelial function in human saphenous veins. J Thorac Cardiovasc Surg 2000;120:66871.
  • 184
    Heller R, Unbehaun A, Schellenberg B, Mayer B, Werner-Felmayer G, Werner ER. L-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J Biol Chem 2001;276:407.
  • 185
    Bingham S, Luben R, Welch A, Low YL, Khaw KT, Wareham N et al . Associations between dietary methods and biomarkers, and between fruits and vegetables and risk of ischaemic heart disease, in the EPIC Norfolk Cohort Study. Int J Epidemiol 2009 [Epub ahead of Print].
  • 186
    Khaw KT, Bingham S, Welch A, Luben R, Wareham N, Oakes S et al . Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study. European Prospective Investigation into Cancer and Nutrition. Lancet 2001;357:65763.
  • 187
    Schectman G, Byrd JC, Gruchow HW. The influence of smoking on vitamin C status in adults. Am J Public Health 1989;79:15862.
  • 188
    Blanchard J, Tozer TN, Rowland M. Pharmacokinetic perspectives on megadoses of ascorbic acid. Am J Clin Nutr 1997;66:116571.
  • 189
    Nakata Y, Maeda N. Vulnerable atherosclerotic plaque morphology in apolipoprotein E-deficient mice unable to make ascorbic Acid. Circulation 2002;105:148590.