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From I Clinica Medica, University of Pisa, Italy.
Correspondence to Stefano Taddei, MD, I Clinica Medica, University of Pisa, Via Roma, 67, 56100 Pisa, Italy.
Background—Essential hypertension is
associated with impaired endothelium-dependent
vasodilation. Inactivation of endothelium-derived
nitric oxide by oxygen free radicals participates in
endothelial dysfunction in experimental hypertension.
To test this hypothesis in humans, we evaluated the effect of
antioxidant vitamin C on endothelium-dependent
responses in essential hypertensive patients.
Methods and Results—In 14 healthy subjects (47.1±4.8 years;
blood pressure, 120.6±4.5/80.9±3.5 mm Hg) and 14 essential
hypertensive patients (47.3±5.1 years; blood pressure,
153.9±7.1/102.3±4.1 mm Hg), we studied forearm blood flow
(strain-gauge plethysmography) modifications induced by intrabrachial
acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 µg · 100
mL-1 · min-1) or sodium nitroprusside
(1, 2, and 4 µg/100 mL forearm tissue per minute), an
endothelium-dependent and -independent vasodilator,
respectively, in basal conditions and during infusion of intrabrachial
vitamin C (2.4 mg/100 mL forearm tissue per minute). In hypertensive
patients but not in control subjects, vitamin C increased
(P<0.01) the impaired vasodilation to acetylcholine,
whereas the response to sodium nitroprusside was unaffected. Moreover,
in another 14 hypertensive patients (47.1±5.2 years; blood pressure,
155.2±6.9/103.7±4.5 mm Hg), the facilitating effect of vitamin
C on vasodilation to acetylcholine was reversed by
NG-monomethyl-L-arginine
(100 µg/100 mL forearm tissue per minute), a nitric oxide synthase
inhibitor, suggesting that in essential hypertension
superoxide anions impair endothelium-dependent
vasodilation by nitric oxide breakdown. Finally, because in adjunctive
7 hypertensive patients (47.8±6.1 years; blood pressure,
155.3±6.8/103.5±4.3 mm Hg), indomethacin (50
µg/100 mL forearm tissue per minute), a
cyclooxygenase inhibitor, prevented the
potentiating effect of vitamin C on vasodilation to acetylcholine, it
is possible that in essential hypertension a main source of superoxide
anions could be the cyclooxygenase pathway.
Conclusions—In essential hypertensive patients, impaired
endothelial vasodilation can be improved by the
antioxidant vitamin C, an effect that can be reversed by the nitric
oxide synthase inhibitor
NG-monomethyl-L-arginine.
These findings support the hypothesis that nitric oxide inactivation by
oxygen free radicals contributes to endothelial
dysfunction in essential hypertension.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Vitamin C Improves Endothelium-Dependent Vasodilation by Restoring Nitric Oxide Activity in Essential Hypertension
Key Words: hypertension • endothelium • nitric oxide • endothelium-derived factors • free radicals • antioxidants
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M. Imamura, S. Biro, T. Kihara, S. Yoshifuku, K. Takasaki, Y. Otsuji, S. Minagoe, Y. Toyama, and C. Tei Repeated thermal therapy improves impaired vascular endothelial function in patients with coronary risk factors J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1083 - 1088. [Abstract] [Full Text] [PDF]
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A. Virdis, L. Ghiadoni, H. Cardinal, S. Favilla, P. Duranti, R. Birindelli, A. Magagna, G. Bernini, G. Salvetti, S. Taddei, et al. Mechanisms responsible for endothelial dysfunction induced by fasting hyperhomocystinemia in normotensive subjects and patients with essential hypertension J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1106 - 1115. [Abstract] [Full Text] [PDF]
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 D C Chambers and J G Ayres Effects of nitrogen dioxide exposure and ascorbic acid supplementation on exhaled nitric oxide in healthy human subjects Thorax, October 1, 2001; 56(10): 774 - 778. [Abstract] [Full Text] [PDF]
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J. P. Bell, S. I. Mosfer, D. Lang, F. Donaldson, and M. J. Lewis Vitamin C and quinapril abrogate LVH and endothelial dysfunction in aortic-banded guinea pigs Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1704 - H1710. [Abstract] [Full Text] [PDF]
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X. Chen, R. M. Touyz, J. B. Park, and E. L. Schiffrin Antioxidant Effects of Vitamins C and E Are Associated With Altered Activation of Vascular NADPH Oxidase and Superoxide Dismutase in Stroke-Prone SHR Hypertension, September 1, 2001; 38(3): 606 - 611. [Abstract] [Full Text] [PDF]
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S. Taddei, A. Virdis, L. Ghiadoni, G. Salvetti, G. Bernini, A. Magagna, and A. Salvetti Age-Related Reduction of NO Availability and Oxidative Stress in Humans Hypertension, August 1, 2001; 38(2): 274 - 279. [Abstract] [Full Text] [PDF]
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F. Perticone, R. Ceravolo, A. Pujia, G. Ventura, S. Iacopino, A. Scozzafava, A. Ferraro, M. Chello, P. Mastroroberto, P. Verdecchia, et al. Prognostic Significance of Endothelial Dysfunction in Hypertensive Patients Circulation, July 10, 2001; 104(2): 191 - 196. [Abstract] [Full Text] [PDF]
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K. K. A. Witte, A. L. Clark, and J. G. F. Cleland Chronic heart failure and micronutrients J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1765 - 1774. [Abstract] [Full Text] [PDF]
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 J. A. Simon, E. S. Hudes, and J. A. Tice Relation of Serum Ascorbic Acid to Mortality Among US Adults J. Am. Coll. Nutr., June 1, 2001; 20(3): 255 - 263. [Abstract] [Full Text] [PDF]
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D. Rizzoni, E. Porteri, D. Guelfi, M. L. Muiesan, U. Valentini, A. Cimino, A. Girelli, L. Rodella, R. Bianchi, I. Sleiman, et al. Structural Alterations in Subcutaneous Small Arteries of Normotensive and Hypertensive Patients With Non-Insulin-Dependent Diabetes Mellitus Circulation, March 6, 2001; 103(9): 1238 - 1244. [Abstract] [Full Text] [PDF]
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Y. Higashi, S. Sasaki, K. Nakagawa, H. Matsuura, G. Kajiyama, and T. Oshima Effect of the angiotensin-converting enzyme inhibitor imidapril on reactive hyperemia in patients with essential hypertension: relationship between treatment periods and resistance artery endothelial function J. Am. Coll. Cardiol., March 1, 2001; 37(3): 863 - 870. [Abstract] [Full Text] [PDF]
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S. Taddei, A. Virdis, L. Ghiadoni, A. Magagna, S. Favilla, A. Pompella, and A. Salvetti Restoration of Nitric Oxide Availability After Calcium Antagonist Treatment in Essential Hypertension Hypertension, March 1, 2001; 37(3): 943 - 948. [Abstract] [Full Text] [PDF]
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M. Grossmann, D. Dobrev, H. M. Himmel, U. Ravens, and W. Kirch Ascorbic Acid-Induced Modulation of Venous Tone in Humans Hypertension, March 1, 2001; 37(3): 949 - 954. [Abstract] [Full Text] [PDF]
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S. J. Duffy, N. Gokce, M. Holbrook, L. M. Hunter, E. S. Biegelsen, A. Huang, J. F. Keaney Jr., and J. A. Vita Effect of ascorbic acid treatment on conduit vessel endothelial dysfunction in patients with hypertension Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H528 - H534. [Abstract] [Full Text] [PDF]
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G. P. Rossi, S. Taddei, A. Virdis, L. Ghiadoni, G. Albertin, S. Favilla, I. Sudano, A. C. Pessina, and A. Salvetti Exclusion of the ACE D/I Gene Polymorphism as a Determinant of Endothelial Dysfunction Hypertension, February 1, 2001; 37(2): 293 - 300. [Abstract] [Full Text] [PDF]
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 F. Perticone, R. Ceravolo, M. Candigliota, G. Ventura, S. Iacopino, F. Sinopoli, and P. L. Mattioli Obesity and Body Fat Distribution Induce Endothelial Dysfunction by Oxidative Stress: Protective Effect of Vitamin C Diabetes, January 1, 2001; 50(1): 159 - 165. [Abstract] [Full Text]
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O. A. Paniagua, M. B. Bryant, and J. A. Panza Transient Hypertension Directly Impairs Endothelium-Dependent Vasodilation of the Human Microvasculature Hypertension, December 1, 2000; 36(6): 941 - 944. [Abstract] [Full Text] [PDF]
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L. Ghiadoni, A. E. Donald, M. Cropley, M. J. Mullen, G. Oakley, M. Taylor, G. O'Connor, J. Betteridge, N. Klein, A. Steptoe, et al. Mental Stress Induces Transient Endothelial Dysfunction in Humans Circulation, November 14, 2000; 102(20): 2473 - 2478. [Abstract] [Full Text] [PDF]
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A. Natali, A. M. Sironi, E. Toschi, S. Camastra, G. Sanna, A. Perissinotto, S. Taddei, and E. Ferrannini Effect of Vitamin C on Forearm Blood Flow and Glucose Metabolism in Essential Hypertension Arterioscler. Thromb. Vasc. Biol., November 1, 2000; 20(11): 2401 - 2406. [Abstract] [Full Text] [PDF]
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J. W. E. Rush, M. H. Laughlin, C. R. Woodman, and E. M. Price SOD-1 expression in pig coronary arterioles is increased by exercise training Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2068 - H2076. [Abstract] [Full Text] [PDF]
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T. Rankinen, T. Rice, L. Perusse, Y. C. Chagnon, J. Gagnon, A. S. Leon, J. S. Skinner, J. H. Wilmore, D. C. Rao, and C. Bouchard NOS3 Glu298Asp Genotype and Blood Pressure Response to Endurance Training : The HERITAGE Family Study Hypertension, November 1, 2000; 36(5): 885 - 889. [Abstract] [Full Text] [PDF]
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P. A. Kaufmann, T. Gnecchi-Ruscone, M. di Terlizzi, K. P. Schafers, T. F. Luscher, and P. G. Camici Coronary Heart Disease in Smokers : Vitamin C Restores Coronary Microcirculatory Function Circulation, September 12, 2000; 102(11): 1233 - 1238. [Abstract] [Full Text] [PDF]
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C. M. Oomen, M. J. van Erk, E. J. M. Feskens, F. J. Kok, and D. Kromhout Arginine Intake and Risk of Coronary Heart Disease Mortality in Elderly Men Arterioscler. Thromb. Vasc. Biol., September 1, 2000; 20(9): 2134 - 2139. [Abstract] [Full Text] [PDF]
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D. Tomasian, J. F. Keaney Jr., and J. A. Vita Antioxidants and the bioactivity of endothelium-derived nitric oxide Cardiovasc Res, August 18, 2000; 47(3): 426 - 435. [Full Text] [PDF]
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A. Schrammel, D. Koesling, K. Schmidt, and B. Mayer Inhibition of purified soluble guanylyl cyclase by L-ascorbic acid Cardiovasc Res, August 18, 2000; 47(3): 602 - 608. [Abstract] [Full Text] [PDF]
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G. Lembo, C. Vecchione, R. Izzo, L. Fratta, D. Fontana, G. Marino, G. Pilato, and B. Trimarco Noradrenergic Vascular Hyper-Responsiveness in Human Hypertension Is Dependent on Oxygen Free Radical Impairment of Nitric Oxide Activity Circulation, August 1, 2000; 102(5): 552 - 557. [Abstract] [Full Text] [PDF]
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S. Taddei, F. Galetta, A. Virdis, L. Ghiadoni, G. Salvetti, F. Franzoni, C. Giusti, and A. Salvetti Physical Activity Prevents Age-Related Impairment in Nitric Oxide Availability in Elderly Athletes Circulation, June 27, 2000; 101(25): 2896 - 2901. [Abstract] [Full Text] [PDF]
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A. Virdis, L. Ghiadoni, S. Pinto, M. Lombardo, F. Petraglia, A. Gennazzani, S. Buralli, S. Taddei, and A. Salvetti Mechanisms Responsible for Endothelial Dysfunction Associated With Acute Estrogen Deprivation in Normotensive Women Circulation, May 16, 2000; 101(19): 2258 - 2263. [Abstract] [Full Text] [PDF]
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O. T. Raitakari, M. R. Adams, R. J. McCredie, K. A. Griffiths, R. Stocker, and D. S. Celermajer Oral vitamin C and endothelial function in smokers: short-term improvement, but no sustained beneficial effect J. Am. Coll. Cardiol., May 1, 2000; 35(6): 1616 - 1621. [Abstract] [Full Text] [PDF]
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D. L. Sherman, J. F. Keaney Jr, E. S. Biegelsen, S. J. Duffy, J. D. Coffman, and J. A. Vita Pharmacological Concentrations of Ascorbic Acid Are Required for the Beneficial Effect on Endothelial Vasomotor Function in Hypertension Hypertension, April 1, 2000; 35(4): 936 - 941. [Abstract] [Full Text] [PDF]
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 T. Stefanec Endothelial Apoptosis: Could It Have a Role in the Pathogenesis and Treatment of Disease? Chest, March 1, 2000; 117(3): 841 - 854. [Abstract] [Full Text] [PDF]
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N. Fujiwara, T. Osanai, T. Kamada, T. Katoh, K. Takahashi, and K. Okumura Study on the Relationship Between Plasma Nitrite and Nitrate Level and Salt Sensitivity in Human Hypertension : Modulation of Nitric Oxide Synthesis by Salt Intake Circulation, February 29, 2000; 101(8): 856 - 861. [Abstract] [Full Text] [PDF]
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