(Circulation. 1997;95:2068-2074.)
© 1997 American Heart Association, Inc.
Articles |
Biochemical Evidence for Impaired Nitric Oxide Synthesis in Patients With Peripheral Arterial Occlusive Disease
From the Institute of Clinical Pharmacology and Department of Angiology (K.A.), Medical School, Hannover, Germany.
Background We studied urinary nitrate and cGMP excretion rates, indices of systemic NO formation, and plasma concentrations of L-arginine and the endogenous NO synthase inhibitor asymmetrical dimethylarginine (ADMA) and its inactive stereoisomer, symmetrical dimethylarginine, in 77 patients with peripheral arterial occlusive disease (PAOD) in Fontaine stages IIb through IV and in 47 young and 37 elderly healthy control subjects.
Methods and Results Urinary nitrate excretion was 182.0±11.4 µmol/mmol creatinine and cGMP excretion was 186.2±13.0 nmol/mmol creatinine in young healthy control subjects. In elderly control subjects, both excretion rates were slightly lower (nitrate, 156.0±7.8 µmol/mmol creatinine; cGMP, 150.0±8.3 nmol/mmol creatinine; P=NS). In PAOD patients, there was a significant, progressive reduction of urinary nitrate (IIb, 138.4±11.9; III, 128.6±11.3; and IV, 91.9±8.0 µmol/mmol creatinine; P<.05) and cGMP (IIb, 139.9±25.2; III, 115.6±13.1; and IV, 76.9±7.9 nmol/mmol creatinine; P<.05) excretion rates related to the Fontaine stage of PAOD. These changes were independent of changes in renal excretory function. Plasma L-arginine concentrations were not significantly different between the groups, but ADMA concentrations were elevated in PAOD patients (young control subjects, 1.25±0.11; elderly control subjects, 1.01±0.05 µmol/L; IIb, 2.62±0.24; III, 3.06±0.48; and IV, 3.49±0.26 µmol/L; P<.05 for PAOD versus control subjects). There was a significant linear correlation between urinary nitrate and cGMP excretion rates and a significant negative linear correlation between plasma ADMA concentrations and urinary nitrate excretion.
Conclusions In PAOD patients, there is a progressive reduction in urinary nitrate and cGMP excretion rates, which may be caused in part by accumulation of ADMA, an endogenous inhibitor of NO synthase.
Key Words: hypercholesterolemia • atherosclerosis • endothelium-derived factors • risk factors
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A. Fard, C. H. Tuck, J. A. Donis, R. Sciacca, M. R. Di Tullio, H. D. Wu, T. A. Bryant, N.-T. Chen, M. Torres-Tamayo, R. Ramasamy, et al. Acute Elevations of Plasma Asymmetric Dimethylarginine and Impaired Endothelial Function in Response to a High-Fat Meal in Patients With Type 2 Diabetes Arterioscler Thromb Vasc Biol, September 1, 2000; 20(9): 2039 - 2044. [Abstract] [Full Text] [PDF]
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R. H. Boger, K. Sydow, J. Borlak, T. Thum, H. Lenzen, B. Schubert, D. Tsikas, and S. M. Bode-Boger LDL Cholesterol Upregulates Synthesis of Asymmetrical Dimethylarginine in Human Endothelial Cells : Involvement of S-Adenosylmethionine-Dependent Methyltransferases Circ. Res., July 21, 2000; 87(2): 99 - 105. [Abstract] [Full Text] [PDF]
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R. H. Boger, S. M. Bode-Boger, K. Sydow, D. D. Heistad, and S. R. Lentz Plasma Concentration of Asymmetric Dimethylarginine, an Endogenous Inhibitor of Nitric Oxide Synthase, Is Elevated in Monkeys With Hyperhomocyst(e)inemia or Hypercholesterolemia Arterioscler Thromb Vasc Biol, June 1, 2000; 20(6): 1557 - 1564. [Abstract] [Full Text] [PDF]
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R. H. Boger, S. M. Bode-Boger, H. Matsuoka, H. Miyazaki, M. Usui, S. Ueda, S. Okuda, T. Imaizumi, and J. P. Cooke Is Asymmetric Dimethylarginine a Novel Marker of Atherosclerosis? • Response Circulation, April 11, 2000; 101 (14): e160 - e161. [Full Text] [PDF]
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J. R. Chan, R. H. Boger, S. M. Bode-Boger, O. Tangphao, P. S. Tsao, T. F. Blaschke, and J. P. Cooke Asymmetric Dimethylarginine Increases Mononuclear Cell Adhesiveness in Hypercholesterolemic Humans Arterioscler Thromb Vasc Biol, April 1, 2000; 20(4): 1040 - 1046. [Abstract] [Full Text] [PDF]
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L. Vergnani, S. Hatrik, F. Ricci, A. Passaro, N. Manzoli, G. Zuliani, V. Brovkovych, R. Fellin, and T. Malinski Effect of Native and Oxidized Low-Density Lipoprotein on Endothelial Nitric Oxide and Superoxide Production : Key Role of L-Arginine Availability Circulation, March 21, 2000; 101(11): 1261 - 1266. [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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K. J. Osterziel, S. M Bode-Boger, O. Strohm, A. E Ellmer, N. Bit-Avragim, D. Hanlein, M. B Ranke, R. Dietz, and R. H Boger Role of nitric oxide in the vasodilator effect of recombinant human growth hormone in patients with dilated cardiomyopathy Cardiovasc Res, January 14, 2000; 45(2): 447 - 453. [Abstract] [Full Text] [PDF]
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 W. C. Hooper, C. Lally, H. Austin, J. Benson, A. Dilley, N. K. Wenger, C. Whitsett, P. Rawlins, and B. L. Evatt The Relationship Between Polymorphisms in the Endothelial Cell Nitric Oxide Synthase Gene and the Platelet GPIIIa Gene With Myocardial Infarction and Venous Thromboembolism in African Americans Chest, October 1, 1999; 116(4): 880 - 886. [Abstract] [Full Text] [PDF]
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A. Ito, P. S. Tsao, S. Adimoolam, M. Kimoto, T. Ogawa, and J. P. Cooke Novel Mechanism for Endothelial Dysfunction : Dysregulation of Dimethylarginine Dimethylaminohydrolase Circulation, June 22, 1999; 99(24): 3092 - 3095. [Abstract] [Full Text] [PDF]
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T. Murohara, B. Witzenbichler, I. Spyridopoulos, T. Asahara, B. Ding, A. Sullivan, D. W. Losordo, and J. M. Isner Role of Endothelial Nitric Oxide Synthase in Endothelial Cell Migration Arterioscler Thromb Vasc Biol, May 1, 1999; 19(5): 1156 - 1161. [Abstract] [Full Text] [PDF]
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H. Miyazaki, H. Matsuoka, J. P. Cooke, M. Usui, S. Ueda, S. Okuda, and T. Imaizumi Endogenous Nitric Oxide Synthase Inhibitor : A Novel Marker of Atherosclerosis Circulation, March 9, 1999; 99(9): 1141 - 1146. [Abstract] [Full Text] [PDF]
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J. T. KIELSTEIN, R. H. BÖGER, S. M. BODE-BÖGER, J. SCHÄFFER, M. BARBEY, K. M. KOCH, and J. C. FRÖLICH Asymmetric Dimethylarginine Plasma Concentrations Differ in Patients with End-Stage Renal Disease: Relationship to Treatment Method andAtherosclerotic Disease J. Am. Soc. Nephrol., March 1, 1999; 10(3): 594 - 600. [Abstract] [Full Text]
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R. H. Boger, S. M. Bode-Boger, A. Szuba, P. S. Tsao, J. R. Chan, O. Tangphao, T. F. Blaschke, and J. P. Cooke Asymmetric Dimethylarginine (ADMA): A Novel Risk Factor for Endothelial Dysfunction : Its Role in Hypercholesterolemia Circulation, November 3, 1998; 98(18): 1842 - 1847. [Abstract] [Full Text] [PDF]
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R. H. Boger, S. M. Bode-Boger, W. Thiele, A. Creutzig, K. Alexander, and J.u. C. Frolich Restoring vascular nitric oxide formation by L-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease J. Am. Coll. Cardiol., November 1, 1998; 32(5): 1336 - 1344. [Abstract] [Full Text] [PDF]
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J. Mair, B. Puschendorf, R. H. Boger, and S. M. Bode-Boger Is Measurement of Cyclic Guanosine Monophosphate in Plasma or Urine Suitable for Assessing In Vivo Nitric Oxide Production? • Response Circulation, March 31, 1998; 97(12): 1209 - 1210. [Full Text] [PDF]
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