Biochemical Evidence for Impaired Nitric Oxide Synthesis in Patients With Peripheral Arterial Occlusive Disease

• Published in: Circulation (New York, N.Y.) Vol. 95; no. 8; pp. 2068 - 2074
• Main Authors: Böger, Rainer H., Bode-Böger, Stefanie M., Thiele, Wolfgang, Junker, Wolfgang, Alexander, Klaus, Frölich, Jürgen C.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 15.04.1997; American Heart Association, Inc
• Subjects: Adult; Aged; Aged, 80 and over; Aging - metabolism; Arginine - analogs & derivatives; Arginine - blood; Arginine - pharmacology; Arterial Occlusive Diseases - metabolism; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cyclic GMP - urine; Disease Progression; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Enzyme Inhibitors - pharmacology; Female; Humans; Male; Medical sciences; Middle Aged; Nitrates - urine; Nitric Oxide - biosynthesis; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Peripheral Vascular Diseases - metabolism; Vasodilation - physiology; Human; Urine; Enzyme; Enzyme inhibitor; Cardiovascular disease; 3',5'-GMP; Nitrates; Cholesterol; Nitric-oxide synthase; Blood plasma; Arterial disease; Vascular disease; Arginine; Nitric oxide; Risk factor; Occlusive arterial disease; Oxidoreductases
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.95.8.2068

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.