Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1455-1459
Published online before print June 12, 2003, doi: 10.1161/01.ATV.0000081742.92006.59
Published online before print June 12, 2003, doi: 10.1161/01.ATV.0000081742.92006.59
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© 2003 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Asymmetric Dimethylarginine Causes Hypertension and Cardiac Dysfunction in Humans and Is Actively Metabolized by Dimethylarginine Dimethylaminohydrolase
From the Centre for Clinical Pharmacology and Therapeutics, British Heart Foundation Laboratories, University College London, and Department of Biochemistry and Immunology (G.W.), St George’s Hospital Medical School, London, UK.
Correspondence to Patrick Vallance, MD, FRCP, FMedSci, Centre for Clinical Pharmacology and Therapeutics, British Heart Foundation Laboratories, University College London, 5 University St, London WC1 6JJ, UK. E-mail patrick.vallance{at}ucl.ac.uk
Objective— Plasma levels of an endogenous nitric oxide (NO) synthase inhibitor, asymmetric dimethylarginine (ADMA), are elevated in chronic renal failure, hypertension, and chronic heart failure. In patients with renal failure, plasma ADMA levels are an independent correlate of left ventricular ejection fraction. However, the cardiovascular effects of a systemic increase in ADMA in humans are not known.
Methods and Results— In a randomized, double-blind, placebo-controlled study in 12 healthy male volunteers, we compared the effects of intravenous low-dose ADMA and placebo on heart rate, blood pressure, cardiac output, and systemic vascular resistance at rest and during exercise. We also tested the hypothesis that ADMA is metabolized in humans in vivo by dimethylarginine dimethylaminohydrolase (DDAH) enzymes. Low-dose ADMA reduced heart rate by 9.2±1.4% from 58.9±2.0 bpm (P<0.001) and cardiac output by 14.8±1.2% from 4.4±0.3 L/min (P<0.001). ADMA also increased mean blood pressure by 6.0±1.2% from 88.6±3.4 mm Hg (P<0.005) and SVR by 23.7±2.1% from 1639.0±91.6 dyne · s · cm-5 (P<0.001). Handgrip exercise increased cardiac output in control subjects by 96.8±23.3%, but in subjects given ADMA, cardiac output increased by only 35.3±10.6% (P<0.05). DDAHs metabolize ADMA to citrulline and dimethylamine. Urinary dimethylamine to creatinine ratios significantly increased from 1.26±0.32 to 2.73±0.59 after ADMA injection (P<0.01). We estimate that humans generate approximately 300 µmol of ADMA per day, of which approximately 250 µmol is metabolized by DDAHs.
Conclusions— This study defines the cardiovascular effects of a systemic increase in ADMA in humans. These are similar to changes seen in diseases associated with ADMA accumulation. Finally, our data also indicate that ADMA is metabolized by DDAHs extensively in humans in vivo.
Key Words: asymmetric methylarginine • dimethylarginine dimethylaminohydrolase • nitric oxide • hypertension • cardiac output
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