Asymmetric Dimethylarginine Causes Hypertension and Cardiac Dysfunction in Humans and Is Actively Metabolized by Dimethylarginine Dimethylaminohydrolase

Abstract

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 9.2Ϯ1.4% from 58.9Ϯ2.0 bpm (PϽ0.001) and cardiac output by 14.8Ϯ1.2% from 4.4Ϯ0.3 L/min (PϽ0.001).ADMA also increased mean blood pressure by 6.0Ϯ1.2% from 88.6Ϯ3.4 mm Hg (PϽ0.005) and SVR by 23.7Ϯ2.1% from 1639.0Ϯ91.6 dyne · s · cm Ϫ5 (PϽ0.001). Handgrip exercise increased cardiac output in control subjects by 96.8Ϯ23.3%, but in subjects given ADMA, cardiac output increased by only 35.3Ϯ10.6% (PϽ0.05). DDAHs metabolize ADMA to citrulline and dimethylamine. Urinary dimethylamine to creatinine ratios significantly increased from 1.26Ϯ0.32 to 2.73Ϯ0.59 after ADMA injection (PϽ0.01). We estimate that humans generate approximately 300 mol of ADMA per day, of which approximately 250 mol 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 Ⅲ dimethylarginine dimethylaminohydrolase Ⅲ nitric oxide Ⅲ hypertension Ⅲ cardiac output N itric oxide (NO) plays an important role in the regulation of cardiovascular function, and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthesis, has been implicated in the impairment of NO generation in a variety of cardiovascular diseases. 1 The finding that plasma ADMA levels are elevated in chronic renal failure led to speculation that ADMA may in part be responsible for increased cardiovascular risk and hypertension in these patients. 2 Subsequent studies have shown strong associations between raised ADMA levels and cardiovascular risk factors, endothelial dysfunction, hypertension, atherosclerosis, and cardiovascular mortality. 3-7 ADMA levels are also significantly raised in patients with chronic heart failure, 8 rats with heart failure induced by coronary artery ligation, 9 and dogs with heart failure induced by rapid pacing. 10 A recent analysis of a large group of patients with end-stage renal failure demonstrated an inverse relationship between ADMA levels and left ventricular (LV) ejection fraction; in a multivariate analysis that included L...

Developmental changes in the L-arginine/nitric oxide pathway from infancy to adulthood: plasma asymmetric dimethylarginine levels decrease with age

“…Both ADMA and DMA are excreted in urine. Rough estimates indicate that approximately 80% of daily produced ADMA is eliminated by the kidney as DMA (13).…”

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

“…Upon proteolysis, methylarginines are released into the circulation. Although ϳ15% of ADMA are excreted via the urine, the major elimination occurs through enzymatic degradation (ϳ85%) (1). The enzyme dimethylarginine dimethylaminohydrolase (DDAH), of which two isoforms with distinct tissue distribution have been described, catalyzes the hydrolysis of ADMA to L-citrulline and dimethylamine (38).…”

C-Reactive Protein and Asymmetric Dimethylarginine: Markers or Mediators in Cardiovascular Disorders?

“…Chronic renal failure associated with hypertension [1,3,14,15] Stroke [16,17] Pulmonary hypertension [18][19][20] Left ventricular hypertrophy [21,22] Type II diabetes [23][24][25] Pre-eclampsia [26,27] Heart failure [28] Ischaemia [29,30] Hypercholesterolemia [31,32] Atherosclerosis [33,34] Alzheimers* [35,36] …”

“…2; [106][107]. DDAH metabolises 250 mol/L of the 300 mol/L generated daily, based upon urinary excretion of dimethylamine [108]. Two isoforms of DDAH have been identified [109]: human DDAHI was mapped to chromosome 1p22 and is more prevalent in the nervous system [110].…”