Cardiovascular effects of asymmetric dimethylarginine.

Asymmetric Dimethylarginine To the Editor: Kielstein et al1 describe the effects of the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine (ADMA), in humans in vivo but do not make reference to two previous human studies.2,3 In the original paper describing the presence of ADMA in human plasma and its accumulation in chronic renal failure, Vallance et al2 also described the effects of ADMA in isolated blood vessels, on blood pressure in the guinea pig, and on forearm blood flow in healthy human subjects. They described an 8.3% fall in forearm blood flow after an 8 mol/min ADMA infusion.2 It was this finding that led the authors to first suggest in 1992 that changes in ADMA could account for cardiovascular abnormalities in humans. We have recently published a randomized, double-blind, placebo-controlled study in healthy volunteers, looking at the cardiovascular effects of ADMA in humans in vivo.3 We showed that an intravenous injection of ADMA (3 mg/kg up to a maximum of 250 mg) significantly reduced heart rate and cardiac output (by 9.2% and 14.8%, respectively) and increased blood pressure and systemic vascular resistance (by 6.0% and 23.7%, respectively). Subjects receiving ADMA also showed an impaired cardiac output response to upper limb exercise. Thirdly, our data suggested that ADMA may be extensively metabolized by dimethylarginine dimethylaminohydrolase (DDAH) in humans in vivo. The experiments by Kielstein et al1 now confirm our own published findings and support the conclusions described therein, namely, (1) that increased plasma ADMA concentrations measured in cardiovascular diseases can be associated with prolonged and major cardiovascular effects in humans and (2) that the metabolism of ADMA by DDAH may be an important regulatory mechanism in the human cardiovascular system.