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Effects of asymmetric dimethylarginine (ADMA) infusion in humans

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Abstract

Increased blood concentrations of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) can be found in patients with cardiovascular risk factors such as age, hypertension, diabetes, insulin resistance, hypercholesterolemia, hypertriglyceridemia, chronic kidney disease, and hyperhomocystinemia. ADMA has been shown to be a strong and independent predictor of cardiovascular and overall mortality in selected patient populations. Furthermore, in patients with chronic kidney disease, it is a strong and independent risk marker for decrease of renal function, progression to end-stage renal disease, and mortality. Infusion of exogenous ADMA in humans helped to elucidate its role in the pathogenesis of endothelial dysfunction. Pathophysiologically relevant concentrations of ADMA have been shown to decrease heart rate and cardiac output and to increase systemic vascular resistance and pulmonary vascular resistance. ADMA decreases effective renal plasma flow and increases renovascular resistance in a dose-related manner. Moreover, administration of ADMA causes significant sodium retention and blood pressure increase. These studies also revealed that ADMA is less potent than the synthetic NOS inhibitor N G-nitro-L-arginine methyl ester (L-NAME) and behaves differently in respect to onset of action, which can be explained by the different routes of elimination as well as different cellular transport mechanisms. Collectively these results document that ADMA has well-defined effects on cardiovascular and renal function in healthy subjects. It is therefore conceivable that ADMA causes sustained changes in vascular function through an intracellular action in endothelial cells at blood concentrations found in patients with cardiovascular pathology.

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Acknowledgements

This work was supported by a grant (Ki 8591/–1) of the DFG (Deutsche Forschungsgemeinschaft)

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Authors and Affiliations

  1. Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305-5406, USA

    Jan T. Kielstein

  2. Department of Internal Medicine, Division of Nephrology, Medical School Hannover, Hannover, Germany

    Jan T. Kielstein & Danilo Fliser

  3. Institute of Clinical Pharmacology, Medical School Hannover, Hannover, Germany

    Dimitrios Tsikas

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  1. Jan T. Kielstein
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  2. Dimitrios Tsikas
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Correspondence to Jan T. Kielstein.

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Kielstein, J.T., Tsikas, D. & Fliser, D. Effects of asymmetric dimethylarginine (ADMA) infusion in humans. Eur J Clin Pharmacol 62 (Suppl 1), 39–44 (2006). https://doi.org/10.1007/s00228-005-0010-1

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