Published Online
on June 29, 2006

A more recent version of this article appeared on August 1, 2006

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Submitted on January 11, 2006
Revised on April 18, 2006
Accepted on April 28, 2006

ADMA Increases Arterial Stiffness and Decreases Cerebral Blood Flow in Humans

Jan T. Kielstein MD^*; Frank Donnerstag MD; Sandra Gasper MD; Jan Menne MD; Anousheh Kielstein MD; Jens Martens-Lobenhoffer PhD; Fortunato Scalera PhD; John P. Cooke MD, PhD; Danilo Fliser MD; and Stefanie M. Bode-Böger MD, MPH

From the Departments of Nephrology (J.T.K., S.G., J.M., D.F.), Neuroradiology (F.D.), and Psychiatry (A.K.), Medical School, Hannover, and the Institute for Clinical Pharmacology (J.M.-L., F.S., S.M.B.-B.), Otto von Guericke Universität, Magdeburg, Germany, and the Division of Cardiovascular Medicine (J.T.K., J.P.C.), Stanford University School of Medicine, Stanford, Calif.

^* To whom correspondence should be addressed. E-mail: adma{at}stanford.edu.

Background and Purpose--Preclinical studies have revealed that the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine (ADMA), increases vascular tone in cerebral blood vessels. Marked elevations of ADMA blood levels were found in patients with diseases characterized by decreased cerebral perfusion, such as ischemic stroke. Arterial stiffness is an independent predictor of stroke and other adverse cardiovascular events. The aim of this study was to investigate the influence of a systemic subpressor dose of ADMA on arterial stiffness and cerebral perfusion in humans.

Methods--Using a double-blind, vehicle-controlled study design, we allocated 20 healthy men in random order to infusion of either ADMA (0.10 mg ADMA/kg per min) or vehicle over a period of 40 minutes. Arterial stiffness was assessed noninvasively by pulse wave analysis. All volunteers underwent measurement of cerebral perfusion by dynamic contrast-enhanced perfusion magnetic resonance imaging of the brain.

Results--Infusion of ADMA significantly decreased total cerebral perfusion by 15.1±4.5% (P=0.007), whereas blood flow in the vehicle group increased by 7.7±2.8% (P=0.02). ADMA also increased arterial stiffness as assessed by measurement of the augmentation index (-12.6±1.9 to -9.6±1.5, P=0.007).

Conclusions--Our results document for the first time that subpressor doses of ADMA increase vascular stiffness and decrease cerebral perfusion in healthy subjects. Thus, ADMA is an important endogenous modulator of cerebral vascular tone and may be involved in the pathogenesis of cerebrovascular disease.

Key words: cerebral blood flow • hemodynamics • nitric oxide • stroke, ischemic • vascular resistance

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