ADMA increases arterial stiffness and decreases cerebral blood flow in humans.
OBJECTIVE
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.
Kielstein
Jan T
JT
Department of Nephrology, Medical School, Hannover, Germany. adma@stanford.edu
Donnerstag
Frank
F
Gasper
Sandra
S
Menne
Jan
J
Kielstein
Anousheh
A
Martens-Lobenhoffer
Jens
J
Scalera
Fortunato
F
Cooke
John P
JP
Fliser
Danilo
D
Bode-Böger
Stefanie M
SM
D000328:Adult; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D002536:Cerebral Arteries / Q000187:drug effects* / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D003187:Compliance; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007275:Injections, Intravenous; D008279:Magnetic Resonance Imaging; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D012016:Reference Values; D014666:Vasomotor System / Q000187:drug effects*
D004791:Enzyme Inhibitors; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase