ADMA and the brain: an unfolding story.

I n 1971, Nakajama et al. isolated abundant amounts of asymmetric dimethylarginine (ADMA) in bovine brain.1 Over 20 years later ADMA was found to be the most potent endogenous inhibitor of nitric oxide synthase (NOS), counteracting the antiatherosclerotic effects of nitric oxide (NO). NO is responsible for acute changes of cerebral blood flow as well as for preventing chronic alterations of the (cerebral) blood vessel by inhibiting fibrosis and the proliferation of smooth muscle cells in the arterial wall. It also facilitates vascular repair by endothelial progenitor cells. The combination of acute and chronic paucity of bioavailable NO causes ischemia in deep white matter and is the main factor responsible for microangiopathy-related cerebral damage (MARCD). In this issue of the American Journal of Hypertension, Notsu et al.2 present an interesting cross-sectional clinical study in which they evaluated the impressive number of 712 asymptomatic Japanese subjects by magnetic resonance imaging as part of a health examination study. Based on this technique they identified 146 patients with MARCD and compared the concentration of the old cardiovascular risk factor homocysteine and the new cardiovascular risk factor ADMA to that of subjects without MARCD. Patients with MARCD were older, had a higher blood pressure, a lower glomerular filtration rate (GFR), and higher ADMA levels than subjects without MARCD. They also exhibited a lower l-arginine/ADMA ratio, a marker of NO production capacity. On multivariate analysis the l-arginine/ ADMA ratio and the triglyceride levels were the only independent risk factors for MARCD. Elevated triglyceride levels could represent a sign of increased insulin resistance that was not measured in the study by Notsu et al.2 but which has previously been shown to be associated with high ADMA levels.3 An interesting additional finding was the fact that estimated GFR showed significant better inverse correlations with symmetric dimethylarginine (SDMA) than with homocysteine, indicating that SDMA is the better “expensive creatinine” than homocysteine, underlining once more the importance of carefully assessing renal function as an important, if not THE confounder influencing homocysteine. Previous studies have shown that ADMA is almost an order of magnitude more potent in inhibiting neuronal NOS than endothelial NOS in vitro.4 In healthy volunteers, acute infusion of ADMA decreases cerebral blood flow.5 Although the nature of this cross-sectional study prohibits any firm conclusions on cause and effect, the results are compatible with the notion that ADMA is involved in the pathophysiology of cerebrovascular disease. This has potential implications above and beyond stroke and macrovascular events, namely it might be important for the pathophysiology of cognitive impairment. Long-term administration of the synthetic NOS inhibitor N-nitro-l arginine methyl ester in rats resulted in spatial memory impairment, an effect that could be overcome by administration of the NOS substrate l-arginine, suggesting that NO may play a critical role in spatial memory function.6 Moreover ADMA is elevated in the plasma of patients with Alzheimer’s disease.7 Epidemiological studies also support this potential among ADMA, cerebrovascular disease, and cognitive impairment as both MARCD and chronic renal failure are associated with elevated ADMA levels as well as cognitive impairment. Accumulating evidence supports the notion that ADMA is not only a marker but possibly a mediator of cerebral perfusion, cerebral events, and cognitive impairment. Although it is not yet time to accept ADMA as causative agent in cerebral pathophysiology the article by Notsu et al. advances the proposition.