Association of an endogenous inhibitor of nitric oxide synthase with cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage.
OBJECTIVE
Delayed cerebral vasospasm after subarachnoid hemorrhage (SAH) may be evoked by the decreased availability of nitric oxide (NO). Increased cerebrospinal fluid (CSF) levels of asymmetric dimethyl-L-arginine (ADMA), an endogenous inhibitor of NO synthase (NOS), have been associated with the course and degree of cerebral vasospasm in a primate model of SAH. In this study, the authors sought to determine if similar changes in CSF ADMA levels are observed in patients with SAH, and whether these changes are associated with NO and NOS metabolite levels in the CSF and the presence of cerebral vasospasm.


METHODS
Asymmetric dimethyl-L-arginine, L-arginine, L-citrulline, and nitrite levels were measured in CSF and serum samples collected during the 21-day period after a single aneurysmal SAH in 18 consecutive patients. Samples were also obtained in a control group consisting of seven patients with Chiari malformation Type I and five patients with spontaneous intracerebral hemorrhage without SAH. Vasospasm, defined as a greater than 11% reduction in the anterior circulation vessel diameter ratio compared with the ratio calculated from the initial arteriogram, was assessed on cerebral arteriography performed around Day 7.


RESULTS
In 13 patients with SAH, arteriographic cerebral vasospasm developed. Cerebrospinal fluid ADMA levels in patients with SAH were higher than in those in the control group (p < 0.001). The CSF ADMA level remained unchanged in the five patients with SAH without vasospasm, but was significantly increased in patients with vasospasm after Day 3 (6.2 +/- 1.7 microM) peaking during Days 7 through 9 (13.3 +/- 6.7 microM; p < 0.001) and then gradually decreasing between Days 12 and 21 (8.8 +/- 3.2 microM; p < 0.05). Nitrite levels in the CSF were lower in patients with vasospasm compared to patients without vasospasm (p < 0.03). Cerebrospinal fluid ADMA levels positively correlated with the degree of vasospasm (correlation coefficient [CC] = 0.88, p = 0.0001; 95% confidence interval [CI] 0.74-0.95) and negatively correlated with CSF nitrite levels (CC = -0.55; p = 0.017; 95% CI -0.81 to -0.12).


CONCLUSIONS
These results support the hypothesis that ADMA is involved in the progression of cerebral vasospasm. Asymmetric dimethyl-L-arginine and its metabolizing enzymes may be a future target for treatment of cerebral vasospasm after SAH.
Jung
Carla S
CS
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Oldfield
Edward H
EH
Harvey-White
Judith
J
Espey
Michael G
MG
Zimmermann
Michael
M
Seifert
Volker
V
Pluta
Ryszard M
RM
D000328:Adult; D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid; D001139:Arnold-Chiari Malformation / Q000134:cerebrospinal fluid; D002956:Citrulline / Q000134:cerebrospinal fluid; D004791:Enzyme Inhibitors / Q000134:cerebrospinal fluid*; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm / Q000150:complications*; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009573:Nitrites / Q000134:cerebrospinal fluid; D013345:Subarachnoid Hemorrhage / Q000134:cerebrospinal fluid / Q000209:etiology*; D020301:Vasospasm, Intracranial / Q000134:cerebrospinal fluid* / Q000201:enzymology
D004791:Enzyme Inhibitors; D009573:Nitrites; D002956:Citrulline; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase