title: Association between cerebrospinal fluid levels of asymmetric dimethyl-L-arginine, an endogenous inhibitor of endothelial nitric oxide synthase, and cerebral vasospasm in a primate model of subarachnoid hemorrhage.
abstract: OBJECTIVE
  Decreased availability of nitric oxide (NO) has been proposed to evoke delayed cerebral vasospasm after sub-arachnoid hemorrhage (SAH). Asymmetric dimethyl-L-arginine (ADMA) inhibits endothelial NO synthase (eNOS) and, therefore, may be responsible for decreased NO availability in cases of cerebral vasospasm. The goal of this study was to determine whether ADMA levels are associated with cerebral vasospasm in a primate model of SAH.
  
  
  METHODS
  Twenty-two cynomolgus monkeys (six control animals and 16 with SAH) were used in this study. The levels of ADMA, L-arginine, L-citrulline, nitrites, and nitrates in cerebrospinal fluid (CSF) and serum were determined on Days 0, 7, 14, and 21 following onset of SAH. Cerebral arteriography was performed to assess the degree of vasospasm. Western blot analyses of the right and left middle cerebral arteries (MCAs) were performed to assess the expression of eNOS, type I protein-arginine methyl transferase (PRMT1) and dimethylarginine dimethylaminohydrolase (DDAH2). Cerebrospinal fluid levels of ADMA remained unchanged in the control group (six animals) and in animals with SAH that did not have vasospasm (five animals; p = 0.17), but the levels increased in animals with vasospasm (11 animals) on Day 7 post-SAH (p < 0.01) and decreased on Days 14 through 21 (p < 0.05). Cerebrospinal fluid levels of ADMA correlated directly with the degree of vasospasm (correlation coefficient = 0.7, p = 0.0001; 95% confidence interval: 0.43-0.83). Levels of nitrite and nitrate as well as those of L-citrulline in CSF were decreased in animals with vasospasm. Furthermore, DDAH2 expression was attenuated in the right spastic MCA on Day 7 post-SAH, whereas eNOS and PRMT1 expression remained unchanged.
  
  
  CONCLUSIONS
  Changes in the CSF levels of ADMA are associated with the development and resolution of vasospasm found on arteriograms after SAH. The results indicate that endogenous inhibition of eNOS by ADMA may be involved in the development of delayed cerebral vasospasm. Inhibition of ADMA production may provide a new therapeutic approach for cerebral vasospasm after SAH.
authors.affiliation: National Institute of Neurological Disorders and Stroke, and National Institute of Alcohol Abuse and Alcoholism; and National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Carla S
authors.initials: CS
authors.lastname: Jung
authors.forename: Brian A
authors.initials: BA
authors.lastname: Iuliano
authors.forename: Judith
authors.initials: J
authors.lastname: Harvey-White
authors.forename: Michael G
authors.initials: MG
authors.lastname: Espey
authors.forename: Edward H
authors.initials: EH
authors.lastname: Oldfield
authors.forename: Ryszard M
authors.initials: RM
authors.lastname: Pluta
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood* / Q000134:cerebrospinal fluid*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000097:blood* / Q000134:cerebrospinal fluid*; D008252:Macaca fascicularis; D020768:Middle Cerebral Artery / Q000378:metabolism; D009569:Nitric Oxide / Q000134:cerebrospinal fluid; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000378:metabolism*; D013997:Time Factors; D020301:Vasospasm, Intracranial / Q000209:etiology / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase