title: Increased cerebral blood flow but no reversal or prevention of vasospasm in response to L-arginine infusion after subarachnoid hemorrhage.
abstract: OBJECTIVE
  The reduction in the level of nitric oxide (NO) is a purported mechanism of delayed vasospasm after subarachnoid hemorrhage (SAH). Evidence in support of a causative role for NO includes the disappearance of nitric oxide synthase (NOS) from the adventitia of vessels in spasm, the destruction of NO by hemoglobin released from the clot into the subarachnoid space, and reversal of vasospasm by intracarotid NO. The authors sought to establish whether administration of L-arginine, the substrate of the NO-producing enzyme NOS, would reverse and/or prevent vasospasm in a primate model of SAH.
  
  
  METHODS
  The study was composed of two sets of experiments: one in which L-arginine was infused over a brief period into the carotid artery of monkeys with vasospasm, and the other in which L-arginine was intravenously infused into monkeys over a longer period of time starting at onset of SAH. In the short-term infusion experiment, the effect of a 3-minute intracarotid infusion of L-arginine (intracarotid concentration 10(-6) M) on the degree of vasospasm of the right middle cerebral artery (MCA) and on regional cerebral blood flow (rCBF) was examined in five cynomolgus monkeys. In the long-term infusion experiment, the effect of a 14-day intravenous infusion of saline (control group, five animals) or L-arginine (10(-3) M; six animals) on the occurrence and degree of cerebral vasospasm was examined in monkeys. The degree of vasospasm in all experiments was assessed by cerebral arteriography, which was performed preoperatively and on postoperative Days 7 (short and long-term infusion experiments) and 14 (long-term infusion experiment). In the long-term infusion experiment, plasma levels of L-arginine were measured at these times in the monkeys to confirm L-arginine availability. Vasospasm was not affected by the intracarotid infusion of L-arginine (shown by the reduction in the right MCA area on an anteroposterior arteriogram compared with preoperative values). However, intracarotid L-arginine infusion increased rCBF by 21% (p < 0.015; PCO2 38-42 mm Hg) in all vasospastic monkeys compared with rCBF measured during the saline infusions. In the long-term infusion experiment, vasospasm of the right MCA occurred with similar intensity with or without continuous intravenous administration of L-arginine on Day 7 and had resolved by Day 14. The mean plasma L-arginine level increased during infusion from 12.7+/-4 microg/ml on Day 0 to 21.9+/-13.1 microg/ml on Day 7 and was 18.5+/-3.1 microg/ml on Day 14 (p < 0.05).
  
  
  CONCLUSIONS
  Brief intracarotid and continuous intravenous infusion of L-arginine did not influence the incidence or degree of cerebral vasospasm. After SAH, intracarotid infusion of L-arginine markedly increased rCBF in a primate model of SAH. These findings discourage the use of L-arginine as a treatment for vasospasm after SAH.
authors.affiliation: Surgical Neurology Branch and Clinical Neuroscience Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA. rysiek@helix.nih.gov
authors.forename: R M
authors.initials: RM
authors.lastname: Pluta
authors.forename: J K
authors.initials: JK
authors.lastname: Afshar
authors.forename: B G
authors.initials: BG
authors.lastname: Thompson
authors.forename: R J
authors.initials: RJ
authors.lastname: Boock
authors.forename: J
authors.initials: J
authors.lastname: Harvey-White
authors.forename: E H
authors.initials: EH
authors.lastname: Oldfield
mesh_terms: D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000494:pharmacology*; D002343:Carotid Artery, Internal; D002533:Cerebral Angiography; D002560:Cerebrovascular Circulation; D004195:Disease Models, Animal; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D008252:Macaca fascicularis; D020768:Middle Cerebral Artery / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D011897:Random Allocation; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D020301:Vasospasm, Intracranial / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D001120:Arginine; D019001:Nitric Oxide Synthase