Reversal of cerebral vasospasm using an intrathecally administered nitric oxide donor.
OBJECTIVE
Intrathecal bolus administration of (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)aminio]diazen++ +-1-ium-1,2-diolate (DETA/NO), a long half-life diazeniumdiolate-class nitric oxide (NO) donor, was evaluated for safety and efficacy in the treatment of delayed cerebral vasospasm in a canine model of subarachnoid hemorrhage (SAH).


METHODS
The baseline basilar artery (BA) diameter of 25 dogs was measured with the aid of angiography on Day 0. Vasospasm was then induced by intracisternal injection of autologous arterial blood on Days 0 and 2. Repeated arteriography on Day 7 revealed an average BA diameter of 58% of baseline. Each dog was then randomized to one of four groups: a pathology control group (SAH only, four animals); a treatment control group (SAH plus 2 micromol of the inactive drug carrier DETA, eight animals); a low-dose treatment group (SAH plus 0.2 micromol DETA/NO, six animals); or a high-dose treatment group (SAH plus 2 micromol DETA/NO, six animals). The drugs were administered in a 2-ml intrathecal bolus via the cisterna magna. Arterial caliber was monitored by angiography over the subsequent 4 hours. A 2-micromol dose of the drug was then given and serial arteriography continued for an additional hour to screen for tachyphylaxis. Intracranial pressure and respiratory and hemodynamic parameters were continuously monitored. Histopathological analyses of the animals' brains were performed after the dogs were killed on Day 8. The drug DETA/NO produced reversal of vasospasm in a dose-dependent fashion that roughly followed a double exponential time course. Doses of 2 micromol DETA/NO resulted in restoration of the angiographically monitored BA diameter to the prevasospasm size at 1.5 hours posttreatment, and this was sustained at 88% of baseline at 4 hours (p < 0.01, independent samples t-test). By contrast, the treatment control group remained on average at 54% of baseline diameter. The low-dose treatment group achieved only partial and more transitory relaxation. Histopathological analyses showed findings consistent with chronic SAH but did not demonstrate any toxicity associated with the NO donor. No adverse physiological changes were seen.


CONCLUSIONS
This study indicates that long-acting NO donors are potentially useful as agents to restore circulation in patients suffering from cerebral vasospasm.
Department of Neurosurgery, University of Tennessee Center for the Health Sciences, Memphis 38163, USA. ewolf@utmem1.edu
E W
EW
Wolf
A
A
Banerjee
J
J
Soble-Smith
F C
FC
Dohan
R P
RP
White
J T
JT
Robertson
D000704:Analysis of Variance; D000818:Animals; D001488:Basilar Artery / Q000000981:diagnostic imaging / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002496:Central Venous Pressure / Q000187:drug effects; D002533:Cerebral Angiography; D002946:Cisterna Magna; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D006339:Heart Rate / Q000187:drug effects; D007091:Image Processing, Computer-Assisted; D007278:Injections, Spinal; D007427:Intracranial Pressure / Q000187:drug effects; D002546:Ischemic Attack, Transient / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D009569:Nitric Oxide / Q000008:administration & dosage / Q000627:therapeutic use*; D011897:Random Allocation; D012119:Respiration / Q000187:drug effects; D012449:Safety; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000473:pathology; D013618:Tachyphylaxis / Q000502:physiology; D014226:Triazenes / Q000008:administration & dosage / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*
C105351:1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene; D004337:Drug Carriers; D014226:Triazenes; D014665:Vasodilator Agents; D009569:Nitric Oxide