doi: 10.1161/01.STR.0000033931.62992.B1
(Stroke. 2002;33:2681.)
© 2002 American Heart Association, Inc.
Original Contributions |
Prevention of Experimental Cerebral Vasospasm by Intracranial Delivery of a Nitric Oxide Donor From a Controlled-Release Polymer
Toxicity and Efficacy Studies in Rabbits and Rats
From the Departments of Neurological Surgery (P.G., R.E.C., B.M.T., T.S.T., R.J.T.) and Pathology (C.G.E.), Johns Hopkins University School of Medicine, Baltimore, Md.
Correspondence to Rafael J. Tamargo, MD, FACS, Department of Neurosurgery, Johns Hopkins Hospital, Meyer 7-113, 600 N Wolfe St, Baltimore MD 21287-7713. E-mail rtamarg{at}jhmi.edu
Background and Purpose— A reduction in the local availability of nitric oxide (NO) may play a role in the etiology of chronic cerebral vasospasm after subarachnoid hemorrhage (SAH). We investigated the toxicity and efficacy of a locally delivered NO donor from a controlled-release polymer in preventing experimental cerebral vasospasm in rats and rabbits, respectively.
Methods— Diethylenetriamine/NO (DETA/NO) was incorporated into controlled release ethylene-vinyl acetate (EVAc) polymers. Twenty-eight rats were used in a dose-escalation toxicity study to establish a maximally tolerated dose of DETA/NO-EVAc polymer. In the efficacy experiment, 20 rabbits were assigned to 4 experimental groups (n=5 per group): sham operation; SAH only; SAH+empty EVAc polymer; and SAH+DETA/NO-EVAc polymer. Treatment was initiated 30 minutes after blood deposition. Basilar artery lumen patency was assessed 72 hours after hemorrhage to evaluate the efficacy of DETA/NO in preventing cerebral vasospasm.
Results— In the toxicity study, a dose of 3.4 mg/kg was identified as the LD20 (dose with 20% mortality during the study period) of this DETA/NO formulation. Brain histology revealed hemorrhage and ischemic changes at the implantation site associated with high concentrations of DETA/NO. In the efficacy study, treatment with DETA/NO-EVAc polymer resulted in a significant decrease in basilar artery vasospasm compared with no treatment (93.0±4.9% versus 71.4±11.9%; P=0.035) or compared with treatment with blank EVAc polymer (93.0±4.9% versus 73.2±6.4%; P=0.003).
Conclusions— Local delivery of DETA/NO prevents vasospasm in the rabbit basilar artery. Local delivery of DETA/NO via polymers is a safe and effective strategy for preventing cerebral vasospasm after SAH in this model.
Key Words: nitric oxide • polymers • subarachnoid hemorrhage • vasospasm, intracranial • rabbits • rats
This article has been cited by other articles:
 |
|
 |
|
  K. L. Chaichana, A. P. Levy, R. Miller-Lotan, S. Shakur, and R. J. Tamargo Haptoglobin 2-2 Genotype Determines Chronic Vasospasm After Experimental Subarachnoid Hemorrhage Stroke, December 1, 2007; 38(12): 3266 - 3271. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Zemke, M. U Farooq, A. Mohammed Yahia, and A. Majid Delayed ischemia after subarachnoid hemorrhage: result of vasospasm alone or a broader vasculopathy? Vascular Medicine, August 1, 2007; 12(3): 243 - 249. [Abstract] [PDF]
|
|
|
|
 |
|
 C. E. Teixeira, F. B.M. Priviero, J. Todd Jr, and R. C. Webb Vasorelaxing Effect of BAY 41-2272 in Rat Basilar Artery: Involvement of cGMP-Dependent and Independent Mechanisms Hypertension, March 1, 2006; 47(3): 596 - 602. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Pluta, A. Dejam, G. Grimes, M. T. Gladwin, and E. H. Oldfield Nitrite Infusions to Prevent Delayed Cerebral Vasospasm in a Primate Model of Subarachnoid Hemorrhage JAMA, March 23, 2005; 293(12): 1477 - 1484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. O. Borel, A. McKee, A. Parra, M. M. Haglund, A. Solan, V. Prabhakar, H. Sheng, D. S. Warner, L. Niklason, and A. Bhardwaj Possible Role for Vascular Cell Proliferation in Cerebral Vasospasm After Subarachnoid Hemorrhage * Editorial Comment Stroke, February 1, 2003; 34(2): 427 - 433. [Abstract] [Full Text] [PDF]
|
|