Prevention of cerebral vasospasm by local delivery of cromakalim with a biodegradable controlled-release system in a rat model of subarachnoid hemorrhage.
OBJECTIVE
One mechanism that contributes to cerebral vasospasm is the impairment of potassium channels in vascular smooth muscles. Adenosine triphosphate-sensitive potassium channel openers (PCOs) appear to be particularly effective for dilating cerebral arteries in experimental models of subarachnoid hemorrhage (SAH). A mode of safe administration that provides timed release of PCO drugs is still a subject of investigation. The authors tested the efficacy of locally delivered intrathecal cromakalim, a PCO, incorporated into a controlled-release system to prevent cerebral vasospasm in a rat model of SAH.


METHODS
Cromakalim was coupled to a viscous carrier, hyaluronan, 15% by weight. In vitro release kinetics studies showed a steady release of cromakalim over days. Fifty adult male Sprague-Dawley rats weighing 350-400 g each were divided into 10 groups and treated with various doses of cromakalim or cromakalim/hyaluronan in a rat double SAH model. Treatment was started 30 minutes after the second SAH induction. Animals were killed 3 days after treatment, and the basilar arteries were processed for morphometric measurements and histological analysis.


RESULTS
Controlled release of cromakalim from the cromakalim/hyaluronan implant at a dose of 0.055 mg/kg significantly increased lumen patency in a dose-dependent manner up to 94 +/- 8% (mean +/- standard error of the mean) of the basilar arteries of the sham group compared with the empty polymer group (p = 0.006). Results in the empty polymer group were not different from those in the SAH-only group, with a lumen patency of 65 +/- 12%. Lumen patencies of the cromakalim-only groups did not differ in statistical significance at low (64 +/- 9%) or high (66 +/- 7%) doses compared to the SAH-only group.


CONCLUSIONS
Treatment of SAH with a controlled-release cromakalim/hyaluronan implant prevented experimental cerebral vasospasm in this rat double hemorrhage model; this inhibition was dose-dependent. The authors' results confirm that sustained delivery of cromakalim perivascularly to cerebral vessels could be an effective therapeutic strategy in the treatment of cerebral vasospasm after SAH.
Omeis
Ibrahim
I
Departments of Neurosurgery, New York Medical College, Munger Pavilion, 3rd Floor, Valhalla, New York 10595, USA. Ibrahim_Omeis@nymc.edu
Chen
Weiliam
W
Jhanwar-Uniyal
Meena
M
Rozental
Renato
R
Murali
Raj
R
Abrahams
John M
JM
D020341:Absorbable Implants; D000818:Animals; D019806:Cromakalim / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D006820:Hyaluronic Acid; D008297:Male; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D014665:Vasodilator Agents / Q000008:administration & dosage*; D020301:Vasospasm, Intracranial / Q000517:prevention & control*
D015221:Potassium Channels; D014665:Vasodilator Agents; D019806:Cromakalim; D006820:Hyaluronic Acid