Dose-related efficacy of a continuous intracisternal nimodipine treatment on cerebral vasospasm in the rat double subarachnoid hemorrhage model.
OBJECTIVE
Intracisternal continuous therapy is a concept in the treatment of cerebral vasospasm after subarachnoid hemorrhage. The purpose of the current study was to investigate the effect of intracisternal nimodipine after induced vasospasm.


METHODS
Sixty-five male Wistar rats were randomized into 4 groups: the control sham-operated group, the control subarachnoid hemorrhage-only group, and the treatment groups receiving 5 or 10 microL/hour of intracisternal nimodipine continuously for 5 days via subcutaneously implanted Alzet osmotic pumps (Durect Corp., Cupertino, CA). Vasospasm was analyzed 5 days later by means of digital subtraction angiography. Morphological examination of the brain parenchyma was performed using Nissl-staining, c-Fos immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling.


RESULTS
Detailed analysis of the digital subtraction angiography was possible for 31 animals. Significant angiographic vasospasm was induced in the double hemorrhage-only group compared with the sham-operated group (P = 0.002). Among the 4 groups, there were statistically significant differences of the arterial vessel caliber as measured by digital subtraction angiography (P = 0.001, Kruskal-Wallis test). The treatment group receiving 5 microL/hour of nimodipine and the control sham-operated group demonstrated the largest intracranial artery diameters with a significant difference between control subarachnoid hemorrhage-only group and the treatment group receiving 10 microL/hour of nimodipine (P = 0.0328, Wilcoxon rank-sum test). Variation in vessel calibers, however, did not result in different brain tissue alterations, even when using sensitive markers for the induction of the stress response or apoptosis.


CONCLUSIONS
Intracisternal nimodipine lavage with 5 microL/hour, but not with 10 microL/hour leads to significant arterial relaxation. Further research is needed to elucidate the underlying cause of the decreasing nimodipine effect at higher dosage.
Hänggi
Daniel
D
Department of Neurosurgery, Heinrich-Heine University, Düsseldorf, Germany. daniel.haenggi@ uniduesseldorf.de
Eicker
Sven
S
Beseoglu
Kerim
K
Rapp
Marion
M
Perrin
Jason
J
Nawatny
Jens
J
Turowski
Bernd
B
Sommer
Clemens
C
Steiger
Hans-Jakob
HJ
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D002533:Cerebral Angiography / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004340:Drug Contamination; D008297:Male; D009553:Nimodipine / Q000008:administration & dosage*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000209:etiology*
D000959:Antihypertensive Agents; D009553:Nimodipine